American Diabetes Association 69th Scientific Sessions

June 5 – 9, 2009; New Orleans, LA — Full Report draft

In this final report, we provide our coverage of the 69th Scientific Sessions of the American Diabetes Association, held at the Morial Convention Center in New Orleans. While slightly scaled back from last year’s sessions, ADA 2009 was still a massive affair, with around 15,000 physicians, diabetes educators, industry professionals, and researchers in attendance, down about 25% (particularly international attendance, presumably due to the economy). The five-day conference consisted of eight tracks, 139 exhibits, and 2,028 oral and poster sessions.

We’ve ramped up our coverage this year to bring you extensive commentary on 401 presentations, up from the 217 we covered last year – generally, there were more therapies and technologies in more advanced stages on which to report and certain areas like continuous glucose monitoring veritably exploded. To help guide you, our complete conference notes are organized into 12 sections: (1) Pivotal trials (RECORD, BARI-2D, NICE-SUGAR, ACCORD, VADT); (2) Incretin therapies; (3) PPAR modulating agents and other non-incretin/non-insulin therapies; (4) Novel drug therapies; (5) CGM and closing the loop; (6) Developments in insulin delivery; (7) Obesity and obesity treatments; (8) Cardiovascular disease and other complications/comorbidities; (9) Type 1 diabetes therapies; (10) Prediction, prevention, lifestyle, and behavior; (11) Healthcare structuring, treatment guidelines, and provider education; and (12) Background science. Our exhibit report and survey results complete the document. Below we outline, in our view, the major takeaway themes from ADA 2009, followed by a comprehensive table of contents for ease of reference.

  • A new ACCORD study analysis disputes the notion that hypoglycemia was responsible for the excess mortality observed in the intensive treatment arm of the study. A year after ACCORD results were presented to the public, the cause of the mortality imbalance between the two study arms remains a mystery. However, Dr. Denise Bonds (National Heart, Lung, and Blood Institute, NIH, Bethesda, MD) showed that A1c level, rate of reduction of A1c, and amount of severe hypoglycemia did not explain the excess mortality in the intensive treatment group. While last year’s headlines warned us of the potential dangers of intensive therapy, new analyses of ACCORD and VADT this year suggest that some people can safely achieve A1c levels below 7% using an intensive treatment strategy. Interestingly, Dr. Denise Bonds (National Heart, Lung, and Blood Institute, NIH, Bethesda, MD) showed that severe hypoglycemia did not account for the mortality difference in ACCORD and that the specific causes of mortality remain unclear. Furthermore, patients with higher baseline A1c or higher average A1c were at higher risk of severe hypoglycemia and all-cause mortality overall, perhaps giving credence to the calls for earlier and more aggressive treatment in diabetes before patients progress to the point of having high A1cs. Also of note, higher mortality was not observed with lower A1cs in the intensive group, although this relationship was seen in the conventional group. This association highlights the need for continuous glucose monitoring (CGM) to better understand glycemic trends and variability as well as glycemia during time of death. Patients with episodes of severe hypoglycemia in the intensive group had a lower risk of death than those in theconventional arm; however, this lower risk of mortality balanced out with the increase in hypoglycemic events in the intensive group.
  • We heard extensive criticism regarding the FDA’s new (2008) guidelines requiring cardiovascular safety studies for new diabetes drugs, especially in light of the RECORD trial. Interim results from the RECORD trial concluded that rosiglitazone (GlaxoSmithKline’s Avandia) displayed no increased cardiovascular risk compared with the active comparator of metformin or sulfonylurea. These findings directly contradict the controversial and highly publicized meta-analysis from Dr. Steven Nissen (Cleveland Clinic) and indicate Avandia more than adequately meets the latest FDA criteria for cardiovascular (CV) safety. More problematic from our view is that the FDA changed its diabetes guidance immediately after Dr. Nissen’s meta-analysis and now requires companies developing diabetes treatments to prove that the therapies don’t prompt an unduly high number of CV events. We believe pre-market testing is onerous; if there were no signal of CV risk, we would advocate post-market CV follow-up. We also heard complaints about FDA hypersensitivity regarding pancreatitis and C-cell cancer, specifically referring to GLP-1 analogs such as liraglutide (Novo Nordisk’s Victoza).
  • Overall, we were impressed by the considerable amount of attention given to continuous glucose monitoring (CGM) devices, as evidenced by the packed lecture halls during CGM talks. One-year data from the JDRF CGM trial shed mostly positive light on prolonged CGM use in adults. CGM use drastically reduced the rates of hypoglycemia (not one incidence of severe hypoglycemia was reported in children with A1cs <7%), and was found to be significant in lowering the A1c of adults and children with A1cs ≥7% after one year. CGM garnered lots of support at this year’s ADA as a useful tool in combating hypoglycemia, controlling A1c, and measuring data during trials. We hope that this support translates into better reimbursement and greater clinical acceptance.
  • On the drug front, incretins and specifically long-acting GLP-1 analogs were front and center at ADA 2009. Encouragingly, two-year treatment data for liraglutide (Novo Nordisk’s Victoza) (LEAD-3 extension study) and Amylin’s exenatide once-weekly (Duration-1 extension study) showed that both drugs can elicit a remarkably durable response. We also saw results from a 14-week extension study of LEAD-6 that switched patients on exenatide BID (Amylin/Eli Lilly’s Byetta) to liraglutide for an additional 14 weeks. We also heard the results from the DURATION-2 study, which compared Amylin/Eli Lilly/Alkermes’ exenatide once- weekly to Actos (Takeda) and Januvia (Merck). Data were also provided from phase 2 studies on the upcoming GLP-1 therapies albiglutide (GSK) and LY2189265 (Eli Lilly). The general consensus regarding liraglutide and exenatide once weekly is positive. Overall, as more data are released from GLP-1 analog trials citing improvements in blood pressure, cholesterol, weight gain, and a protective effect on beta cell function, we are noticing a trend of physicians and experts suggesting a potential benefit of early treatment with GLP-1 analogs.
  • One new drug class receiving lots and lots of attention during ADA 2009 was the SGLT2 inhibitors. Dr. John Wilding (University of Liverpool, Liverpool, UK) provided an excellent review of SGLT2 inhibitors and an overview of positive dapagliflozin (BMS/AZ) phase 2b study results. Phase 1 data was also presented on ISIS388626 (ISIS Pharmaceuticals), a novel SGLT2 inhibitor candidate, as well as early data on JNJ-28431754 (canagliflozin), J&J’s SGLT2 inhibitor in development. Despite the success of dapagliflozin in clinical trials thus far, many physicians noted the need for additional safety data regarding the potential for the SGLT2 inhibitor class to cause urinary tract infections (UTI). Positivity surrounding the class centered on glucose reduction combined with weight loss.
  • We attended a multitude of other lectures covering exciting novel drug therapies. A one-year study found no significant difference in A1c reduction between the inhalable insulin Afresa (MannKind) and NovoLog (Novo Nordisk) and no significant pulmonary damage with Afresa. Although the FDA recently accepted MannKind’s NDA for Afresa, we believe this therapy stands at a disadvantage in light of Pfizer’s inhalable insulin, Exubera, which was pulled from the market after weak commercialization stemming from inconveniences associated with the device. Later concerns arose regarding lung cancer incidence. 11βHSD-1 inhibitors were also showcased at the meeting. Drugs targeting the inflammatory components of type 2 diabetes were also highlighted, though physicians expressed concerns about modulating the immune response in their patients. The consensus was that Xoma’s IL-1b antibody has worked well thus far, but the local and systemic processes affected by the drug must be better explored.
  • Several talks addressed the controversial role of bariatric surgery in diabetes. Dr. Louis Aronne (Weill Cornell Medical College, New York, NY) suggested that we're moving to an obesity-centric view of type 2 diabetes rather than a glucose-centric one. To standardize bariatric surgery as a treatment for diabetes and obesity, better-designed and longer-term studies will be needed as well as greater acceptance from the medical community of bariatric surgery as a metabolic treatment. From our view, even that this is under discussion indicates a major change, and while bariatric surgery seems unlikely to be widely adopted as a treatment for diabetes, the mechanisms involved in the remission of diabetes are an important opportunity for research.
  • There was also a focus on obesity therapies and a theme of cross-indicating treatments for obesity and diabetes. Most notably on the obesity front, Orexigen’s Contrave, in a phase 3 study, failed to meet the FDA’s suggested endpoints for obesity therapies, likely because the placebo group did very well with just behavioral modification. We learned of the potential of Vivus’ Qnexa, currently being evaluated for the treatment of obesity, to also significantly decrease A1c. Similarly, we learned more about the currently unapproved use of pramlintide (Amylin’s Symlin) with basal insulin in the absence of mealtime insulin, especially in light of its weight profile.
  • The vast majority of healthcare providers approve A1c test as an accurate and effective tool for diagnosing diabetes. An expert committee assembled by the ADA, EASD, and IDF, in an article published in Diabetes Care, recommended the A1c test as a standardized tool for diagnosing diabetes, in the hope that more people will be screened and diagnosed. They noted the convenience of an A1c test (no fasting required) as well as its superior reliability compared to fasting plasma glucose. Although we acknowledge A1c is not perfect, we believe the benefits of earlier diagnosis from this test far outweigh any potential drawbacks and we eagerly wait for ADA to ‘ratify’ this result via a position paper. We see this as very positive for industry since we believe more people will be diagnosed earlier with diabetes as a result.
  • Close Concerns conducted a survey of 102 healthcare providers (HCP) during ADA 2009. Assuming regulatory approval, GLP-1 analogs liraglutide and exenatide once-weekly topped the list of drugs that respondents were likely to use. Basal and mealtime insulin were perceived as safe by over 96% of the HCPs surveyed. Interestingly, an overwhelming majority of respondents (92%) thought that new and faster insulin’s are critical for better diabetes management. About 80% of HCPs reported that they would use Biodel’s VIAject if approved, compared to about 50% for MannKind’s Afresa (an increase from 30% at least year’s ADA). A striking 60% of respondents expect to use more CGM in the next year. For thiazolidinediones (TZDs), HCPs view of GSK’s Avandia has considerably improved; however, the data imply that HCPs are switching from TZDs and sulfonylureas to incretins.

 

Table of Contents 

 

RECORD, BARI-2D, NICE-SUGAR, and ACCORD/VADT

This year’s ADA included the fascinating results of the RECORD and BARI-2D trials, as well as some critical further analyses of ACCORD, VADT, and NICE-SUGAR. The safety of intensive glycemic control was thrown into serious doubt with last year’s ACCORD results, and the new results reveal additional complexities to the data and confuse the issue even further. The results are detailed below, but it seems that neither hypoglycemia nor a rapid decrease in A1c can fully explain the increased rate of death in ACCORD. The re-analysis of VADT was more straightforward, showing that severe and repeated hypoglycemia increased the risk of death in both groups.

On the in-hospital side, Dr. Silvio Inzucchi (Yale Diabetes Center, New Haven, CT) discussed the strengths and limitations of NICE-SUGAR, focusing on the number of drop-outs and calling for a ‘per protocol’ analysis that would take this factor into account. Additional difficulties include the non- attainment of planned separation between the intensive and standard groups, and the non-attainment of glycemic targets in the intensive group. There seems to be no full explanation for the NICE-SUGAR findings that has been unearthed at this time.

It appears that the RECORD study, showing that rosiglitazone carries no increased CV risk after five and half years, will go a long way toward checking the push toward cardiovascular thinking we saw after Dr. Nissen’s meta-analysis. It certainly won’t eliminate the focus on CV complications (nor should it!), but we expect it to temper some of the agitation we’ve seen in the past year and help GSK with its declining Avandia sales.

Finally, the BARI-2D study compared different ways to treat coronary artery disease patients with type 2 diabetes, and found no difference in five-year survival rates between patients given swift revascularization versus medical therapy, and no difference between an insulin-sensitizing and insulin- provision approach. In high-risk patients, however, there may have been a benefit from prompt revascularization and insulin-sensitizing agents compared to medical therapy or insulin provision, and this might be positive for TZDs in the long run.

RECORD, BARI-2D, NICE-SUGAR, and ACCORD/VADT Highlights

  • We saw full results from the RECORD trial, after five and a half years. The trial included nearly 4,500 patients. This trial concludes that rosiglitazone has no increased cardiovascular risk overall compared to the active comparator of metformin or sulfonylureas – contradicting the NEJM Nissen meta-analysis. In the rosiglitazone arm, there was double the risk of heart failure, so the good cardiovascular result must be because of a compensating factor – it sounds like it is due to a lower rate of stroke with rosiglitazone, quite fascinating. Also, as expected, blood glucose control was significantly better with rosiglitazone vs. metformin and SFUs– the A1c curves look exactly like ADOPT. Weight gain and effect on lipids were as expected. Additionally, rosiglitazone also caused increased risk of fractures, notably in women, as we had first seen in ADOPT. The overall conclusion was that rosiglitazone can be prescribed in patients who would otherwise receive metformin or sulfonylurea, unless contra-indicated (e.g., susceptibility to fractures, existing heart disease). The results from RECORD more than adequately meet the latest FDA criteria for cardiovascular safety. They also refute the Nissen meta-analysis in terms of MI death, but don’t have enough events to refute it for total number of MIs. We think this calls into question the validity of FDA requirements for pre-approval CVD cardiovascular requirement that was in fact based on an increased risk with Avandia – and yet it’s something not seen in ACCORD, the VADT, and RECORD.
  • The BARI-2D study compared different ways to treat coronary artery disease patients with type 2 diabetes and found no significant differences in mortality outcomes between the different treatment strategies. The results of this trial do not appear to suggest the need for any drastic changes in current thinking especially since this trial was not designed to answer questions on macrovascular benefit of tight glycemic control, nor was it designed to compare cardiovascular impact of specific drugs. One potential hypothesis coming out of this study may prove positive for the use of TZDs (over insulin) in patients with very severe coronary artery disease but future studies must be conducted to confirm this hypothesis. It will also be important to see data from longer-term follow-up studies of all the different arms of this study to see if the results change with time.
  • Sheryl F. Kelsey, PhD (University of Pittsburgh, Pittsburgh, PA) was the first in the three-speaker lineup to present the results of the widely-awaited Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI-2D) study. She described the rationale, fairly complex design, and implementation of the study. BARI-2D, a study with a 2x2 factorial design, investigated two pairs of treatment strategies to see which was better for treating coronary artery disease in 2,368 patients with type 2 diabetes. The first pair consisted of either a combined surgical and intensive medical approach, or an intensive medical approach alone. The second consisted of insulin-sensitizing therapy or insulin-provision therapy. It is important to note that enrolled patients were selected to receive a particular surgical intervention (bypass surgery or angioplasty/stenting) based on physician judgment of the severity of their coronary artery disease.
  • Robert Frye, MD (Mayo Clinic, Minneapolis, MN) presented the results of BARI-2D. The study showed no significant difference in the five-year survival rate between patients in the prompt revascularization group (88.3% survival) and those in the medical therapy group (87.8% survival). Nor was there a significant difference in mortality between the insulin-sensitizing (88.2% survival) and insulin-provision groups (87.9% survival). When the patients were stratified by type of revascularization, there was a significant reduction in cardiovascular events in the group selected to the coronary artery bypass graft (CABG) arm/stratum who underwent prompt revascularization compared to those in this stratum who underwent medical therapy. In the group selected to receive percutaneous coronary intervention (PCI), there was no difference in cardiovascular events between those who actually underwent revascularization and those who were treated with medical therapy.
  • In high-risk patients (i.e., those in the CABG stratum), the benefit associated with prompt revascularization was shown to be greater than that obtained from medical therapy. Another interesting hypothesis-generating result in this high-risk group was the positive impact of insulin sensitizers versus SFUs/insulin compared to the other three cohort combinations. There was no difference in rates of congestive heart failure or bone fractures, which bodes well for TZD therapy.
  • Trevor Orchard, M.B.B.Ch., M.Med.Sci (Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA) provided valuable commentary on the results of the BARI 2D trial in the context of current medical practices and recent trials. Despite failing to find significant differences in outcome between the revascularization and medical therapy groups as well as between the insulin sensitization and insulin replacement groups, the results of this trial were consistent with other major trials. Although the results of BARI-2D do not call for dramatic changes in diabetes management, it raises the hypothesis that insulin- sensitizing therapy could be better than insulin-provision therapy in those very ill patientsselected to undergo revascularization via coronary artery bypass graft (CABG). Dr. Orchard emphasized that this study did not address the question of macrovascular benefit of intensive glycemic control – all subjects were treated with a target A1c of less than 7% – and did not assess therapeutic advantages associated with particular drugs. Dr. Orchard concluded the talk by providing physicians with one take-home lesson: therapeutic decisions regarding the management of coronary artery disease and glycemia in type 2 diabetes patients should be made jointly by patients, cardiologists, diabetologists, and/or primary care physicians.
  • Harold Lebovitz, MD (SUNY Brooklyn Health Sciences Center, New York, NY) summarized the findings from the NICE-SUGAR (NEJM, 2009) study to set the stage for the discussion. NICE-SUGAR (Normoglycemia in Intensive Care Evaluation and Survival Using Glucose Algorithm Regulation) compared tight glucose control (81-108 mg/dl [4.5- 6 mmol/l]) to conventional control (144-180 mg/dl [8 – 10 mmol/l]). As a reminder (let us know if you need detailed Closer Look reports from Brussels), the primary outcome measure of the study was all-cause mortality within 90 days of admission, and the results showed a significantly greater 90-day mortality in the intensively treated group compared to the conventionally treated group. The background set the stage for the broader discussion. Similar to ACCORD a year ago, a number of key opinion leaders continue to question these non-intuitive results.
  • Silvio Inzucchi, MD (Yale Diabetes Center, New Haven, CT) delivered a thorough examination of the various strengths, limitations, and unanswered questions of NICE-SUGAR. This talk drove home to us the danger of “headline” results given without a thorough analysis of trials and the negative implications for associated therapies. In particular, he raised a very important point regarding the need for a “per protocol analysis” to explain the data not included in the intent to treat analysis of mortality. He noted that data for 79 people included in the intent to treat analysis withdrew from the study (and were thus not receiving their assigned treatment algorithms). These people came from both arms of the study. Since 78 more subjects died in the intensive group versus the conventional group, he speculated that the dropouts could fully account for excess mortality. This raises the question of whether investigators should perform a “per protocol analysis” to accurately record the outcomes of patients who were in compliance with their assigned insulin regimen. He characterized NICE-SUGAR as a negative study and stressed the importance of addressing these questions. We believe compliance is a major question to address when interpreting this study; we wonder, for example, what compliance was in terms of adherence to required blood glucose monitoring. There has been no data on this but presumably this would be possible to get, and we would like to see it, in particular, for those in the intensively controlled group that died.
  • Dr. Inzucchi described the strengths and limitations of NICE-SUGAR. It was a large, multicenter study with patients who were characteristic of a general ICU population. Limitations include the lack of proper separation of specified glycemic targets and lack of target attainment in intensive group. In addition, there were variable methods for blood glucose measurement and more steroid therapy in the intensive arm. As well, there was 15-fold increase in hypoglycemic events. There were no data presented to help explain excess mortality. We would also point out there was not good data on the actual adherence to blood glucose checks; we also believe the conventional target was far more “intensive” than in most ICUs in the US at present, which from our view makes the entire study more difficult to interpret. Notably, Dr. Inzucchi emphasized that there was very little representation of the cardiac population meaning that the NICE-SUGAR findings are not generalizable to the cardiac surgery population.
  • Dr. Inzucchi concluded with a comparison of NICE-SUGAR to the Leuven I study that may shed some light on the different outcomes from the two studies. In particular, he pointed out that the targets in the conventional arm of Leuven I (180-200 mg/dl or 10–11.1 mmol/l) were higher than that for NICE-SUGAR (140-180 mg/dl or 7.8 – 10.0 mmol/l). NICE-SUGAR was unable to achieve aggressive targets in the intensive arm (81-108 mg/dl or 4.5- 6 mmol/l) whilst Leuven did achieve its targets (80-110 mg/dl).
  • Guillermo Umpierrez, MD (Emory University School of Medicine, Atlanta, GA) discussed recommendations for managing patients with diabetes in the hospital setting. He focused on the use of insulin protocols and basal/bolus vs. sliding scale insulin. His key learning point was the need to reduce insulin doses in patients treated with insulin prior to admission in order to reduce the risk of hypoglycemia.
  • Etie Moghissi, MD (University of California, Los Angeles, CA) described the AACE/ADA consensus statement on inpatient glycemic control. She highlighted the remarks made during the special in-patient glycemic control session at the recent AACE meeting in Houston, TX. Dr. Moghissi stressed that the process of developing the AACE/ADA guidelines was not a knee jerk reaction to the results of NICE-SUGAR.
  • Mary Korythowski, MD (University of Pittsburgh, Pittsburgh, PA) noted that AACE/ADA recommended glycemic targets were now 140-180 mg/dl (7.8 – 10.0 mmol/l) in most critically ill patients, up from 80-110 mg/dl (4.4 -6.1 mmol). For the majority of non-critically ill patients, they recommended targeting pre-meal blood glucose under 140 mg/dl (<7.8 mmol/l) as well as random blood glucose below 180 mg/dl (10.0 mmol/l). She also that non-insulin therapies should not be used in the hospital. SFUs are a major cause of hypoglycemia, metformin is contraindicated in patients with impaired renal function, TZDs cause edema and CHF, and pramlintide/GLP-1 agonists can cause nausea and have greater effect on postprandial glucose (we didn’t know what the last point meant, since this is generally a positive).
  • The statement does note the importance of further study to define a role of continuous monitoring technologies in critically ill patients. In Q&A, Dr. Inzucchi said that the authors did not feel they could say 110-140 mg/dl (6.1-7.7 mmol/l) as a target was wrong, assuming that people are able to do it well. (We point out that accurate CGM would make this easier.)
  • Matthew Riddle, MD (Oregon Health & Science University, Portland, OR) presented the topic of A1c and mortality risk in the ACCORD trial. From 2008, we know that in ACCORD, an intensive glycemic treatment strategy was associated with a higher risk of death over three to four years of follow-up. However, we learned this year that in the whole ACCORD population, a 20-22% greater risk of death was associated with each 1% higher average A1c, confirming results from other trials like UKPDS and HOPE. Dr. Riddle said that the paradox was likely related to the different relationships between risk of death and average A1c between the two groups: the excess risk of death with intensive treatment occurred in patients who had average A1c over 7% (not below 7%, as had been previously speculated) as well as those who did not reduce A1c during the first year of treatment (not in those who had faster A1c drops). In contrast, mortality in the standard arm occurred at A1c <7% or A1c >8% and there was no association between A1c drop in the first four months and mortality. Dr. Riddle concluded that these findings do not support the view that rapid reduction of glucose values or lower A1c values, independent of other factors, led to the excess risk of death in the intensive strategy in ACCORD. (Media headlines last year said the opposite, of course.) They also do not identify the causes of the excess risk associated with an intensive treatment strategy. Further analyses are needed to understandthese findings. However, these analyses do suggest that some persons with type 2 diabetes can safely achieve A1c levels below 7% using an intensive strategy, whereas other persons who do not readily achieve these lower A1c levels may be at risk if they persist in this strategy. Riddle emphasized that early, aggressive therapy to avoid long-term complications and use of CGM to avoid hypoglycemia both seemed wise strategies.
  • Denise E. Bonds, MD (National Heart, Lung, and Blood Institute, IH, Bethesda, MD) introduced the topic of hypoglycemia in ACCORD. Hypoglycemia was more common in the intensive arm of ACCORD (2-3.5% vs. 1% incidence). Women, African Americans, older participants, those with fewer years of education, and those with more complications at baseline were at higher risk of hypoglycemia. Patients with higher baseline A1c or higher average A1c were at higher risk of severe hypoglycemia (HR 1.15 in the intensive arm and HR 1.76 in standard arm per 1% rise in A1c). In the intensive arm, patients who had large reductions in A1c between baseline and four months were at a lower risk of hypoglycemia. Diet-related behavior change was the most common antecedent to severe hypoglycemia in ACCORD, which Dr. Bonds said suggested that interventions could be implemented to reduce hypoglycemia. Severe hypoglycemia was associated with increased mortality in both arms, with a greater association in the standard arm than in the intensive arm (HR 2.87 in standard arm and HR 1.28 in intensive arm for prior episode of severe hypoglycemia vs. no hypoglycemia). Among patients who had at least one episode of severe hypoglycemia, intensive arm patients had a lower risk of death than standard arm patients (HR 0.55 intensive vs. standard). Among patients who had no episodes of severe hypoglycemia, intensive arm patients had a higher risk of death than standard arm patients (HR1.24 intensive vs. standard). Hypoglycemia was felt to play no direct causal role in most deaths(we question this since we aren’t sure how this is known). Few deaths occurred within 90 days of a documented episode of severe hypoglycemia. The number of deaths that potentially would be eliminated if there had been no hypoglycemia was similar in each arm. Dr. Bonds finished with three takeaway points: 1) We should expect severe hypoglycemia when intensive therapy, particularly with women, African Americans, and patients with other diabetes complications; 2) severe hypoglycemia is associated with a higher risk of mortality regardless of treatment, but the risk was lower in the intensive arm (this raises questions in our view whether glycemic variability played a protective role); 3) severe hypoglycemia did not account for the mortality difference in ACCORD.
  • William Duckworth, MD (Phoenix VA Health Care System, Phoenix, AZ) began by discussing the primary goal of the VADT study – to investigate the relative risk of cardiovascular death (CVD) and all cause death when using intensive glucose control in type 2 diabetes patients with suboptimal response to maximum oral agents or insulin. The role of factors outside of glycemic control, such as blood pressure management or lipid therapy, was also investigated to evaluate their place in the risk/benefits profile of intensive control. The results of this study indicate that both duration of disease and severe hypoglycemia have significant effects on the risk of CVD. In the first three years after diagnosis, the intensive treatment group had a higher risk of death; however, after four years of diagnosis, the risk of death was higher in the standard treatment group and remained so until over 20 years after diagnosis. Interestingly, it was those individuals in the intensive control group with intractable symptoms who showed increased risk of CVD. History of recent severe hypoglycemic events greatly increased the risk of CVD, with a hazard ratio of 3.7. For all cause mortality, the hazard ratio associated with a recent severe hypoglycemic event rose to 6.4. Increased HDL levels were associated with reduced CVD. According to Dr. Duckworth, this data suggests that duration since diagnosis should be heavily considered when initiating intensiveglycemic control. It also showed that severe hypoglycemia should alter treatment approaches and goals as it is a major risk factor for all cause mortality and CVD. Finally, non-glucose factors such as HDL should also be considered when planning treatment strategies.
  • Stephen N. Davis, MD (Vanderbilt University, Nashville, TN) presented fascinating analyses of the role of hypoglycemia in the VADT study. As a reminder, the VADT study found no impact of intensive glucose monitoring on mortality outcomes in older people with longstanding diabetes.
  • Hypoglycemia has been put forward as a factor in diabetes complications, particularly cardiovascular complications, and Dr. Davis’s analysis examined this issue from many different angles. In summary, the intensive group had about four times more hypoglycemia than the conventionally treated group. Having a low A1c was associated with increased severe hypoglycemia in the intensive group (perhaps reflecting the diversity or intensity of medications necessary to reach low glycemic targets) but was not associated with severe hypoglycemia in the conventional group. Lower BMI and diabetes duration greater than 10 years were predictors of severe hypoglycemia in both groups. Predictors of all-cause death in VADT were severe hypoglycemia reported in the last three months, four to six months, and over the entire study. Repeated hypoglycemia increased this risk overall, but did so to a much greater degree in the conventional group than in the intensive group.
  • The new messages from the VADT, while not entirely straightforward, seem to fit more closely with general expectations than the new analyses of the ACCORD data. The hypoglycemia story seems to reflect what we’ve thought since before last year’s ADA—the main danger of intensive therapy is hypoglycemia (particularly severe hypoglycemia), and caution should be taken with any intensive treatment regimen that is associated with hypoglycemia. We believe it reinforces the importance of individualized therapy and glycemic targets, and should be favorable for diabetes drugs that do not increase the risk of hypoglycemia and for continuous glucose monitoring (to detect asymptomatic hypoglycemia).

Symposium: Results of the RECORD Clinical Trial

The RECORD trial was undertaken as a post-marketing study of cardiovascular outcomes for rosiglitazone (Avandia, GSK), after suspicion it caused heart failure during the European approval process. After the controversial and highly publicized meta-analysis from Dr. Steven Nissen (Cleveland Clinic), interim results were reported; now we are seeing full results from the trial, after five and a half years. The trial included nearly 4,500 patients.

This trial concludes that rosiglitazone has no increased cardiovascular risk overall compared to the active comparator of metformin or sulfonylureas – contradicting the Nissen meta-analysis, which was published in NEJM. In the rosiglitazone arm, there was double the risk of heart failure, so the good cardiovascular result must be because of a compensating factor – which may be due to a lower rate of stroke with rosiglitazone. Also, as expected, blood glucose control was better with rosiglitazone – the A1c curves look exactly like ADOPT, which were strikingly in favor of rosiglitazone (vs. metformin and SFUs). Weight gain (more with rosiglitazone) and effect on lipids were as expected. Additionally, rosiglitazone also caused increased risk of fractures, notably in women, as we had first seen in ADOPT.

The overall conclusion was that rosiglitazone can be prescribed in patients who would otherwise receive metformin or sulfonylurea, unless contra-indicated (e.g., susceptibility to fractures, existing heart disease). The results from RECORD more than adequately meet the latest FDA criteria for cardiovascular safety. They also refute the Nissen meta-analysis in terms of MI death, but don’t have enough events to refute it for total number of MIs.

Professor Home criticized Dr. Nissen’s work, calling it a “funny” and “weak” meta-analysis. He believes that the choice of studies for the analysis was not appropriate because they were small and heterogeneous.

After the Nissen publicity, the ADA revised their guidelines, ultimately removing rosiglitazone from the list of recommended treatments. Dr. Nathan, as Chairman of the committee responsible said that rosiglitazone would be re-examined as a result of this trial, since randomized controlled trial data is the gold standard of evidence. However, reading between the lines, he still seemed skeptical – as he had made clear in an editorial at the time of the interim RECORD results.

We think this result calls into question the validity of FDA requirements for pre-approval CVD cardiovascular requirement that was in fact based on an increased risk with Avandia – and yet it’s something not seen in ACCORD, the VADT, and RECORD.

 

RECORD TRIAL RESULTS

Dr. Home and his fellow panel covered the final results of the RECORD study, which aimed to assess the safety of rosiglitazone. He noted it was nice not to be accompanied by Dr. Nissen this time around, as compared with his last venture at ADA and the presentation of the interim analysis.

 

INTRODUCTION AND RATIONALE

Philip D. Home, DM, DPhil (Newcastle Diabetes Centre and Newcastle University, Newcastle upon Tyne, UK)

  • The RECORD study was a randomized, controlled trial designed to quantify the cardiovascular risks associated with the use of rosiglitazone to treat type 2 diabetes versus a combination of metformin and a sulfonylurea. Given oral glucose-lowering therapies are often utilized in combination, the trial was designed to evaluate rosiglitazone in combination with metformin or sulfonylureas as found in common usage.
  • RECORD was initiated as a condition of the European licensing in order to address the known effects of rosiglitazone on fluid retention and heart failure. The trial was analogous to the PROactive study carried out in the evaluation of pioglitazone; both drugs were FDA approved in 1999.

 

DESIGN AND CONDUCT

Stuart Pocock, PhD (London School of Hygiene and Tropical Medicine, London, UK)

RECORD started as a cardiovascular outcomes study, and was set up as a post-marketing safety trial. After ADOPT, the group incorporated fractures as a secondary outcome together with malignancies (after concern about bladder cancer). The trial turned out to be underpowered in theory – estimating cardiovascular events as 11%/year, when the reality was 2.8% per year – although in practice this turned out not to be a limitation. After the Nissen meta-analysis, interim results were published, which were valuable in ensuring the minimum of patients left the study. It’s believed that if the trial had been carried out in the USA, dropout rates would have been much higher.

  • RECORD aimed to evaluate the non-inferiority of rosiglitazone in combination with metformin or sulfonylurea compared against a metformin and sulfonylurea dual therapy. The primary endpoint was time to first cardiovascular (CV) hospitalization or CV death. The non- inferiority criterion was an upper 95% confidence interval of HR < 1.20. Estimated rate of events was 11% per year in the control group, ensuring 99% statistical power. Although the study was open-label, adjudication of cardiovascular events was blinded to ensure integrity in diagnoses. Secondary outcomes included CV death, myocardial infarction (MI), stroke, and heart failure, as well as a composite of CV death, MI, or stroke. Other outcomes evaluated included A1c values, body weight, and safety measures such as fractures and malignancies.
  • A total of 4,447 patients were randomized, with 2,220 assigned to rosiglitazone (in addition to their previous regimen of metformin and/or a sulfonylurea) and 2,227 assigned to metformin plus a sulfonylurea. All patients had not achieved adequate glycemic control on metformin and/or a sulfonylurea (A1c >7.0-9.0%). The choice of sulfonylurea was not dictated by the study; rather, this choice was left to physicians at each of the 364 study centers. Patients were aged between 40 and 75 years, had a body mass index (BMI) of >25 kg/m2, and had not experienced any major cardiovascular event within three months of the trial. Subjects in the rosiglitazone group and taking a single additional oral medication (metformin or a sulfonylurea) were assigned to receive a third oral medication or transferred to insulin if A1c was confirmed to be ≥8.5%. If a participant taking all three oral medications had a confirmed A1c of≥8.5%, they were taken off of rosiglitazone and put on insulin.
  • An interim analysis of RECORD (NEJM) was carried out in 2007 in response to Dr. Nissen’s meta-analysis (NEJM). The interim analysis was required to prevent patient dropout due to the scare from Dr. Nissen’s findings that rosiglitazone increased MI and risk of death from CV causes. However, estimates suggest only an excess of p32 patients (1.4%) were lost in response to the meta-analysis, which likely would have no effect on results. The findings of the final analysis add about 50% more patient-years follow-up, up to a total of 24,610 patient-years follow-up (12,338 years in the rosiglitazone group and 12,272 years in the active control) with a mean follow-up of 5.5 years. (We note that the low dropout rate probably reflected low confidence by study PIs in Dr. Nissen’s analysis.)

 

CARDIOVASCULAR RESULTS

Michel Komajda, MD (Université Pierre et Marie Curie, Paris, France)

The cardiovascular results for RECORD show that on balance, rosiglitazone is as safe as metformin or sulfonylurea, providing the patient hasn’t a history of heart disease. The non-inferiority appears to be a balance of higher risk of heart failure and lower risk of other cardiovascular events, such as stroke. The overall result and also all-cause death strongly refute the Nissen meta-analysis. There weren’t enough events to indicate the effect of rosiglitazone on MIs – the hazard ratio was 1.14, but was not significant. Patients with prior ischemic heart disease showed higher levels of cardiovascular events compared to control. (Bringing to mind the ACCORD result…)

  • There were significant increases in the use of all CV medications throughout the course of the trial. Of note, the rosiglitazone group showed a 9.2% excess use of statins and 4.9% excess use of loop diuretics as compared to the control group after five years of study.
  • No increased risk was detected in the primary endpoint of cardiovascular death and/or cardiovascular hospitalization (HR 0.99, 95% CI 0.85-1.16), notably below the non-inferiority margin of 1.20. The event rate was 2.8% per year, far below the predicted value of11% because of better therapies. No increased risk was found for the secondary endpoints of all- cause death (HR 0.86, 95% CI 0.68-1.08), cardiovascular death (HR 0.84, 95% CI 0.59-1.18), or stroke (HR 0.72, 95% CI 0.49-1.06) as well. For comparison, Dr. Nissen’s 2007 meta-analysis calculated an odds ratio for death from cardiovascular causes of 1.64 (95% CI 0.98 to 2.74, p= 0.03).
  • There was a highly significant increase of heart failure leading to death or hospitalization in the rosiglitazone arm (HR 2.10, 95% CI 1.35-3.27), with an early divergence between the groups that continued to grow throughout the trial. However, this is an expected result, since an increased rate of heart failure is generally accepted as a class effect of TZDs.
  • There were not enough myocardial infarctions to indicate any effect or lack of effect of rosiglitazone. Though there were an excess of events of myocardial infarction in the rosiglitazone group (64 events as compared to 56 in the active control), this was shown to be non- significant (HR 1.14, 95% CI 0.80-1.63; p =0.47). This is unfortunate, since Dr. Nissen’s meta- analysis showed a significantly greater risk of myocardial infarctions in people taking rosiglitazone (odds ratio of 1.43, 95% CI 1.03 to 1.98, p= 0.06).
  • Patients in the rosiglitazone arm with prior ischemic heart disease (IHD) showed higher levels of CV death or hospitalization as compared to controls. This was the only evidence of heterogeneity in the results (p = 0.055), with no differences in sex, age, duration of diabetes, BMI, ACE inhibitor use, statin use, or nitrate use.

 

METABOLIC AND SAFETY RESULTS

Henning Beck-Nielsen, MD (Department of Endocrinology and Metabolism, Odense, Denmark)

For aficionados of the ADOPT study, there was no news on the metabolic front in RECORD. The results were very similar to ADOPT, showing an early drop in A1c and upwards progression with all three drugs – but much faster progression with SFUs and metformin (this again raises the question whether SFUs cause beta cell burnout – we wish there would be a safety study done on this question but needless to say, as a generic, there is no one to fund it). Rosiglitazone provided the best control after one year onwards. As first seen in ADOPT, rosiglitazone led to an increased number of bone fractures, particularly in women. There was a four kg weight gain (8.8 pounds) over five years with rosiglitazone, and suggestions of improvement in microvascular complications, although these weren’t significant. At the end of the presentation, Prof. Home showed some compelling charts overlaying the ADOPT A1c results directly on top of the RECORD charts and the graphs were uncannily similar – giving greater credence to RECORD, in our opinion. All slides from this presentation are available at xxx.

  • The addition of rosiglitazone produced a significantly lower mean A1c (p <0.0001) than the active control groups at the end of the five-year period (baseline A1c was 7.8% in the background metformin group and 8.0% in the background sulfonylurea group). Though the addition of a sulfonylurea to background metformin therapy first produced a precipitous decline in A1c, this increased back to initial values at the end of the trial. Notably, the graphs of mean A1c over time mimicked the results of ADOPT (Dr. Home later produced a convincing overlay), suggesting that findings of RECORD were relatively robust. As could be predicted, serious hyperglycemic events were significantly more frequent for the control group (p = 0.0027); all adverse events of hypoglycemia only notably increased following the addition of a sulfonylurea.
  • There was a significantly higher incidence of bone fractures in the rosiglitazone arm, particularly in women. The risk ratio for bone fractures in the total population was 1.57 (95% CI 1.26-1.97). In women, the risk ratio was 1.82 (95% CI 1.37-2.41) vs. 1.23 (95% CI 0.85-1.77) in men. However, Dr. Beck-Nielsen was careful to highlight that greater events may haveoccurred for men in a longer trial.
  • Body weight, LDL, and HDL cholesterol levels were all higher in the rosiglitazone treatment arm. He noted that the increased body weight is expected given the effect of rosiglitazone on fat cell differentiation (from our view, patients don’t really care if they are gaining “the good fat (subcutaneous)” or the “bad fat (visceral)” – most just want to avoid weight gain from drugs, particularly because most are struggling with it already.) There was no significant difference in diabetes-related eye or foot events, though both events were less frequent in the rosiglitazone arm (42 eye events vs. 52 events in the control and 19 foot events vs. 28 in the control). Mean urinary albumin excretion was lower in the rosiglitazone group as well, suggestive of a possible protective effect on renal function.

 

COMMENTARY AND CONCLUSIONS

Philip D. Home, DM, DPhil (Newcastle Diabetes Centre and Newcastle University, Newcastle upon Tyne, UK)

In an impressive tour-de-force set of conclusions, Prof. Home anticipated potential objections to the trial and presented his response. The overall effect was a very credible defense of the trial as valid and correct, at the same time casting further doubt on the Nissen paper. Earlier in the day, Prof. Home called the Nissen analysis “weak” and “funny” (meaning funny peculiar), on the basis that it was based on an odd selection of small, heterogeneous trials. He denounced Dr. Nissen’s objections that the dropout rate was too high (because the number of patient days on drug was 88%) and that statin use was too high in the rosiglitazone group (he didn’t think that it would be enough to influence the result).

  • Based on the results of RECORD, Dr. Home concluded that rosiglitazone can be used without fear of increased overall risk of CV morbidity or mortality. However, given the heart failure and IHD history results, he cautioned against its use in patients with a history of heart failure and cautioned those with any prior problem that may have lead to myocardial damage. He also advised caution in female patients with a high risk of fractures.
  • Even if rosiglitazone increases the occurrence of MI, the finding would have no effect on death. The relative risk of MI was 1.14 in the rosiglitazone group, but was not significant. Even if we assume that MI rates are in fact higher, we saw fewer MI deaths in the study (seven MI deaths in the rosiglitazone arm vs. 10 in the control arm).
  • The remarkably low event rate and increased use of statins likely had no effect on results. Given that the results for the primary endpoint were near unity, the statistical power of the results was not weakened, despite the relative infrequency of events. Likewise, the estimated 10% increase in the use of statins would only lead to a 2.5% risk reduction, not more than a 0.02 change in HR. Dr. Home was unsure why patients in the rosiglitazone arm exhibited increased loop diuretic use and was unable predict its effect on the overall results.
  • RECORD confirms that rosiglitazone would meets the new CV standards for safety of glucose-lowering medications proposed by the FDA if it were considered like a new drug. New FDA criteria require a non-inferiority for CV death, MI, and stroke, measured by the upper 95% confidence interval under 1.30, which is more than the stricter margin of 1.20utilized by RECORD. Even if the FDA were to demand heart failure data in the case of a drug criticized for heart failure such as rosiglitazone, the drug still meets the 1.30 requirement when data for heart failures is included in the calculations (the upper 95% CI for the composite of CV death, MI, and stroke was 1.15 and 1.20 with the addition of heart failure). From our view, this calls into serious question the FDA’s decision to require CVD trials pre-approval for a large group of drugs (of course we support the trials if the drugs show a CVD signal – otherwise, we think pre- approval is overly harsh, given the huge unmet need for new therapies for patients.
  • The total exposure to the drug in the trial was 88% for rosiglitazone and 83% for the control group (meaning the percentage of potential patient years). At the end of the trial the percentage of patients remaining on rosiglitazone was 61% and 51% for the control group. Although one criticism of the study is the low number of people on TZDs at the end of the trial, from our view, it’s obvious that over so many years, it’s unlikely that TZDs will be enough for glycemic control – as type 2 diabetes is progressive, it is obvious from our view that patients would progress to other therapy beyond TZDs; in other words, it’s difficult ethically to keep patients on the same regimen over a five-year trial. Prof. Home took the view that it was the exposure that was the most important factor in a safety trial.

Questions and Answers:

Q: Were your hazard ratios adjusted for differences in A1c?

Dr. Home: The results were not corrected for A1c, though it would be an interesting study to do in the future. Again, this is just the first round. UKPDS made it clear that it takes time for the lowered MI to appear as well; we didn’t see the effects with metformin here even at five years, so we hate to speculate.

Q: Are you planning a five-year follow-up, given the importance of follow-up for meta events?

Dr. Home: Sadly not, except in some cases, possibly malignancies and fractures.

Q: How do you explain the disparity in event rates, particularly in light of the higher event rates seen in Dr. Nissen’s meta-analysis?

Dr. Home: Higher event rates seen in the previous meta-analysis were based on recent as well as historic data, in a time when certain CV drugs, such as statins, were not so available to patients. The reduced event rate thus may partly be the result of better care—2.8% is wonderful news for people with diabetes.

Q: Did the groups differ in the time to progress from two to three drugs?

Dr. Home: Yes, we have to be extremely careful—we’re currently struggling with that bit of analysis right now. The problem is that one group moved to another oral agent, while the other we set to defined insulin therapy. Due to reluctance to start insulin, many did not start.

 

Symposium: Results of the BARI 2D Clinical Trial

Sheryl F. Kelsey, PhD (Pittsburgh Graduate School of Public Health, University of Pittsburgh, PA)

Dr. Kelsey was the first in the three-speaker lineup to present the results of the widely-awaited Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI-2D) study. She described the rationale, fairly complex design, and implementation of the study. BARI-2D, a study with a 2x2 factorial design, investigated two pairs of treatment strategies to see which was better for treating coronary artery disease in 2,368 patients with type 2 diabetes. The first pair consisted of either a combined surgical and intensive medical approach, or an intensive medical approach alone. The second consisted of insulin- sensitizing therapy or insulin-provision therapy. It is important to note that enrolled patients were selected to receive a particular surgical intervention (bypass surgery or angioplasty/stenting) based on physician judgment of the severity of their coronary artery disease.

  • Few studies have investigated the treatment of patients with type 2 diabetes and coronary artery disease. Research in patients with ischemic heart disease (but not necessarily with diabetes) has shown that revascularization is only effective at reducing the rate of death and subsequent myocardial infarction in high-risk patients or those presenting with acute coronary syndromes. However, the optimal treatment of ischemic heart disease in the diabetes population has not been addressed. Given that diabetes patients have a higher risk of cardiovascular events and death, they may be considered “high-risk” and respond differently to revascularization treatments than patients without diabetes.
  • BARI-2D compared rates of mortality and cardiovascular events in 2,368 type 2 diabetes patients with heart disease receiving either prompt revascularization 0r medical therapy alone. The method of revascularization, either percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG), was non-randomized and selected a priori by the physician to be in the best interest of the patient. PCI involves a balloon catheter to unblock clogged blood vessels. CABG surgery is more involved and creates new routes (bypass) around blocked blood vessels. Patients selected to receive CABG had more severe coronary disease and were more likely to have a history of myocardial infarction. Before randomization, 68% of patients were selected for PCI, whereas 32% of patients were selected for CABG. The primary endpoint was identified as all-cause mortality and the principle secondary endpoint was major cardiovascular events.
  • The study randomized patients to receive insulin-sensitizing therapies (rosiglitazone and metformin) or insulin replacement/provision therapies (exogenous insulin or insulin secretagogues). By treating half of the patients with insulin- sensitizing drugs and the other half with exogenous insulin, the authors attempted to study whether high levels of insulin are associated with cardiovascular complications. It has been noted that people with prediabetes and type 2 diabetes have significantly increased levels of macrovascular complications, however it is unclear whether this is caused by high glucose or the high levels of insulin used to lower glucose in the context of insulin resistance. Some studies have proposed that hyperinsulinemia is directly or indirectly responsible for an increase in cardiovascular complications. In this study, a finding of reduced cardiovascular complications in the insulin-sensitizing arm of the study would have given credence to this theory.

Figure 1: Patient enrollment and stratification (The BARI 2D Study Group. N Engl J Med, June 2009)

 

BARI-2D FIVE-YEAR RESULTS

Robert Frye, MD (Mayo Clinic, Minneapolis, MN)

Dr. Robert Frye presented the results of BARI-2D. The study showed no significant difference in the five- year survival rate between patients in the prompt revascularization group (88.3% survival) and those in the medical therapy group (87.8% survival). Nor was there a significant difference in mortality between the insulin-sensitizing (88.2% survival) and insulin-provision groups (87.9% survival). When the patients were stratified by type of revascularization, there was a significant reduction in cardiovascular events in the group selected to the coronary artery bypass graft (CABG) arm/stratum who underwent prompt revascularization compared to those in this stratum who underwent medical therapy. In the group selected to receive percutaneous coronary intervention (PCI), there was no difference in cardiovascular events between those who actually underwent revascularization and those who were treated with medical therapy.

In high-risk patients (i.e., those in the CABG stratum), the benefit associated with prompt revascularization was shown to be greater than that obtained from medical therapy. Another interesting hypothesis-generating result in this high-risk group was the positive impact of insulin sensitizers versus SFUs/insulin compared to the other three cohort combinations. There was no difference in rates of congestive heart failure or bone fractures, which bodes well for TZD therapy.

  • Dr. Frye emphasized that this was not a trial to compare CABG and PCI since higher risk patients were more likely to be randomized to the CABG arm. BARI-2D enrollment was stratified based on which patients needed prompt revascularization and this wasdetermined a priori. The investigators pre-specified the stratification according to selection by cardiologists.
  • As a result of this stratification, patients randomized to the CABG stratum had a greater degree of cardiovascular disease. There was more three-vessel disease, proximal LAD (one of two branches of left coronary artery), and higher myocardial jeopardy index in the CABG-selected patients. All these data point to higher risk in the patients selected for the CABG arm. As predicted, patients in the CABG stratum had higher death/MI/stroke composite outcomes.
  • The study showed no significant difference in the five-year survival rate between patients in the prompt revascularization group (88.3% survival) and those in the medical therapy group (87.8% survival). Nor was there a significant difference in mortality between the insulin-sensitizing (88.2% survival) and insulin-provision groups (87.9% survival). When the patients were stratified by type of revascularization, there was a significant reduction in cardiovascular events in the group selected to the coronary artery bypass graft (CABG) stratum who underwent prompt revascularization compared to those in this stratum who underwent medical therapy. In the group selected to receive percutaneous coronary intervention (PCI), there was no difference in cardiovascular events between those who actually underwent revascularization and those who were treated with medical therapy.
  • In high-risk patients (i.e., those selected for CABG), the benefit associated with prompt revascularization was shown to be greater than that obtained from medical therapy. Patients in the CABG stratum had fewer cardiovascular events in those who underwent revascularization (22.4%) compared to those treated with intensive medical therapy alone (30.5%). In particular, this revascularization group had fewer nonfatal myocardial infarctions. There was significant difference in major cardiovascular events between the four groups in the CABG stratum (p = 0.02). The lowest rate of cardiovascular events occurred for revascularized patients that received insulin sensitization therapy. In lower risk patients (selected for PCI), prompt revascularization and medical therapy had similar rates for major events.
  • Dr. Frye emphasized the value of collaboration between the cardiology and diabetology/endocrinology communities. Speaking from a cardiologist’s perspective, he noted that it was intriguing that after several years of CABG studies from the cardiology community, it took a study presented at the ADA to show this new finding of better cardiovascular outcomes from prompt surgical intervention vs. medical intervention in high risk patients.
  • Another interesting hypothesis-generating result in the high-risk group was the positive impact of insulin sensitizers vs. SFUs/insulin compared to the other three cohort combinations. As mentioned above, the CABG/prompt revascularization/insulin sensitizer cohort had the lowest rate of macrovascular events. This suggests that insulin sensitizers may be enhancing the benefit of revascularization especially in CABG patients. The use of insulin sensitizers was also associated with improved lipid profiles.
  • There was no difference in rates of congestive heart failure or bone fractures, which bodes well for TZD therapy. There was greater hypoglycemia in the insulin-provision arm, but greater peripheral edema in the insulin-sensitizing arm.

 

BARI-2D SUMMARY AND IMPLICATIONS

Trevor Orchard, M.B.B.Ch., M.Med.Sci (Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA)

Dr. Orchard provided valuable commentary on the results of the BARI 2D trial in the context of current medical practices and recent trials. Despite failing to find significant differences in outcome between the revascularization and medical therapy groups as well as between the insulin sensitization and insulin replacement groups, the results of this trial were consistent with other major trials. Although the results of BARI-2D do not call for dramatic changes in diabetes management, it raises the hypothesis that insulin-sensitizing therapy could be better than insulin-provision therapy in those very ill patients selected to undergo revascularization via coronary artery bypass graft (CABG). Dr. Orchard emphasized that this study did not address the question of macrovascular benefit of intensive glycemic control – all subjects were treated with a target A1c of less than 7% – and did not assess therapeutic advantages associated with particular drugs. Dr. Orchard concluded the talk by providing physicians with one take-home lesson: therapeutic decisions regarding the management of coronary artery disease and glycemia in type 2 diabetes patients should be made jointly by patients, cardiologists, diabetologists, and/or primary care physicians.

  • BARI 2D results were consistent with other relevant large-scale trials relating to diabetes and cardiovascular procedures and outcomes. The results of the PCI arm were consistent with the COURAGE trial – non-diabetes patients, no CABG intervention – where PCI and medical therapy had similar primary outcomes (mortality and non-fatal MI). Rosiglitazone (Avandia by GlaxoSmithKline) treatment outcomes were also consistent with data from the recently released RECORD trial.
  • Dr. Orchard placed the macrovascular outcomes of glucose lowering from BARI-2D in the context of ACCORD, ADVANCE, and the VADT. Though BARI-2D was not designed to address the cardiovascular benefit of glucose lowering, the data largely confirm what the three glycemia lowering trials found. Decreases in A1c did not have a positive impact on macrovascular disease.
 

Change in A1c (%)

Change in CVD

BARI 2D

-0.5

Not Significant

ADVANCE

-0.6

Not Significant

ACCORD

-1.1

Not Significant

VADT

-1.6

Not Significant

  • Dr. Orchard presented data comparing changes in weight and A1c between insulin- sensitizing therapy and insulin replacement therapy. Weight gain in patients treated with insulin-sensitizing therapy (0.3 kg) was far less than the weight gain reported from insulin replacement therapy (2.1 kg). The following table provides data describing the effect of various treatment combinations on A1c levels:

Treatment type

Treatment subcategory

A1c (%) (Baseline = 7.7%)

   

Insulin-sensitizing therapy

Insulin replacement therapy

PCI

Revascularization

6.9

7.5

 

Medical

7.2

7.5

CABG

Revascularization

6.9

7.4

 

Medical

7.1

7.5

  • Severe hypoglycemia was reduced in the insulin-sensitizing group. This is an interesting finding, since severe hypoglycemia has been linked with a potential risk of developing arrhythmias and other cardiovascular events. Dr. Orchard suggested that adoption of an insulin- sensitizing therapy may be considered in those undergoing (CABG) revascularizations, however, further studies must be conducted before adoption of this approach.
  • Dr. Orchard extrapolated important implications from the results of the BARI 2D trial. Overall, he claimed that insulin-sensitizing therapy and insulin replacement therapy appear to be appropriate for BARI 2D eligible patients. Evidence suggests that insulin-sensitizing therapy may offer advantages over insulin replacement therapy given the reduction in cardiovascular events in patients undergoing CABG and receiving insulin-sensitizers. He pointed out thatinsulin-sensitizing therapy also displayed borderline (non-significant, p = 0.07) benefit over insulin replacement therapy. However, further analysis must be performed to determine whether strategies differ in secondary outcomes.
  • Finally, Dr. Orchard outlined his suggestions for future studies. He advised categorizing patients in future studies based on age, gender, baseline insulin use, baseline A1c levels, creatinine, left ventricular failure status, and a history of revascularization. More secondary outcomes can also be measured including individual cardiovascular diseases, myocardial infarction, angina, left ventricular function, NMR analysis of lipid proteins, quality of life, and cost effectiveness. Lastly, he stated that long-term follow up studies should be conducted to truly understand the durable effects of any treatment strategy. He concluded the talk by providing physicians with one take-home lesson: therapeutic decisions regarding the management of coronary artery disease and glycemia in type 2 diabetes patients should be made jointly by patients, cardiologists, diabetologists, and/or primary care physicians.

 

Interest Group Discussion on Clinical Endocrinology, Health Care Delivery, and Public Health: In-patient Glycemic Control After NICE-SUGAR. How Low Should We Go?

THE NICE-SUGAR TRIAL: SUMMARY

Harold Lebovitz, MD (SUNY Brooklyn Health Sciences Center, New York, NY)

Dr. Lebovitz summarized the findings from the NICE-SUGAR (NEJM, 2009) to set the stage for the broader discussion. NICE-SUGAR (Normoglycaemia in Intensive Care Evaluation and Survival Using Glucose Algorithm Regulation) compared tight glucose control (81-108 mg/dl) to conventional control (144-180 mg/dl). The primary outcome measure of the study was all-cause mortality within 90 days of admission, and the results showed a significantly greater 90-day mortality in the intensively treated group compared to the conventionally treated group. Similar to ACCORD a year ago, a number of key opinion leaders continue to question these non-intuitive results.

  • The NICE-SUGAR (Normoglycaemia in Intensive Care Evaluation and Survival Using Glucose Algorithm Regulation) study was a multi-center randomized controlled trial of blood glucose management comparing two insulin regimens for patients in critical care. One regimen was designed to maintain blood glucose between 81-108 mg/dl (4.5-6.0 mmol/l) versus another to maintain blood glucose between 144-180 mg/dl (8.0-10.0 mmol/l). Patients included in the study were selected on the basis of their likelihood ofstaying in the ICU for three or more consecutive days.
  • The primary outcome measure of the study was all-cause mortality within 90 days of admission, and the results showed a significantly greater 90-day mortality in the intensively treated group compared to the conventionally treated group. Incidence of severe hypoglycemia (<40 mg/dl; 2.2 mmol/l) was significantly greater in the intensively treated group. The subgroup analyses did not reveal any treatment-specific effect based on the presence of diabetes, comparison of operative versus non-operative patients, the presence of sepsis, or APACHE II score (a quantitative estimation of a patient’s predicted death rate in the ICU). At this point it remains unclear whether the increased mortality seen in the intensive group was due to the lowering of glucose levels, increased use of insulin, hypoglycemia, or some other factor specific to NICE-SUGAR. As in the recent ACCORD trial, hypoglycemia is currently receiving the most speculation.

 

THE NICE-SUGAR TRIAL: A CRITIQUE AND COMPARISON TO PRIOR STUDIES

Silvio Inzucchi, MD (Yale Diabetes Center, New Haven, CT)

Dr. Inzucchi delivered a thorough examination of the various strengths, limitations, and unanswered questions of NICE-SUGAR. He raised a fascinating point to ponder regarding the need for a “per protocol analysis” to explain the data not included in the intent to treat analysis of mortality. He calculated that data for 79 people were included in the intent to treat analysis even though they discontinued from the study (and were thus not receiving their assigned treatment algorithms). These people came from both arms of the study. Also, there were 78 people who died in excess in the intensive vs. conventional group. One could speculate that the dropouts could fully account for excess mortality. This highlights the need for the investigators to perform a “per protocol analysis” to present the outcomes of the patients who were in compliance with their assigned insulin regimen. He emphasized that he clearly believed NICE-SUGAR was a negative study but that these questions were important questions to address nonetheless. We wonder whether the last comment was mostly political. Notably, Dr. Inzucchi emphasized that there was very little representation of the cardiac population meaning that the NICE-SUGAR findings are not generalizable to the cardiac surgery population.

  • Dr. Inzucchi highlighted a number of features of the trial design to provide context for interpretation of the findings in the study. More than two-thirds of patients in the conventional arm received intravenous insulin and about a third of the cohort was operative. There was very little representation of the cardiac population meaning that the NICE-SUGAR findings are not generalizable to the cardiac surgery population. Notably, the glucose curves do not begin to separate until a few days out. He postulated that the overlap has likely had some impact on the findings from the study.
  • Both 28-day and 90-day mortality was increased though only 90-day mortality was significant. Oddly there was no difference between rates of new organ failure, which you would expect given the differences in mortality.
  • There are other risks of IV insulin in addition to hypoglycemia. These include stimulation of the sympathetic nervous system, increased myocardial oxygen demand, and the mitogenic effects (possibly pro-atherogenic). Interestingly, he alluded to the idea of competing clinical priorities where a concentrated focus on glucose control could detract from other important treatment priorities. From a patient perspective, this underscores even more the importance of getting the right tools in hospitals; if a good continuous glucose monitoring system existed, so many labor resources wouldn’t need to be given to making sure glucose levels were so closely followed. Also, a closed loop system would enable more physiological control of glucose levels, which we believe testing will prove to be a positive.
  • Dr. Inzucchi described the strengths and limitations of NICE-SUGAR. It was a large, multicenter study with patients who were characteristic of a general ICU population. Limitations include the lack of proper separation of specified glycemic targets and lack of target attainment in intensive group (though he said it was less of an issue since there was actually increased mortality). In addition, there were variable methods for blood glucose measurement and more steroid therapy in the intensive arm. As well, there was 15-fold increase in hypoglycemic events but it’s not clear that this fact is driving mortality since the Leuven I study also had excess hypoglycemia in the intensive arm. There were no data presented to help explain excess mortality. We would also point out there was not good data on the actual adherence to blood glucose checks; we also believe the conventional target was far more “intensive” than in most ICUs in the US at present, which from our view makes the entire study more difficult to interpret.
  • Dr. Inzucchi raised a very important point regarding the need for a “per protocol analysis” to explain the data in addition to the intent to treat analysis of mortality. He calculated that data for 79 people included in the intent to treat analysis discontinued from the study (and presumably no longer received their assigned treatment algorithms). These people came from both arms of the study. Since there were 78 people who died in excess in the intensive vs. conventional group, one could speculate that the dropouts could fully account for excess mortality. This raises the question of whether investigators should perform a “per protocol analysis” to present the outcomes of the patients who were in compliance with their assigned insulin regimen. He emphasized that he clearly believed NICE-SUGAR was a negative study but that these questions were important questions to address nonetheless. We believe compliance is a major question to address when interpreting this study; we wonder, for example, what compliance was in terms of adherence to required blood glucose monitoring. There has been no data on this but presumably this would be possible to get, and we would like to see it, in particular, for those in the intensively controlled group that died.
  • He concluded with a comparison of NICE-SUGAR to the Leuven I study that may shed some light on the different outcomes from the two studies. Patients in NICE- SUGAR had higher APACHE scores than those in Leuven I (21 vs. 9) meaning that patients in NICE-SUGAR were much sicker. The targets in the conventional arm of Leuven I (180-200 mg/dl or 10–11.1 mmol/l) were higher than that for NICE-SUGAR (140-180 mg/dl or 7.8 – 10.0 mmol/l). NICE-SUGAR was unable to achieve aggressive targets in the intensive arm (81-108 mg/dl or 4.5-6 mmol/l) whilst Leuven did achieve its targets (80-110 mg/dl). NICE-SUGAR used a computer-based insulin infusion protocol compared to the paper-based protocol in Leuven I. There were marked differences in nutrition in the two studies with a greater proportion of LeuvenI patients receiving total parenteral nutrition. In our view, it is quite possible that these differences contribute to the hypoglycemia, mortality, and relative risk reduction differences between the two studies; we believe the differences undoubtedly make it harder to assess the impact of tight glycemic control. To be sure, this also highlights the difficulty and complexity of trial design.

 

WHAT ARE THE STRATEGIES FOR ACHIEVING REASONABLE, ACHIEVABLE AND SAFE GLYCEMIC TARGETS FROM ADMISSION TO DISCHARGE?

Guillermo Umpierrez, MD (Emory University School of Medicine, Atlanta, GA)

Dr. Umpierrez discussed recommendations for managing patients with diabetes in the hospital setting. He focused on the use of insulin protocols and basal/bolus vs. sliding scale insulin. His key learning point was the need to reduce insulin dose in patients treated with insulin prior to admission in order to reduce the risk of hypoglycemia.

  • Dr. Umpierrez emphasized that none of the insulin infusion protocols in major trials in the last three to four years have shown any benefit from intensive insulin therapy. All protocols appear to be similar, and all seem to have resulted in excessive hypoglycemia. This could mean that we need to have better protocols. We would also suggest that it underscores the need for better tools, notably continuous glucose monitoring.
  • He again described the study by Newton et al.(Diabetes, 2008) comparing computer-based vs. paper/column based insulin infusion protocols. The study showed differences in glucose control achieved (103 mg/dl vs. 12o mg/dl for the computer-based vs. column based algorithm). In terms of target attainment, 69% vs. 46% achieved targets in the computer-based vs. column-based protocols, respectively.
  • He stressed the need to improve protocols to reduce insulin rates before glucose levels reach <70 mg/dl. He also criticized the use of a hypoglycemia definition of blood glucose <40 mg/dl (2.2 mmol) as seen in most studies.
  • Upon admission, it is important to reduce patients’ insulin dose in patients treated on insulin prior to admission in order to reduce hypoglycemia. It is also important not to use protocols that rely solely on sliding scale insulin. He reiterated the findings from the RABBIT-2 trial, which showed better glycemic control of basal-bolus therapy compared to sliding scale insulin regimen. He also brought up the DEAN trial, which showed greater hypoglycemia with a detemir/glargine regimen compared to an NPH/regular regimen.

 

THE AACE/ADA CONSENSUS STATEMENT ON IN-PATIENT GLYCEMIC CONTROL - BACKGROUND

Etie Moghissi, MD (University of California at Los Angeles, Los Angeles, CA)

Dr. Moghissi described the AACE/ADA consensus statement on inpatient glycemic control. She highlighted the points made during the special in-patient glycemic control session at the recent AACE meeting in Houston, TX. Dr. Moghissi stressed that the process of developing the AACE/ADA guidelines was not a knee-jerk reaction to the results of NICE-SUGAR.

  • In her talk, Dr. Moghissi emphasized that the process of developing the AACE/ADA guidelines was not a knee-jerk reaction to the results of NICE-SUGAR. A decade ago,acute hyperglycemia was thought to be benign, sliding scale insulin was the norm, and there were no published standards of care or guidance from medical societies about glucose levels in the ICU. Early evidence suggesting the harm of hyperglycemia prompted the 2004 ADA Technical Review. AACE convened a Consensus Conference around the same time to recommend targets. In 2005, the ADA included inpatient glycemic control as part of Standards of Care.
  • As practices began paying attention to the issue, barriers to implementation became clear and the 2006 AACE/ADA guidelines were designed to address these barriers. Recently, newer evidence has suggested that the targets of 80-110 mg/dl may not result in a mortality benefit – and may even cause harm. All these studies were taken into account in setting up the new AACE/ADA guidelines. From a patient perspective, we hope that the AACE/ADA guidelines that put forward standards of 140-180 mg/dl won’t encourage doctors to be lax in reaching even these targets. We wonder what the trials would have shown had there been continuous glucose monitoring in the studies.

 

THE AACE/ADA CONSENSUS STATEMENT ON IN-PATIENT GLYCEMIC CONTROL - DETAILS

Mary Korythowski, MD (University of Pittsburgh, Pittsburgh, PA)

Dr. Korythowski noted that AACE/ADA recommended glycemic targets were now 140-180 mg/dl (7.8 – 10.1 mmol/l) in most critically ill patients, up from 80-110 mg/dl (4.4 -6.1 mmol). For majority of non- critically ill patients, they recommended targeting pre-meal blood glucose under 140 mg/dl (<7.8 mmol/l) as well as random blood glucose below 180 mg/dl (10.0 mmol/l).

  • Dr. Korythowski pointed out that the studies discussed thus far compare tight glycemic control with good glycemic control. She warned against regressing to the era of poor glycemic control where outcomes have clearly been shown to result in worse outcomes.
  • She provided a summary of the recent AACE/ADA consensus statement on in- patient glycemia management. This consensus statement was published in the May issue of Endocrine Practice and concurrently in Diabetes Care. The two associations recommended glycemic targets of 140-180 mg/dl (7.8 – 10.0 mmol/l) in most critically ill patients. For majority of non-critically ill patients, they recommended targeting pre-meal blood glucose under 140 mg/dl (<7.8 mmol/l) as well as random blood glucose below 180 mg/dl (10.0 mmol/l). In the latter group, there is noticeably more leeway for healthcare providers to determine appropriate targets – more stringent in stable patients who were previously well controlled; less so in terminally ill patients or those with severe comorbidities. Another noticeable distinction is the use of intravenous insulin versus subcutaneous insulin in the critically ill versus non-critically ill populations respectively.
  • Non-insulin therapies should not be used in the hospital. SFUs are a major cause of hypoglycemia, metformin is contraindicated in patients with impaired renal function, TZDs cause edema and CHF, and pramlintide/GLP-1 agonists can cause nausea and have greater effect on postprandial glucose (we didn’t know what the last point meant, since this is generally a positive).
  • The consensus statement is not positive on the use of currently available point of care meters, continuous interstitial fluid glucose measurement, or glucose measurement using indwelling lines. Encouragingly however, it does note the importance of further study to define a role of continuous monitoring technologies in critically ill patients.
  • Administration and financial support is essential for promoting a rational systems approach to inpatient glycemia management. The components of such an approach include personnel resources, staff education, coordination of protocols, treatment order sets, and electronic records.

 

Questions and Answers

Q: Who is the recommendation of 110-140 mg/dl for?

Dr. Korythowski: We did not state whom this recommendation should be for. NICE-SUGAR did not include many cardiac surgery patients. In our institution, we will use it for cardiac surgery patients and pancreas transplant patients.

Dr. Inzucchi: We did not feel we could say 110-140 mg/dl is wrong, assuming that people are able to do it well.

Q: The data is mostly in non-diabetes patients. We know the mortality curves in non- diabetics show marked mortality increases with hyperglycemia. Doesn’t this mean that we should be trying to get them as close to normal as possible?

Dr. Lebovitz: That would require a prospective study.

Q: The pregnancy population and a few subpopulations have not been mentioned.

Dr. Moghissi: These are not practice guidelines. These are consensus recommendations. We need to look at the evidence with an open mind – is it safe and achieving better outcomes. We don’t have the studies to guide us. Therapy should be individualized.

Dr. Inzucchi: There are entrenched interests not based on evidence at play here. The cardiac surgery evidence is based on Dr. Furnary’s data, which is limited. When the evidence changes, we should be prepared to change as well.

Dr. Umpierrez: Only a single study has shown benefit of 110-140 mg/dl.

Dr. Lebovitz: A consensus statement is based on the best available evidence. Physicians should take this evidence and make the best judgment that they can.

Comment: Speaking of thinking with an open mind, we have to recognize there is a role for orals in the hospital since many patients are not capable of managing insulin and will have to have started on orals to continue on them on discharge.

Q: Targeting 140 mg/dl – it’s so easy to overshoot to get to 200 mg/dl. How do you address that?

Dr. Moghissi: We have to look at risk/benefit ratios. The consensus is set for a broad audience and should be applied in context of your particular institution.

Dr. Lebovitz: I think there is a lot of focus on hypoglycemia. There was an increase in mortality of 14% in 90 days. Until we understand the cause of mortality, we cannot attribute everything to hypoglycemia.

Comment: There should be a brain inserted between the protocol and the patient. The statement should address that and the patient has to be looked at individually.

Comment: I think we need to know why hypoglycemia occurs. We need to know the cause, timing, and specific nature of mortality in NICE-SUGAR.

 

Symposium: New Analyses from ACCORD and VADT

Here is our coverage of the analysis presented at ADA on June 9 that sought to explain the curious results of the ACCORD and VADT trials – we point out that there were a lot of non-intuitive and mysterious findings from the analysis, leaving participants scratching their heads as they left the enormous hall E in New Orleans). There’s undoubtedly a lot of learning from these follow – up results, and we present the details below.

Last year, the headlines screamed ‘intensive glucose therapy will kill you!” (we exaggerate for effect). This year, the combined learning from ACCORD and VADT says that some people (who have type 2 diabetes and cardiovascular disease) can safely achieve A1c levels below 7% using an intensive strategy.

But this doesn’t work for everyone – some clinicians may interpret the results as saying that if such a patient doesn’t respond quickly to glucose lowering therapy, and/or gets a lot of severe hypoglycemia – then we might be putting them at extra risk. This viewpoint forces us to think more about the world of individualized medicine.

What else have we learned? There has been a longstanding view that severe hypoglycemia was bad for cardiovascular risk – this has been shown beyond all reasonable doubt in both ACCORD and VADT. If we need to obtain low A1cs with zero severe hypoglycemia, this seems like a job for CGM.

One lesson of ACCORD and VADT from last year was that it’s hard to treat glycemia in sicker, older patients and get a positive result within five years. To underscore this, this new analysis emphasizes the need for early aggressive treatment. It appears that in both the macrovascular and microvascular setting, cumulative damage is being done, and we get diminishing returns by waiting. In this sense, dyslipidemia and dysglycemia are very similar.

 

The ACCORD Trial

After a year of seemingly endless speculation and inaccurate interpretations of the ACCORD trial, we had a great opportunity to see some in-depth analysis of the excess mortality we saw in the intensive glucose management group, compared to the standard group. It turns out that the investigators don’t believe that A1c level, the rate of reduction of A1c at the beginning of the trial, or the amount of severe hypoglycemia explain these excess deaths, and we should be looking for another explanation (or explanations).

For A1c, we learned that a higher A1c has a higher risk of death – yet the intensive group had lower A1cs. There wasn’t an excess of death in the intensive group related to A1c below 7%, for example. Also, the patients who lowered their A1c faster at the beginning of the trial had lower risk of death – not higher as some postulated at the time.

For hypoglycemia, there was no doubt that severe hypoglycemia led to a greater risk of death. So far, so good, but patients with episodes of severe hypoglycemia in the intensive group surprisingly had a lower risk of death than those in the standard treatment arm. There was more hypoglycemia in the intensive group, but it balanced out with the lower risk. If we were to remove all severe hypoglycemia, there would be no significant differences in the number of deaths we would avoid in each group.

We certainly have learned a lot from these analyses, but have not solved the mystery. Ongoing analysis on weight gain and drug choice/drug dosing or drug interactions will be illuminating, although we expect that the drug analysis will be challenging because of the variability of the data and overlap between the two groups.

 

A1C AND MORTALITY RISK IN ACCORD

Matthew Riddle, MD (Oregon Health & Science University, Portland, OR)

An intensive glycemic treatment strategy was associated with a higher risk of death over 3.4 years of follow-up. However, in the whole ACCORD population, a 20-22% greater risk of death was associated with each 1% higher average A1c, confirming results from other trials like UKPDS and HOPE. Dr. Riddle said that the paradox was likely related to the different relationships between risk of death and average A1c between the two groups: the excess risk of death with intensive treatment occurred in patients who had average A1c over 7% (not below 7%, as had been previously speculated) as well as those who did not reduce A1c during the first year of treatment (not in those who had faster A1c drops). In contrast, mortality in the standard arm occurred at A1c <7% or A1c >8% and there was no association between A1c drop in the first four months and mortality.

Dr. Riddle concluded that these findings do not support the view that rapid reduction of glucose values or lower A1c values, independent of other factors, led to the excess risk of death in the intensive strategy in ACCORD. They also do not identify the causes of the excess risk associated with an intensive treatment strategy. Further analyses are needed to understand these findings. However, these analyses do suggest that some persons with type 2 diabetes can safely achieve A1c levels below 7% using an intensive strategy, whereas other persons who do not readily achieve these lower A1c levels may be at risk if they persist in this strategy.

  • The ACCORD trial included 10,251 patients, in a double 2x2 factorial design to study treatment for glycemia, blood pressure, and lipids across 77 sites in the US and Canada. The key question for the glycemia study was whether targeting an A1c < 6% (intensive arm actually achieved 6.4%) would improve cardiovascular outcomes compared to a treatment strategy that achieved an A1c of 7-7.9%. The therapy for the intensive group varied in many ways from the standard group, with more visits, follow up, training, intensity of initial therapy, and more use of insulin and combination oral therapy. Recruitment finished in October 2005, the full trial will end in June 2009, and there will be extended data collection beyond that.
  • The glycemia trial portion of ACCORD was stopped for safety reasons early in 2008, because the incidence of total mortality in the intensive arm was 1.41% vs. 1.14% per year for the standard arm for a hazard ratio (HR) of 1.22 (p=0.04). Hypotheses raised to explain the excess mortality included: hypoglycemia, weight gain, certain drugs/drug combos/drug dosages, and/or rapid reduction or near-normal levels of A1c.
  • Epidemiology data from other trials have shown a positive relationship between higher A1c and increased mortality. In UKPDS the hazard ratio was 1.14 for every 1% increase in A1c. In the HOPE trial, the adjusted relative risk was 1.12 for each 1% increase in A1c.
  • Consistent with previous trials, higher A1c in ACCORD was actually associated with increased mortality in both arms. This relationship was more significant in the intensive arm, (which had on average a lower A1c). Overall, for every 1% increase in A1c, the risk of death increased by 22%. In the intensive arm, the hazard ratio for each 1%increase in A1c was 1.66 (p=0.0001) whereas the HR for each 1% in the standard arm was 1.14 (p=0.17).
  • An excess risk of death in the intensive strategy vs. the standard strategy occurred in patients with A1c >7%, not in the lower ranges of A1c as previously hypothesized. For the intensive strategy, there was a steady increase of mortality risk for increasing A1c from 6% to 9% A1c. In contrast, A1c values between 7% and 8% were associated with the lowest mortality in the standard strategy, with higher mortality for A1c<7% or A1c >8%.
  • Contrary to prior speculation, in the intensive group the overall rate of death (for the 3.4 years of treatment) was highest for patients who did not have a reduction in A1c in the first year. The rate of death in the standard group was constant regardless of the drop in A1c during the first year. A bigger drop in A1c was not associated with higher mortality in either arm.

 

PREDICTORS OF HYPOGLYCEMIA AND ITS ASSOCIATION WITH MORTALITY

Denise E. Bonds, MD (National Heart, Lung, and Blood Institute, IH, Bethesda, MD)

Denise E. Bonds, MD (National Heart, Lung, and Blood Institute, IH, Bethesda, MD) introduced the topic of hypoglycemia in ACCORD. Hypoglycemia was more common in the intensive arm of ACCORD (2-3.5% vs. 1% incidence).

Women, African Americans, older participants, those with fewer years of education, and those with more complications at baseline were at higher risk of hypoglycemia. Patients with higher baseline A1c or higher average A1c were at higher risk of severe hypoglycemia (HR 1.15 in the intensive arm and HR in standard arm per 1% rise in A1c).

In the intensive arm, patients who had large reductions in A1c between baseline and four months were at a lower risk of hypoglycemia. Diet-related behavior change was the most common antecedent to severe hypoglycemia in ACCORD. This finding, Dr. Bonds, noted, suggests that dietary interventions could be implemented to decrease hypoglycemia.

Severe hypoglycemia was associated with increased mortality in both arms, with a greater association in the standard arm than in the intensive arm (HR 2.87 in standard arm and HR 1.28 in intensive arm for prior episode of severe hypoglycemia vs. no hypoglycemia). Among patients who had at least one episode of severe hypoglycemia, intensive arm patients had a lower risk of death than standard arm patients (HR 0.55 intensive vs. standard). Among patients who had no episodes of severe hypoglycemia, intensive arm patients had a higher risk of death than standard arm patients (HR 1.24 intensive vs. standard).

Hypoglycemia was felt to play no direct causal role in most deaths since few deaths occurred within 90 days of a documented episode of severe hypoglycemia. The number of deaths that potentially would be eliminated if there had been no hypoglycemia was similar in each arm. Dr. Bonds finished with three takeaway points: 1) We should expect severe hypoglycemia when intensive therapy, particularly with women, African Americans, and patients with other diabetes complications; 2) Severe hypoglycemia is associated with a higher risk of mortality regardless of treatment, but the risk was lower in the intensive arm; 3) Severe hypoglycemia did not account for the mortality difference in ACCORD.

  • In ACCORD, severe hypoglycemia was defined as an episode of BG <50 mg/dl (2.8 mmol) or symptoms that resolved with carbohydrate. Participants were asked at eachvisit about any such episodes. Participants were also asked if they required medical assistance for any episodes of hypoglycemia or required assistance from another individual. Analyses for episodes of hypoglycemia requiring assistance did not differ from those for overall severe hypoglycemia and were not reported in this talk. For the rest of this report, we’ll use the term ‘hypoglycemia’ to refer to severe hypoglycemia as defined above.
  • Severe hypoglycemia was more frequently seen in the intensive arm of the study. The annual incidence of hypoglycemia was 2 to 3.5% compared to about 1% in the standard arm.
  • Risk factors for hypoglycemia in both arms were diabetes complications, race, gender, older age and lower weight. Worse complications, African American race, female gender, older age and lower weight were found to be risk factors for severe hypoglycemia. Specifically with regards to age, for every one-year increase in age, there was a 3% increase in risk of severe hypoglycemia, an important consideration particularly in the case of the ACCORD population. See Appendix A for more details.
  • Risk factors that differed between treatment arms were baseline A1c, use of insulin at baseline, cholesterol level, and education level. See Appendix B for more details.
    • Baseline A1c was associated in the standard arm but not in the intensive arm. A 1% A1c increase was associated with a 30% increase risk for hypoglycemia in the standard arm. There was no association in the intensive arm.
    • Use of insulin at baseline was associated with an increased risk in both arms but the degree of risk was much higher in the standard arm than in the intensive arm.
    • Cholesterol - a higher LDL was associated with a lower risk of hypoglycemia in the standard arm but not in the intensive arm.
    • Lower education level - in the standard arm, fewer years of formal education were associated with an increased risk of severe hypoglycemia but in the intensive arm this was only seen in participants with less than a high school education.
  • Counter-intuitively, higher average A1c was associated with more hypoglycemia in both arms, with a stronger association in the standard arm. As we said above, the intensive group (with on average lower A1c) did have higher overall hypoglycemia at the same A1c as the standard group – it’s just that in both groups as A1c increased so did severe hypoglycemia. Average A1c was calculated as an average of A1c values from baseline to the latest visit prior to the hypoglycemia event. The hazard ratio for hypoglycemia for each 1% increase in average A1c relative to an average A1c of 7.5% was 1.15 in the intensive arm and 1.76 in the standard arm.
  • Also surprisingly, a greater drop in A1c during the first four months was associated with a lower risk of hypoglycemia in both groups. When ACCORD glycemia data were first released, one of the major hypotheses behind the increased mortality in the intensive group was that the A1c was reduced too quickly. In this new analysis, when comparing patients who had a 2% drop in A1c in the first four months to those who had a 1% drop in A1c during the first four months, the HR for incidence of hypoglycemia was 0.86 in the intensive arm and 0.72 in standard arm.
  • Most self-reported causes just before a hypoglycemic event were behavioral. By far, the most common antecedent event was a delayed meal or consumption of fewer calories than anticipated (58% of respondents). There were 9% of respondents who took an incorrect medication dose and 3% who had started/increased a new medication. See Appendix C.
  • Some manner of cognitive impairment was the most-cited immediate consequence of severe hypoglycemia. There were 38% of respondents who noted confusion/irrational behavior as an immediate consequence of severe hypoglycemia and another 30% who cited loss of consciousness/coma/seizure. See Appendix D.
  • There was greater mortality in patients who had hypoglycemia vs. those who did not have hypoglycemia, but unexpectedly, this relationship was only significant in the standard arm, not the intensive arm. The hazard ratio of death for hypoglycemia vs. no hypoglycemia in the standard arm was 2.87 and the hazard ratio of death for hypoglycemia vs. no hypoglycemia in the intensive arm was 1.28.
  • Surprisingly, the risk of death was higher in the intensive arm for patients who had no hypoglycemia but lower in the intensive arm for patients who had at least one hypoglycemia event. The hazard ratio of death for the intensive vs. standard arm in patients who had no hypoglycemia was 1.24 and the that for the intensive vs. standard arm in patients who had hypoglycemia was 0.55. See Appendix E.
  • Investigators were confident that hypoglycemia was not a significant direct cause of death in the intensive group. This analysis called for investigators to adjudicate the direct role of hypoglycemia in causing deaths. In the standard arm, hypoglycemia was rated as no role (92%), possible role (7%), probable role (1%), and definite role (0%). In the intensive arm, hypoglycemia was rated as no role (88%), possible role (10%), probable role (1%), and definite role (1%). See Appendix F.
  • Time to death after the last severe hypoglycemic event was similar in both arms. Similar numbers of death occurred in both groups at 30, 60, and 90 days after a severe hypoglycemia event.
  • Hypoglycemia did not account for the increased mortality in the intensive arm. We know that hypoglycemia was associated with increased mortality in both arms and that hypoglycemia was more frequent in the intensive arm. To evaluate whether this accounted for the excess mortality, the investigators calculated the etiologic fraction for hypoglycemia, which is defined as the product of relative risk and prevalence of the risk factor in the population. In other words, it is the proportion of deaths that would disappear if the exposure (hypoglycemia) were eliminated from the population. The etiologic fraction was 3.4% (9 deaths) in the intensive arm and 5.4% (11 deaths) in the standard arm – no significant difference. Effectively, the higher prevalence of hypoglycemia in the intensive arm was balanced by the lower risk of death, leading to no excess deaths over the standard group.
  • There was a lower risk of death among those who experienced mild hypoglycemia (glucose <70 mg/dl; 3.9 mmol) compared to those with no episodes of mild hypoglycemia (HR 0.67). Glucose meter records were sampled every four months. The number of fingerstick blood glucose values <70 mg/dl was 1.21 per week in intensive arm vs. 0.32 per week in the standard arm. However, when controlled for the number of fingersticks that were performed, there was no difference in the incidence of mild hypoglycemia between the two arms. In addition, this relationship only holds true for those with a previous severe hypoglycemia episode.

 

The VADT Trial

DURATION OF DIABETES AND SEVERE HYPOGLYCEMIA AND CARDIOVASCULAR DISEASE OUTCOMES IN THE VADT

William C. Duckworth, MD (Phoenix VA Health Care System, Phoenix, AZ)

Dr. Duckworth delivered a talk on the relative effects of standard glucose control compared to intensive glucose control in the VADT study. The study covered 20 centers and 1,791 patients. Specifically, the effects of different glucose control strategies were compared on their associated risk of cardiovascular morbidity and cardiovascular death (CVD). Duckworth et al. were also interested in determining whether treatment should focus on other factors outside of glycemic control, such as blood pressure management or lipid therapy.

This was a prospective, randomized study of older patients with type 2 diabetes with suboptimal response to maximum oral agents or insulin. Primary outcomes covered a number of diabetes related complications including major cardiovascular events or death. At baseline, average A1c was 9.4%, with average blood pressure of 132/76, average LDL of 108, and average HDL 0f 35. Many of these patients (72%) had previous history of hypertension and previous macrovascular events (40%). Average A1c fell to 6.9% in the intensive group and to 8.4% in the standard treatment group.

The results of this study indicate that duration of disease and severe hypoglycemia haves a significant effect on the risk of CVD. In the first three years after diagnosis, the intensive treatment group had higher risk of death; however, after four years of diagnosis, the risk of death is higher in the standard treatment group and remains so until over 20 years after diagnosis. Interestingly, it was those individuals in the intensive control group with intractable symptoms who showed increased risk of CVD. History of recent severe hypoglycemic events greatly increased the risk of CVD, with a hazard ratio of 3.7. For all cause mortality, the hazard ratio associated with a recent severe hypoglycemic event rose to 6.4. Increased HDL levels were associated with reduced CVD. According to Dr. Duckworth, this data suggests that duration of diagnosis should be heavily considered when initiating intensive glycemic control therapy. It also showed that severe hypoglycemia should alter treatment approaches and goals as it is a major risk factor for all cause mortality and CVD. Finally, non-glucose factors such as HDL should be considered when planning treatment strategies.

  • The primary goal of the VADT study was to investigate the relative risk of cardiovascular death (CVD) and all cause death when using intensive glucose control. The role of factors other than other factors outside of glycemic control such as blood pressure management or lipid therapy were also investigated to evaluate their place in the risk/benefits profile of intensive control.
  • The VADT study covered 20 centers, 1,791 older (average age 60 years old) patients of type 2 diabetes with suboptimal response to maximum oral agents or insulin.
  • At baseline, average A1c was 9.4%, and most patients had previous history of hypertension (72%) and/or macrovascular events (40%). Sixty-nine percent of the patients entering the study were on metformin, 61% were on sulfonylureas, and 52% were using insulin. All patients were achieving sub-optimal control on their current therapy regimens.
  • Duration of diagnosed disease was a major risk factor for CVD and all cause mortality. The intensive treatment group showed higher risk of death within the first three years of diagnosis. For years four through sixteen years of diagnosis, the risk of death is higher in the standard treatment group. It is important to note that the individuals most at risk in the intensive treatment group were those who were unresponsive to therapy.
  • Hypoglycemia is a major risk factor for CVD and all cause death. The hazard ratio for CVD after a recent hypoglycemic event was 3.726 while the hazard ratio for all cause death rose to6.370 after such an event.
  • Improved HDL levels appeared to be protective against the risk of mortality.
  • Dr. Duckworth concluded by emphasizing that the duration of diagnosed type 2 diabetes and recent hypoglycemic event are both serious risk factors for CVD and general mortality.

HYPOGLYCEMIA AND OUTCOMES IN THE VADT

Stephen N. Davis, MD (Vanderbilt University, Nashville, TN)

Dr. Davis presented fascinating analyses of the role of hypoglycemia in the VADT study. As a reminder, the VADT study investigated the effectiveness of intensive glycemic control on the rates of diabetes complications in a population of people with generally long-standing diabetes. While the results may have showed a trend toward a protective effect of intensive glycemic control, the difference between the two groups was not statistically significant.

Hypoglycemia has been put forward as a factor in diabetes complications, particularly cardiovascular complications, and Dr. Davis’s analysis examined this issue from many different angles. In summary, the intensive group had about four times more hypoglycemia than the conventionally treated group. Having a low A1c was associated with increased severe hypoglycemia in the intensive group (perhaps reflecting the diversity or intensity of medications necessary to reach low glycemic targets) but was not associated with severe hypoglycemia in the conventional group. Lower BMI and diabetes duration greater than 10 years were predictors of severe hypoglycemia in both groups. Predictors of all-cause death in VADT were severe hypoglycemia reported in the last three months, four to six months, and over the entire study. Repeated hypoglycemia increased this risk overall, but did so to a much greater degree in the conventional group than in the intensive group.

The new messages from the VADT, while not entirely straightforward, seem to fit more closely with general expectations than the new analyses of the ACCORD data. The hypoglycemia story seems to reflect what we’ve thought since before last year’s ADA—the main danger of intensive therapy is hypoglycemia (particularly severe hypoglycemia), and caution should be taken with any intensive treatment regimen that is associated with hypoglycemia. We believe it reinforces the importance of individualized therapy and glycemic targets, and should be favorable for diabetes drugs that do not increase the risk of hypoglycemia and for continuous glucose monitoring (to detect asymptomatic hypoglycemia).

  • As a reminder, the VADT study investigated the effectiveness of intensive glycemic control on the rates of diabetes complications in a population of people with generally long-standing diabetes. The intensive treatment group was treated to an A1c goal of less than 7%, while the conventional group was treated to a target of less than 8.5%. In the analyses presented by Dr. Davis, severe hypoglycemia was defined as hypoglycemia requiring assistance of another person. The primary outcome of the study was MI, stroke, CV death, etc., and the current analysis includes all-cause mortality.
  • The intensive group experienced approximately four times the rate of hypoglycemia compared to the conventional group and 3.5 times more severe hypoglycemia. Predictors of the first event of severe hypoglycemia were age, duration of diabetes, low c-peptide and insulin at baseline, being in the intensive treatment group, a low BMI, low A1c, highcreatinine levels, micro- or macroalbumin, and a prior CV event. Breaking some of these down by treatment group, lower BMI was shown to predict severe hypoglycemia more strongly in the intensive group, but there was not an interaction with mortality. Furthermore, low A1c was predictive of severe events in the intensively treated group but not in the conventional group. Gender, race, exercise habits, or history of hypertension did not predict severe events. In the intensive group, age had a significant effect, but this was not true in the standard group. Similarly, a history of microvascular disease was a significant predictor in the intensive group but not in the standard group. A history of hypoglycemia was not a significant predictor in the intensive group, but was predictive for subjects in the conventional group. Most events happened during the day, but the timing of the event was unknown for a significant percentage (~30%). Overall, rates of severe hypoglycemia were much higher than in the ACCORD study.
  • Predictors of all cause mortality in the VADT were severe hypoglycemia in the last three months, the last four to six months, or during the entire study. Those subjects with severe hypoglycemia had about a two-fold increased risk of having a primary cardiovascular event in both treatment groups. There was no significant increase in risk for myocardial infarction in those with prior severe hypoglycemia overall, but there was a significant increased risk in the standard group. The relative risk for death after a cardiovascular event in those who had had severe hypoglycemia was greater in the standard group, but not in the intensive group. The risk of death from any cause was higher in those who had had severe hypoglycemia in both groups. Repeated hypoglycemia increased the predictive power of hypoglycemia for all-cause mortality (p=0.05 vs. p=0.002). Interestingly, there was a decreased hazard ratio for all cause mortality with repeated hypoglycemia in the intensive group compared to the conventional group. The average time to death after a severe hypoglycemia event was six months in the standard group and 17 months in the intensive group.
  • The results reaffirm the importance of avoiding hypoglycemia (and particularly severe hypoglycemia) to decrease the risk of death in type 2 diabetes patients, regardless of the intensity of therapy. While some results of the hypoglycemia analyses have not been explained (for example, the finding that repeated hypoglycemia seemed to have a more negative impact on the intensively treated group compared to the conventional group), the overall impact on clinical thought and practice seems that it will be relatively straightforward: pick a glycemic target as low as is possible to achieve without a significant risk of severe hypoglycemia, and put a priority on the individualization of therapy to optimize the risk:benefit ratio for each patient.
  • A particularly interesting takeaway from all this is the potential clarification continuous glucose monitoring could have provided during this trial and ACCORD. CGM would have been instrumental in recognizing asymptomatic/unrecognized hypoglycemia and would have provided a wealth of additional information with which additional correlations could have been deduced. It will be interesting to see if anybody begins to advocate for CGM use in older populations with long standing diabetes as their physicians try to bring them down from dangerously high glycemia to more acceptable levels without increased hypoglycemia.

 

Panel Discussion

Q: The observation of increased mortality/higher A1c in ACCORD is fascinating. Do we know if that same relationship exists in VADT?

Dr. Duckworth: We haven’t looked at that yet.

Q: What were the types/patterns of insulin/SFU use in the VADT and how does this contrast with ACCORD?

Dr. Davis: Glimepiride was used fairly frequently in both arms and insulin use in both arms was very high (90-80%). Analog insulins are not freely available in VA centers but there was a greater use in this study than usual.

Q: I have an alternate hypothesis for increased hypoglycemia seen at higher A1c. We have shown differences between people in how effectively glucose gets into the red blood cell and have also shown difference in red blood cell survival. Different people will have a different relationship between blood glucose and A1c such that it may be more difficult for certain people to get to goal A1c and they may incur greater hypoglycemia trying to get to goal.

Dr. Riddle: It is important to recognize that investigators changed glucose management based on glucose results and not just A1c.

Dr. Bonds: The selection of medication in ACCORD was left to the discretion of the investigators. We’re just starting to look at the relationship between medication and hypoglycemia. Those participants who had a higher A1c may have had many factors (physiological and social) that put them at risk for both hypoglycemia and poor control.

Dr. Duckworth: We have had a hard time centrally evaluating diet and such so I can’t go much further than that.

Q: Is it fair to say that the greatest excess mortality in ACCORD was seen in those subjects in the intensive arm who had the lowest rates of A1c change and highest baseline A1c?

Dr. Davis: Yes. Many of us believe there is a strong behavioral component, which creates a problem particularly in the intensive arm.

Comment: Our studies have shown that those patients most difficult to treat have the most hypoglycemia as we struggle to treat them. You create hypoglycemia unawareness due to prior hypoglycemia. It’s a shame we don’t have CGM data.

Q: Did these patients have some recognizable phenotype that you can identify a priori?

Dr. Riddle: We have not looked at those in the intensive arm to figure out factors that determine who is at greatest risk.

Q: Those with severe hypoglycemia in the ACCORD intensive group had lower hazard ratio for mortality than those with severe hypoglycemia in the conventional arm. Wouldn’t you say that those who had a single severe hypoglycemia event were lucky because investigators backed off on intensifying glycemic control?

Dr. Riddle: This raises the question of behavioral differences. We are starting to look at that.

Dr. Bonds: I should point out that after the third hypoglycemic event, investigators were mandated to reduce the A1c goal. It’s true we do not have CGM on ACCORD participants so there was likely a lot of missed hypoglycemia.

Q: What is the takeaway from these analyses? Can you tell us anything about which therapy combinations to recommend or avoid?

Dr. Bonds: I can’t tell you which drug combinations are good or bad. Even when the answer comes out, it will be very difficult to have an overarching answer.

Dr: Rizza: I would stick with what the ADA/EASD guidelines said. We are all striving to be guided by evidence-based data but we first have to understand what the evidence is.

Q: We have to remember these individuals had near critical insulin insufficiency, meaning they look a lot like type 1 patients. If you look at type 1 patients they will also have A1cs of 8- 9% with severe hypoglycemia. We should not think that severe hypoglycemia only occurs at low A1cs with complex insulin regimens.

Dr. Riddle: The ACCORD trial is not over so these are just preliminary reports.

Comment: I was alarmed by the conclusion that hypoglycemia is not the cause of increased mortality since there was no continuous monitoring in the minutes leading up to their death to prove this.

Dr. Bonds: In both standard and intensive arms – having hypoglycemia was associated with increased risk of death. You are at higher risk if you have hypoglycemia. But the risk is lower in the intensive arm. There is a caveat that we did not have continuous glucose monitoring so we don’t know how much hypoglycemia was missed. I wish we had used CGM.

Q: Can we conclude that those with longer duration of diabetes should be treated less intensively?

Dr. Duckworth: That’s something to consider with the patient. My belief is that I would be cautious of treating long-standing diabetes with an intensive regimen. That doesn’t mean I wouldn’t try and improve glycemic control. I would just be less inclined to push hard and intensify therapy if it’s difficult to get additional A1c improvement.

Dr. Riddle: There is going to have to be careful thinking by groups writing the guidelines. I think it’s more likely that we will move to individualized targets.

Q: There is evidence that A1c is not equivalent to blood glucose in some patients. In such patients, trying treat to an A1c target, you could cause a lot of hypoglycemia and severe hypoglycemia. Controlling A1c for fasting glucose can show what kind of glycator the patient is. Can’t we go back to the data and test for it?

Dr. Bonds: That’s an excellent idea I think is worth pursuing.

Comment: Maybe we should wait for all the data to be available to make predictions.

Q: The U-shaped curve of mortality in the standard group did not make sense. Could you address that?

Dr. Riddle: I believe the subgroup of interest is the group with A1c below 7% with higher mortality risk. It could be a behavioral thing – not following instructions – or they could by very ill.

Q: Is a possible explanation for the U-shaped curve that the people with high A1c actually had longer disease duration and had more hypoglycemia unawareness, and then those with low A1c just had lower sugars?

A: I don’t think that this would be supported by the data. We could not adjust for unrecognized hypoglycemia because it was unrecognized. We still don’t have the data saying hypoglycemia caused mortality.

Q: Did hypoglycemia increase cardiovascular mortality?

Dr. Davis: It did in the VADT.

 

Appendix A: Risk Factors For Hypoglycemia That Were Similar In Both Arms

Risk Factor

Association to hypoglycemia

Hazard Ratio (95% CI)

Complications

Individuals with an

albumin:creatinine >300 (indicating kidney disease) had increased risk of hypoglycemia

1.74 [1.37-2.21]

Race

African Americans race predicted higher race

1.43 [1.20-1.71]

Gender

Women were at higher risk for

hypoglycemia

1.21 [1.02-1.43]

Age

For every one-year increase in

age, there was a 3% increase in risk of hypoglycemia

1.03 [1.02-1.05]

Weight

Obesity (BMI >30 kg/m2) was associated with less hypoglycemia

0.65 [0.50-0.85]

Appendix B: Risk Factors For Hypoglycemia That Were Different In Both Arms

Risk Factor

Standard arm HR (95% CI)

Intensive arm HR (95% CI)

Baseline A1c (1% increase)

1.30 [1.15, 1.47]

1.01 (0.94, 1.10)

Being on insulin

4.08 [2.88, 5.76]

1.95 [1.62, 2.35]

LDL (100+ vs. <100 mg/dl; 5.6

mmol)

0.59 [0.44, 0.80]

1.04 [0.87, 1.24]

Less than high school education

1.74 [1.02, 2.95]

1.38 [1.06, 1.81]

High school grad

2.31 [1.46, 3.66]

1.15 [0.90, 1.47]

Some college

1.62 [1.01, 2.62]

1.02 [0.80, 1.31]

College grad or more

1.0

1.0

Appendix C: Immediate Antecedents To Severe Hypoglycemia (Self-Reported)

Event preceding severe hypoglycemia

Number of

respondents (%) N = 875 events

Delayed/missed meal or ate fewer carbohydrates

510 (58%)

None

148 (17%)

Took incorrect dose of glucose lowering medication

82 (9%)

Cognitive decline

8 (70%)

Intercurrent illness

44 (5%)

Ingested alcohol

26 (3%)

Recent weight loss

29 (3%)

Started or increased other medication

28 (3%)

Appendix D: Immediate Consequences Of Severe Hypoglycemia (Self-Reported)

Consequence of severe hypoglycemia

Number of

respondents (%) N = 875 events

Confusion/irrational behavior

336 (38%)

Loss of consciousness/coma/seizure

262 (30%)

Hospitalization

181 (17%)

Personal accident/injury or injury to another (mostly

lacerations, bruises, and sometimes fractures)

55 (6%)

Other consequence

58 (7%)

Appendix E: Mortality And Hypoglycemia By Treatment Arm

 

Mortality in

standard arm

Mortality in

intensive arm

 

No severe

hypo

1.0% per year

1.3% per year

Intensive vs. Standard

HR 1.24 [1.02-1.52]

Had severe

hypo

4.9% per year

2.8% per year

Intensive vs. Standard

HR 0.55 [0.31-0.99]

 

Severe hypo vs. no hypo

HR: 2.87 [1.73-4.76]

Severe hypo vs. no hypo

HR: 1.28 [0.88-1.85]

 

Appendix F: Adjudicated Role Of Hypoglycemia In Direct Cause of Death

 

Standard arm

Intensive arm

No role

92%

88%

Possible role

7%

10%

Probable role

1%

1%

Definite role

0%

1%

Incretin Therapies

The emerging class of GLP-1 receptor agonists (GLP-1s) dominated the headlines for incretin therapies at this year’s ADA. GLP-1s have gained popularity as type 2 diabetes therapies for their stimulation of glucose-dependent insulin secretion, inhibition of glucose-dependent glucagon secretion, and associated weight loss. While GLP-1s have other known functions, including delaying gastric emptying and promoting satiety, several talks focused on their newfound cardioprotective effects. Data from comparative studies including DURATION-1 and DURATION-2 illustrated both the long-term efficacy of Amylin’s exenatide once-weekly and its superiority over the market leading TZD (Takeda’s Actos) and DPP-4 (Merck’s Januvia) therapies. Data was also presented from LEAD-3 and LEAD-6, which described how Novo Nordisk’s liraglutide (Victoza) led to greater glycemic control than Sanofi-Aventis’ sulfonylurea glimepiride and exenatide twice-daily, respectively. Several companies also presented data on their early stage GLP-1s, including Eli Lilly (LY2189265) and MannKind (MKC253). While GLP-1s appear to offer the best glycemic control of commercialized non-insulin therapies, DPP-4 inhibitors are still popular due to their safety and tolerability profiles. Overall, GLP-1 receptor agonists offer great potential for improving glycemic control in patients with type 2 diabetes and may also have therapeutic potential in patients with type 1 diabetes.

Incretin Therapies Highlights

  • Terri Kim, MD (Amylin Pharmaceuticals, San Diego, CA) discussed a 70-week open- label extension study of the 30-week DURATION-1 trial for exenatide (Byetta by Amylin/Lilly) once-weekly, which demonstrated that EOW provides sustained glucose control and weight loss. At the final two-year endpoint, the mean A1c reduction from baseline for exenatide once-weekly was 1.7%. This compared to an A1c reduction of 2.0% at the one-year endpoint (as reported at ADA 2008), and 1.9% A1c reduction at the 30-week endpoint. Weight loss was also sustained at two years, with an average weight loss at 2 years of 3.6 kg (7.9 pounds). Notably, approximately two-thirds of patients treated with exenatide once-weekly were at an A1c of less than 7% percent and 42% were at an A1c of less than 6.5% at the two-year end point. Weight loss was also sustained at two years, with an average weight loss at two years of 3.6 kg (7.9 pounds). A clinically significant reduction in systolic blood pressure was also noted at the end of the study and perhaps most impressively, incidence of nausea in the extension study was just 12%. As expected, no severe hypoglycemia was observed. Healthcare providers with whom we have spoken certainly think the product could be transformational in terms of efficacy and convenience – we look forward to learning more about how patients like it. Early data at ADA 2008 was encouraging on this front and we look forward to hearing from larger groups of patients.
  • Richard Bergenstal, MD (International Diabetes Center, Minneapolis, MN) presented the results for the highly anticipated DURATION-2 superiority study comparing exenatide once-weekly with pioglitazone (Actos) and sitagliptin (Januvia) as a late-breaking poster. Overall the results were very positive for exenatide once-weekly, with the drug demonstrating superiority over Actos and Januvia with regard to A1c and weight loss. In the study, exenatide once-weekly posted a 1.55% A1c drop compared to 1.23% for Actos and 0.92% for Januvia at 26 weeks from a baseline of ~8.5%. The proportion of patients achieving an A1c of less than or equal to 7% was 66% for exenatide once-weekly vs. 56% for Actos and 42% for Januvia. Furthermore, exenatide once-weekly was associated with 2.7% weight loss, as compared to 0.9% weight loss for Januvia and 3.2% weight gain for Actos. Exenatide once- weekly was associated with improvements in a variety of cardiovascular risk markers and wasgenerally well tolerated with low incidence of hypoglycemia. Broadly speaking, the results of this somewhat daring superiority study against a TZD and a DPP-4 inhibitor bode well for long-acting GLP-1s as a class and exenatide once-weekly in particular since it has what is for now a unique combination of superior A1c drop and significant weight loss.
  • John Buse, MD, PHD (University of North Carolina School of Medicine, Chapel Hill, NC) presented data from the first 26-weeks of the LEAD-6 study comparing 464 patients randomized to be treated with once-daily 1.8 mg liraglutide or twice-daily 10 microgram exenatide (Eli Lilly/Amylin’s Byetta) while continuing metformin and/or sulfonylurea background therapy. The study showed that liraglutide produced a greater reduction in A1c (1.12%) compared to Byetta (0.79%) from a baseline of slightly over 8%, with the difference reaching statistical significance. This was likely driven by the significant reduction in fasting blood glucose seen in the liraglutide patients (-16.2 mg/dl) compared to Byetta patients (-3.6 mg/dl), from baselines of 176 mg/dl and 169 mg/dl respectively. The percentage of patients achieving the ADA target A1c of <7% was approximately 55% for liraglutide compared to 45% for Byetta. Weight loss was similar between the two groups (liraglutide –32 kg or 7 lbs vs. Byetta –29 kg or 6.4 lbs). Liraglutide patients showed a significantly greater increase in beta cell function (by 40%) compared to Byetta patients as measured by HOMA-B. Although a similar percentage of patients reported nausea in each treatment arm at the beginning of the study (~13%), nausea resolved much more quickly in the liraglutide arm with only 2% of patients reporting persistent nausea beyond 12 weeks compared to 10% in the Byetta arm. Minor hypoglycemia (blood glucose of ≤56 mg/dl) was reported less frequently in the liraglutide arm of the study than in the Byetta arm, with generally low rates in both study arms (193 vs. 260 events per patient per year). There were only two serious hypoglycemic episodes reported in the study, both occurring in the Byetta arm with a background of sulfonylurea treatment. Adverse events were similar in the two treatment arms.

Accompanying the LEAD-6 study published in The Lancet was an editorial that embraces wider use of GLP-1s and in particular liraglutide over Byetta in light of the results of LEAD-6. However, it notes that the FDA has observed a rate of papillary thyroid cancer of 1.6% for patients taking liraglutide vs. 0.6% for Byetta per 1000 patient-years of treatment with each drug. In the 26-week LEAD-6 data Dr. Buse presented at ADA, no clinically significant changes in calcitonin levels in either treatment arm. The significance of these findings is still being debated, and what bearing this will have on the liraglutide approval process remains to be seen. Novo Nordisk is currently in open communication with the FDA over these concerns and management has mentioned that new data becoming available should address the issue favorably. Overall, we consider LEAD-6 to be a win for Novo Nordisk, given that liraglutide was generally better tolerated than Byetta and produced a more significant reduction in A1c. We are not sure of the implications of this, however, since LAR has an improved dosing regimen and may not be as far behind liraglutide on the approval front as previously thought.

  • John Buse, MD, PhD (University of North Carolina, Chapel Hill, NC) and colleagues additionally presented the results of the LEAD-6 extension trial. Following the conclusion of the primary LEAD-6 liraglutide vs. Byetta trial, this extension study showed the effects of switching from exenatide to liraglutide for 14 weeks. After the conclusion of the extension period, patients who had switched to liraglutide treatment achieved an additional A1c decrease of 0.3% (from a baseline of 7.2%). Fasting plasma glucose also improved in the switching group, and body weight decreased by 0.9 kg (2 lbs) in the switching group compared to a 0.4 kg(0.9 lb) decrease in those subjects who continued on liraglutide. Liraglutide was well tolerated in both groups. This study helps to establish the benefits of liraglutide as an important agent forimproving diabetes outcomes; we would be very interested to see similar data compared to exenatide once-weekly.
  • John Buse, MD, PhD (University of North Carolina, Chapel Hill, NC) presented on the DURATION-1, DURATION-2, and LEAD-6 trials. Overall, he expressed tremendous enthusiasm for long acting GLP-1s (specifically exenatide once-weekly and liraglutide), and he predicted that these two agents will essentially replace Byetta in clinical use. He also discussed competitive compounds, including taspoglutide (Roche), another GLP-1 in development that is based on the human GLP-1. Dr. Buse briefly reviewed phase 2 data for taspoglutide, demonstrating that it produces impressive weight loss and A1c reduction. Albiglutide (GlaxoSmithKline) is another GLP-1 in late-stage clinical trials. This is a much larger molecule that is bound to albumin. Dr. Buse predicted that this drug could produce as much as a 1.5% or 2.0% A1c reduction over a year but didn’t talk at length about other important factors such as weight loss, impact on blood pressure and cholesterol, and nausea.
  • Larry Shen, PhD (Amylin Pharmaceuticals, San Diego, CA) discussed a cardiovascular meta-analysis of the exenatide twice-daily (BID) database, including 12 longer-term trials with a total of 39,245 subjects and 1,072 subject-years of exenatide exposure. The analysis showed that the exenatide group had a lower incidence of cardiovascular (CV) events after 400 days of exposure by both the major adverse cardiovascular events (MACE) definition as well as the broad CV endpoint definition. Notably, the point estimate for CV risk using the MACE endpoint was 0.7, with a 95% confidence interval of 0.38-1.31. Using the broad CV endpoint, the point estimate was 0.69, with a confidence interval of 0.46-1.03. We would note that these results appear to meet the FDA’s criteria for approval—the important point, in our view, is that the FDA has said that Byetta safety data can be used for the exenatide EOW review process.
  • Alan Garber, MD (Baylor College of Medicine, Houston, TX) provided results for the one-year extension study of the original year-long LEAD-3 study (liraglutide monotherapy compared with a sulfonylurea). Starting from an A1c of approximately 8.0% at the study baseline (very low), the mean A1cs at the two-year endpoint were 6.9%, 7.1% and 7.5% for patients randomized to liraglutide 1.2 mg, liraglutide 1.8 mg, and sulfonylurea respectively. Patients randomized to liraglutide also achieved a mean weight loss of more than 2 kg (4.4 pounds), compared to 1 kg (2.2 pounds) of weight gain for the sulfonylurea arm. Notably, dose-dependent responses to liraglutide were more pronounced for patients with a shorter duration of diabetes, which Dr. Garber used to justify earlier interventions in diabetes when beta cell function is intact. Overall, the results are very impressive, but we cannot help but compare them to the even more remarkable A1c results that were described in the two-year exenatide (Byetta by Amylin/Lilly) once-weekly results presented in the same session. The market is big – currently we estimate there are over seven million people in the US alone failing oral therapy – definitely room for more than one great GLP-1. The potential for the long acting incretin market is vast in terms of those with diabetes and ultimately, we believe, prediabetes – makes one think a little about the $26 billion statin market and how many patients were helped by this.
  • Philip Barrington, MD (Lilly Research Laboratories, Indianapolis, IN) reported positive glycemic results for a phase 2 trial of LY2189265, a long-acting GLP-1 being developed by Eli Lilly. The compound consists of a GLP-1 analog protected by DPP-4 that is covalently linked to an Fc fragment of human IgG4. A1c reductions were impressive (up to 1.3% after only five weeks), and statically significant weight loss was noted. The present five week study evaluated safety, tolerability and pharmacokinetics of LY2189265 in 43 patients with type 2diabetes. Patients were randomized to doses of LY2189265 ranging from 0.5 mg to 8 mg, or placebo. We believe that this is one of the most promising GLP-1s in development in terms of glucose reduction. Given that this is a very large GLP-1 compound however, we expect that a low concentration of the drug will cross the blood-brain barrier and therefore weight loss may prove to be less than some other GLP-1s in development. At the end of five weeks, average A1c was reduced from 0.7% to 1.3% in the LY2189265 treatment arms; baseline A1c was not given. The most commonly reported adverse event was nausea; more concerning however was an increase in heart rate in the 5 mg dose. We await further clinical data before drawing clear comparisons to other long-acting GLP-1s.
  • The goal of Jennie H. Best, MA (Roche Global Pharmacoeconomic Research, Palo Alto, Ca) and colleagues’ study was to extrapolate, using currently available data on exenatide’s effects on cardiovascular risk factors, the relative risk of cardiovascular events following ten years of using exenatide BID in addition to metformin and/or sulfonylurea therapy compared to using metformin and/or a sulfonylurea alone. The authors projected that there was an estimated 40% risk reduction in myocardial infarction in patients using an exenatide BID combination therapy compared to using metformin and/or a sulfonylurea alone. These data indicate that significant reductions in cardiovascular risk can be achieved with adjunctive exenatide therapy.
  • Nick Finer, MD (University of Cambridge, UK) presented a sub-analysis that drew data from a study of liraglutide whose primary endpoint of weight loss was presented at the Obesity Society Annual Meeting in 2008. Five hundred and sixty-four subjects without diabetes (75 with prediabetes, defined as either impaired fasting glucose (IFG) or impaired glucose tolerance (IGT)) were randomized to a placebo, 120 mg orlistat or a dose- titration of liraglutide (Novo Nordisk’s Victoza, submitted to FDA for approval) for 20 weeks. Patients taking liraglutide had a significantly higher chance of having normal glucose tolerance at the end of the study, with odds ratios compared to placebo of 3.0, 26.1, 10.7 and 12.5 for the 1.2 mg, 1.8 mg, 2.4 mg, and 3.0 mg groups respectively (all statistically significant).
  • Murray W. Stewart, DM (GlaxoSmithKline, Harlow, UK) hypothesized that since albiglutide is a Glucagon-Like Peptide-1 (GLP-1) agonist, which takes longer to reach maximal plasma concentration, it may have fewer of the gastrointestinal (GI) side effects stimulated by other GLP-1’s. In a 16-week treatment, 10-week follow-up, 10-arm study enrolling 356 patients, the occurrence, duration, and intensity of nausea and/or vomiting (N/V) were measured. Patients received either weekly albiglutide or placebo (4, 15, or 30 mg), biweekly albiglutide or placebo (15, 30, or 50 mg), monthly albiglutide or placebo (50 or 100 mg), or twice daily, self-administered exenatide as prescribed. Overall rates of N/V were found to be lower with all doses of albiglutide than with exenatide. Albiglutide 30 mg weekly had the best N/V profile. Rates of N/V decreased in all albiglutide groups over time and N/V was correlated with albiglutide exposure. N/V rates seemed to be correlated to frequency of albiglutide dosing and peak/trough plasma concentration ratios, with those patients with more infrequent treatment regimens having higher rates of N/V (when peak/trough ratios were highest). Efficacy of albiglutide doses was not correlated with GI side effects.
  • Jane EB Reusch, MD (University of Colorado, Denver, CO) studied the effectiveness and pharmacologic profile of albiglutide, an investigational long-acting GLP-1 by GSK. 361 Patients with type 2 diabetes were randomized to 16 weeks of either 4, 15, or 30 mg ALB once weekly, 15, 30, or 50 mg ALB biweekly, 50 or 100 mg ALB monthly, open-label exenatide, or placebo. There were significant improvements in A1c and FPG with albiglutide, andthe results were the same for the weekly, biweekly, and monthly dosing regimens. After 16 weeks, there was a 0.9% A1c decrease with the highest dose of weekly ALB, 0.8% with biweekly dosing, and 0.9% in monthly dosing, compared to a decrease of 0.5% in the exenatide arm and 0.2% with placebo.
  • Ralph DeFronzo, MD (Texas Diabetes Association, Austin, TX) described a study in which the relative effectiveness of treatment with either rosiglitazone, exenatide, or both exenatide and rosiglitazone was examined. One hundred and thirty-seven patients were assigned for 20 weeks to one of the three groups in a randomized trial. A randomized subgroup of 50 patients underwent a hyperinsulinemic-euglycemic clamp at baseline and 20 weeks to assess insulin secretion and sensitivity in each of the three groups. While exenatide robustly preserved beta cells, it did not improve insulin sensitivity. Rosiglitazone, on the other hand, did not improve beta-cell function but did have a positive effect on insulin sensitivity. Patients receiving exenatide lost weight, while those on rosiglitazone gained weight. Combination therapy with both rosiglitazone and exenatide had the best results, increasing insulin sensitivity and secretion, lowering A1c, and causing weight loss.
  • Julio Rosenstock, MD (University of Texas Southwestern, Dallas, TX) examined the differences in pharmacokinetics between liraglutide in exenatide in a sub-study of the LEAD-6 trial. Subjects were dosed with one of the two drugs, and the plasma concentration of the drug in question was measured throughout a 24-hour period. The results showed a significantly flatter profile with liraglutide, confirming its suitability for use as a longer-acting GLP-1 agonist. The researchers suggested that fluctuating GLP-1 concentrations with exenatide might result in increased nausea, but to our knowledge this has not been confirmed.
  • Ted Okerson, MD (Sanofi-Aventis, San Diego, CA) To examine the correlation between baseline BMI and changes in CV risk factors, data was taken from the subgroup of patients in the DURATION-1 trial treated with exenatide once weekly (EQW). 148 patients constituting EQW group in the DURATION-1 trial were classified according to BMI (overweight, nonobese between a BMI of 25 and <30 kg/m2, and 3 obese subgroups with BMIs of 30 to <35, 35 to <40 and >40 kg/m2 respectively). An ANCOVA test examined the relationship between baseline BMI and A1c, weight, systolic blood pressure, LDL levels, total cholesterol, and triglycerides. While all measures improved with EQW treatment, none of the improvements varied by BMI subgroup. This suggests that EQW is efficacious across all BMI ranges and not just in obese subgroups.
  • Bernard Zinman, MD (University of Toronto, Ontario, Canada) presented a meta- analysis of the 6 LEAD studies, in which it was shown that liraglutide allowed more patients to achieve glycemic control (A1C <7.0%) and the ADA-defined composite outcome (A1C<7.0%, systolic blood pressure <130 mmHg, and no weight gain) than did active comparators. The LEAD studies examined liraglutide’s effectiveness as compared to combinations of rosiglitazone, exenatide, glimepride, metformin, sulfonylureas, and placeo, and individually showed liraglutide’s ability to reduce or sustain A1C and systolic blood pressure and increase weight loss better than these comparators. This meta-analysis found that a significantly higher proportion of patients taking either 1.8 or 1.2 mg of liraglutide once daily achieved an A1C of <7.0% and the ADA-defined composite outcome than those taking active comparators. The study also found that a dose of 1.8 mg provides A1C reductions for more patients than a 1.2 mg dose, though no difference is seen between the two dosings for achievement of a composite outcome.
  • Kun Ho Yoon, MD, PhD (The Catholic University of Korea, Seoul, Korea) presented a study that investigated the efficacy of combination therapy with sitagliptin and pioglitazone (PIO) versus pioglitazone alone. After 24 weeks, patients in the combination group saw an A1c decrease of 2.4%, while those in the PIO-only group had a 1.5% decrease. FPG, insulinogenic index, and c-peptide AUC were all better with combination treatment relative to pioglitazone alone. Body weight increased by 1.1 kg (2.4 pounds) in the combination group relative to the monotherapy group. The rate of drug-related AEs were slightly higher in the combination group, as were serious AEs, but the rate of withdrawal due to adverse events was similar between the groups. The rate of hypoglycemia was also slightly higher in the combination group.
  • Robert A. Baughman, PhD (MannKind Corporation, Danbury, CT) presented early- stage clinical data for MKC253, a GLP-1 that is absorbed in MannKind’s proprietary microparticles for oral inhalation. Pharmacokinetic data from 20 human subjects shows that MKC253 has an onset of insulin action in 10 minutes with a peak at 60 minutes. Dr. Baughman spoke about the potential advantages of inhaled GLP-1 over injected GLP-1, including lower levels of nausea and increased endogenous insulin secretion. On the minus side, inhaled GLP-1 did not slow gastric emptying.
  • Elena Sebokova, PhD (Hoffman-La Roche AG, Basel, Switzerland) presented preclinical data on taspoglutide. In a rodent model of type 2 diabetes (ZDF rats), a single subcutaneous injection of 1 mg taspoglutide reduced the glucose area-under-the-curve by 50% during a two-hour oral glucose tolerance test (OGTT) given after three weeks. Insulin levels were unaffected, suggesting that taspoglutide may chronically enhance insulin sensitivity. Taspoglutide also reduced the post-challenge rise in peptide YY and GIP, suggesting that it has a negative feedback effect on endogenous incretin action. Dr. Sebokova suggested that taspoglutide’s effects on these intestinal peptides might be important for its effects on post-meal glucose and insulin secretion.
  • Patricia Brubaker, PhD (University of Toronto, Toronto, Canada) discussed a number of clinically important but somewhat obscure consequences of GLP-1 therapy. In particular, she focused on the recent discovery of a metabolite of GLP-1 called 9-36 that may be cardioprotective. If this is finding is confirmed, this would suggest an additional advantage of GLP-1s over DPP-4 inhibitors because only GLP-1s would be expected to increase the concentration of 9-36.
  • A talk on the pathogenesis of type 2 diabetes and implications for therapy by Ralph DeFronzo, MD (Texas Diabetes Association, Austin, TX) provided an overview of the many pathogenic abnormalities that are present in type 2 diabetes. Given the wide range of abnormalities that present early in the course of type 2 diabetes, Dr. DeFronzo argued that patients should be treated more aggressively with combination therapy. His own treatment algorithm includes Byetta, metformin, and Actos triple therapy right from the start. We look forward to seeing data on this. Dr. DeFronzo warned against using sulfonylureas because they do not prevent beta cell burnout and they do not address underlying pathogenic abnormalities of diabetes. Many characterized this talk as basically a repeat of the renowned 2008 Banting Lecture; it was probably given again because not everyone heard it then.
  • Vandana S. Raman, MD (Texas Children’s Hospital, Houston, TX) discussed her group’s study on prandial combined exenatide and basal insulin therapy in adolescents with type 1 diabetes. Studies have shown exenatide (an incretin mimetic) to be effective in the treatment of type 2 diabetes, but only one study has targeted type 1 diabetes inadults and no studies have been done in children. In this study, patients administered exenatide with insulin before meals demonstrated significantly reduced glucose excursions as well as delayed gastric emptying. Altogether, these results suggest that adjunctive prandial exenatide therapy could be a promising and safe treatment for adolescents with type 1 diabetes. Interestingly, when asked in Q&A if similar studies with pramlintide had been done, Dr. Raman said yes, and that more postprandial hyperglycemia was seen. She said she would like to do a head-to-head comparison.
  • At the Roche symposium, John Buse, MD, PhD (University of North Carolina School of Medicine, Chapel Hill, NC) jokingly lamented that a whopping 31% of the audience was “industry/other” there for competitive information, while 45% was “MD/DO” and 5% were “RN” in an audience survey. MDs were mostly endocrinologists, half US- based and half foreign. The huge room was packed, and ultimately accommodated a line that seemed to snake far into the halls of the Marriott before doors opened. Dr. Buse started with a brief history lesson suggesting that obesity’s been known to be unhealthy and difficult to treat for millennia – Dante even reserved the third ring of Hell for the “gluttonous.” Dr. Buse’s main message to kick off the session was that obesity is largely a genetic, physiologic dysfunction that is treatable with lifestyle, drugs, and surgery.
  • Louis Aronne, MD, FACP (Weill Cornell Medical College, New York, NY) focused on the fact that we are moving toward a weight-centric, rather than glucose-centric, approach in the treatment of obesity and type 2 diabetes. An audience survey at the beginning of the talk showed 17% disagreed with that concept (“those who disagree haven’t seen the ACCORD trial”), while at the end of the talk only 4% disagreed. Along that vein, Dr. Aronne emphasized that significant weight gain is a reason to alter a patient’s therapy even if A1c is at goal. To manage obesity, combinations of pramlintide, leptin, sibutramine, and bariatric surgery seem to be the most promising treatments.
  • Before David Kendall, MD (University of Minnesota, Minneapolis, MN) began speaking, 97% of the audience already agreed with the statement: “GLP-1 agonists provide clinically significant benefits beyond glucose control.” The most significant of these benefits was said to be weight loss by 70% of attendees, beta cell preservation by 28%, lipid- lowering by 1%, and blood pressure reduction by 1%. Furthermore, 88% of attendees agreed that “long-acting GLP-1 agonists offer clinically meaningful advantages over short-acting formulations.” In his talk, Dr. Kendall praised exenatide, the GLP-1 analog with the most data, and suggested exenatide once weekly (EOW) was an improvement. Incretins should replace insulin for some patients. He was lackluster on DPP-4 inhibitors, which at best restore normal endogenous levels of GLP-1.
  • Richard E. Pratley, MD (The University of Vermont College of Medicine, Burlington, VT) provided a balanced talk about the clinical differences between DPP-4 inhibitors and GLP-1s, including exenatide. Overall, he said that although Byetta and sitagliptin have similar efficacy, long-acting GLP-1s will have better efficacy than any DPP-4 inhibitor. Nonetheless, Dr. Pratley said that DPP-4s will continue to be used because of their tolerability and oral dosing. From our understanding the efficacy with Januvia is usually less than that seen with Byetta, though healthcare providers are certainly demonstrating Dr. Pratley’s prediction that the simplicity of Januvia will carry it in the market.
  • Rodolfo Alejandro, MD (University of Miami Miller School of Medicine, Miami, FL) summarized his research supporting the use of exenatide in islet transplantation. Due to its corrective effect on hyperglycemia, exenatide aids in the maintenance of both long-termtransplanted beta cell function and patient insulin independence. This may be bolstered by a possible effect on anti-inflammatory and anti-apoptotic pathways. Use, however, is not yet perfected for this purpose, with many patients reporting bouts of extreme nausea.
  • Dana Andersen, MD (Johns Hopkins University Medical School, Baltimore, MD) summarized the current research supporting the use of GLP-1 in the hospital setting. An initial investigation with GLP-1 infusion during major surgery has suggested that GLP-1 may be an effective means of achieving euglycemia without the need for insulin or risk of hypoglycemia – this is certainly a very valuable treatment given the constant risk of hypoglycemia that has plagued all studies of intensive glucose control in the hospital. Dr. Andersen also discussed the recently uncovered metabolic activity of GLP-1[9-36], the primary metabolite of GLP-1. Given that DPP-4 inhibitors are known to reduce the concentrations of the metabolite, he speculated whether this finding could have implications in their continued use. Lastly, Dr. Andersen said that there is some evidence that viral pre-infection of islet cells to introduce a gene for GLP-1 production before transplantation can preserve function and prevent apoptosis. In this manner, islet cells (which cannot produce endogenous GLP-1) may be allowed to generate their own incretins, thus promoting survival in islet cell recipients.
  • In a corporate symposium sponsored by Novo Nordisk titled “Learn it Today, Use it Tomorrow: Practical Strategies for the Clinical Use of Incretin Mimetics” Michael Nauck, MD, PhD (Diabeteszentrum Bad Lauterberg) presented an overview of the incretin effect and how it can be leveraged in the treatment of type 2 diabetes. Both GLP-1 and GIP are incretin hormones. GLP-1 plays an important role in glycemic control as it stimulates glucose-dependent insulin secretion, delays gastric emptying, inhibits glucose- dependent glucagon secretion, promotes satiety and reduces body weight. Thus, GLP-1 is a target for treatment of type 2 diabetes. There are two drug classes that are being used to leverage GLP-1 to treat type 2 diabetes: incretin mimetics and DPP-4 inhibitors.
  • Alan Garber, MD (Baylor College of Medicine, Houston, TX) gave an overview of the safety, efficacy, and tolerability of exenatide (Byetta by Amylin/Lilly), liraglutide (Victoza by Novo Nordisk) and exenatide once weekly (EOW). He differentiated between the therapies based on their half-lives, likelihood to cause nausea, and formation and effect of antibodies. He mentioned the faster tapering of nausea with the longer acting GLP-1 formulations and the finding that a small number of exenatide/EOW patients have antibody formation that leads to decreased drug efficacy.
  • Robert Henry, MD (University of California at San Diego, La Jolla, CA) presented two case studies and asked the audience how they would approach treatment for each. He asked the audience how they would intensify therapy to achieve better glycemic control and in both cases the audience favored the use of incretin mimetics. Regarding the first case, he also asked the audience what was the principle consideration in deciding which drug to prescribe and the audience leaned towards concern over patient weight.
  • During the Current Issue session on “What to Do When Glycemic Control is Inadequate on Oral Agents” Matthew Riddle, MD (Oregon Health & Science University, Portland, OR) advocated the addition of basal insulin. He is, of course, the author of the famous Treat to Target study and very well known for his research in this area. He argued that insulin is efficacious and has many non-glycemic benefits—the health care provider (HCP) and patient’s challenge is simply to limit hypoglycemia. He emphasized that, of the therapies available, insulin has shown itself to have the best-proven effects on microvascular complications, to be the best tested, and to offer the best in safety. He suggested that if one believes in evidence-based medicine, they would strongly consider insulin. We know, of course, of the many barriers (physician resistance is the one we think is the biggest, which is exacerbated by a system that doesn’t encourage doctors to learn more). Notably, Dr. Riddle advocates the use of basal insulin alone as the standard introductory insulin therapy because it offers the best benefits to risk ratio in terms of efficacy and low risk of hypoglycemia – it is also much easier because dosing isn’t based on food intake.
  • In opposition, Vivian Fonseca, MD (Tulane University, New Orleans, LA) argued that incretins should be the next step because while insulin is very effective in lowering glucose, it is associated with many problems including weight gain, hypoglycemia, and perhaps even CV risk (due to hypoglycemia). This is the first time we’ve heard outright an expert identify explicitly potential silent ischemia as a disadvantage of insulin (we’re used to hearing weight gain and hypoglycemia). In contrast, he showed data suggesting comparable efficacy with GLP-1 therapy but without hypoglycemia and with weight loss as well as benefits to CV risk factors. He commented that liraglutide in particular reduces blood pressure, possibly by a mechanism independent of weight loss. He concluded that long-term data are needed and that we should explore combinations of insulin and incretin based-therapy, which has not been studied much thus far.
  • During the Q&A the consensus seemed to be that basal insulin and Byetta should both be options, possibly together, in patients failing orals. Dr. Fonseca made the case that doctors should move to using explicitly different targets for different subpopulations of patients rather than a one-A1c-for-all model. Dr. Riddle admitted that the failure rate for basal insulin, like any other treatment, is probably similar to the 0.2 to 0.3% A1c rise per year seen in all of the UKPDS arms and he mentioned adding prandial Byetta as an option at that point. One audience member asked about combining exenatide and pramlintide in difficult type 2 patients (hasn’t been tested yet).
  • In the symposium on Novel Aspects of GLP-1 Action, Remy Burcelin, PhD (Research Director, French National Medical Research Institute) emphasized that the effects of GLP-1 in the brain are different for different end organs; brain GLP-1 signals to beta cells to increase insulin secretion whereas it causes relative insulin resistance in muscle cells by inhibiting the vasodilation of blood vessels supplying muscle cells, thus decreasing muscle glucose uptake. We note that this is a very counterintuitive finding; indeed, during the Q&A one audience member pointed out that the peripheral effect of GLP-1 is to cause vasodilation by a direct effect on endothelial cells. Dr. Burcelin agreed, saying that physiologically GLP-1 may have many different effects that overall lead to physiologic balance. The central effects of GLP-1 are clearly an area that needs much more research.
  • Richard Shannon, MD (University of Pennsylvania, Philadelphia, PA) showed data that GLP-1 increases cardiac glucose uptake and restores cardiac contractile performance in dogs with chronic heart failure. It increases glycolysis but not glucose oxidation, thus reducing the formation of damaging reactive oxygen species. On a broader level, he believes that there are species- and tissue-specific differences in the mechanism of GLP-1 signaling in cells and that studying these differences may be important in learning more about the glucoregulatory and cardioprotective effects of GLP-1 and its analogs. Right now it appears that native GLP-1 has a stronger affinity for cardiac GLP-1 receptors than GLP-1 analogs.
  • Alan Cherrington, MD (Vanderbilt University Medical School, Nashville, TN) made a case for beta cell independent actions of GLP-1 in muscle and liver cells based on a series of in vitro, canine, and human studies. He cautioned that this topic can becontroversial because there have been both positive and negative findings for beta cell- independent actions of GLP-1. He reminded the audience that it can be difficult to detect small effects, implying that what we are looking for is a small effect. He felt that finding these subtle influences can depend heavily on the design of the study. The method of action of GLP-1 on the muscle cell is still unclear and it is not yet known whether there is a direct effect or if there are afferent nerves in the liver that can process and relay the GLP-1 signal.
  • Eric A. Schwartz, PhD (Phoenix VA HealthCare System, Phoenix, AZ) reported an exciting study (n = 35) in which a single acute dose of 10 mcg exenatide in healthy exenatide-naïve patients produced a significant suppression of postprandial excursions of several lipids and apolipoproteins associated with dyslipidemia and type 2 diabetes. Elevated levels of several of these molecules are known or suspected to be risk factors for cardiovascular disease. Despite the relatively small number of subjects in the study, the results suggest a protective effect of exenatide on lipids and lipoproteins. We are very interested to see more work to determine the potential of Amylin/Lilly’s cardiovascular outcomes trial for Byetta.
  • Michael Brownlee, MD (Albert Einstein College of Medicine, New York, NY) discussed the possible therapeutic value of GLP-1 (9-36) amide in slowing the progression of diabetic complications. Reactive oxygen species (ROS) induced by hyperglycemia can inactivate several anti-atherogenic enzymes, and GLP-1 (9-36) amide may possess the ability to prevent this inhibition by reducing the formation of ROS. With an increase in intracellular hyperglycemia comes an increase in production of ROS, ultimately leading to a cascade of cellular changes that leads to increased insulin resistance. Dr. Brownlee concluded by suggesting that the GLP-1 (9-36) amide could potentially be used as a therapy for preventing progression of complications related to atherosclerosis.
  • Susan Samson, MD (Baylor College of Medicine, Houston, TX) discussed possible mechanisms of action of exendin-4. She began with a general discussion of GLP-1 and its usefulness in the treatment of diabetes. She went on to describe her study of exendin-4, a peptide that resembles GLP-1 found in the saliva of the Gila monster, in diet-induced obese mice. Interestingly, mice treated with exendin-4 show improved blood glucose tolerance without elevated insulin levels or changes in plasma glucagon levels. As highlighted by Dr. Samson, these results are intriguing because they suggest that exendin-4 may work in an islet-independent fashion, perhaps directly on hepatocytes. More work is necessary to elucidate what signal transduction pathways are activated by exendin-4 and what the direct contribution of the hepatocytes are to the regulation of gluconeogenesis.

 

ADA/Lancet Symposium

A RANDOMIZED TRIAL OF LIRAGLUTIDE VS. EXENATIDE FOR THE TREATMENT OF TYPE 2 DIABETES

John Buse, MD, PHD (University of North Carolina School of Medicine, Chapel Hill, NC)

Dr. Buse presented data from the first 26-weeks of the LEAD-6 study comparing 464 patients randomized to be treated with once-daily 1.8 mg liraglutide or twice-daily 10 microgram exenatide (Eli Lilly/Amylin’s Byetta) while continuing metformin and/or sulfonylurea background therapy. The study showed that liraglutide produced a greater reduction in A1c (1.12%) compared to Byetta (0.79%) from a baseline of slightly over 8%, with the difference reaching statistical significance. This was likely driven by the significant reduction in fasting blood glucose seen in the liraglutide patients (-16.2 mg/dl) compared to Byetta patients (-3.6 mg/dl), from baselines of 176 mg/dl and 169 mg/dl respectively. The percentage of patients achieving the ADA target A1c of <7% was approximately 55% for liraglutide compared to 45% for Byetta. Weight loss was similar between the two groups (liraglutide –32 kg or 7 lbs vs. Byetta –29 kg or 6.4 lbs). Liraglutide patients showed a significantly greater increase in beta cell function (by 40%) compared to Byetta patients as measured by HOMA-B. Although a similar percentage of patients reported nausea in each treatment arm at the beginning of the study (~13%), nausea resolved much more quickly in the liraglutide arm with only 2% of patients reporting persistent nausea beyond 12 weeks compared to 10% in the Byetta arm. Minor hypoglycemia (blood glucose of ≤56 mg/dl) was reported less frequently in the liraglutide arm of the study than in the Byetta arm, with generally low rates in both study arms (193 vs. 260 events per patient per year). There were only two serious hypoglycemic episodes reported in the study, both occurring in the Byetta arm with a background of sulfonylurea treatment. Adverse events were similar in the two treatment arms.

Accompanying the LEAD-6 study published in The Lancet was an editorial that embraces wider use of GLP-1s and in particular liraglutide over Byetta in light of the results of LEAD-6. However, it notes that the FDA has observed a rate of papillary thyroid cancer of 1.6% for patients taking liraglutide vs. 0.6% for Byetta per 1000 patient-years of treatment with each drug. In the 26-week LEAD-6 data Dr. Buse presented at ADA, no clinically significant changes in calcitonin levels in either treatment arm. The significance of these findings is still being debated, and what bearing this will have on the liraglutide approval process remains to be seen. Novo Nordisk is currently in open communication with the FDA over these concerns and management has mentioned that new data becoming available should address the issue favorably. Overall, we consider LEAD-6 to be a win for Novo Nordisk, given that liraglutide was generally better tolerated than Byetta and produced a more significant reduction in A1c. We are not sure of the implications of this, however, since LAR has an improved dosing regimen and may not be as far behind liraglutide on the approval front as previously thought.

  • LEAD 6 was designed to compare the efficacy and safety of liraglutide and twice daily Byetta over 26 weeks. It involved 464 type 2 patients inadequately controlled on metformin and/or sulfonylureas. Those in the liraglutide arm were started at 0.6 mg and up- titrated in 0.6 mg increments to 1.8 mg over three weeks. For the Byetta group, individuals were started at 5 micrograms twice daily and were up-titrated to 10 micrograms twice daily over four weeks. Byetta was administered within an hour before breakfast and dinner (or before each of the two main daily meals, as long as they were six hours or more apart). Top-line data from this study was shared during the Novo Nordisk Capital Markets Day on September 26, 2008, first announced in June 2008 (coinciding with ADA 2008), and also presented in poster form at the Canadian Diabetes Association meeting in Montreal, Quebec.
  • The study provides a good overview of the molecular and pharmacokinetic differences of liraglutide and Byetta. While both drugs are designed to mimic native human and achieve a longer half-life, their structures are very different. Byetta (exenatide) is exendin- based sharing only a 53% homology with the human GLP-1, whereas liraglutide has only a single amino acid substitution from human GLP-1 thereby having a 97% homology. This by itself has no clinical significance, however because Byetta is more dissimilar from human GLP-1, it is more often induces an immune response. In LEAD-6, antibody production was observed in 9% of patients treated with liraglutide vs. 44% of patients treated with Byetta. Some studies have previously suggested that high levels of antibodies can significantly interfere with the activity of the drug. Liraglutide is almost entirely bound to albumin and has a half life of 13 hrs, compared toByetta’s shorter half life of 2.4 hrs. This allows liraglutide to be injected only once a day, while Byetta is a twice-daily injection (and would optimally be injected even more often).
  • The study found greater improvement in A1c, fasting plasma glucose, beta cell function in liraglutide treated patients versus Byetta treated patients. Liraglutide produced a greater reduction in A1c (1.12%) compared to Byetta (0.79%) from a baseline of slightly over 8%, with the difference reaching statistical significance. This was likely driven by the significant reduction in fasting blood glucose seen in the liraglutide patients (-16.2 mg/dl) compared to Byetta patients (-3.6 mg/dl), from baselines of 176 mg/dl and 169 mg/dl respectively. The percentage of patients achieving the ADA target A1c of <7% was approximately 55% for liraglutide compared to 45% for Byetta. Weight loss was similar between the two groups (liraglutide –32 kg or 7 lbs vs. Byetta –29 kg or 6.4 lbs). Liraglutide patients showed a significantly greater increase in beta cell function (by 40%) compared to Byetta patients as measured by HOMA-B.
  • Nausea resolved more rapidly in the liraglutide group compared to the Byetta group. Although a similar percentage of patients reported nausea in each treatment arm at the beginning of the study (~13%), nausea resolved much more quickly in the liraglutide arm with only 2% of patients reporting persistent nausea beyond 12 weeks compared to 10% in the Byetta arm.
  • Minor hypoglycemia (blood glucose of ≤56 mg/dl) was reported less frequently in the liraglutide arm of the study than in the Byetta arm, though rates were generally low in both study arms (193 vs. 260 events per patient per year). There were only two serious hypoglycemic episodes reported in the study, both occurring in the Byetta arm with a background of sulfonylurea treatment.
  • Data from a 14-week non-randomized LEAD-6 extension study were presented as a poster at ADA 2009 (591-P). See the poster presentations in this category for a summary of the study.
  • Overall, we consider LEAD-6 to be a big win for Novo Nordisk, given that liraglutide was generally better tolerated than Byetta and produced a more significant reduction in A1c. In addition, patients on liraglutide reported higher treatment satisfaction than patients on Byetta as measured by the diabetes treatment satisfaction questionnaire (DTSQ), the difference being statistically significant (DTSQ score of 33.2 compared to 30.6). When top- line LEAD-6 results were published last year, some complained that the full results were not available and therefore it was impossible to evaluate the methods used. Now that the data are published in an impressive, peer-reviewed journal, we don’t find any particular flaws with the study design. Some had previously contended that the Byetta results were less impressive than other Byetta studies suggesting improper titration of the Byetta cohort. However, participants in the Byetta study arm were properly titrated up to the standard 10 microgram dose over four weeks, with a 19% withdrawal rate – similar to the 14% withdrawal rate of the liraglutide arm. The 0.79% A1c reduction reported in the Byetta arm of the study is at the lower end of the range from previously reported studies, with Byetta achieving as high as 1.5% A1c in the recent phase 3 trial of exenatide once-weekly (which, by comparison, achieved a 2% A1c reduction in that trial). Given the different glucose-lowering properties of liraglutide and Byetta (liraglutide produces more dramatic reductions in fasting glucose, whereas Byetta is slightly more effective at lowering post- prandial glucose), one possible explanation is that the study population had higher fasting glucose. However, contrary to such a theory the baseline fasting plasma glucose wasapproximately 175 mg/dl for patient enrolled in the study. It is still unclear why Byetta did not perform as well as it has in previous studies.
  • In an editorial accompanying the LEAD-6 results, the authors note that one safety concern that has come to light with liraglutide is an increase in thyroid c-cell tumors observed in rodent models. Furthermore, the FDA has observed a rate of papillary thyroid cancer of 1.6% for patients taking liraglutide vs. 0.6% for Byetta for 1000 patient-years of treatment with each drug. In the 26-week LEAD-6 data Dr. Buse presented, no elevated levels of calcitonin were observed in either treatment arm. The significance of these findings is still being debated and what bearing this will have on the liraglutide approval process remains to be seen.
  • Although LEAD-6 compared liraglutide to Byetta, we cannot help but speculate on what a liraglutide trial against exenatide once-weekly would look like. Given that the molecules in question are the same, many of the differences between liraglutide and exenatide that were observed in LEAD-6, including better tolerability overall, would likely be unchanged. There is some speculation that the longer half-life of EOW may attenuate the nausea rates as seen in DURATION-1 (26% vs. 35% for EOW vs. Byetta respectively) but this is yet to be borne out fully. While once-weekly dosing would likely be considered advantageous for patients, liraglutide benefits from having a smaller needle. However, we continue to view exenatide once-weekly as the leader in efficacy. The 1.9% A1c reduction that was achieved in the phase 3 program of exenatide once-weekly exceeds the A1c reductions that have been published for liraglutide. Indeed, if both exenatide once-weekly and liraglutide are eventually approved, a head-to-head comparison of the two drugs would likely be widely called for.

 

Summary of LEAD-6 results:

 

Liraglutide

(1.8 mg once daily)

Byetta

(10 mcg twice daily)

P-value

Number of participants

233

231

 

Baseline BMI (kg/m2)

33

33

 

Baseline A1c

8.2%

8.1%

 

Duration of diabetes (yrs)

8.5

7.9

 

Mean FPG (mmol/L)

9.8 (176.4 mg/dl)

9.5 (171 mg/dl)

 

Number completed (%)

202 (86%)

187 (81%)

 

Change in A1c

-1.12%

-0.79%

<0.0001

% achieving an A1c <7.0%

54%

43%

0.0015

% achieving an A1c <6.5%

35%

21%

<0.0001

Change in FPG (mmol/L)

-1.61 (-29 mg/dL)

-0.60 (-10 mg/dL)

0.0001

% achieving an FPG <7.2 mmol/L (130 mg/dL)

42%

26%

0.0001

 

Liraglutide

(1.8 mg once daily)

Byetta

(10 mcg twice daily)

P-value

Change in PPG after breakfast (mmol/L)

-3.2 (-58 mg/dL)

-3.9 (-70 mg/dL)

0.0124

Change in PPG after dinner (mmol/L) -3.1 (-56 mg/dL) -3.6 (-65 mg/dL) 0.038
Change in weight (kg) -3.24 (-7.0 lbs.) -2.87 (-6.4 lbs) NS
Change in weight for individuals also on metformin (kg) -4.08 (-9.0 lbs) -3.05 (-6.1 lbs) NS
Change in HOMA-B +40% +3% <0.0001
Number of major hypoglycemic events 0 2  
Minor hypoglycemic events (events/patient/year) 1.9 2.6 0.0131
Nausea (5 weeks) 8% 18%  
Nausea (10 weeks) 4% 13%  
Nausea (26 weeks) 2% 10%  

Symposium: Clinical Use of Incretins

INCRETIN MIMETIC AGENTS CURRENTLY AVAILABLE AND IN DEVELOPMENT – ARE THERE MEANINGFUL DIFFERENCES?

John B. Buse, MD, PhD (The University of North Carolina School of Medicine, Chapel Hill, NC)

Dr. Buse spoke about exenatide (Byetta and exenatide once-weekly) and liraglutide, highlighting differences in molecular structures and clinical data. Notably, overall, Dr. Buse said that he believes patients will greatly prefer longer-acting GLP-1s (including exenatide once-weekly and liraglutide) over Byetta – it was good to hear this from a patient perspective as we haven’t seen extensive (though we have seen some at ADA 2008) patient preference data. He reviewed the results of the LEAD studies (including LEAD-6) and DURATION-1. Touching on drug safety, Dr. Buse said that there has been little or no signal of rodent medullary thyroid cancer with exenatide, and some signal in liraglutide. Dr. Buse said that the mechanism of any potential association here is not understood.

  • Exendin-4, derived originally from the saliva of the Gila monster, is known to bind to the pancreatic GLP-1 receptor in humans. Exenatide, an exendin-based GLP-1, has about a 50% homology to the human GLP-1 and a half-life of about two hours. Exenatide causes about a 1.1% A1c drop with 5.3 kg (12 lbs) of weight loss, which is sustained for three years or more. Almost 50% of patients report at least one episode of nausea, but only about 5% will stop the therapy due to nausea. Sulfonylurea-related hypoglycemia can be increased with exenatide. Antibodies are formed in up to half of patients treated with exenatide, but the significance of these antibodies is unclear. Presumably, in some patients with especially high levels of antibodies, the effect of exenatide may be diminished. Speaking about pancreatitis and exenatide, Dr. Buse said that pancreatitis remains “a possibility in my mind,” but if there is an association it is a tenuous one.
  • Exenatide improves many cardiovascular risk factors. Statistically significant improvements in cholesterol, LDL, HDL, triglycerides, ALT (a marker of fatty liver disease), and markers of inflammation have all been noted with exenatide.
  • Dr. Buse highlighted differences between exenatide once weekly and Byetta. He began his discussion by reviewing the findings of the DURATION-1 trial (comparing exenatide once-weekly with Byetta). Exenatide once weekly achieves mean steady state concentration of 71 pmol/L, much higher than Byetta. In the study, exenatide once weekly produced a 1.9% reduction in A1c as compared to a 1.5% reduction for Byetta. Exenatide once weekly also produced more dramatic reductions in plasma glucagon, total cholesterol, and LDL-cholesterol, but less of a reduction in postprandial glucose. A1c reductions were more pronounced in patients with a higher baseline. The two formulations of exenatide have nearly identical weight loss.
  • Dr. Buse compared exenatide with liraglutide, touching on the recent LEAD-6 study. Liraglutide has only a one-amino acid substitution from the human GLP-1 (97% homology), and it is bound to a C-16 fatty acid that allows it to circulate bound to albumin. It has a long half-life of about 13 hours and can be administered at any time during the day (whereas exenatide must be administered before breakfast and dinner). In the LEAD-6 study (comparing Byetta to liraglutide), liraglutide produced superior reductions in A1c with statistically identical weight loss. Nausea was less persistent in the liraglutide treatment group.
  • One advantage of Byetta over longer acting agents is that it produces a more significant slowing of gastric emptying and postprandial glucose. However, longer- acting agents have better tolerability and a more pronounced effect on fasting glucose and A1c.There has been little or no signal of rodent medullary thyroid cancer with exenatide, and some signal in liraglutide. Dr. Buse said that the mechanism of any association here is not understood.

 

DPP-4 INHIBITORS – HOW DO THEIR EFFECTS DIFFER FROM THOSE OF GLP-1 OR EXENATIDE?

Richard E. Pratley, MD (The University of Vermont College of Medicine, Burlington, VT)

Dr. Pratley provided a balanced talk about the clinical differences between DPP-4 inhibitors and GLP- 1s, including exenatide. Overall, he said that although Byetta and sitagliptin have similar efficacy, long- acting GLP-1s will have better efficacy than any DPP-4 inhibitor. Nonetheless, Dr. Pratley said that DPP-4s will continue to be used because of their tolerability and oral dosing. From our understanding the efficacy with Januvia is usually less than that seen with Byetta, though healthcare providers are certainly demonstrating Dr. Pratley’s prediction that the simplicity of Januvia will carry it in the market.

  • Sitagliptin and alogliptin have half-lives of 12 hours, whereas saxagliptin and vildagliptin have half-lives of about 2 hours. All four DPP-4 inhibitors have similar inhibition of DPP-4. Elimination of sitagliptin and alogliptin is renal (mostly un-metabolized), whereas saxagliptin and vildagliptin are metabolized in the liver. Very little clinical data exists comparing DPP-4 inhibitors. However, one recent three-month head-to-head study was published comparing sitagliptin vs. vildagliptin. In this study, vildagliptin produced a 1% A1c reduction whereas sitagliptin produced only a 0.8% A1c reduction, starting from a baseline of about 8.3%.
  • Comparing DPP-4 inhibitors to glipizide as add-on to metformin, Dr. Pratley showed that DPP-4 inhibitors have better tolerability, side effects, and efficacy. Although DPP-4 inhibitors have modest efficacy alone, they have synergistic activity with metformin. One recent study showed that sitagliptin plus metformin can produce similar efficacy as metformin plus a TZD.
  • Dr. Pratley spoke about clinical differences in DPP-4 inhibitors and GLP-1 agonists. He suggested that the efficacy of Byetta is similar in monotherapy to the efficacy of DPP-4 inhibitors, although he conceded that longer-acting GLP-1s will have much better efficacy. There aren’t very many comparator studies between GLP-1s and DPP-4 inhibitors. However, a recent 60-patient crossover study published by Dr. Ralph DeFronzo showed that GLP-1 levels are increased much more dramatically with exenatide than sitagliptin. Gastric emptying is slowed only with exenatide and not with sitagliptin. Also, insulin secretion is increased more dramatically with exenatide than with DPP-4 inhibitors. On the other hand, sitagliptin has better tolerability. Although Dr. Pratley complimented Amylin on developing a “handy” Byetta pen, he said that nothing beats the ease-of-use of a pill. For this reason alone, Dr. Pratley said that he expects that there will remain an important role for DPP-4 inhibitors in the management of type 2 diabetes.
  • Dr. Pratley spoke about the DURATION-2 study (comparing exenatide once-weekly to sitagliptin and pioglitazone). He showed that at 27 weeks, there was a 1.55% reduction with exenatide once weekly, compared to a 0.92% reduction with sitagliptin and 1.23% reduction with pioglitazone (intention-to-treat analysis). Significantly, there was a 2.3 kg (5.1 lbs) weight loss with exenatide, weight neutrality with sitagliptin, and weight gain with pioglitazone.

 

THE USE OF EXENATIDE IN ISLET CELL TRANSPLANTATION

Rodolfo Alejandro, MD (University of Miami Miller School of Medicine, Miami, FL)

Dr. Alejandro summarized his research supporting the use of exenatide in islet transplantation. Due to its corrective effect on hyperglycemia, exenatide aids in the maintenance of both long-term transplanted beta cell function and patient insulin independence. This may be bolstered by a possible effect on anti- inflammatory and anti-apoptotic pathways. Use, however, is not yet perfected for this purpose, with many patients reporting bouts of extreme nausea.

  • Though immensely beneficial for insulin independence, hypoglycemia awareness, and patient quality of life, islet cell transplantation exhibits a gradual loss of efficacy as beta cell function is lost. Loss of transplanted beta cell function is likely the combined result of many sources, including glucotoxicity, lipotoxicity, immunological effects, exhaustion, toxicity of the required immunosuppressive drugs, lack of regeneration, and timed cell death.
  • Exenatide may prevent beta cell failure. The insulin produced following transplantation stimulates lipogenesis, increasing lipid levels—this lipid toxicity was shown to be a contributing source of islet cell loss. Exenatide may address both glucotoxicity and lipotoxicity to stop this degradation. Exenatide use may also reduce the need for supplementary insulin following transplantation and help beta cells exhibit regenerative potential.
  • Dr. Alejandro’s recent research confirms the benefits of exenatide use following transplantation. In a small population of post-islet transplant patients with type 1 patients, the administration of 5 µg exenatide twice-daily improved insulin independence. A significant average weight loss of 2.7 kg (6.0 lbs) was also observed, with a mean 28% drop in supplementary insulin requirements. No change in A1c was observed, though this may have been due to initially low baseline levels (~6.5%). The effects of exenatide were most obvious after meals, with softer peaks in postprandial glucose levels in treated patients. However, 25% of the initial population dropped out from the study, citing excess nausea. Reports of nausea were common within the remaining patient population as well. Further studies following a mixed meal suggested exenatide use additionally blunted glucagon release and promoted insulin release. A ten-month studyconfirmed that the benefits of exenatide could be maintained for longer periods of time, with multiple patients exhibiting insulin independence and significantly increased C-peptide levels throughout the duration of the trial.
  • Overall, Dr. Alejandro was optimistic about the effects of exenatide in islet cell transplantation. Recent evidence suggests exenatide may activate the anti-inflammatory and anti-apoptotic pathways in human islets, in addition to its metabolic effects. Dr. Alejandro finished by expressing enthusiasm about once-weekly exenatide.

Questions and Answers:

Q: As the capacity for islet transplantation declines with aging, is the effect of exenatide more potent in younger patients than older patients?

A: We actually have lots of problems with this, as most of the donor pancreatic cells we get for transplantation come from older patients; this leads to early failure. There is no question that transplants fare better in younger patients.

Q: How might you mitigate nausea in further trials?

A: It wasn’t said, but I should note that patients were using antiemetics in the long term. We had to greatly reduce the dosages of exenatide as well. Patients can tolerate it, but it never goes away.

 

INCRETIN MIMETICS – CLINICAL, CARDIOVASCULAR AND OTHER METABOLIC EFFECTS

Dana Andersen, MD (Johns Hopkins University Medical School, Baltimore, MD)

Dr. Andersen summarized the current research supporting the use of GLP-1 in the hospital setting. An initial investigation with GLP-1 infusion during major surgery has suggested that GLP-1 may be an effective means of achieving euglycemia without the need for insulin or risk of hypoglycemia – this is certainly a very valuable treatment given the constant risk of hypoglycemia that has plagued all studies of intensive glucose control in the hospital. Dr. Andersen also discussed the recently uncovered metabolic activity of GLP-1[9-36], the primary metabolite of GLP-1. Given that DPP-4 inhibitors are known to reduce the concentrations of the metabolite, he speculated whether this finding could have implications in their continued use. Lastly, Dr. Andersen said that there is some evidence that viral pre- infection of islet cells to introduce a gene for GLP-1 production before transplantation can preserve function and prevent apoptosis. In this manner, islet cells (which cannot produce endogenous GLP-1) may be allowed to generate their own incretin, thus promoting survival in islet cell recipients.

  • GLP-1 may be useful for achieving euglycemia in hospital patients without the need for insulin. In an initial investigation of the effects of an eight-hour infusion of GLP-1 during major surgery, patients receiving GLP-1 had a dramatic lowering of blood glucose levels into the euglycemic range, followed by a transient increase of insulin. Dr. Andersen suggested that this could make GLP-1 very valuable for safe intensive glucose control in the hospital. A study of burn patients (a population that has particular trouble with glycemic control due to need for constant grafts) confirmed GLP-1 infusion could maintain euglycemia without the need for insulin. He noted jokingly, however, that these studies are difficult to blind because the nurses can immediately discern GLP-1 patients from controls due to the drop in their need for fingersticks.
  • GLP-1[9-36], the primary metabolite of GLP-1, is a metabolically active agent both in the heart and the liver. In an animal model of cardiac failure, treatment with GLP-1 improved both cardiac output and left ventricular ejection fraction (LVEF); interestingly, GLP-1[9-36] wasjust as potent as GLP-1, suggesting the metabolite may be as effective as the intact compound. This effectiveness is even in GLP-1 receptor knockout mice, indicating GLP-1[9-36] may interact with a novel class of receptors. The metabolite also slightly increased glucose uptake, leading researchers to believe that it may play a role in glucose metabolism. Later results showed that obese individuals treated with synthetic GLP-1[9-36] exhibited decreased hepatic glucose production. This effect remained (and appeared in a population of lean individuals) after the blockage the GLP-1 receptor, suggesting that GLP-1[9-36] was indeed metabolically active; it is unclear what implications this may have for use of DPP-4 inhibitors, which reduce the concentrations of the metabolite.
  • There is some evidence that viral pre-infection of islet cells to introduce a gene for GLP-1 production before transplantation can preserve function and prevent apoptosis. In this manner, islet cells (which cannot produce endogenous GLP-1) may be allowed to generate their own incretin, thus promoting survival in islet cell recipients.

Questions and Answers:

Q: Can you comment how the utilized 9-36 pharmacological levels compared to physiological levels?

A: I don’t know of any data on physiologic levels of 9-36; in these studies the levels were near those of GLP-1.

 

Symposium: Novel Aspects of GLP-1 Action

METABOLIC AND VASCULAR CONTROL BY BRAIN GLP-1 SIGNALING

Remy Burcelin, PhD (Research Director, French National Medical Research Institute)

Dr. Burcelin emphasized that the effects of GLP-1 in the brain are different for different end organs; brain GLP-1 signals to beta cells to increase insulin secretion whereas it causes relative insulin resistance in muscle cells by inhibiting the vasodilation of blood vessels supplying muscle cells, thus decreasing muscle glucose uptake. We note that this is a very counterintuitive finding; indeed, during the Q&A one audience member pointed out that the peripheral effect of GLP-1 is to cause vasodilation by a direct effect on endothelial cells. Dr. Burcelin agreed, saying that physiologically GLP-1 may have many different effects that overall lead to physiologic balance. The central effects of GLP-1 are clearly an area that needs much more research.

  • The current dogma on the mechanism of action of incretins is that ingested glucose triggers GLP-1 release, which goes to beta cells, increases insulin secretion, and thus decreases glucose. However, only 5-10% of secreted GLP-1 actually reaches the beta cells because of rapid degradation by DPP-4. An alternate hypothesis is that glucose is sensed peripherally, the signal goes to the central and enteric nervous system, and those nervous systems then act on end organs such as pancreas, muscle, fat, etc.
  • Insulin release in response to hyperglycemia is increased greatly when exendin-4, a GLP-1 agonist, is injected directly into the brain – at a plasma level of 20 mmol (360 mg/dl) glucose, insulin secretion is 461 uU/ml with GLP-1 infusion vs. 85 uU/mol with control. This effect is not seen when exendin-9, a GLP-1 antagonist, is infused into the brain.
  • GLP-1 inhibits muscle utilization of glucose by inhibiting vasodilation of the blood vessels supplying muscles. In mice, infusion of GLP-1 into the brain inhibits vasodilation of muscle blood vessels and decreases muscle uptake of glucose. Exendin-4 infusion decreasesmuscle glycogen storage by about one-half while exendin-9 infusion increases muscle glycogen storage about two-fold.
  • Brain GLP-1 signaling activates protein kinase C, which blocks muscle glucose utilization and causes insulin resistance. In mice subjected to high fat diets, there is increased GLP-1 signaling in the brain, with recruitment of more protein kinase C activity, which in turn causes peripheral insulin resistance through effects on muscle vessel vasodilation.

Questions and Answers:

Q: In humans, peripheral GLP-1 actually causes vasodilation by an endothelial-mediated system.

A: Yes, the brain seems to be doing the opposite thing of the periphery. From a physiological point of view, this may represent a balancing of several different glucose sensing mechanisms.

 

INCRETINS AND CARDIOPROTECTION

Richard Shannon, MD (University of Pennsylvania, Philadelphia, PA)

Dr. Shannon showed data that GLP-1 increases cardiac glucose uptake and restores cardiac contractile performance in dogs with chronic heart failure. It increases glycolysis but not glucose oxidation, thus reducing the formation of damaging reactive oxygen species. On a broader level, he believes that there are species- and tissue-specific differences in the mechanism of GLP-1 signaling in cells and that studying these differences may be important in learning more about the glucoregulatory and cardioprotective effects of GLP-1 and its analogs. Right now it appears that native GLP-1 has a stronger affinity for cardiac GLP-1 receptors than GLP-1 analogs.

  • Dr. Shannon began by saying that the question of CV safety has been raised about diabetes drugs and while he doesn’t share that concern, it will be important to keep cardiovascular effects in mind going forward.
  • Some definitions: Preconditioning is a reduction in myocardial infarct size or mitigation of contractile dysfunction following brief repetitive bouts of ischemia or pharmacological treatment in advance of the sustained insult (i.e., a prior event that decreases the severity of a subsequent heart attack). Postconditioning is the restitution of contractile dysfunction following an insult that has already happened.
  • The majority of incretin studies have looked at the early phase of cardiac preconditioning in rodents. What we’ve learned is that GLP-1 administered just before an ischemic insult to the heart is protective. The pharmacological doses required vary depending on which peptide is being used; higher doses are required for exendin-4 compared to native GLP-1. In mice, this preconditioning effect is dependent upon cellular pathways involving cAMP, PI-3 kinase, and Akt.
  • Dr. Shannon has studied a canine model of chronic progressive heart failure induced through rapid cardiac pacing. First, he found that GLP-1 receptors are present in canine myocardium and that there are two isoforms of the receptor. The expression of the larger 65 kD isoform was upregulated in advanced heart failure but there was also increasing cardiac insulin resistance as heart failure worsened, suggesting GLP-1 resistance occurs in stressed hearts. Nonetheless, infusion of pharmacological doses of GLP-1 over 48 hours significantly increased glucose uptake in the heart (by about two-fold) and improved left ventricular function in dogs with end-stage heart failure. GLP-1 increased glycogen synthesis in cardiomyocytes butdid not increase oxidative phosphorylation; overall it decreased levels of reactive oxygen species (Circulation 2004:110;114-20).

Questions and Answers:

Q: You published a human study on GLP-1 infusion after an acute coronary event.

A: Yes, we did a study in patients undergoing percutaneous angioplasty for acute coronary events in which we found that 72-hour infusion of GLP-1 during angioplasty improved left ventricular function (from 29% to 39% ejection fraction) and left ventricular wall motion. We plan to do some biopsy studies to find the mechanism of this.

Q: What was the effect of GLP-1 on adrenergic hormone levels?

A: Norepinephrine levels rise increasingly with advanced heart failure but GLP-1 dramatically reduces plasma norepinephrine and cardiac norepinephrine levels. This may be an important mechanism of cardioprotection.

Q: (Lilly rep): Does the 9-36 GLP-1 fragment play a role?

A: We showed in the dog that infusion of GLP-1[9-36] peptide recapitulates the findings with the GLP-1[7- 36] fragment, but this is a question that bears more investigation.

 

EFFECTS OF GLP-1 ON MUSCLE AND LIVER INDEPENDENT OF CHANGES IN INSULIN AND GLUCAGON

Alan D. Cherrington, MD (Vanderbilt University Medical School, Nashville, TN)

Dr. Cherrington devoted his talk to making a case for beta cell independent actions of GLP-1 in muscle and liver cells based on a series of in vitro, canine, and human studies. He cautioned that this topic can be controversial because there have been both positive and negative findings for beta cell-independent actions of GLP-1. He reminded the audience that it can be difficult to detect small effects, implying that what we are looking for is a small effect. He felt that finding these subtle influences can depend heavily on the design of the study. The method of action of GLP-1 on the muscle cell is still unclear and it is not yet known whether there is a direct effect or if there are afferent nerves in the liver that can process and relay the GLP-1 signal.

 

GLP-1 (9-36NH2) AND DIABETIC COMPLICATIONS

Michael A. Brownlee, MD (Albert Einstein College of Medicine, New York, NY)

Beginning with a review of the problem of diabetic complications including retinopathy, nephropathy, neuropathy, cardiovascular disease, and stroke, Dr. Brownlee went on to describe the role that mitochondrial over-production of reactive oxygen species (ROS) plays in diabetic cellular damage. With an increase in intracellular hyperglycemia comes an increase in production of ROS, ultimately leading to a cascade of cellular changes that leads to increased insulin resistance. The ROS induced by hyperglycemia inactivates several anti-atherogenic enzymes. GLP-1 (9-36) amide, one of two products produced by the cleavage of DPP-4, may prevent the inhibition of anti-atherogenic enzyme activity. Dr. Brownlee concluded by suggesting that the GLP-1 (9-36) amide could potentially be used as a therapy for preventing progression of complications related to atherosclerosis.

  • According to Dr. Brownlee, intracellular hyperglycemia leading to an increase in the production of ROS is a contributing cause of the complications that arise in diabetes patients. ROS can cause cellular damage that leads to retinopathy, nephropathy, neuropathy, cardiovascular disease, and stroke.
  • The ROS produced by hyperglycemia seen in patients with diabetes causes the inactivation of several anti-atherogenic enzymes. Patients with diabetes rarely maintain the glucose levels obtained in normal glucose homeostasis because they are essentially always playing catch up to the changes in their glucose levels based on diet, exercise, and insulin dosing. Dr. Brownlee suggests that anti-atherogenic enzymes are always inhibited because of various hyperglycemic incidences throughout the day.
  • Dr. Brownlee advocates the investigation of GLP-1 (9-36) amide for its therapeutic potential in preventing the progression of complications related to atherosclerosis. The cleaved product of GLP-1, GLP-1 (9-36) amide, may possess the ability to prevent the inhibition of anti-atherogenic enzyme activity.

 

Current Issue: What to Do When Glycemic Control is Inadequate on Oral Agents

ADD BASAL OR MIXED INSULIN

Matthew C. Riddle, MD (Oregon Health & Science University, Portland, OR)

Dr. Riddle advocated the addition of insulin in response to the question, “What to do when glycemic control is inadequate on oral agents?” He is, of course, the author of the famous Treat to Target study and very well known for his research in this area. After briefly covering the history of insulin, he went on to highlight what he considers a simple fact: “there is a lot to like about insulin”. He argued that insulin is attractive not only because of its clear efficacy in controlling hyperglycemia, but also because of many non-glycemic effects that are positive. He remarked that one of the benefits of insulin is there will be no big surprises—the health care provider (HCP) and patient’s challenge is simply to limit hypoglycemia. According to Dr. Riddle, of the therapies available, insulin has shown itself to have the best proven effects on microvascular complications, to be the best tested, and to offer the best in safety. He suggested that if one believes in evidence-based medicine, they would strongly consider insulin. We know, of course, of the many barriers (physician resistance is the one we think is the biggest, which is exacerbated by a system that doesn’t encourage doctors to learn more). Notably, Dr. Riddle advocates the use of basal insulin alone as the standard introductory insulin therapy because it offers the best benefits to risk ratio in terms of efficacy and low risk of hypoglycemia – it is also much easier because dosing isn’t based on food intake.

  • Insulin has been proven to be efficacious and reliable. The only major safety concern is hypoglycemia – after ADA 2008 and the VADT trial results, hypoglycemia as a risk has received more visibility. Dr. Riddle argues that it is an attractive therapy because of its efficacy in preventing microvascular complications and its many “off-target” positive effects such as improving lipid profiles, improving vasodilatory responses, suppressing inflammatory markers and improving myocardial metabolism under stress. He emphasized his belief that insulin is the best mechanism for limiting hyperglycemia. An interesting point he made was that the problems often cited with insulin arise from issues outside of the molecule’s structure or mechanism – we agree, but note that the use of insulin involves more than its molecular structure or mechanism!
  • The second half of Dr. Riddle’s discussion involved the comparison of different insulin choices when beginning insulin therapy. He related the most important thing when choosing an insulin regimen: optimizing the risk-to-benefit ratio. The choice a HCP has to make is whether to prescribe basal insulin alone, premixed insulin, or basal insulin with prandialinsulin. Educating the patient so that they understand the importance of frequency of testing and how to make decisions is key. He made the argument that basal insulin is the best standard method to use because it can help most patients achieve lower A1c levels with fewer incidences of hypoglycemia. At the same time, he extended his theme of evidence-based medicine in advocating individual evaluation of the patient because not all patients can obtain optimal benefit from basal insulin alone. He concluded with the note that while insulin is his first choice in add-on therapy when oral agents no longer adequately control hyperglycemia, it will be important to address the ongoing weight gain and hypoglycemia issues associated with insulin use.

 

ADD INCRETIN MIMETIC

Vivian Fonseca, MD (Tulane University, New Orleans, LA)

Dr. Fonseca argued that incretins should be the next step because while insulin is very effective in lowering glucose, it is associated with many problems including weight gain, hypoglycemia, and perhaps even CV risk (due to hypoglycemia). This is the first time we’ve heard outright an expert identify explicitly potential silent ischemia as a disadvantage of insulin (we’re used to hearing weight gain and hypoglycemia). In contrast, he showed data suggesting comparable efficacy with GLP-1 therapy but without hypoglycemia and with weight loss as well as benefits to CV risk factors. He commented that liraglutide in particular reduces blood pressure, possibly by a mechanism independent of weight loss. He concluded that long-term data are needed and that we should explore combinations of insulin- and incretin based-therapy, which has not been studied much thus far.

  • Even with insulin, glycemic control keeps getting worse. Even in the insulin-treated group, glycemic control deteriorated in the UKPDS study.
  • Barriers to insulin therapy include patient concerns about weight gain and hypoglycemia as well as the potential risk of increased CV risk. Weight gain was a major problem in the DCCT and UKPDS. There was a vicious cycle with weight, with greater insulin use leading to greater weight gain leading to greater insulin use. Hypoglycemia was a major issue in ACCORD, VADT, and ADVANCE. Over time the dose of insulin increased in the VADT trial (leading to a 117% increase in severe hypoglycemia) whereas metformin doses actually decreased, possibly because of declining kidney function and greater retention of the drug. Severe hypoglycemia increases with longer duration of disease in both type 1 and type 2 diabetes, possibly because of reduced counterregulatory mechanisms.
  • There may be a relationship between hypoglycemia and cardiac ischemia and atherosclerosis. In ACCORD, the people who had more cardiac events may have had more hypoglycemia. Desouza et al. (Diabetes Care, 2003) showed that cardiac ischemia may be increased in hypoglycemia. The growth-promoting effects of insulin may increase the endothelial smooth muscle proliferation responsible for the progression of atherosclerosis, although Dr. Fonseca believes that the benefits of glucose control probably outweigh this theoretical possibility.
  • GLP-1 improves the physiological balance of insulin and glucagon during times of hyperglycemia and hypoglycemia. This explains the low risk of hypoglycemia with GLP-1 or DPP-4 inhibitors in the absence of sulfonylureas. Glucagon plays a large role in postprandial hyperglycemia. Suppressing glucagon is an effective way to lower postprandial glucose values.
  • Heine et al. (Annals of Int Med, 2005) showed that exenatide and insulin glargine achieved similar reductions in A1c with 25 U/day glargine and 10 ug BID exenatide. Whereas glargine brought down all glucose values throughout the day (as seen by seven-pointSMBG profiles), exenatide flattened out the glucose profile, acting more on postprandial glucose than fasting glucose.
  • Weight loss is the greatest benefit of GLP-1 therapy and outweighs the tolerability issues with nausea and vomiting, which Dr. Fonseca believes can be overcome with optimal management. Addition of exenatide improves cardiovascular risk factors and there are also other theoretical benefits of GLP-1 on other organ systems.
  • Liraglutide reduces blood pressure as well as weight, particularly systolic blood pressure. Like exenatide it also reduces cardiovascular risk factors. Dr. Fonseca promised there would be more info at EASD, but mentioned that the blood pressure drop with liraglutide usually happens in about two weeks, which is faster than the weight loss and may represent a separate mechanism of action of liraglutide on the vasculature.
  • Adding a DPP-4 inhibitor like vildagliptin to insulin reduces A1c by 0.51% vs. 0.24% with placebo while at the same time reducing hypoglycemia (Fonseca, Diabetologia, 2007) – Dr. Fonseca attributed this to a restoration of alpha-cell function because GLP-1 improves hypoglycemia-stimulated glucagon secretion as well as hyperglycemia-stimulated insulin secretion.

QUESTION AND ANSWER

During the Q&A the consensus seemed to be that basal insulin and Byetta should both be options, possibly together, in patients failing orals. Dr. Fonseca made the case that doctors should move to using explicitly different targets for different subpopulations of patients rather than a one-A1c-for-all model. Dr. Riddle admitted that the failure rate for basal insulin, like any other treatment, is probably similar to the 0.2 to 0.3% A1c rise per year seen in all of the UKPDS arms and he mentioned adding prandial Byetta as an option at that point. One audience member asked about combining exenatide and pramlintide in difficult type 2 patients (hasn’t been tested yet).

Q: Why can’t we combine exenatide and pramlintide in difficult type 2 diabetes patients?

Dr. Fonseca: There are no studies yet, but that’s a good idea to test.

Q: I’m concerned that there’s so much emphasis on determining which of these alternate therapies should be used next. I think we haven’t learned how to use insulin well yet.

Dr. Fonseca: I agree that we have overemphasized standardized targets. We’re going to have to move in the direction of subpopulations of patients.

Comment: I agree with Dr. Riddle that basal insulin is a simple and usually successful therapy to normalize fasting glucose. But, in my experience, Byetta does improve weight and CV risk factors. Patients should be individualized to basal insulin or Byetta depending on what they’re willing to take.

Q: How long do patients continue on once-daily basal insulin before they need more intensive insulin treatment?

Dr. Riddle: Anecdotally, pretty long in some cases. From the literature, we know that all of the stable therapy treatments in the UKPDS led to linear A1c increases of 0.2 to 0.3% per year, so I would predict that this is the same rise you would see with basal insulin. Practically speaking, within a year a great many patients who are successful with basal insulin will need some addition of prandial therapy and the real question is how to tailor that therapy. Should it be a single dose of prandial insulin? Two doses of Byetta?

Dr. Fonseca: So 40-50% of people are not going to succeed on basal insulin to begin with so they will need prandial therapy from the beginning.

Q: Should SFUs be discontinued when insulin is added?

Dr. Riddle: The modern SFUs ought to be continued when additional therapy is added because they do not lead to much hypoglycemia.

 

Oral Presentations: Incretin Therapies

EXENATIDE ONCE WEEKLY TREATMENT ELICITS SUSTAINED GLYCEMIC CONTROL AND WEIGHT LOSS OVER 2 YEARS

Terri Kim, MD (Amylin Pharmaceuticals, San Diego, CA)

Dr. Kim discussed a 70-week open-label extension study of the 30-week DURATION-1 trial for exenatide once-weekly that demonstrated that EOW provides sustained glucose control and weight loss. At the final two-year endpoint, the mean A1c reduction from baseline for exenatide once-weekly was 1.7%. This compared to an A1c reduction of 2.0% at the one-year endpoint (as reported at ADA 2008), and 1.9% A1c reduction at the 30-week endpoint. Notably, approximately two-thirds of patients treated with exenatide once-weekly were at an A1c of less than 7% percent and 42% were at an A1c of less than 6.5% at the two-year end point. Weight loss was also sustained at two years, with an average weight loss at 2 years of 3.6 kg (7.9 pounds). A clinically significant reduction in systolic blood pressure was also noted at the end of the study and perhaps most impressively, incidence of nausea in the extension study was just 12%. As expected, no severe hypoglycemia was observed. Healthcare providers with whom we have spoken certainly think the product could be transformational in terms of efficacy and convenience – we look forward to learning more about how patients like it. Early data at ADA 2008 was encouraging on this front and we look forward to hearing from larger groups of patients.

  • Interim results for patients who enrolled in a 70-week open-label extension study of original 30-week DURATION-1 exenatide once-weekly trial were presented. Impressively, 73.2% of the 181 people who enrolled in the original DURATION-1 study chose to enroll in the 70-week extension study. Equally encouraging, the most common reason for withdrawal in the extension study was withdrawal of consent. Mean A1c at baseline (entry of the original DURATION-1 study) for those that completed the extension study was 8.3%; mean body weight was 100 kg (220 pounds), and BMI was 34.7.
  • At the end of the two-year study, the mean A1c reduction from baseline for exenatide once-weekly was 1.7%. This compared to an A1c reduction of 2.0% at the one-year endpoint, and 1.9% A1c reduction at the 30-week endpoint. Overall, this suggests that exenatide once-weekly provides a durable improvement in A1c. While it would have been ideal to see no increase in A1c between the end of the one-year and two-year extension studies, the result is still highly impressive in our view. To date, of all the long-acting GLP-1s, exenatide once-weekly has the longest duration of action of any current anti-diabetic class. (To be fair, none of the other long-acting GLP-1s have been tested long enough to know if they could best this result.) Notably, approximately two-thirds of patients treated with exenatide once-weekly were at an A1c of less than 7% percent and 42% were at an A1c of less than 6.5% at the two-year end point.
  • Weight loss was also sustained at two years, with an average weight loss of 3.6 kg (7.9 pounds). By comparison, weight loss at one-year was 4.3 kg (9.5 pounds). A clinically significant reduction in systolic blood pressure was also noted at the end of the study. Incidence of nausea in the extension study was 12%, and no severe hypoglycemia was observed.

 

CARDIOVASCULAR SAFETY OF EXENATIDE BID: AN INTEGRATED ANALYSIS FROM LONG-TERM CONTROLLED CLINICAL TRIALS IN SUBJECTS WITH TYPE 2 DIABETES

Larry Shen, PhD (Amylin Pharmaceuticals, San Diego, CA)

Dr. Shen discussed a cardiovascular meta-analysis of the exenatide BID database, including 12 longer- term trials with a total of 39,245 subjects and 1,072 subject-years of exenatide exposure. The analysis showed that the exenatide group had a lower incidence of CV events by both the MACE and the broad CV endpoint definition out to 400 days of exposure. The point estimate for CV risk using the MACE endpoint was 0.7, with a 95% confidence interval of 0.38-1.31. Using the broad CV endpoint, the point estimate was 0.69, with a confidence interval of 0.46-1.03. We would note that these results appear to meet the FDA’s criteria for approval—the important point in our minds is how much weight Byetta safety data will carry during the exenatide EOW review process.

  • Dr. Shen reviewed 2008 results showing positive effects of exenatide BID on CV risk factors. These results included reduced A1c, body weight, improved lipid profile (increased HDL cholesterol and reduced LDL cholesterol), and decreased blood pressure. He stated that there has been no identified CV risk of Byetta based on post-marketing studies.
  • The current meta-analysis examined the overall CV risk in selected studies from the Byetta program. Part of the rationale for the meta-analysis was to meet the FDA’s new CV guidance for diabetes drugs. As a reminder, the guidance specified that new drugs have to have a 95% confidence interval that fall below 1.8 for approval (or below 1.3 for approval without a required post-marketing safety study). The analysis included 12 longer-term trials with a total of 39,245 subjects, 1,072 subject-years of exenatide exposure, and an average exposure of 24 weeks. The endpoints were MACE (consistent with the FDA guidance) and a broad CV endpoint including heart failure and arrhythmias. 38 patients had at least one MACE, and slightly over 100 had a CV event by the broad definition.
  • The exenatide group had a lower incidence of CV events by both the MACE and the broad CV endpoint definition out to 400 days of exposure. The point estimate for CV risk using the MACE endpoint was 0.7, with a 95% confidence interval of 0.38-1.31. Using the broad CV endpoint, the point estimate was 0.69, with a confidence interval of 0.46-1.03. The results were not sensitive to the method of analysis—Dr. Shen showed multiple alternatives, and the highest upper bound of a confidence interval was 1.47 for the MACE endpoint and 1.17 for the broad CV endpoint. We would note that these results appear to meet the FDA’s criteria for approval—the important point in our minds is how much weight Byetta safety data will carry during the exenatide EOW review process.

Questions and Answers:

Q: You reported a 5 kg (11 lb) weight loss for long-term treatment—what percent dropped out from the beginning to the end of the treatment?

A: I don’t have that percent right now.

Q: I think that you showed a protective effect. How do you think that happens?

A: We saw a benefit in CV risk factors and weight loss, and these could all contribute.

Q: The difference in survival curves was much smaller in MACE than with the broad CV endpoint. Did exenatide prevent heart failure?

A: We don’t know the answer right now. I can’t remember for heart failure, but we did see a decrease in arrhythmia.

 

MONOTHERAPY WITH LIRAGLUTIDE, A ONCE-DAILY HUMAN GLP-1 ANALOG, PROVIDES SUSTAINED REDUCTIONS IN A1C, FPG, AND WEIGHT COMPARED WITH GLIMEPIRIDE IN TYPE 2 DIABETES: LEAD-3 MONO 2-YEAR RESULTS

Alan J. Garber, MD (Baylor College of Medicine, TX)

Dr. Garber provided results for the one-year extension study of the original year-long LEAD-3 study (liraglutide monotherapy compared with a sulfonylurea). Starting from an A1c of approximately 8.0% at the study baseline (very low), the mean A1cs at the two-year endpoint were 6.9%, 7.1% and 7.5% for patients randomized to liraglutide 1.2 mg, liraglutide 1.8 mg, and sulfonylurea respectively. Patients randomized to liraglutide also achieved a mean weight loss of more than 2 kg (4.4 pounds), compared to 1 kg (2.2 pounds) of weight gain for the sulfonylurea arm. Notably, dose-dependent responses to liraglutide were more pronounced for patients with a shorter duration of diabetes, which Dr. Garber used to justify earlier interventions in diabetes when beta cell function is intact. Overall, the results are very impressive, but we cannot help but compare them to the even more remarkable A1c results that were described in the two-year exenatide once-weekly results presented in the same session. The market is big – currently we estimate there are over seven million people in the US alone failing oral therapy – definitely room for more than one great GLP-1. The potential for the long acting incretin market is vast in terms of those with diabetes and ultimately, we believe, prediabetes – makes one think a little about the $26 billion statin market and how many patients were helped by this.

  • Liraglutide 1.2 mg and 1.8 mg were compared to glimepiride (8 mg QD) (Sanofi- Aventis’ Amaryl) in a 52-week randomized control study called LEAD3. Dr. Garber shared the results of a one-year open-label extension study of patients who participated in LEAD3. The study population at baseline in LEAD 3 had a mean A1c of 8.0% (relatively low, to be sure) and mean BMI of 33.
  • At the end of the one-year extension study (two-year study endpoint), mean A1cs were 6.9%, 7.1% and 7.5% for patients randomized to liraglutide 1.8 mg, liraglutide 1.2, and sulfonylurea respectively. This amounts to an A1c reduction of approximately 1.2%, 0.9%, and 0.5% for the liraglutide 1.2 mg, liraglutide 1.8 mg, and sulfonylurea treatment arms, respectively. Approximately 58% of patients randomized to liraglutide 1.8 mg achieved an A1c of 7.0%, compared to only 37% for patients randomized to the sulfonylurea.
  • Importantly, at the end of two years patients randomized to the 1.2 mg and 1.8 mg doses of liraglutide lost on average 2.1 kg (4.6 pounds) and 2.3 kg (5.1 pounds) respectively, compared to 1 kg (2.2 pounds) of weight gain for the sulfonylurea arm. The results call attention to the durability of the weight loss that is achieved with liraglutide.
  • Patient responses to liraglutide were more pronounced for patients with a shorter duration of diabetes, which Dr. Garber used to justify earlier interventions in diabetes when beta cell function is intact.
  • The overall adverse event rates were similar in the liraglutide and sulfonylurea treatment arms. One of the more common side effects reported with liraglutide was nausea, but most cases of nausea were transient and less than 2% of patients experienced sustained nausea. There was more than six times more hypoglycemia in the glimepiride arm of the study than the liraglutide arm. The average rates of hypoglycemia for the liraglutide (1.2 mg and 1.8 mg) and sulfonylurea arms of the study were 0.28, 0.26, and 1.82 events per subject per year, respectively.

 

REDUCTIONS IN GLYCEMIA AND WEIGHT WITH ONCE WEEKLY DOSING OF LY2189265, A LONG-ACTING GLUCAGON-LIKE PEPTIDE 1 (GLP-1) ANALOG IN PATIENTS WITH TYPE 2 DIABETES MELLITUS

Philip Barrington, MD (Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN)

Dr. Barrington reported positive glycemic results for a phase 2 trial of LY2189265, a long-acting GLP-1 being developed by Eli Lilly. The compound consists of a GLP-1 analog protected by DPP-4 that is covalently linked to an Fc fragment of human IgG4. A1c reductions were impressive (up to 1.3% after only five weeks), and statically significant weight loss was noted. The present five-week study evaluated safety, tolerability and pharmacokinetics of LY2189265 in 43 patients with type 2 diabetes. Patients were randomized to doses of LY2189265 ranging from 0.5 mg to 8 mg, or placebo. We believe that this is one of the most promising GLP-1s in development in terms of glucose reduction. Given that this is a very large GLP-1 compound however, we expect that a low concentration of the drug will cross the blood-brain barrier and therefore weight loss may prove to be less than some other GLP-1s in development. At the end of five weeks, average A1c was reduced from 0.7% to 1.3% in the LY2189265 treatment arms; baseline A1c was not given. The most commonly reported adverse event was nausea; more concerning however was an increase in heart rate in the 5 mg dose. We await further clinical data before drawing clear comparisons to other long-acting GLP-1s.

  • LY2189265 is a once-weekly GLP-1 analog in development from Eli Lilly. It is to our knowledge the largest GLP-1 compound in development – it consists of a GLP-1 analog protected by DPP-4 that is covalently linked to an Fc fragment of human IgG4.
  • The present five-week study evaluated safety, tolerability and pharmacokinetics of LY2189265 in 43 patients with type 2 diabetes. Patients were randomized to doses of LY2189265 ranging from 0.5 mg to 8 mg, or placebo.
  • At the end of five weeks, reductions in A1c ranging from 0.69% to 1.34% were observed in the LY2189265 treatment arms. The most commonly reported adverse event was nausea; more concerning however was an increase in heart rate in the 5 mg dose.

 

INHALED GLP-1 AND EXENATIDE: DIFFERENT EFFECTS ON PANCREATIC AND GASTRIC ACTIVITY

Robert A. Baughman, PhD (MannKind Corporation, Danbury, CT)

Dr. Baughman presented early-stage clinical data for MKC253, a GLP-1 that is absorbed in MannKind’s proprietary microparticles for oral inhalation. Pharmacokinetic data from 20 human subjects shows that MKC253 has an onset of insulin action in 10 minutes with a peak at 60 minutes. Dr. Baughman spoke about the potential advantages of inhaled GLP-1 over injected GLP-1, including lower levels of nausea and increased endogenous insulin secretion. On the minus side, inhaled GLP-1 did not slow gastric emptying.

 

PRANDIAL ADJUNCTIVE THERAPY WITH EXENATIDE IS EFFECTIVE IN REDUCING POST-PRANDIAL HYPERGLYCEMIA IN ADOLESCENTS WITH TYPE 1 DIABETES MELLITUS

Vandana S. Raman, MD (Texas Children’s Hospital, Houston, TX)

Dr. Vandana S. Raman discussed her group’s study on prandial combined exenatide and basal insulin therapy in adolescents with type 1 diabetes. Studies have shown exenatide (an incretin mimetic) to be effective in the treatment of type 2 diabetes, but only one study has targeted type 1 diabetes in adults and no studies have been done in children. In this study, patients administered exenatide with insulin before meals demonstrated significantly reduced glucose excursions as well as delayed gastric emptying. Altogether, these results suggest that adjunctive prandial exenatide therapy could be a promising and safe treatment for adolescents with type 1 diabetes.

  • Dr. Raman presented a study examining the role of adjunctive prandial exenatide in the treatment of adolescent with type 1 diabetes. Eight subjects with type 1 diabetes (mean age 17 ± 1 year, duration 5 ± 3.3 years, HbA1c 7.4±0.7%, total daily dose of insulin 0.9±0.2 units/kg/day) underwent three studies: a baseline study with insulin only and then two randomized studies to either 1.25 or 2.5 mcg doses of exenatide. Patients were given exenatide before breakfast with a prandial insulin dose that was reduced by 20% from insulin monotherapy. In all studies, gastric emptying was assessed and plasma glucose, glucagon, insulin, and exenatide concentrations were measured for 300 minutes following the meal.
  • Glucose excursions were significantly reduced in both doses of exenatide compared to insulin monotherapy. No significant difference in glycemic excursion was found between the two doses of exenatide.
  • Adjunctive therapy with exenatide also delayed gastric emptying, but did not suppress glucagon: There was a significant difference in the 2.5 mcg dose compared to insulin monotherapy.
  • No significant differences in insulin, glucagon, or C-peptide levels were revealed.
  • Subjects generally tolerated both doses of exenatide well. Notably, there was only one incidence of nausea, which we found interesting – we wondered if since it was such a small study, there was more focus on titration. There was also one incidence of pre-meal hypoglycemia, but no episode of severe hypoglycemia.
  • Dr. Raman suggested that given these findings, adjunctive prandial exenatide therapy with insulin has potential in the management of T1D in adolescents. She suggested that further studies to understand mechanisms were needed, and long-term trials in adults and preadolescents with type 1 diabetes would be valuable.

Questions and Answers

Q: Have you done this study with pramlintide?

A: Yes, many studies. We see a lot of postprandial hyperglycemia that was not seen in this study (with exenatide). Eventually we want to do head to head comparison with pramlintide and exenatide. One difference is that pramlintide needs multiple injections; exenatide is only two a day. Also important is potential for exenatide once a day and once a week.

Q: Any effect on weight?

A: This study was conducted over only five hours. We intend to conduct this study over a longer period of time where we will take weight into consideration.

Q: Can you speculate on the absent effect on glucagon?

A: The mechanism for glucagon suppression is unclear. It is a question of whether exenatide can bind on the alpha, possible GLP-1, receptor. Data varies across studies. It is possible that the suppressed glucagon effect is lost in type 1 diabetes because no insulin is released. This study was not designed to look at this mechanism, but we will consider it for future studies.

 

EFFECTS OF ACUTE EXENATIDE ADMINISTRATION ON POSTPRANDIAL LIPIDS AND LIPOPROTEINS IN INDIVIDUALS WITH IMPAIRED GLUCOSE METABOLISM

Eric A. Schwartz, PhD (Phoenix VA HealthCare System, Phoenix, AZ)

Dr. Schwartz reported an exciting study (n = 35) that showed that a single acute dose of 10 mcg exenatide in healthy exenatide-naïve patients produced a significant suppression of postprandial excursions of several lipids and apolipoproteins associated with dyslipidemia and type 2 diabetes. Elevated levels of several of these molecules are known or suspected to be risk factors for cardiovascular disease. Despite the relatively small number of subjects in the study, the results suggest a protective effect of exenatide on lipids and lipoproteins. We are very interested to see the ultimate results of Amylin/Lilly’s cardiovascular outcomes trial for Byetta.

  • The exact mechanism and effects of exenatide on lipid and apolipoprotein profiles are uncertain. Previously hypothesized mechanisms include inhibition of gastric emptying, alteration of gastric lipase activity, and altered absorption in the intestine. As a reminder, apolipoproteins are associated with cholesterol trafficking and levels of cholesterol.
  • The primary aim of this study was to determine the acute effects of exenatide on postprandial triglyceride levels in healthy exenatide-naïve patients. Secondary aims included determining the acute effect of exenatide on postprandial plasma lipids, apolipoproteins (Apo48B, LDL, HDL). Well controlled, double blinded crossover studies (n = 35) were performed and statistically analyzed. Due to limited resources and funding, the study was heavily biased towards male patients with an average age of 61 years, body mass index (BMI) of 33.4, normal fasting blood glucose of 108 mg/dl (6 mmol/l) and two-hour blood glucose level of 187 mg/dl(10.4 mmol/l).
  • A single acute dose of exenatide produced significant suppression of postprandial excursions of several lipids and apolipoproteins associated with insulin resistance and type 2 diabetes. Exenatide suppressed postprandial rises in glucose and insulin, the latter likely due to suppression of glucose concentrations. The placebo group experienced a rise in triglycerides, beginning after two hours and peaking at four hours. Exenatide completely suppressed this peak and substantially delayed the subsequent rise (p <0.0001). Similar trends were noticed for ApoB48. In placebo-treated patients, ApoB48 levels gradually rose and peaked after six hours. However, with the administration of exenatide, the peak was completely suppressed and the rise in ApoB48 levels was delayed (p<0.0001). Remnant lipoproteins, RLP- cholesterol and RLP-triglycerides displayed the exact same trends, with exenatide significantly suppressing RLP-cholesterol (p=0.008) and RLP-triglycerides (p<0.0001). For serum free fatty acids (FFA), the placebo group experienced fluctuations, whereas exenatide non-significantly suppressed substantial drops in FFAs (p=0.08). There were no GI complaints reported.

 

TASPOGLUTIDE, A ONCE-WEEKLY HUMAN GLP-1 ANALOGUE, REDUCES POSTPRANDIAL RESPONSE OF INTESTINAL PEPTIDES PYY AND GIP IN ZDF RATS

Elena Sebokova, PhD (Hoffman-La Roche AG, Basel, Switzerland)

In a rodent model of type 2 diabetes (ZDF rats), a single subcutaneous injection of 1 mg taspoglutide reduced the glucose area-under-the-curve by 50% during a two-hour oral glucose tolerance test (OGTT) given after three weeks; insulin levels were unaffected, suggesting that taspoglutide may have a chronic effect to improve insulin sensitivity. Taspoglutide also reduced the post-challenge rise in peptide YY and GIP, suggesting that it has a negative feedback effect on endogenous incretin action. Dr. Sebokova suggested that taspoglutide’s effects on these intestinal peptides may be important for its effects on post- meal glucose and insulin secretion.

  • Some background on taspoglutide: taspoglutide is human GLP-1 with amino acid substitutions at positions eight and 35 of the peptide, which serve to block N-terminal cleavage by DPP-4 and C-terminal cleavage by other proteases. It has 93% homology to human GLP-1. In humans, it has a half-life of 14o to 150 hours.
  • This experiment evaluated the chronic effects of taspoglutide in ZDF rats, a model of type 2 diabetes. A total of 12 male five-week old ZDF rats were injected with a single dose of 1 mg taspoglutide (n=6) or vehicle (n=6) and then subjected to three weeks of a diabetogenic diet. At day 21, rats were given two-hour oral glucose tolerance tests (OGTT). Levels of glucose, insulin, peptide YY (PYY), and GIP were also measured throughout the OGTT. PYY and GIP were measured as a proxy for endogenous incretin function.
  • Taspoglutide appeared to have an insulin-sensitizing effect to reduce post-challenge glucose levels. At day 21, the OGTT glucose area-under-the-curve (AUC) was 50% lower in the taspoglutide group, but the concentrations of insulin did not change. As expected, taspoglutide suppressed a rise in PYY during the OGTT and decreased the GIP response during the OGTT, indicating a negative feedback effect to reduce endogenous incretin activity. Taspoglutide reduced body weight gain as well, with a 7% difference in body weight between the two groups of rats.

Questions and Answers:

Q: What are the kinetics of taspoglutide in rats?

A: Over the four weeks of the experiment the level of taspoglutide dropped over the first nine days and stabilized between 0.1 and 1.0 ng/mL out to 28 days.

Q: What do you deliver the compound in? What is the formulation?

A: I can’t tell you.

Q: Why didn’t you do OGTTs earlier on to see if there was a difference in insulin response earlier on vs. at three weeks?

A: The objective of this study was to look at chronic effects. You can see Poster 593 for more on acute effects of taspoglutide.

Q: What was the eating behavior and gastric emptying in these animals?

A: There was an effect to decrease food intake in the first week, which then normalized by two weeks. We didn’t measure gastric emptying.

Q: You stressed the importance of the suppression of the PYY increase after taspoglutide. Is this any different from other GLP-1 agonists or DPP-4 inhibitors? There seems to be a well-established feedback loop that the L cell decreases GLP-1 release and consequently PYY and GLP-2 release.

A: We used PYY as a surrogate for endogenous GLP-1 but we speculated that this could be a mechanism for the decrease in body weight. Additional studies are underway.

 

EXENDIN 4 DOWNREGULATES GLUCONEOGENIC GENE EXPRESSION AND GLUCONEOGENESIS IN VIVO AND IN ISOLATED HEPATOCYTES IN VITRO

Susan L. Samson MD (Baylor College of Medicine, Houston, TX)

Dr. Samson began with a general discussion of GLP-1 and its usefulness in the treatment of diabetes. She went on to describe her study of exendin-4, a peptide that resembles GLP-1 found in the saliva of the Gila monster, in diet-induced obese mice. Interestingly, mice treated with exendin-4 show improved blood glucose tolerance without elevated insulin levels or changes in plasma glucagon levels. As highlighted by Dr. Samson, these results are intriguing because they suggest that exendin-4 may work in an islet- independent fashion, perhaps directly on hepatocytes. More work is necessary to elucidate what signal transduction pathways are activated by exendin-4 and what the direct contribution of the hepatocytes are to the regulation of gluconeogenesis.

  • The study investigated the effect of exendin-4 on gluconeogenesis in diet-induced obese mice. In fasting mice, three injections were delivered every three hours daily, and phosphate buffered saline injections were used as a control. A pyruvate tolerance test was performed after the series of injections (one hour later) and blood glucose was monitored.
  • The results of the study indicate that blood glucose tolerance could be improved without elevated insulin levels using exendin-4. Ex4 mice showed lower blood glucose at all time points measured; however, plasma glucagon levels did not differ between the experimental and control groups. Dr. Sansom suggested that this may indicate that the decreased gluconeogenesis is due to a glucagon-independent mechanism.
  • In vitro studies suggest that Ex4 directly affects hepatocytes by suppressing gluconeogenic enzyme expression and decreasing glucose production. Based on the findings of in vitro studies, Dr. Sansom suggests that Ex4 acts directly on the liver by reducing hepatic glucose output and that this effect may be independent of Ex4’s effects on glucagon secretion. More work is necessary to understand the mechanisms involved.

 

Poster Presentations: Incretin Therapies

(6-LB) DURATION-2: EXENATIDE ONCE WEEKLY DEMONSTRATED SUPERIOR GLYCEMIC CONTROL AND WEIGHT REDUCTION COMPARED TO SITAGLIPTIN OR PIOGLITAZONE AFTER 26 WEEKS OF TREATMENT

Bergenstal R, Wysham C, Yan P, Macconell L, Malloy J, Porter L

The DURATION-2 study was a randomized, double-blind, 26-week study comparing the safety, efficacy, and tolerability of the GLP-1 receptor agonist exenatide once weekly (EQW) to the DPP-4 inhibitor sitagliptin or the TZD pioglitazone in patients with type 2 diabetes already taking metformin (n = 491). EQW resulted in a significantly greater reduction in A1c, fasting plasma glucose (FPG), and weight compared to sitagliptin or pioglitazone (baseline values: A1c = 8.5%, FPG = 164 mg/dl (9.2 mmol/l), weight = 88 kg (193.6 lb)). Generally all treatments were well tolerated, with nausea being the most common side effect. Exenatide once weekly appeared to result in the greatest improvements in glycemic control with a favorable side effect profile.

  • The DURATION-2 study examined the safety, efficacy, and tolerability of exenatide once weekly (EQW) compared to the DPP-4 inhibitor sitagliptin or the TZD pioglitazone, all on top of metformin therapy. The trial lasted for 26 weeks, and compareda 2 mg weekly dose of EQW with a 100 mg daily dose of sitagliptin and a 45 mg daily dose of pioglitazone. 491 patients were included in the analysis. Subjects had an average baseline A1c of 8.5%, an FPG of 164 mg/dL (9.2 mmol/l), and a weight of 88 kg (193.6 lb).
  • EQW produced a statistically significant reduction in A1c, FPG, and weight loss compared to sitagliptin or pioglitazone. Subjects treated with EQW had a 1.55% decrease in A1c, compared to a decrease of 0.92% with sitagliptin and a 1.23% decrease with pioglitazone. Decreases in FPG were 32 mg/dl (1.8 mmol/l) in the EQW group, 16 mg/dL (0.9 mmol/l) in the sitagliptin group, and 27 mg/dL (1.5 mmol/l) in the pioglitazone group. Subjects in the EQW group experienced a 2.7% reduction in body weight compared to a 0.9% reduction in the sitagliptin group and a 3.2% increase in the pioglitazone group.
  • The most common side effects of EQW treatment were nausea (24%) and diarrhea (18%). There was no severe hypoglycemia, and the rate of minor hypoglycemia was actually lower in the EQW group than in the sitagliptin group (1.3% EQW, 3% sitagliptin, and 0.6% pioglitazone). Serious adverse events were 2.5% with EQW, 3.0% with sitagliptin, and 6.1% with pioglitazone. Two cases of pancreatitis were reported in the pioglitazeone group, but none in the EQW or sitagliptin groups.
  • In conclusion, the once-weekly use of EQW was shown to be well tolerated and efficacious compared with sitagliptin or pioglitazone. We are particularly impressed by the weight loss seen in this trial—while 2.7% is not enough weight loss to be clinically meaningful in most cases, the weight factor is become more and more prominent in the debate about diabetes drugs in today’s scientific and regulatory environment.

 

(1202-P) ESTIMATING THE POTENTIAL CARDIOVASCULAR BENEFIT OF A1C REDUCTION AND WEIGHT LOSS IN PATIENTS WITH TYPE 2 DIABETES TREATED WITH EXENATIDE FOR AT LEAST THREE YEARS.

Best J, Herman W, Wintle M

The goal of this study was to extrapolate, using currently available data on exenatide’s effects on cardiovascular risk factors, the relative risk of cardiovascular events following ten years of using exenatide BID in addition to metformin and/or sulfonylurea therapy compared to using metformin and/or a sulfonylurea alone. The authors projected that there was an estimated 40% risk reduction in myocardial infarction in patients using an exenatide BID combination therapy compared to using metformin and/or a sulfonylurea alone. These data indicate that significant reductions in cardiovascular risk can be achieved with adjunctive exenatide therapy.

  • The authors used a statistical model to estimate the projected clinical outcomes of adding exenatide BID to a background of metformin and/or sulfonylurea therapy. Specifically, they investigated the potential CV risk reduction from sustaining the effects of exenatide BID therapy at three years for ten additional years and the difference in CV risk reduction at ten years for patients who lost weight compared to patients who gained weight on exenatide therapy at three years. They used a validated Markov model for type 2 diabetes, incorporating a Monte Carlo simulation to assess the potential cardiovascular risk reduction associated with glycemic control and weight loss.
  • The incidence of myocardial infarction (MI) was projected to be 40% lower in patients who received exenatide adjunctive therapy compared to patients who received no additional treatment beyond metformin and/or sulfonylurea. Furthermore, patients with significant weight loss had a 50% reduction in risk for MI compared to 34% in patients who gained a small amount of weight. Patients on adjunctive therapy also had 45% reduction in risk for end-stage renal disease.
  • The authors concluded that adjunctive exenatide therapy may be effective in achieving clinically meaningful reductions in the 10-year risk for CV outcomes.

(1729-P) LIRAGLUTIDE, A ONCE-DAILY HUMAN GLP-1 ANALOG, REVERSES INDICES OF PREDIABETES IN OBESE SUBJECTS: A RANDOMIZED PLACEBO-CONTROLLED 20- WEEK TRIAL

Finer N, Al Hakim M, Astrup A, Harper A, Lean M, Niskanen L, Rasmussen M, Rissanen A, Rössner S, Van Gaal L

This sub-analysis drew data from a study of liraglutide whose primary endpoint of weight loss was presented at the Obesity Society Annual Meeting in 2008. Five hundred and sixty-four subjects without diabetes (75 with prediabetes, defined as either impaired fasting glucose (IFG) or impaired glucose tolerance (IGT)) were randomized to a placebo, 120 mg orlistat or a dose-titration of liraglutide (Novo Nordisk’s Victoza, submitted to FDA for approval) for 20 weeks. Patients taking liraglutide had a significantly higher chance of having normal glucose tolerance at the end of the study, with odds ratios compared to placebo of 3.0, 26.1, 10.7 and 12.5 for the 1.2 mg, 1.8 mg, 2.4 mg, and 3.0 mg groups respectively (all statistically significant).

  • This sub-analysis drew data from a study whose primary endpoint (weight loss) was presented at the Obesity Society Annual Meeting in 2008. Five hundred and sixty-four subjects without diabetes (75 with prediabetes, defined as either impaired fasting glucose (IFG) or impaired glucose tolerance (IGT)) were randomized to subcutaneous injections of a placebo, 120 mg orlistat, a dose-titration of liraglutide (Novo Nordisk’s Victoza, submitted to FDA for approval), or 3.0 mg daily for 20 weeks. Drug administration was initiated after a two-week placebo run-in. Liraglutide was titrated by weekly increments of 0.6 mg to 1.2 mg, 1.8 mg, 2.4 mg, or 3.0 mg. All subjects were put on a diet with a 500 kcal/day reduction from the date of screening and were encouraged to increase their physical activity.
  • There were dose-dependent improvements in weight with liraglutide administration compared to placebo. See table below for breakdown of weight loss.
  • All four doses of liraglutide showed a higher incidence of conversion from prediabetes to normal status and a lower incidence of conversion from normal to prediabetes status compared to placebo or orlistat. See table below for breakdown of conversion rates and odds ratios for having normal glucose tolerance at the end of the study.
  • There were high rates of adverse events (AEs) in all groups, including the placebo and orlistat groups. The most common AEs for liraglutide were nausea and vomiting, most of which occurred in the first four weeks after randomization. There was a high rate of AEs in all groups, with reports of AEs in 85.3%, 87.8%, 90.3%, and 94.6% of subjects in the liraglutide 1.2 mg, 1.8 mg, 2.4 mg, and 3.0 mg groups, respectively. AEs were reported in 82.7% of patients in the placebo group and 85.3% orlistat group. A total of 11 (3%) of the subjects in the liraglutide groups withdrew due to AEs.
 

Liraglutide

Orlistat

Placebo

 

1.2 mg

1.8 mg

2.4 mg

3.0 mg

120 mg

 

Change from screening (week -2) to week 20

Change in weight from screening (Δkg)

-6.7

-4.8

-7.9

-9.1

-5.5

-4.1

Preiabetes to normal status

69%

96%

88%

96%

41%

46%

Normal to prediabetes

staus

6%

0%

2%

4%

19%

23%

Odds ratio to normal glucose tolerance at week 20 (versus placebo); OR, (95% Confidence Interval)

Versus placebo

3.0 (1.1-8.1)

26.1 (3.8-181)

10.7 (2.4-47)

12.5 (2.9-55)

 

Versus orlistat

3.0 (1.1-8.3)

26.3 (3.7-185)

10.8 (2.4-48)

12.6 (2.9-56)

 

(598-P) THE GASTROINTESTINAL ADVERSE EVENT PROFILE OF ALBIGLUTIDE, A LONG-ACTING GLP-1-RECEPTOR AGONIST, IN TYPE 2 DIABETES

Stewart M, Reusch J, Bush M, Yang F, Rosenstock J

The authors of this study hypothesized that since albiglutide is a Glucagon-Like Peptide-1 (GLP-1) agonist, which takes longer to reach maximal plasma concentration, it may have fewer of the gastrointestinal (GI) side effects stimulated by other GLP-1’s. In a 16-week treatment, 10-week follow- up, 10-arm study enrolling 356 patients, the occurrence, duration, and intensity of nausea and/or vomiting (N/V) were measured. Patients received either weekly albiglutide or placebo (4, 15, or 30 mg), biweekly albiglutide or placebo (15, 30, or 50 mg), monthly albiglutide or placebo (50 or 100 mg), or twice daily, self-administered exenatide as prescribed. Overall rates of N/V were found to be lower with all doses of albiglutide than with exenatide. Albiglutide 30 mg weekly had the best N/V profile. Rates of N/V decreased in all albiglutide groups over time and N/V was correlated with albiglutide exposure. N/V rates seemed to be correlated to frequency of albiglutide dosing and peak/trough plasma concentration ratios, with those patients with more infrequent treatment regimens having higher rates of N/V (when peak/trough ratios were highest). Efficacy of albiglutide doses was not correlated with GI side effects.

  • Glucagon Like Peptide-1 (GLP-1) therapies stimulate GLP-1 receptors in the periphery or CNS and can provoke gastrointestinal (GI) adverse events. Albiglutide is a GLP-1 receptor agonist whose differentiation from other members of the GLP-1 class is its extended duration of action. The authors hypothesized that the increased time to maximal concentration of albiglutide in the plasma may decrease the gastrointestinal side effects usually associated with GLP-1s.
  • The 16 week treatment, 10 week follow-up, 10 arm study enrolled 356 type 2 diabetic subjects. The incidence, duration, and intensity of nausea and/or vomiting (N/V) were monitored weekly. Treatment arms included: 4, 15, or 30 mg of albiglutide or placebo given weekly, 15, 30, or 50 mg of albiglutide or placebo given biweekly, 50 or 100 mg of albiglutide or placebo given monthly, or self-administered exenatide twice daily administered with prescribing information. The study also looked at efficacy, pharmacokinetics,immunogenicity, and other safety parameters. Baseline characteristics were similar across all treatment arms (mean age 50.4-55.5, 60.4% of subjects were white and 52.2% female, 71.6% of subjects were on metformin, mean A1C was 8.0%).
  • Overall rates of N/V were lower with albiglutide regimens as compared to exenatide. For the highest doses in each albiglutide schedule, rates of N/V were 29% for albiglutide 30 mg weekly, 54.3% for albiglutide 50 mg biweekly, and 55.9% for albiglutide 100 mg monthly. The incidence of N/V was 45.7% with exenatide and 11.8% with placebo. While 31.4% of exenatide patients reported N/V >7 days, only 0-15.6% of patients did in all albiglutide groups.
  • Albiglutide 30 mg weekly had the best N/V profile. Rates of N/V decreased in all albiglutide groups over time and N/V was correlated with albiglutide exposure. All patients in the 30 mg weekly albiglutide group and >90% of patients in the 50 mg biweekly or 100 mg monthly groups reported mild N/V episodes, while 63.6% of N/V events were mild and 36.4% were moderate with exenatide. Those patients receiving 30 mg weekly of albiglutide had the lowest N/V rates and in this group, no N/V was seen after 8 weeks of administration. Additionally, the incidence of N/V was lower with 30 mg weekly albiglutide than with exenatide. N/V rates were reduced in all albiglutide groups over the course of the study.
  • N/V rates correlated with peak/trough albiglutide plasma concentration ratios, explaining why those receiving more infrequent doses had higher rates of N/V. Peak N/V rates occurred directly following each dose administration. Higher peak/trough plasma concentrations of albiglutide were higher with less frequent albiglutide doses. The highest ratios were seen immediately after each administration and were associated with a greater incidence of N/V. Those receiving 100 mg monthly albiglutide had the highest peak/trough albiglutide plasma concentration ratio (20), coinciding with the highest rates of GI adverse events. Those receiving a 30 mg weekly dose had the lowest, steady peak/trough ratio (1.4), perhaps explaining the lowest rate of events. Along this line of reasoning, those receiving 50 mg biweekly albiglutide had a peak/trough ratio of 3 and thus had N/V rates intermediate to those of the weekly and monthly arms.
  • GI tolerability did not appear to be related to albiglutide dosing efficacy. A1c reductions were the same for all of the highest dose regimens (30 mg weekly, 50 mg biweekly, 100 mg monthly) but these groups had distinct differences in GI tolerability.

(461-P) ALBIGLUTIDE, A LONG-ACTING GLP-1 RECEPTOR AGONIST, IMPROVES GLYCEMIA IN TYPE 2 DIABETES: TIME-COURSE ANALYSIS

Reusch J, Rosenstock J, Bush M, Yang F, Stewart M

The authors studied the effectiveness and pharmacologic profile of albiglutide, an investigational long- acting GLP-1 by GSK. 361 Patients with type 2 diabetes were randomized to 16 weeks of either 4, 15, or 30 mg ALB once weekly, 15, 30, or 50 mg ALB biweekly, 50 or 100 mg ALB monthly, open-label exenatide, or placebo. There were significant improvements in A1c and FPG with albiglutide, and the results were the same for the weekly, biweekly, and monthly dosing regimens. After 16 weeks, there was a 0.9% A1c decrease with the highest dose of weekly ALB, 0.8% with biweekly dosing, and 0.9% in monthly dosing, compared to a decrease of 0.5% in the exenatide arm and 0.2% with placebo.

  • Reusch et al. studied the effectiveness and pharmacologic profile of albiglutide (ALB), an investigational long-acting GLP-1 agonist in development by GSK. 361 patients with type 2 diabetes were randomized to 4, 15, or 30 mg ALB once weekly, 15, 30, or 50mg ALB biweekly, 50 or 100 mg ALB monthly, open-label exenatide, or placebo. The trial ran for 16 weeks.
  • The trial showed a significant effect of albiglutide on A1c and FPG that did not seem to differ materially between weekly, biweekly, and monthly dosing. After 16 weeks, there was a 0.9% A1c decrease with the highest dose of weekly ALB, 0.8% with biweekly dosing, and 0.9% in monthly dosing, compared to a decrease of 0.5% in the exenatide arm and 0.2% with placebo. The concentration of albiglutide and FPG tended to vary more with more prolonged dosing, as the drug concentration reached higher spikes and lower troughs. Of the 361 subjects, 54 discontinued therapy due to adverse events (likely GI-related).
  • The idea of a GLP-1 with such an extended duration of action is exciting, and we look forward to seeing more data. While such a drug would offer benefits in terms of patient convenience, we could envision the possibility of difficulties arising due to thyroid cancer—we’ve heard speculation that cancer may become a higher risk when the GLP-1 receptor is stimulated over a longer period of time.

(501-P) EFFECTS OF EXENATIDE PLUS ROSIGLITAZONE ON BETA CELL FUNCTION AND INSULIN SENSITIVITY IN SUBJECTS WITH TYPE 2 DIABETES WITH METFORMIN

Defronzo R, Triplitt C, Qu Y, Lewis M, Gray A, Maggs D, Glass L

The relative effectiveness of treatment with either rosiglitazone, exenatide, or both exenatide and rosiglitazone was examined in this study. One hundred and thirty-seven patients were assigned for 20 weeks to one of the three groups in a randomized trial. A randomized subgroup of 50 patients underwent a hyperinsulinemic-euglycemic clamp at baseline and 20 weeks to assess insulin secretion and sensitivity in each of the three groups. While exenatide robustly preserved beta cells, it did not improve insulin sensitivity. Rosiglitazone, on the other hand, did not improve beta-cell function but did have a positive effect on insulin sensitivity. Patients receiving exenatide lost weight, while those on rosiglitazone gained weight. Combination therapy with both rosiglitazone and exenatide had the best results, increasing insulin sensitivity and secretion, lowering A1c, and causing weight loss.

  • 137 type 2 diabetic subjects were randomized into groups receiving exenatide, rosiglitazone, or a combination of exenatide and rosiglitazone for 20 weeks. Patient mean age at enrollment was 55.7 years, mean weight was 92.9 kg (204.4 lb), and A1c was 7.8%. Patients in the exenatide group received 10 µg twice daily, those in the rosiglitazone received 4 µg twice daily, and patients in the combination group received both 4 µg rosiglitazone and 10 µg exenatide twice daily. A subgroup of 50 patients was randomized to undergo a hyperinsulinemic-euglycemic clamp at baseline and 20 weeks to assess insulin secretion and sensitivity. All patients were assessed for A1c and weight changes.
  • Those patients receiving exenatide in their treatment lost weight and had improved insulin secretion. Insulin sensitivity was improved most in the rosiglitazone or rosiglitazone + exenatide groups. Subjects receiving rosiglitazone had significant weight gain (1.5 ±0.5 kg, 3.3 ±1.1 lb) while those on exenatide only or exenatide + rosiglitazone had net weight loss (-2.8 ±0.5 kg (6.2 ±1.1 lb) and -1.2 ±0.5 kg (-2.6 ±1.1 lb) respectively). Insulin secretion was markedly higher in the exenatide and exenatide + rosiglitazone groups after 20 weeks than in the rosiglitazone only group. Insulin sensitivity as measured by the hyperglycemic- euglycemic clamp was highest in the rosiglitazone or rosiglitazone + exenatide groups. Thus, while rosiglitazone improved insulin sensitivity, it had little effect on the beta cell. Exenatide hadminimal effect on insulin sensitivity but a strong effect on the beta-cell and insulin secretion. A1C decreased in all groups.
  • Combination therapy was the most effective, integrating positive aspects of both monotherapy treatments. Those patients on combination exenatide + rosiglitazone therapy had improved insulin sensitivity, improved insulin secretion, and weight loss (average -1.2 ±0.5 kg). They also had the greatest A1C decrease (-1.3 ±0.1). This combination targeted the major defects seen in type 2 diabetes and thus could be a very promising combination therapy, particularly if weight gain and other AEs associated with TZDs are mitigated by lower doses.

(558-P) PHARMACOKINETICS OF LIRAGLUTIDE VS EXENATIDE IN TYPE 2 DIABETES: SUSTAINED VS FLUCTUATING CONCENTRATIONS OVER 24 HOURS (LEAD-6)

Rosenstock J, Gumprecht J, Szyprowska E, Bednarczyk-Karuzny M, Zychma M, During N, Buse J

Dr. Rosenstock et al. examined the differences in pharmacokinetics between liraglutide in exenatide in a sub-study of the LEAD-6 trial. Subjects were dosed with one of the two drugs, and the plasma concentration of the drug in question was measured throughout a 24-hour period. The results showed a significantly flatter profile with liraglutide, confirming its suitability for use as a longer-acting GLP-1 agonist. The researchers suggested that fluctuating GLP-1 concentrations with exenatide might result in increased nausea, but to our knowledge this has not been confirmed.

  • This poster described a sub-study of the LEAD-6 trial investigating the differences in pharmacokinetics between liraglutide and twice-daily exenatide. 24-hour serial blood sampling was done on the day before the final visit for LEAD-6 participants. Liraglutide or exenatide was administered to each participant according to their LEAD-6 randomization, and immunosorbent assays were used to measure the concentrations of exenatide and liraglutide in subjects’ blood over the next day.
  • Not surprisingly, the study found significant differences between the two groups, with liraglutide exhibiting a much flatter profile than exenatide. The researchers concluded that the profile confirmed the suitability of liraglutide for once-daily dosing, and suggested that this stability might explain both the increased efficacy with liraglutide and the greater nausea with exenatide. Overall concentrations of liraglutide were higher because the assays measured both free and bound (inactive) liraglutide in the blood.

(506-P) EXENATIDE ONCE WEEKLY REDUCED A1C, WEIGHT, AND CARDIOVASCULAR RISK FACTORS ACROSS A WIDE BMI RANGE

Okerson T, Yan P, Miller S, Kim T

To examine the correlation between baseline BMI and changes in CV risk factors, data was taken from the subgroup of patients in the DURATION-1 trial treated with exenatide once weekly (EQW). 148 patients constituting EQW group in the DURATION-1 trial were classified according to BMI (overweight, nonobese between a BMI of 25 and <30 kg/m2, and 3 obese subgroups with BMIs of 30 to <35, 35 to <40 and >40 kg/m2 respectively). An ANCOVA test examined the relationship between baseline BMI and A1c, weight, systolic blood pressure, LDL levels, total cholesterol, and triglycerides. While all measures improved with EQW treatment, none of the improvements varied by BMI subgroup. This suggests that EQW is efficacious across all BMI ranges and not just in obese subgroups.

  • Data was taken from those 148 patients receiving exenatide once weekly in the DURATION-1 trial. DURATION-1 was a 30 week randomized phase 3 clinical trial which showed that patients receiving exenatide once weekly (EQW) as opposed to twice daily had a greater improvement in glycemic control. Data was taken from the intent to treat group receiving EQW. At baseline, this group had an A1C of 7.1-11%, a fasting plasma glucose of <280 mg/dL, and a BMI of 25 to 45 kg/mL2. The group was stratified according to weight: overweight, non obese was classified as having a BMI of between 25 and 30 kg/m2, and three subgroups of obese were classified as: BMI between 30 and <35, 35 and <40, and BMI >40 kg/m2 respectively.
  • Changes from baseline in A1c, weight, blood pressure, total cholesterol, and triglycerides were measured for each subgroup. The study aimed to see if baseline BMI correlated with changes in any of these measures after EQW treatment.
  • Neither A1C, weight, systolic blood pressure, LDL, triglyceride or cholesterol levels changed by BMI subgroups. At week 30, weight and A1c were reduced in all subgroups. However, neither A1C nor weight reduction correlated with patients’ BMI. While systolic blood pressure was reduced over a wide range of BMIs (reduction was significant in the obese groups), reductions did not vary by BMI subgroup. Similarly, LDL, triglyceride, and total cholesterol changes did not correlate with baseline BMI. Total cholesterol and LDL were significantly reduced in the BMI 30 to <35 kg/m2 subgroup and triglycerides were significantly reduced in the BMI 25 to <30, 30 to <35, and 35 to <40 kg/m2 subgroups.

(591-P) SWITCHING FROM TWICE-DAILY EXENATIDE TO ONCE-DAILY LIRAGLUTIDE IMPROVES GLYCEMIC CONTROL IN TYPE 2 DIABETES ON ORAL AGENTS (LEAD-6)

Buse J, Sesti G, Schmidt W, Montanya E, Chang CT, Xu Y, Blonde L, Rosenstock J

Following the conclusion of the primary LEAD-6 liraglutide vs. Byetta trial, this extension study showed the effects of switching from exenatide to liraglutide for 14 weeks. After the conclusion of the extension period, patients who had switched to liraglutide treatment achieved an additional A1c decrease of 0.3% (from a baseline of 7.2%). Fasting plasma glucose also improved in the switching group, and body weight decreased by 0.9 kg (2 lbs) in the switching group compared to a 0.4 kg (0.9 lb) decrease in those subjects who continued on liraglutide. Liraglutide was well tolerated in both groups. This study helps to establish the benefits of liraglutide as an important agent for improving diabetes outcomes; we would be very interested to see similar data compared to exenatide once-weekly.

  • All 389 subjects who completed LEAD-6 entered the 14-week non-randomized extension study. Patients on 10 micrograms Byetta switched to 1.8 mg liraglutide over a period of two weeks. Those patients previously treated with liraglutide at 1.8 mg daily remained on that dose.
  • Significant changes in A1c, fasting plasma glucose (FPG), body weight, and systolic blood pressure (SBP) were seen in patients who were switched to liraglutide. Those switching from Byetta to liraglutide experienced an A1c decrease of 0.3% (p<0.0001; from a baseline of 7.2%), while those continuing on liraglutide saw a non-significant decrease of 0.1% (from a baseline of 7.0%). Patients switching to liraglutide achieved a mean A1c of less than 7%, the first time during the study that the ADA A1c target was achieved on average in this group (the percentage meeting the target increased from 43% to 57%). FPG improved by 16.2 mg/dL in patients who were switched to liraglutide (p<0.0001), but there was no significant change in the continued liraglutide group. Bodyweight decreased by 0.9 kg (2.0 lbs; p<0.0001) in the switchinggroup and by 0.4 kg (0.9 lbs; p<0.01) in the continuation group. Baseline weigh tat the start of the extension study was 91 kg (200 lbs). Finally, systolic blood pressure decreased by 3.8 mmHg in the switchers (p<0.0001) and by 2.2 mmHg in the continuation group (p<0.05).
  • Liraglutide was well tolerated in both groups. The rate of minor hypoglycemia was reduced from 2.6 to 1.3 events/subject/year in patients switching to liraglutide. Nausea was reported by 3.2% of patients, and 0.5% of patients withdrew from the extension study due to nausea. No pancreatitis was reported during the extension phase, and no clinically significant changes in calcitonin occurred in either group. Mean calcitonin levels were at the low end of the normal range.

(537-P) LIRAGLUTIDE MORE EFFECTIVELY ACHIEVES A COMPOSITE ENDPOINT FOR A1C, SYTOLIC BLOOD PRESSURE AND WEIGHT CHANGE THAN OTHER DIABETES THERAPIES (LEAD)

Zinman B, Buse J, Falahati A, Moses A, Gough S

In this meta-analysis of the 6 LEAD studies, it was shown that liraglutide allowed more patients to achieve glycemic control (A1C <7.0%) and the ADA-defined composite outcome (A1C<7.0%, systolic blood pressure <130 mmHg, and no weight gain) than did active comparators. The LEAD studies examined liraglutide’s effectiveness as compared to combinations of rosiglitazone, exenatide, glimepride, metformin, sulfonylureas, and placeo, and individually showed liraglutide’s ability to reduce or sustain A1C and systolic blood pressure and increase weight loss better than these comparators. This meta-analysis found that a significantly higher proportion of patients taking either 1.8 or 1.2 mg of liraglutide once daily achieved an A1C of <7.0% and the ADA-defined composite outcome than those taking active comparators. The study also found that a dose of 1.8 mg provides A1C reductions for more patients than a 1.2 mg dose, though no difference is seen between the two dosings for achievement of a composite outcome.

  • The study, a meta-analysis of the 6 LEAD studies, assessed liraglutide’s effectiveness as compared to that of a wide range of comparators in type-2 diabetic patients. Liraglutide is a glucagon-like peptide 1 (GLP-1) receptor agonist. In the individual LEAD trials, it proved better than or equally capable of reducing A1C against comparators. It also demonstrated reductions in systolic blood pressure and facilitated weight loss. LEAD-1 examined liraglutide vs. glimepride each as monotherapy; LEAD-2 examined liraglutide vs. glimepride (each plus metformin); LEAD-3 examined liraglutide vs. rosiglitazone (each plus glimepride); LEAD-4 examined liraglutide vs. placebo (each plus metformin and rosiglitazone); LEAD-5 examined liraglutide vs. insulin glargine (each plus metformin and glimepride); LEAD-6 examined liraglutide vs. exenatide (each plus metformin and sulfonylurea). Together, the trials enrolled more than 4000 type 2 diabetes subjects in 39 countries.
  • The meta-analysis’ primary measurement outcomes were the percentage of patients achieving an A1C <7%, the percentage of patients achieving the ADA-recommended composite endpoint, and determination of optimal liraglutide dosings. The ADA Standards of Care have recommended achievement of an A1C <7.0%, a systolic blood pressure<130 mmHg and no weight gain with type-2 diabetes treatment.
  • The study found that the ADA-specified composite outcome and an A1C <7.0% were achieved by significantly more patients taking liraglutide than those receiving active comparators. Odds ratios for achievement of composite target and A1C goals were ten and fivetimes higher, respectively, for liraglutide than for comparators. 26% of patients treated with liraglutide 1.8 mg achieved the ADA composite endpoint versus 3% with rosiglitazone, 8% with glimepride, 6% with glargine, 16% with exenatide, and 6% with placebo. A 1.8 mg dose of liraglutide facilitated more patients’ reaching target A1C as compared to the 1.2 mg dose. No significant difference was seen in the proportion of patients reaching the composite endpoints on the two doses and the 1.2 mg dose reduced A1C more effectively than all comparators.

(522-P) INITIAL COMBINATION THERAPY WITH SITAGLIPTIN AND PIOGLITAZONE IMPROVES GLYCEMIC CONTROL AND MEASURES OF Β-CELL FUNCTION COMPARED WITH PIOGLITAZONE ALONE IN PATIENTS WITH TYPE 2 DIABETES

Yoon K, Shockey G, Teng R, Golm, G Thakkar P, Meehan A, Williams-Herman D, Kaufman K, Amatruda J, Steinberg H

This ADA brought a marked increase in studies evaluating combination therapy for type 2 diabetes. This study investigated the efficacy of combination therapy with sitagliptin and pioglitazone (PIO) versus pioglitazone alone. After 24 weeks, patients in the combination group saw an A1c decrease of a striking 2.4%, while those in the PIO-only group had a 1.5% decrease. FPG, insulinogenic index, and c- peptide AUC were all better with combination treatment relative to pioglitazone alone. Body weight increased by 1.1 kg (2.4 pounds) in the combination group relative to the monotherapy group. The rate of drug-related AEs were slightly higher in the combination group, as were serious AEs, but the rate of withdrawal due to adverse events was similar between the groups. The rate of hypoglycemia was also slightly higher in the combination group.

  • This 24-week study compared the effects of initial combination therapy with sitagliptin (Merck’s Januvia) and pioglitazone (Takeda’s Actos) versus pioglitazone alone. Subjects were randomized to 30 mg pioglitazone and 100 mg sitagliptin or placebo. The pre-specified endpoints were A1c, FPG, fasting insulin and lipids, beta-cell function, and 2-hour post-meal glucose, insulin, proinsulin, and c-peptide.
  • There were significant improvements in A1c, FPG, c-peptide, and other endpoints with combination treatment, and a small increase in weight. Patients in the sitagliptin+pioglitazone group saw an A1c decrease of 2.4%, while those in the pioglitazone-only group had a decrease of 1.5% (p<0.001; from baselines of 9.5%). Fasting plasma glucose decreased 63 mg/dL in the sita+pio group compared to -40.2 mg/dL in the PIO-only group (p<0.001; from baselines of 204.3 mg/dL and 202.1 mg/dL). The insulinogenic index, pro- insulin/insulin ratio, and c-peptide AUC were all significantly improved with combination treatment relative to pioglitazone alone. Body weight increased by 1.1 kg (2.4 pounds) in the combination group relative to pioglitazone.
  • The rate of adverse events considered to be drug-related was 7.3% in the combination group and 6.2% in the pioglitazone only group. Serious AEs were 3.1% in the combination group and 1.9% in the pio group, but withdrawals due to serious AEs were 0.8% in both groups. Hypoglycemia was 1.1% in the combination group and 0.8% in the pio group.

Amylin-Lilly Alliance Sponsored Symposium: The Clinical Relevance of Today’s Incretin Therapies in the Context of the Current Algorithm

BASIC BIOLOGY OF THE GLP-1 SYSTEM AND HOW IT INFORMS CLINICAL USE

Patricia L. Brubaker, PhD (University of Toronto, Toronto, Ontario)

Dr. Patricia Brubaker discussed a number of clinically important but somewhat obscure consequences of GLP-1 therapy. In particular, she focused on the recent discovery of a metabolite of GLP-1 called 9-36 that may be cardioprotective. If this is finding is confirmed, this would suggest an additional advantage of GLP-1s over DPP-4 inhibitors because only GLP-1s would be expected to increase the concentration of 9-36. Dr. Brubaker also reviewed the most recent FDA information regarding GLP-1s and pancreatitis and medullary thyroid carcinomas.

  • When GLP-1 is cleaved by DPP-4, an active metabolite called 9-36 is produced that may have cardioprotective effects. Previous studies have shown that 9-36 itself protects the heart against cardiovascular insult, and it may bind to a separate receptor from the primary GLP- 1 receptor. This second receptor specific for 9-26 has not yet been identified. Only GLP-1s and not DPP-4 inhibitors would be expected to increase 9-26 levels, since the latter therapy does not increase total GLP-1 levels and may even decrease the GLP-1 metabolite levels in the body.
  • Gene studies have identified that the TCF7L2 polymorphism is a predisposing risk factor for type 2 diabetes. The gene is within an intron, and therefore it is unclear how exactly the gene predisposes to type 2 diabetes. Some recent studies have suggested that the TCF7L2 polymorphism may impair the beta cell’s response to GLP-1. If this association is validated, it provides an explanation for why some people do not respond to GLP-1 therapy. Although Dr. Brubaker’s only briefly discussed TCF7L2, we think that this highlights in general the need for more individualized therapies in diabetes. Ideally, patients considering taking an incretin would be given the opportunity to find out if they were positive for TCF7L2, and therefore not ideal candidates for incretin therapy. Unfortunately, unlike many diseases such as cancer, diabetes continues to be treated largely in a one-size-fits-all fashion because the cost of such genetic screenings remains prohibitive.
  • Does Byetta cause pancreatitis? Dr. Brubaker said that the jury is not yet out, but either way the side effect is extremely rare. There is now a warning label on Byetta about pancreatitis. Exendin-4 was originally discovered based on its ability to bind to guinea pigs pancreatic cells, but this may be unique to this animal species. In Byetta’s favor, the absolute risk for pancreatitis is the same for Byetta and metformin.
  • Dr. Brubaker also touched on concerns about liraglutide and medullary thyroid carcinomas. In the rat, normal thyroid gland responds to liraglutide, but the effect is less consistent in people. In a pooled analysis of all liraglutide human trials, there is approximately a 10% rise in calcitonin with people treated with liraglutide. Exenatide has not shown any such signal, which Dr. Brubaker attributed perhaps to a difference in half life between the two drugs (if half life is the difference here, we note that exenatide once-weekly would likely share any thyroid cancer risk that is identified with liraglutide). Liraglutide has also been associated with papillary thyroid cancer in humans, but very little data is present here. In the Byetta trials, there were no reported thyroid cancers. Since Byetta was approved, there have been nine reports of thyroid cancers out of almost seven million users – a very low number that is probably the same as the population baseline.
  • Byetta enhances beta cell mass in rodents, and has also been shown to decrease apoptosis of human islets in vitro. Over the very long-term, GLP-1s may therefore be able to slow the progression of type 2 diabetes, but longer-term data is needed. Dr. Brubaker concluded by proposing the development of a drug that increases GLP-1 secretion from L cells, perhaps incombination with a DPP-4 inhibitor. GPR119 agonists are one drug class in development that may stimulate GLP-1 secretion.

GLP-1 BASED THERAPIES IN PHASE 3 TRIALS AND BEYOND

John B. Buse, MD, PhD (University of North Carolina, Chapel Hill, NC)

Dr. Buse presented on the DURATION-1, DURATION-2, and LEAD-6 trials. Overall, he expressed tremendous enthusiasm for long acting GLP-1s (specifically exenatide once-weekly and liraglutide), and he predicted that these two agents will essentially replace Byetta in clinical use. He also discussed competitive compounds, including taspoglutide (Roche), another GLP-1 in development that is based on the human GLP-1. Dr. Buse briefly reviewed phase 2 data for taspoglutide, demonstrating that it produces impressive weight loss and A1c reduction. Albiglutide (GlaxoSmithKline) is another GLP-1 in late-stage clinical trials. This is a much larger molecule that is bound to albumin. Dr. Buse predicted that this drug could produce as much as a 1.5% or 2.0% A1c reduction over a year but didn’t talk at length about other important factors such as weight loss, impact on blood pressure and cholesterol, and nausea.

  • Dr. Buse began by reviewing the findings of the DURATION-1 trial, a 30 week study comparing exenatide once-weekly with exenatide twice-daily (Byetta). Exenatideonce-weekly takes up to 10 weeks to achieve steady state levels, providing a slow ramp up of GLP- 1 levels and by extension, lower levels of nausea as compared to Byetta. The mean steady-state concentration of exenatide once-weekly is 71.7 pmol/L, which exceeds the maximum blood concentration achieved with Byetta. At the end of the 30 week trial, exenatide once-weekly produced a 1.9% reduction in A1c vs. 1.5% for Byetta. Exenatide once-weekly also provided greater reductions in fasting glucose, glucagon, and LDL cholesterol. Even though exenatide levels were very high, there were less dramatic effects on gastric emptying and post-prandial glucose than with Byetta. With regard to weight loss, both therapies provided weight loss of about 2.3 kg (5.1 pounds). In a 22-week extension of the original study in which all patients were switched to exenatide once-weekly, both arms of the study achieved a reduction in A1c from study baseline of 2.0%.
  • DURATION-2 trial results were also discussed, comparing exenatide once-weekly with Actos and Januvia. In this study, exenatide once-weekly posted a 1.55% A1c drop compared to 1.23% for Actos and 0.92% for Januvia at 26 weeks from a baseline of ~8.5%. The proportion of patients achieving an A1c of less than or equal to 7% was 66% for exenatide once- weekly, vs. 56% for Actos and 42% for Januvia. Furthermore, exenatide once-weekly was associated with 2.7% weight loss, as compared to 0.9% weight loss for Januvia and 3.2% weight gain for Actos. Importantly, 70% of patients randomized to exenatide once-weekly lost weight and experienced a reduction in A1c.
  • LEAD-6 showed that liraglutide produced greater effects on fasting plasma glucose, triglycerides, and beta cell function than Byetta. Liraglutide has only a single amino acid substitution from human GLP-1. It has a long half-life of approximately 15 hours and bound to albumin. LEAD-6 was a 26-week study comparing liraglutide (1.8 mg) vs. Byetta (10 mg) in 464 patients treated with a background of metformin, sulfonylurea, or both. In the study, liraglutide produced a 1.12% A1c reduction vs. a 0.79% A1c reduction for the Byetta group from a baseline of slightly over 8%. Weight change was essentially identical for the two agents (slight advantage for liraglutide that did not reach statistical significance). Liraglutide produced greater effects on fasting plasma glucose, triglycerides, and beta cell function (HOMA-B). Although initial rates ofnausea were similar between the two drugs, the nausea was more transient in the liraglutide study arm.
  • Taspoglutide (Roche) is another GLP-1 in development that is based on the human GLP-1. Dr. Buse briefly reviewed phase 2 data for taspoglutide, demonstrating that it produces impressive weight loss and A1c reduction. Albiglutide (GSK) is another GLP-1 in late-stage clinical trials. This is a much larger molecule that is bound to albumin. Dr. Buse predicted that this drug could produce as much as a 1.5% or 2.0% A1c reduction over a year.

PATHOGENESIS OF TYPE 2 DIABETES: IMPLICATIONS FOR THERAPY

Ralph A. DeFronzo, MD (Texas Diabetes Association, San Antonio, TX)

A talk on the pathogenesis of type 2 diabetes and implications for therapy provided an overview of the many pathogenic abnormalities that are present in type 2 diabetes. Given the wide range of abnormalities that present early in the course of type 2 diabetes, Dr. DeFronzo argued that patients should be treated more aggressively with combination therapy. His own treatment algorithm includes Byetta, metformin, and Actos triple therapy right from the start. Dr. DeFronzo warned against using sulfonylureas because they do not prevent beta cell burnout and they do not address underlying pathogenic abnormalities of diabetes. Many characterized this talk as basically a repeat of the renowned 2008 Banting Lecture; it was probably given again because not everyone heard it then.

  • Beta cell failure occurs much earlier in the development of type 2 diabetes than was previous recognized. The recent San Antonio Metabolism and Vages Studies demonstrated that increased insulin secretion is a common finding in pre--diabetes because the body attempts to compensate for increased insulin resistance. However, insulin secretion is a poor marker of beta cell function, and true beta cell function is declining. By the time that a person has IGT, beta cell function may be 80-85% reduced.
  • Dr. DeFronzo suggested that IGT should be recognized as an early form of diabetes and should become a point of intervention. Supporting this thesis, he showed that 7.9% of people with IGT have retinopathy and 5-10% of people with IGT have neuropathy as a consequence of metabolic disturbance. Unfortunately, the FDA does not accept any protocol from the pharmaceutical industry about treating prediabetes. Dr. DeFronzo suggested that there is now a movement to consider drug therapy for IGT, and that the FDA will follow by changing its rules.
  • Dr. DeFronzo described an “ominous octet” of pathogenic abnormalities present in type 2 diabetes. This “ominous octet” was the centerpiece of Dr. DeFronzo’s Banting lecture at ADA 2008. The abnormalities he mentioned include:
    • Decreased insulin secretion (pancreas)
    • Increased hepatic glucose production (liver)
    • Increased lipolysis (fat cell)
    • Increased glucose reabsorption (kidney)
    • Decreased incretin effect (gut)
    • Decreased glucose uptake (muscles)
    • Increased glucagon secretion (beta cell)
    • Neurotransmitter dysfunction (brain)
  • Dr. DeFronzo criticized the ADA algorithm for “setting patients up to fail” with drugs that don’t preserve beta cell function such as insulin and sulfonylureas. Heproposed that combination therapy is needed early in the course of diabetes to correct the many abnormalities discussed above, and not just to reduce A1c. Specifically, he proposed starting patients with initial triple therapy of metformin, a TZD, and Byetta and targeting a “normal” A1c of 6.0%. Byetta has the unique advantages of weight loss, and augmentation of insulin secretion. A one-year study that randomized patients to Byetta or Lantus insulin showed that there was a marked (three fold) improvement in c-peptide levels for people treated with Byetta.

Roche Sponsored Symposium: The Enduring Challenge of Weight and T2DM: Assessing Current Tools and New Advances with Incretins and Beyond

INTRO: THE SCIENCE OF OBESITY ACROSS TIME AND AGES

John Buse, MD, PhD (University of North Carolina School of Medicine, Chapel Hill, NC)

Dr. Buse jokingly lamented that a whopping 31% of the audience was “industry/other” there for competitive information, while 45% was “MD/DO” and 5% were “RN” in an audience survey. MDs were mostly endocrinologists, half US-based and half foreign. The huge room was packed, and ultimately accommodated a line that seemed to snake far into the halls of the Marriott before doors opened. Dr. Buse started with a brief history lesson suggesting that obesity’s been known to be unhealthy and difficult to treat for millennia – Dante even reserved the third ring of Hell for the “gluttonous.” Dr. Buse’s main message to kick off the session was that obesity is largely a genetic, physiologic dysfunction that is treatable with lifestyle, drugs, and surgery.

  • Obesity is for the most part a genetic disease. A twin study showed that 65% of variance in BMI (i.e., from thin to obese) was related to genetics, while 25% was related to some common environmental component, and 10% was related to some mysterious unshared environmental component (Segel et al., Int J Obes 2009).
  • From the 1970s to 2000, there has been a sinister increase in average caloric intake. Men take in 168 more calories per day than three decades ago, and women take in 335 more calories. This may correlate with an increase in the availability of processed foods, which have higher caloric density (i.e., calories per pound – think corn tortilla chips vs. corn tortillas vs. corn).
  • The audience was equivocal as to whether “the lack of self-control and/or motivation is a greater component of obesity etiology than physiologic dysfunction.” Twenty-seven percent of attendees agreed with some reservations, 25% agreed with major reservations, and 26% disagreed with reservations. We think the question was somewhat vague – Dr. Buse himself said that while obesity should not be attributed to a general lack of self-control, physiologic dysfunction probably causes a lack of self-control when it comes to eating.

MODERN APPROACHES TO WEIGHT MANAGEMENT

Louis Aronne, MD, FACP (Weill Cornell Medical College, New York, NY)

The central thrust of Dr. Aronne’s presentation was that we are moving toward a weight-centric, rather than glucose-centric, approach in the treatment of obesity and type 2 diabetes. An audience survey at the beginning of the talk showed 17% disagreed with that concept (“those who disagree haven’t seen the ACCORD trial”), while at the end of the talk only 4% disagreed. Along that vein, Dr. Aronne emphasized that significant weight gain is a reason to alter a patient’s therapy even if A1c is at goal. To manage obesity, combinations of pramlintide, leptin, sibutramine, and bariatric surgery seem to be the most promising treatments.

  • The onset of type 2 diabetes tends to be preceded by weight gain, which Dr. Aronne contends is causal. This would explain why a small magnitude of weight loss in the DPP made such a big difference – it prevented the ascent to critical fat mass and aborted the process toward diabetes onset. An increase in adipose tissue causes an increase in pro-atherogenic and pro- diabetic factors, like IL-6 and TNF-alpha, as well as a decrease in the anti-atherogenic and anti- diabetic factor adiponectin.
  • People often don’t recognize themselves as overweight, as it has become the norm. Two thirds of Americans are overweight or obese, and surveys suggest that people are less likely to consider themselves overweight than they were years ago, even within the same BMI class.
  • Eating a high glycemic index meal for breakfast can increase that day’s food intake by up to 80% in obese individuals. Dr. Aronne said this impressive finding in 1999 changed the way he discusses diet with his patients. Sometimes switching from a carbohydrate breakfast to a protein breakfast is enough of a change for significant weight loss.
  • We are in the midst of a shift from glucocentric to weight-centric management of type 2 diabetes. The ACCORD trial, which was stopped early due to unexpected higher mortality in the group with tighter glucose control, likely due to weight gain from intensive insulin therapy, supports this shift. Once glucose is in control, a move toward treatments that cause weight loss should be considered. In Q&A, Dr. Aronne further clarified what a weight- centric treatment algorithm would look like: in any category of drug, make it part of the clinical decision to consider the weight effects of the drug, trying to use drugs that produce weight loss.
  • Calorie overload causes leptin resistance, which means your hypothalamus will not know that you have plenty of fat stores. Leptin levels normally tell the hypothalamus how much fat is stored in the body, but its function is impaired by calorie overload. Leptin replacement would produce satiety but has not yet worked because of rapid induction of leptin resistance with administration. Pramlintide seems to be a leptin sensitizer.
  • Pramlintide causes weight loss independent from reduction in insulin use. Pramlintide results are getting “better and better” – pramlintide with sibutramine or phentermine produces a 12% weight loss over 24 weeks. Pramlintide also appears to be a leptin sensitizer. In combination with leptin, there is an additive 13% weight loss over 20 weeks (data on file, Amylin).
  • ​​Surpisingly, we heard that sibutramine (Abbott’s Meridia) use may explode in the next few years. That is, if the large outcomes trial coming out in November is successful. We hadn’t realized that there was a large outcomes trial coming and need to do more investigation!
  • “It may be our cancer colleagues who come in and say we need to do bariatric surgery.” In 15 -year follow-up, bariatric surgery produced huge risk reductions in mortality – total and associated with various diseases. Not only does it reduce the risk of dying from diabetes by 88%, it reduces the risk of cancer death by 59%! Oncologists may start adding weight control to their protocols.
  • An attendee suggested it seems easier to train PCPs on medically managing obesity rather than recommending bariatric surgery for tens of millions of Americans. Dr. Aronne said this is a common sentiment, but that if a patient doesn’t succeed on medication, surgery must be considered. It is cost-effective, taking three or four years to get money investedback. “It sounds like an incredible burden but it is an unbelievably effective, life-changing option, when done by the right people.”
  • When a patient who has had gastric banding begins to eat “soft, meltable calories,” it is a sign they are starting to gain the weight back. Low leptin levels cause decreased energy expenditure during exercise as well as decreased sense of fullness. Weight loss tends to plateau for this reason. After a time, patients who have had gastric bypass surgery tend to start snacking on crackers or ice cream, foods Dr. Aronne called “soft, meltable calories,” which suggests the leptin effect has kicked in.

WHERE DO INCRETINS FIT IN THE DIABETES/OBESITY STORY?

David Kendall, MD (University of Minnesota, Minneapolis, MN)

Before Dr. Kendall began, 97% of the audience already agreed with the statement: “GLP-1 agonists provide clinically significant benefits beyond glucose control.” The most significant of these benefits was said to be weight loss by 70% of attendees, beta cell preservation by 28%, lipid-lowering by 1%, and blood pressure reduction by 1%. Furthermore, 88% of attendees agreed that “long-acting GLP-1 agonists offer clinically meaningful advantages over short-acting formulations.” In his talk, Dr. Kendall praised exenatide, the GLP-1 analog with the most data, and suggested exenatide once weekly (EOW) was an improvement. Incretins should replace insulin for some patients. He was lackluster on DPP-4 inhibitors, which at best restore normal endogenous levels of GLP-1.

  • Dr. Kendall did not seem to have much enthusiasm for DPP-4 inhibitors as compared to GLP-1 agonists. Though the talk was on incretins, he said he’d talk only briefly about DPP-4 inhibitors, which at best restore physiologic levels but cannot provide pharmacological concentrations.
  • There is evidence that longer acting agents may have a greater effect on plasma glucose than once or twice daily injections. Dr. Kendall mentioned that in a head-to-head with exenatide twice-daily, EOW had significantly greater A1c reduction. However, twice-daily exenatide is better at damping postprandial excursions. In terms of liraglutide against exenatide, liraglutide had “modestly” greater A1c reduction, but “the data set is relatively small at present.”
  • Taspoglutide showed a >1% A1c drop in 8 weeks, with a three kilogram (6.6 pounds) weight loss, at the highest 20 mg once-weekly dose. A1c drop and weight loss were dose dependent (Nauck et al., Diabetes Care 2009 – in press).
  • In his treatment plan for type 2 diabetes, Dr. Kendall suggested that where insulin was appropriate to initiate, incretins might be used instead. There is evidence that “incretins may be as and in some cases more effective than starter insulin treatments.”When asked what percent of patients get weight loss with GLP-1 analogs, Dr. Kendall said at least 80%. He said this was from data with exenatide and there may be evidence that EOW is even greater. Non-responders “are most easily identified by their non- response,” so just try it.
  • In Q&A, Dr. Kendall called the association of incretins and pancreatitis “paper thin at best.” He cited the meta-analysis showing that the risk was equal in exenatide vs. other compounds, and that case reports, though they can’t be ignored, “do not have a denominator.”

Novo Nordisk Sponsored Symposium: Learn it Today, Use it Tomorrow: Practical Strategies for the Clinical Use of Incretin Mimetics

INCRETIN HORMONES AND TYPE 2 DIABETES LEVERAGING THE EFFECTS OF NATIVE GLP-1

Michael Nauck, MD, PhD (Diabeteszentrum Bad Lauterberg, Germany)

Dr. Nauck presented an overview of the incretin effect and how it can be leveraged in the treatment of type 2 diabetes. Both GLP-1 and GIP are incretin hormones. GLP-1 plays an important role in glycemic control as it stimulates glucose-dependent insulin secretion, delays gastric emptying, inhibits glucose- dependent glucagon secretion, promotes satiety and reduces body weight. Thus, GLP-1 is a target for treatment of type 2 diabetes. There are two drug classes that are being used to leverage GLP-1 to treat type 2 diabetes: incretin mimetics and DPP-4 inhibitors.

  • Dr. Nauck presented an overview of the incretin effect and how it can be leveraged in the treatment of type 2 diabetes. The incretin effect is a greater insulin response to oral glucose vs. intravenous glucose. This effect is mediated by incretin hormones and is impaired in patients with type 2 diabetes. Both GLP-1 and GIP are incretin hormones. GLP-1 plays an important role in glycemic control as it stimulates glucose-dependent insulin secretion, delays gastric emptying, inhibits glucose-dependent glucagon secretion, promotes satiety and reduces body weight. This compares to GIP which stimulates glucose-dependent insulin secretion, has little effect on gastric emptying, exerts little effect on glucose-dependent glucagon secretion, and has no significant effect on both satiety and body weight
  • GLP-1 is a target for treatment of type 2 diabetes. Levels of GLP-1 are often decreased in patients with type 2 diabetes; however, GLP-1 responsiveness appears to be maintained in patients with type 2 diabetes. GLP-1 plays an important role in glycemic control. Thus using a pharmacological dose of GLP-1 leads to the stimulation of glucose-dependent insulin secretion from beta cells, the inhibition of gastric emptying, the reduction of food intake and body weight, and the inhibition of glucose-dependent glucagon secretion from alpha-cells. Currently other effects of GLP-1 are being investigated including: cardiac effects, direct hepatic effects, effects on insulin sensitivity, and effects on the promotion of beta cell mass and the prevention of apoptosis.
  • There are two drug classes that are being used to leverage GLP-1 to treat type 2 diabetes: incretin mimetics and DPP-4 inhibitors. Incretin mimetics are injectable, result in weight loss, cause nausea, are durable (efficacy maintained over extended periods of time), have a sustained effect, have a low risk of hypoglycemia, and enhance GLP-1 activity. This compares to DPP-4 inhibitors, which are taken orally once daily, are durable, have a low risk of hypoglycemia, have effectiveness limited by endogenous secretion, enhances GIP activity, enhances GLP-1 activity, and have fluctuations in the physiological range. Current incretin mimetics include the exendin-4 based drugs (exenatide, exenatide LAR, and AVE 0010) and the human GLP-1 based drugs (liraglutide, albiglutide, and taspoglutide). Current DPP-4 inhibitors include sitagliptin (Januvia by Merck), saxagliptin (Onglyza by Bristol-Myers Squibb), vildagliptin (Galvus by Novartis), and alogliptin (Takeda).

FOCUSING IN ON INCRETIN MIMETICS: CLINICAL DATA

Alan J. Garber, MD (Baylor College of Medicine, Houston, TX)

Dr. Garber gave an overview of the safety, efficacy, and tolerability of exenatide (Byetta by Amylin/Lilly), liraglutide (Victoza by Novo Nordisk) and exenatide once weekly (EOW). He differentiated between the therapies based on their half-lives, likelihood to cause nausea, and formation and effect of antibodies. He mentioned the faster tapering of nausea with the longer acting GLP-1 formulations and the finding that a small number of exenatide/EOW patients have antibody formation that leads to decreased drug efficacy.

  • A pivotal difference between exenatide BID and liraglutide is their half-lives. Liraglutide has a 12-14 hour half-life compared to two to four hours for exenatide BID. Exenatide once weekly (EOW) has a half-life greater than 1 week. In a pictorial description, Dr. Garber suggested the EOW and liraglutide had similar decreases in fasting blood glucose (both greater than exenatide BID), but suggested that postprandial glucose decreases were greater with EOW. He cited the A1c drops with the three agents as 0.9% (BID), 1.1% (liraglutide), and 1.7% (EOW).
  • Dr. Garber highlighted the LEAD 3 data presentations at this year’s ADA meeting. The new data point from LEAD 3 is that shorter disease duration (<3 years) results in a better A1c drop with liraglutide compared to that for longer duration (1.4% vs. 1%). This effect was also seen with the glimepiride (Amaryl by Sanofi-Aventis) comparator arm and is likely because disease progression is accompanied by decreasing beta cell function.
  • Switching to weight loss, he made the point that GLP-1 mediated weight loss was attenuated when combined with therapies known to cause weight gain.
  • Turning to side effects, he noted that there seems to be an irreducible population of patients with type 2 that reports hypoglycemia on GLP-1 therapy. He also mentioned that longer acting formulations (liraglutide, EOW) have a faster tapering of nausea rates than exenatide BID.
  • There is a small population for whom antibody formation with exenatide/EOW therapy appears to result in decreased efficacy of the drug. About 40-50% of exenatide treated patients and 67% of EOW treated patients develop antibodies. This decrease in efficacy is not seen in liraglutide patients – there is a much smaller (10%) proportion of liraglutide patients that form antibodies to the peptide.
  • Nausea and GI side effects with GLP-1 therapy may lead to a misdiagnosis of clinically relevant pancreatitis. That said, the rate of pancreatitis in the diabetes population is higher than in the non-diabetes population. However, if pancreatitis is suspected, GLP-1 agonist therapy should be stopped.
  • Dr. Garber reviewed a number of head to head trials of GLP-1 agonists and trials with other drugs. To summarize, long acting GLP-1 agonists seem to be better than shorter acting ones, and switching from exenatide BID to EOW seems to result in further improvements in glycemic control. GLP-1 agonists have similar A1c lowering effects to basal insulin but without weight gain.

USING INCRETIN MIMETICS: A CASE-BASED FACULTY ROUNDTABLE

Robert R. Henry, MD (University of California at San Diego, La Jolla, CA)

Dr. Robert Henry presented two case studies and asked the audience how they would approach treatment for each. He asked the audience how they would intensify therapy to achieve better glycemic control and in both cases the audience favored the use of incretin mimetics. Regarding the first case, he also asked the audience what was the principle consideration in deciding which drug to prescribe and the audience leaned towards concern over patient weight.

  • The first case was a metformin treated 52-year old man with a fasting plasma glucose (FPG) of 105 mg/dl, a post prandial glucose (PPG) of 210 mg/dl, an A1c of 8.2% (up from 7.3% six months ago), and a BMI of 34.4 kg/m2. Dr. Henry asked the audience how they would intensify therapy to achieve better glycemic control. Fifty-one percent of the audience said they would treat with an incretin mimetic, 25% said they would add a DPP-4 inhibitor, 9% said they would add insulin, another 9% said they would add sulfonylurea, 4% said they would add TZDs, and 3% said they would add another drug. When Dr. Henry then asked the audience what was the principle consideration in deciding which drug to prescribe, 37% of the audience said the concern was about patient weight, 23% said the expected A1c increase, 12% said an oral agent, another 12% said concern about hypoglycemia, 8% said other, and 7% said concern about patient acceptance.
  • Dr. Henry presented a second case study with a metformin and gliptizide treated 63-year female with an A1c of 8.7% (8.6% six months prior) and a BMI of 29.1 kg/m2. He asked the audience how they would intensify therapy to achieve better glycemic control in the second case study. Forty two percent of the audience said they would treat with an incretin mimetic, 30% said they would add insulin, 14% said they would add a DPP-4 inhibitor, 8% said they would add another drug, and 6% said they would add TZDs.

Questions and Answers

Q: What are liraglutide’s potential for US approval?

Dr. Garber: This is in the hands of the FDA. Risk has become an increasing issue of concern. They want to make sure they are not blamed for future events. I am reasonably persuaded that the benefits outweigh the risk.

Q: Is there a way to know who will be a good responder to GLP-1 therapy?

Dr. Nauck: In many cases it will be a trial and error. The number of non-responders will be very low.

Q: Could you comment on the durability of these compounds?

Dr. Garber: Durability is becoming the holy grail of diabetes drugs characteristics. We don’t want to be changing and adding medications every 6-12 months. When you look at TZDs, one of their best features is durability. The preliminary data from longer acting GLP-1s suggests there seems to be a better durability than with SFUs. These are not randomized controlled trials but I am encouraged with the data so far.

Q: Could you discuss the atypical nausea rates for exenatide in LEAD 6?

Dr. Nauck: If you skip a dose of exenatide, you get much worse nausea. Its possible that some patients had some missed doses.

Q: Discuss CV effects of GLP-1 9-36?

Dr. Nauck: If the data bear out, it’s likely that there may be a second receptor that binds this compound and has interesting vascular health consequences.

PPAR Modulating Agents and Other Non-Incretin/Non-Insulin Therapies

In the midst of the excitement surrounding the incretin therapies, surprisingly little attention was given to the PPAR agonists at ADA 2009. However, the certain focus for the class was mitigating adverse effects. Several presenters focused on minimizing the weight gain and associated congestive heart failure seen with TZDs, both through the use of combination therapies using different PPAR agonists as well as the development of more selective PPAR agonists. Attention was also drawn to risk factors of TZD-associated bone fractures and fluid retention, and how these events can be minimized. Several other non-incretin therapies were discussed, including the use of pramlintide (Symlin) as a glycemic regulator as well as novel combination therapies targeting weight loss. Looking forward, selective PPAR agonists continue to be an area of active research that may yield therapies that can compete with the efficacy and safety profiles of the emerging GLP-1 class.

PPAR Modulating Agents and Other Non-Incretin/Non-Insulin Therapies Highlights

  • Mylène Perreault, PhD (Wyeth, Cambridge, MA) described the results of a preclinical study of Wyeth’s new PPAR candidate indeglitazar, a pan-PPAR agonist with reduced levels of activity on PPAR alpha, delta, and gamma subtypes. Dr. Perreault’s primate study showed a 37% decrease in insulin levels with indeglitazar treatment, compared with a 2% decrease following pioglitazone treatment. Importantly, there was no change in body weight with indeglitazar, compared to a 0.7 kg (1.5 lb) gain with pioglitazone. Dr. Perreault indicated that human studies are currently in progress and that there may even be weight loss potential for this compound. In Q&A, the question of CNS effects came up (the downfall of the CB-1 class in 2008); Dr. Perreault emphasized that this compound doesn’t cross the blood-brain barrier.
  • Alex M. Depaoli, MD (InteKrin Therapeutics, Inc., Los Altos, CA) presented the results of a phase 2a trial of INT131 (InteKrin), a selective PPAR-gamma agonist. Avandia and Actos are the only available insulin sensitizers, but both are plagued by significant side effects, including weight gain, fluid retention, association with congestive heart failure, and association with fractures. INT131 was developed to specifically antagonize the adverse effects of the TZDs such as weight gain and fluid retention without compromising efficacy. In a four-week phase 2a study, INT131 lowered glucose without causing fluid retention or weight gain; a phase 2b study is ongoing. We note that the development of Pars has been especially challenging, with more than 50 INDs filed and all but two terminated before (or after) reaching the market. Nonetheless, we remain encouraged by the clinical data for INT131 and support the clinical need for a more specific activator of PPAR-gamma.
  • Mary Delmedico, MD (Dara Biosciences, Raleigh, NC) praised current PPAR- gamma agonists as effective agents in lowering A1c in type 2 diabetes and explored the potential use of a Dara Biosciences’ candidate DB959. Despite supporting thiazolidinediones (TZD), Dr, Delmedico acknowledged their major undesirable side effects such as weight gain, edema, and association with congestive heart failure and bone fractures. She explored the potential use of a combination therapy consisting of both PPAR-gamma and PPAR- delta, known as DB959 (Dara Biosciences). According to Dr. Delmedico, the PPAR-delta agonist has the potential to decrease PPAR-gamma side effects and improve dyslipidemia. In animal models, DB959 decreased blood glucose levels in a dosage dependent manner comparable to rosiglitazone. The combined therapy also appeared to be efficacious in improving dyslipidemiawithout weight gain. Dr. Delmedico revealed that DB959 has received IND approval for a phase 1 trial. We are excited to see how this drug develops and tests in humans as a TZD without the deleterious side effects.
  • In this randomized, double blind study (called SYNCHRONY) by Robert Henry, MD (University of California at San Diego, La Jolla, CA), the dual PPAR-γ/α agonist aleglitazar was compared in four doses (50, 150, 300 and 600 μg/day) to pioglitazone (50 mg/day) and a placebo. The authors concluded that the 150 μg dose had similar glycemic effects to pioglitazone, but with superior effects on lipid profiles.
  • In his discussion, Nelson Watts, MD (University of Cincinnati, Cincinnati, OH) illustrated that individuals with type 1 and 2 diabetes are at greater risk for bone fractures. Furthermore, he illustrated that specific biochemical abnormalities and bone “quality” indicators are known to contribute to increased risk of fractures. He went on to describe how thiazolidinediones (TZDs) exhibit a class effect of increasing the risk of fractures, likely by altering osteoblast cell (cells responsible for bone formation) development. Finally, Dr. Watts described how women, particularly postmenopausal women, taking TZDs have a significantly greater risk of fractures, while no such conclusions can currently be made for men. These conclusions mirror the recently released RECORD results.
  • Janaka Karalliedde, MD (King’s College London, London, UK) described how PPAR- gamma-mediated fluid retention likely results from a renal mechanism and should be managed by identifying whether TZD use is contributing to the symptoms of congestive heart failure. He illustrated that hematocrit and hemoglobin may be helpful lab markers in determining the cause of symptoms. Further, he described both how the use of spironolactone or HCTZ can treat TZD-induced fluid retention and his suggested algorithm for managing TZD-induced fluid retention.
  • Dennis Karounos, MD (University of Kentucky Medical Center, Lexington, KY) presented the results of a trial comparing the efficacy of pramlintide (Symlin), rapid-acting insulin, or both agents on a background of basal insulin. Overall, the addition of prandial pramlintide provided similar glycemic control to rapid-acting insulin (A1c drops of 0.9% with pramlintide and 1.1% with rapid-acting insulin), yet did not cause weight gain(4.2 kg; 9.3 lbs with insulin) and decreased events of hypoglycemia. The addition of pramlintideto patients taking rapid-acting insulin decreased required dosages for the rapid-acting insulin, as was expected. Although Symlin is not currently approved for use without concurrent rapid-acting insulin treatment, Dr. Karounos was optimistic about its use on top of basal insulin in place of rapid acting insulin.
  • During the Amylin-sponsored symposium on Symlin, Steven R. Smith, MD Louisiana State University, Baton Rouge, LA) provided an overview of the actions of pramlintide (Symlin), demonstrating that it decreases liver gluconeogenesis by reducing glucagon secretion from the alpha cell. He ended his talk by reviewing the effects of amylin on satiety and spoke optimistically about a multi-hormonal approach to weight loss.
  • Louis J. Aronne, MD (Weill-Cornell Medical College, New York, NY), long a champion of combination therapy, spoke optimistically about a multi-hormonal approach to obesity, which produces better efficacy and lower side effects. Reviewing various obesity drugs in development, Dr. Aronne suggested that there may never be a single magic bullet for obesity, but rather significant weight loss will have to be achieved with a low-dose combination approach. Preclinical data have suggested that a combination of the hormonesamylin, leptin, and PYY 3-36 produces as dramatic weight loss as roux-en-Y surgery. We think that combination therapy is a very exciting way of approaching obesity therapy and are closely following leading candidates from Amylin, Vivus, and Orexigen. With a third of the American population obese there is a huge need for medical therapies that can achieve significant weight loss, even if it is not on the same level as that of surgery.
  • David M. Kendall, MD (International Diabetes Center, Minneapolis, MN) concluded the Amylin talks by describing how deficiencies in the hormone amylin contribute to the natural history of type 2 diabetes, through increases in glycemic variability as well as weight gain. He embraced the wider use of pramlintide (Symlin) in the treatment of diabetes and spoke enthusiastically about the currently unapproved use of pramlintide with basal insulin in the absence of mealtime insulin.
  • ​​Simon R. Heller, MD, FRCP (University of Sheffield, Sheffield, England) opened the Takeda-sponsored symposium by stressing the impact of the termination of the ACCORD trial. As we all know, the intensive arm of ACCORD concluded early due to statistically significant increases in mortality. Along that line, Dr. Heller focused on the epidemiology and pathophysiology of hypoglycemia in type 1 and type 2 diabetes. Next, Andrew J. Ahmann, MD (University of Portland, Portland, OR) discussed the logistics of treating type 2 diabetes with the current range of drug treatments. Additionally, he predicted that stabilization of beta cells will become more important in the future.
  • Patrick J. Boyle, MD (New Mexico School of Medicine, Albuquerque, NM) made the interesting point that the data from RECORD may cause us to rethink the absence of rosiglitazone from the 2008 ADA/EASD treatment algorithm, as there was no increased risk of mortality with Avandia in this trial. He was also very positive about combination therapy and had particular success in one unique patient who went off insulin due to hypoglycemia and switched to triple combination therapy incorporating metformin, a TZD, and exenatide. Overall, attendance at this symposium was not very high, reflecting, we believe, the community’s familiarity with the TZDs at this point, even with Dr. Steven Nissen’s (Cleveland Clinic) controversy and all.
  • Andrew J. Ahmann, MD (University of Portland, Portland, OR) discussed the logistics of treating type 2 diabetes with the current range of drug treatments. He was against the idea of glipizide as an add-on therapy to metformin, noting pioglitazone produces lower rates of hypoglycemia. Additionally, he predicted that stabilization of beta cells will become more important in the future.
  • Rasmus Rabol, MD, PhD (University of Copenhagen, Copenhagen, Denmark) examined whether the effects of increased mitochondrial function are responsible for the improved insulin sensitivity seen with thiazolidinedione (TZD) treatment. He treated three groups of patients with rosiglitazone, pioglitazone, or placebo for 12 weeks. While insulin sensitivity increased compared to control in both treatment groups, rosiglitazone decreased skeletal mitochondrial function while pioglitazone increased it. This represents positive data for Takeda’s Actos. The authors thus concluded that the TZD’s influence on insulin sensitivity is independent of their effects on mitochondrial function.
  • Dhananjay Gupta, PhD (University of Vermont College of Medicine, Burlington, VT) discussed a new role for the well-known thiazolidinediones (TZDs) as regulators of the Glucose-Dependent Isulinotropic Peptide Receptor (GIPr). GIP is an incretin secreted from the gut that controls insulin secretion and glucose uptake and binds the GIPr. Afterfinding that the GIPr contains the consensus binding sequence for PPAR-gamma, the authors were able to show that stimulation of the PPAR-gamma pathway with troglitazone, a TZD (this was taken off the market in 2000 due to liver toxicity), increased the GIPr response and that PPAR-gamma expression up-regulates GIPr signaling. This provides information about a new route of action for TZDs, implicating an incretin pathway in their mechanism. This study links PPAR-gamma agonists such as thiazolidinediones (TZDs) to the regulation of the Glucose- Dependent Insulinotropic Peptide Receptor (GIPr). These results give TZDs a new role, making them potentially clinically useful by increasing insulin sensitivity through an incretin-based mechanism.
  • Tina Ken Schramm, MD (Gentofte University Hospital, Hellerup, Denmark) presented recent results examining the relative risk of CV deaths related to the various oral glucose-lowering medications. Through a large-scale analysis of the citizens of Denmark, the sulfonylureas were associated with the greatest risk of CV death, excepting gliclazide. She recommended metformin remain the primary choice in therapy but offered gliclazide (not available in the U.S.) or repaglinide, which produced a lower HR, as possible alternatives.
  • Research by Karen Moeremans, MD (HEDM-IMSHealth, Brussels, Belgium) confirms that after initial success with metformin monotherapy (A1c <7%), it tends to fail in about a third of patients (A1c >7.5% or addition of another agent) within a year. Those who did not fail maintained target A1c throughout the study, at a mean of about two years. High baseline A1c, longer duration of diabetes at initiation, and younger age were associated with earlier failure. The authors suggest that in drug-naive patients with an A1c of over 8.5% (those with baseline A1c >8% were 85% more likely to fail), treatments other than metformin monotherapy might be considered for first-line.
  •  

Current Issue: Mitigating the Side Effects of PPAR-gamma Agonists

MECHANISM AND MANAGEMENT OF PPAR-GAMMA-MEDIATED FLUID RETENTION

Janaka Karalliedde, MD (King’s College London, London, UK)

Dr. Karalliedde described how PPAR-gamma-mediated fluid retention likely results from a renal mechanism and should be managed by identifying whether TZD use is contributing to the symptoms of congestive heart failure. He illustrated that hematocrit and hemoglobin may be helpful lab markers in determining the cause of symptoms. Further, he described both how the use of spironolactone or HCTZ can treat TZD-induced fluid retention and his suggested algorithm for managing TZD-induced fluid retention.

  • Peripheral edema with PPAR-gamma agonists (thiazolidinediones; TZDs) is not uncommon. Edema incidence is 5 to 8% when monotherapy or combination agonists are used, and 10 to 18% when used with insulin. Dr. Karalliedde described how edema incidence was greater in studies using PPAR-gamma agonists (ACCORD: 70% compared with 67% in control, BARI2D: 56.6% compared with 51.9% in control). It is important to note that studies have shown a similar incidence of edema in both rosiglitazone and pioglitazone.
  • It is important to be aware of both laboratory and bedside markers of fluid retention. Although fluid retention is often asymptomatic, indications include peripheral edema, rapid weight gain, breathlessness, and chronic heart failure. Further, PPAR-gamma agonists result in measurable falls in hemoglobin (Hb) (3 to 1 g/dl) and hematocrit (Hct) (4 to2%) typically seen within the first eight weeks of therapy. Other changes associated with fluid retention are serum sodium rises/urine sodium excretion falls and aldosterone falls.
  • Several factors may predispose PPAR-gamma agonist induced fluid retention. These factors include age, female gender, preexisting heart failure, insulin therapy, ethnicity, and polymorphisms of the PPAR-gamma and ENaC proteins.
  • Both a renal-targeted and a vascular-targeted mechanism have been proposed for PPAR-gamma agonist induced fluid retention. The vascular mechanism proposes that TZDs stimulate volume expansion by targeting a complex pathway with downstream targets including renin secretion, insulin sensitization, and vascular endothelial growth factor. However, studies have knocked out the collecting duct specific PPAR-gamma receptor and illustrated a blunted fall in Hct levels; these data indicate that PPAR-gamma agonists most likely work through a renal mechanism.
  • Studies have indicated that spironolactone and HCTZ are the two most effective diuretics for decreasing rosiglitazone-associated fluid retention. With respect to Dr. Karalliedde’s fluid retention management algorithm, spironolactone and HCTZ are last line therapies. Following the prescription of a TZD for diabetes management, physicians should pay attention to increased incidence new edema and factors that may predispose patients to PPAR- gamma agonist induced fluid retention. Based on these factors, physicians must determine whether continuing TZD treatment is most beneficial and prescribe a diuretic if necessary.

Q: Is there any way to pre-identify patients who gain large amounts of weight at the beginning of TZD use?

A: Most people who experience large gains in weight typically have diastolic dysfunction or concomitant use of insulin. Recognizing these factors prior to prescription of a TZD will aid in this pre-identification.

Q: We know that TZDs increase both fatty and fluid weight. Is there any way to assess these effects short of giving patients a TZD and looking at the outcome?

A: We look for any obvious changes in peripheral edema that accompany rapid weight gain. In assessing the effects of TZDs, it is critical to establish a baseline, and compare changes to baseline values.

 

MECHANISM AND MANAGEMENT OF PPAR-GAMMA-MEDIATED BONE FRACTURES

Nelson Watts, MD (University of Cincinnati, Cincinnati, OH)

In this discussion, Dr. Watts illustrated that individuals with type 1 and 2 diabetes are at greater risk for bone fractures. Furthermore, he illustrated that specific biochemical abnormalities and bone “quality” indicators are known to contribute to increased risk of fractures. He went on to describe how thiazolidinediones (TZDs) exhibit a class effect of increasing the risk of fractures, likely by altering osteoblast cell (cells responsible for bone formation) development. Finally, Dr. Watts described how women, particularly postmenopausal women, taking TZDs have a significantly greater risk of fractures, while no such conclusions can currently be made for men. These conclusions mirror the recently released RECORD results.

  • Increased fracture risk is associated with type 1 and 2 diabetes. Patients with type 1 diabetes exhibit decreased body weight and BMI, and reduced bone mineral density (BMD); they have an increased relative risk of 6.9, likely a result of their reduced BMD. Patients with type 2 diabetes (T2DM) exhibit higher body weight, BMI, and BMD. Despite this, they have risk ratios>1.0 for foot, ankle, proximal humerus, and clinical spine fractures. These fractures are likely aresult of the significantly higher risk T2DM patients have of falling due to neuropathy, poor vision, and hypoglycemia.
  • Biochemical abnormalities and reduced bone “quality” contribute to fractures in T2DM patients. Renal calcium loss, abnormal parathyroid hormone levels – both high and low– and vitamin D deficiency are all biochemical factors that contribute to fractures. Furthermore, collagen glycosylation, reduced bone formation, and microarchitectural deterioration all contribute to decreased bone quality. These factors have a cumulative effect in increasing the incidence of fractures.
  • Thiazolidinediones (TZDs) may alter the development of bone progenitor cells. Mesenchymal progenitor cells – the cells that eventually form osteoblasts – have been shown to respond to TZDs by maturing into adipocytes, or fat cells, instead of osteoblasts. This may explain why women taking the TZD rosiglitazone have been shown to have significantly more total fractures than those taking metformin or glyburide.
  • Is there a gender difference for TZDs and fracture risk? The UK GPRD study (n = 66,696, 6% of cases used a TZD) illustrated that women taking TZDs were at a significantly higher risk for all fractures, particularly in postmenopausal women. In men, there was no significant difference in fracture incidence in those taking a TZD. However, these data are insufficient to conclude that men taking TZDs do not have an increased risk. We note that these conclusions agree with those recently released by the authors of RECORD.

 

Oral Presentations: PPAR Modulating Agents and Other Non-Incretin/Non-Insulin Therapies

INDEGLITAZAR IMPROVES INSULIN SENSITIVITY AND DYSLIPIDEMIA IN OBESE AND INSULIN RESISTANT RHESUS MACAQUES IN THE ABSENCE OF WEIGHT GAIN

Mylène Perreault, PhD (Wyeth, Cambridge, MA)

Dr. Perreault discussed Wyeth’s new PPAR candidate indeglitazar. Indeglitazar, a pan-PPAR agonist with reduced levels of activity on PPAR alpha, delta, and gamma subtypes, may improve glucose control and metabolic parameters without causing undue weight gain. Dr. Perreault’s primate study showed a 37% decrease in insulin levels with indeglitazar treatment, compared with a 2% decrease following pioglitazone treatment. Importantly, there was no change in body weight with indeglitazar, compared to a 0.7 kg (1.5 lb) gain with pioglitazone. Dr. Perreault indicated that human studies are currently in progress and that there may even be weight loss potential for this compound. In Q&A, the question of CNS effects came up (the downfall of the CB-1 class in 2008); Dr. Perreault emphasized that this compound doesn’t cross the blood-brain barrier.

  • Dr. Perreault reviewed the rationale behind Wyeth’s new PPAR agonist candidate indeglitazar. She highlighted the shortcomings of current PPARs, such as body weight gain, edema, and congestive heart failure, and suggested that partial activation of PPAR gamma may be sufficient to maintain the positive effects on glycemic control. In addition, simultaneous activation of all three PPAR subtypes (alpha, delta, and gamma) may improve insulin sensitivity, lipid profile, and cause weight loss as well as improvements in glycemic control. Indeglitazar is a balanced PPAR agonist with activity in all PPAR subtypes, but she highlighted its lower PPAR gamma activity compared to rosiglitazone (with an EC50 of 0.85 μM compared to 0.44 μM with rosiglitazone). In rodent models, indeglitazar decreased glucose levels, insulin levels, and triglycerides to a degree similar to that of pioglitazone.
  • The current primate study included ten obese rhesus monkeys that were normoglycemic but hyperinsulinemic. The monkeys were orally dosed with indeglitazar on a daily basis for six weeks, given a placebo washout for four weeks, and then put on pioglitazone for six weeks. Blood was collected at regular intervals and clamp studies were performed at the end of each treatment period.
  • Results showed a 37% decrease in insulin levels with indeglitazar treatment, compared with a 2% decrease with pioglitazone, suggesting that indeglitazar improves insulin sensitivity. The mechanism for this effect was not clear; while both indeglitazar and pioglitazone increased adiponectin, indeglitazar increased it to a greater extent. There was a 54% decrease in triglycerides with indeglitazar compared to 18% with pioglitazone. There were relative increases in HDL and decreases in LDL with indeglitazar treatment. Importantly, there was no change in body weight with indeglitazar, compared to a 0.7 kg (1.5 lb) gain with pioglitazone. Average daily food intake was unchanged between the groups. Indeglitazar was reportedly well tolerated.
  • These results suggest that indeglitazar represents a balanced, lower-level PPAR agonist that may achieve improved metabolic results compared to existing agonists.

Questions and Answers:

Q: The two treatment periods were done in sequence, or were they randomized? Could it be that there was an incomplete washout after the indeglitazar period?

A: No, it was always indeglitazar first. It’s always a possibility, but we don’t believe that this was the case here. After the washout period, all the levels of the measured parameters were back to normal.

Q: Could there be CNS effects?

A: The compound doesn’t cross the blood-brain barrier, so I think it is mostly peripheral.

Q: I take it you are planning to give this to people?

A: Yes—we are doing the studies right now.

 

INT131: A SELECTIVE PPAR-GAMMA MODULATOR (SPPARM) SIGNIFICANTLY LOWERS GLUCOSE WITHOUT TYPICAL THIAZOLIDINEDIONE (TZD) SIDE EFFECTS IN PATIENTS WITH TYPE 2 DIABETES

Alex M. Depaoli, MD (InteKrin Therapeutics, Inc., Los Altos, CA)

Avandia and Actos are the only available insulin sensitizers, but both are plagued by significant side effects, including weight gain, fluid retention, association with congestive heart failure, and association with fractures. INT131 was developed to specifically antagonize the adverse effects of the TZDs such as weight gain and fluid retention without compromising efficacy. In a four-week phase 2a study, INT131 lowered glucose without causing fluid retention or weight gain; a phase 2b study is ongoing. We note that the development of PPARs has been especially challenging, with more than 50 INDs filed and all but two terminated before (or after) reaching the market. Nonetheless, we remain encouraged by the clinical data for INT131 and support the clinical need for a more specific activator of PPAR-gamma.

  • Dr. Depaoli began by discussing the need for a safer insulin sensitizer. PPAR-gamma agonists improve insulin resistance and provide a durable glycemic benefit with the possibility of beta cell preservation. Dr. Depaoli emphasized that both approved PPAR-gamma agonists cause weight gain, fluid retention, and fractures (perhaps by decreasing the conversion of pre-osteoblasts to osteoblasts). Given that PPAR-gamma affects the transcription of a variety of genes that may be responsible for these side effects, there is a need for more selective PPAR-gamma agonists that do not have these side effects.
  • INT131 is a selective PPAR-gamma agonist designed to have similar efficacy as Avandia/Actos but without the side effects that are associated with full PPAR- gamma agonists. This is accomplished by selectively targeting genes involved in insulin resistance, without targeting the genes responsible for other side effects. INT131 was actually developed to specifically antagonize the adverse effects of the TZDs such as weight gain and fluid retention without comprising efficacy. Although INT131 is a PPAR-gamma agonist, it is not technically a thiazolidinedione (TZD).
  • Dr. Depaoli presented the phase 2a data for INT131. In this study, 69 patients with a mean A1c of approximately 8.0% were randomized to one of two doses of INT131 (1 mg, 10 mg), or placebo. There were no serious adverse events in the study and no clinically significant laboratory changes. Using a modeled efficacy analysis, Dr. Depaoli showed that INT131 may be more efficacious than the current TZDs – this would be a major win if it is the case since the current TZDs tend to be very efficacious with the tradeoff of side effects (weight gain, edema, association with CHF and bone fractures). InteKrin is currently conducting a phase 2b study of INT131, with three different doses: 0.5, 1, 2, and 3 mg. We assume something in the 10 mg dose was off-putting, perhaps weight gain, but we do not know. Pioglitazone (Actos) will be used as an active comparator.

Question and Answer:

Q: Any data on bone density?

A: We did not look at bone density markers in this study, but we will be looking at it in our phase 2b study.

Q: What is your dose response for things like adiponectin and lipids?

A: I didn’t show that data, but we have shown it previously. With respect to lipids, we see no change from baseline and a dose-dependent reduction in fatty acids. There was a trend of decreased triglycerides and increased HDL.

 

DB959 IS A NOVEL, DUAL PPARDELTA/GAMMA AGONIST WHICH CONTROLS GLUCOSE AND REGULATES TRIGLYCERIDES AND HDLC IN ANIMAL MODELS OF T2D AND DYSLIPIDEMIA

Mary Delmedico, MD (Dara Biosciences, Raleigh, NC)

Beginning with a discussion of current PPAR-gamma agonists used in treating type 2 diabetes, Dr. Delmedico of Dara Biosciences praised these therapies as effective agents in lowering A1c, while also noting their major undesirable side effects such as weight gain, edema, risk for heart failure, and bone fractures. For the remainder of her talk she explored the potential use of a combination therapy consisting of both PPAR-gamma and PPAR-delta, known as DB959. According to Dr. Delmedico, the PPAR-delta agonist has the potential to decrease PPAR-gamma side effects and also to improve dyslipidemia. In animal models, DB959 decreased blood glucose levels in a dosage dependent manner comparable to rosiglitazone. The combined therapy also appeared to be efficacious in improving dyslipidemia, importantly, without weight gain. Dr. Delmedico revealed that DB959 has received IND approval for a phase 1 trial. We are excited to see how this drug develops and tests in humans as a TZD without the deleterious side effects.

  • This study undertook the initial stages to developing a “poly-pill” that has the ability to normalize blood sugar, HDL, and triglycerides. The prototype for such a therapy was used in this study, consisting of a PPAR-delta/PPAR-gamma combination. DB959, the compound used as treatment in this study, activates PPAR-gamma and PPAR-delta subtypes.
  • In a dosage dependent manner, blood glucose (BG) levels decreased with administration of DB959. Decreases in BG were comparable with rosiglitazone. Animal models also showed improved performance on oral glucose tolerance tests. Furthermore, DB959 appears to be efficacious in improving dyslipidemia. In rodent models, Dr. Delmedico reported increases in HDLs and decreases in triglycerides.
  • Diet induced obese mice show less weight gain on DB959 than on rosiglitazone. Additionally, safety and genotoxicity studies indicate that there is a 100 fold safety margin for Phase 1 dosing.
  • Dr. Delmedico concluded by revealing that IND approval for a phase 1 trial for the dosing and safety of DB959 has been obtained. Dr. Delmedico endorsed DB959 as a drug that could offer the same benefits of TZD’s without the same side effects.

Questions and Answers

Q: Increases in HDL are very impressive. I know you’re studying rodents. Do you know anything about if this is an increase in size of HDL molecules, does the particle concentration alter, what about the quality of the HDL?

A: The only data we have right now is about number of HDL molecules, we would love to follow up on quality and size.

 

COMPARISON OF MEALTIME PRAMLINTIDE, INSULIN, OR A COMBINATION OF BOTH, WHEN ADDED TO BASAL INSULIN TREATMENT IN PATIENTS WITH TYPE 2 DIABETES

Dennis Karounos, MD (University of Kentucky Medical Center, Lexington, KY)

Dr. Karounos presented the results of a trial comparing the efficacy of basal insulin therapy with prandial pramlintide (Symlin), rapid-acting insulin, or both agents. Overall, and notably, the addition of prandial pramlintide provided similar glycemic control to rapid-acting insulin (A1c drops of 0.9% with pramlintide and 1.1% with rapid-acting insulin), yet did not cause weight gain (compared to 4.2 kg; 9.3 lbs with insulin) and decreased hypoglycemia. The addition of pramlintide to patients taking rapid-acting insulin decreased required dosages for the rapid-acting insulin, as was expected. Although Symlin is not currently approved for use without concurrent rapid-acting insulin treatment, Dr. Karounos was optimistic about its use on top of basal insulin in place of rapid acting insulin. This is taken off-label somewhat frequently as is our understanding.

  • Dr. Karounos’s study examined the safety and efficacy of the addition of prandial pramlintide, rapid-acting insulin, or both agents in patients with type 2 diabetes. One hundred thirteen patients (mean baseline A1c = 8.2%) were randomized to receive 120 μg pramlintide three times daily or rapid-acting insulin for a period of 24 weeks. The study continued for an additional 12 weeks, with patients failing to achieve an A1c ≤6.5% at week 24 adding the remaining therapy (pramlintide or rapid-acting insulin) to their treatment regimen.
  • The addition of pramlintide to basal insulin therapy strengthened glycemic control as compared to the addition of rapid-acting insulin. During the first 24 weeks of the trial, pramlintide treatment and rapid-acting insulin treatment exhibited similar decreases in mean A1c (0.9% with pramlintide and 1.1% with rapid-acting insulin). By week 24, 31 patients using pramlintide failed to achieve the ≤6.5% A1c target, slightly less than the 36 using rapid-acting insulin. The addition of the therapy produced no significant effects, with mean A1c levels remaining relatively stable through the end of the trial. Those patients not adding an additional agent exhibited well-maintained mean A1c levels as well. These results suggest prandial pramlintide provides efficacy similar to that of rapid-acting insulin in glycemic control.
  • As compared to rapid-acting insulin, the pramlintide arm had no weight gain and reduced the frequency of hypoglycemic events. By week 24, patients receiving rapid- acting insulin exhibited a significant 4.2 kg (9.2 pounds) weight gain; this was unseen in patients receiving pramlintide. No change in weight occurred during the final 12 weeks of trial, with the suggestion that the addition of pramlintide to rapid-acting insulin inhibited insulin-based weight gain. Hypoglycemic events were less frequent in patients receiving pramlintide as compared to rapid-acting insulin throughout the entirety of the trial. Furthermore, the addition of pramlintide to rapid-insulin treatment allowed for a decrease in insulin dosage in the maintenance of A1c levels.

 

ROSIGLITAZONE AND PIOGLITAZONE HAVE OPPOSITE EFFECTS ON SKELETAL MUSCLE MITOCHONDRIAL CONTENT AND FUNCTION IN TYPE 2 DIABETES

Rasmus Rabol, MD, PhD (University of Copenhagen, Copenhagen, Denmark)

Mitochondrial function is widely thought to be implicated in type 2 diabetes and insulin resistance. The authors examined whether effects on increased mitochondrial function are responsible for the improved insulin sensitivity seen with thiazolidinedione (TZD) treatment. They treated three groups of patients with rosiglitazone, pioglitazone, or placebo for 12 weeks. While insulin sensitivity increased compared to control in both groups, rosiglitazone decreased skeletal mitochondrial function while pioglitazone increased it. The authors thus concluded that the TZDs’ influence on insulin sensitivity is independent of their effects on mitochondrial function.

  • Decreased mitochondrial content and function has an important role in insulin resistance and type 2 diabetes. Mitochondrial dysfunction has been shown to lead to intramuscular fat, which in turn causes insulin resistance. Yet, it is still unknown why type 2 diabetics have mitochondrial dysfunction.
  • The authors assessed the effects of rosiglitazone and pioglitazone on mitochondrial function. TZDs act mainly on adipose tissue, serving as ligands for PPAR-gamma receptors and thus increasing gene expression for insulin creation. Dr. Rabol treated three groups of type 2 diabetes patients with rosiglitazone (n=12), pioglitazone (n=9), or control (n=8) for 12 weeks to assess insulin sensitivity and mitochondrial function. Both drugs increased insulin sensitivity as they were supposed to. Plasma free fatty acids and adiponectin increased in both groups.
  • Skeletal muscle insulin sensitivity improved independently of changes in mitochondrial function. Mitochondrial enzyme activity, triglyceride levels, and mitochondrial protein content were used to gauge mitochondrial function. There is a 25% reduction in mitochondrial respiration in type 2 diabetes; rosiglitazone decreased respiration by 30% and pioglitazone non-significantly increased mitochondrial respiration.

 

INCREASED GIP RECEPTOR EXPRESSION AND GIP-INDUCED INSULIN SECRETION WITH PHYSIOLOGIC AND PHARMACOLOGIC ACTIVATION OF PPARƔ SIGNALLING IN ISLET BETA CELLS

Dhananjay Gupta, PhD (University of Vermont College of Medicine, Burlington, VT)

Dr. Gupta discussed a new role for the well-known thiazolidinediones (TZDs) as regulators of the Glucose-Dependent Isulinotropic Peptide Receptor (GIPr). GIP is an incretin secreted from the gut that controls insulin secretion and glucose uptake and binds the GIPr. After finding that the GIPr contains the consensus binding sequence for PPAR-gamma, the authors were able to show that stimulation of the PPAR-gamma pathway with troglitazone, a TZD (this was taken off the market in 2000 due to liver toxicity), increased the GIPr response and that PPAR-gamma expression up-regulates GIPr signaling. This provides information about a new route of action for TZDs, implicating an incretin pathway in their mechanism. This study links PPAR-gamma agonists such as thiazolidinediones (TZDs) to the regulation of the Glucose-Dependent Insulinotropic Peptide Receptor (GIPr). These results give TZDs a new role, making them potentially clinically useful by increasing insulin sensitivity through an incretin- based mechanism.

DIFFERENCES IN RISK OF CARDIOVASCULAR DEATH ACCORDING TO TYPE OF ORAL GLUCOSE-LOWERING THERAPY IN PATIENTS WITH DIABETES: A NATIONWIDE STUDY

Tina Ken Schramm, MD (Gentofte University Hospital, Hellerup, Denmark)

Dr. Schramm presented recent results examining the relative risk of CV deaths related to the various oral glucose-lowering medications. Through a large-scale analysis of the citizens of Denmark, the sulfonylureas were associated with the greatest risk of CV death, excepting gliclazide. She recommended metformin remain the primary choice in therapy but offered gliclazide (not available in the U.S.) or repaglinide, which produced a lower HR, as possible alternatives.

  • Dr. Schramm’s nationwide study investigated the relative risk of CV deaths associated with different oral medications. The potential risk of CV death associated with the various oral agents is relatively unexplored, in particular for the sulfonylureas.
  • All residents of Denmark greater than 20 years of age and initiating glucose lowering medications were examined for CV death (n = 100,206). Patients with previous history of myocardial infarction were excluded, and maximum follow-up was nine years. Results were adjusted twice, utilizing an age- and sex-adjusted analysis as well as a multivariable adjusted analyses. Metformin use served as a baseline control treatment.
  • All of the sulfonylureas studied, excepting gliclazide (HR 1.11), exhibited a significantly increased risk of CV death. This included glimepiride (HR 1.25), glibenclamide (HR 1.17), glipizide (HR 1.28), and tolbutamide (HR 1.31). Acarbose showed an increased HR of 1.42, though wide CI intervals deterred significance. Repaglinide was the only drug tested to show a decreased risk (HR 0.77) as compared with metformin. Dr. Schramm suggested these results indicated that metformin should be maintained as a primary therapy, with gliclazide and repaglinide serving as possible alternatives. Interestingly, gliclazide is not marketed in the US.

SECONDARY FAILURE FOLLOWING INITIAL SUCCESS OF METFORMIN MONOTHERAPY IN CLINICAL PRACTICE

Karen Moeremans, MD (HEDM-IMS Health, Brussels, Belgium)

After initial success with metformin monotherapy (A1c <7%), it tends to fail in about a third of patients (A1c >7.5% or addition of another agent) within a year. Those who did not fail maintained target A1c throughout the study, at a mean of about two years. High baseline A1c, longer duration of diabetes at initiation, and younger age (perversely) were associated with earlier failure. The authors suggest that in drug-naive patients with an A1c of over 8.5% (those with baseline A1c >8% were 85% more likely to fail), treatments other than metformin monotherapy might be considered for first-line.

 

Poster Presentations: PPAR Modulating Agents and Other Non-Incretin/Non- Insulin Therapies

(917-P) ALEGLITAZAR, A DUAL PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR- Α/Γ AGONIST, PROVIDES BENEFICIAL EFFECTS ON GLYCEMIC CONTROL AND LIPIDS IN PATIENTS WITH TYPE 2 DIABETES

Henry R, Lincoff M, Mudaliar S, Rabbia M, Chognot C, Herz M

In this randomized, double blind study (called SYNCHRONY), the dual PPAR-γ/α agonist aleglitazar was compared in four doses (50, 150, 300 and 600 μg/day) to pioglitazone (50 mg/day) and a placebo. The authors concluded that the 150 μg dose had similar glycemic effects to pioglitazone, but with superior effects on lipid profiles.

  • This poster overviewed the results of the SYNCHRONY study, a phase II, double- blinded, randomized trial for safety and efficacy of the dual PPAR-α/γ agonist aleglitazar. Aleglitazar was developed by Roche and is touted as a more “balanced” dual agonist, meaning that the two receptors are more evenly stimulated compared to other dual agonists. PPAR-γ is the target of thiazolidinediones (TZDs), and stimulation of this receptor leads to increased insulin sensitization. PPAR-α is the target for fibrates, and stimulation of this receptor raises HDL and lowers triglycerides.
  • Four doses of aleglitazar (50, 150, 300, or 600 μg/day) were compared to pioglitazone (Takeda’s Actos, 45mg/day) and a placebo in 332 people with type 2 diabetes for 16 weeks. Before randomization, patients underwent a 4- to 5-week single- blinded placebo run-in period. The primary outcome was change in A1c, and the secondary outcomes were change in lipid profiles and fasting plasma glucose. Safety outcomes included peripheral edema, cardiovascular events, change in body weight, and renal function (estimated glomerular filtration rate; eGFR).
  • Aleglitazar led to a dose-dependent decrease in primary and secondary outcomes. Both glycemic (A1c) and lipid (triglycerides, LDL-C, HDL-C, and ApoB) profiles were improved at the conclusion of this study. The changes can be seen for each group in the table below. Baseline A1c was ~8% and fasting plasma glucose (FPG) was ~10 mmol/l (180 mg/dl) for all groups.
 

Placebo

Aleglitazar

Pioglitazone

    50µg 150µg 300µg 600µg 600µg
Patients  55 55 55 55 55 57
Primary outcome
∆ A1c +0.35 0 -0.49 -0.6 -0.99 -0.35
Secondary outcome
%∆ Triglycerides +13.7 -14.1 -29.7 -35.0 -37.9 -8.6
%∆ LDL-C +5.5 -3.5 -10.0 -7.6 -20.4 +5.3
%∆ HDL-C +4.4 +12.6 +25.1 +27.3 +26.1 +16.5
%∆ ApoB +2.6 -11.5 -17.7 -15.3 -27.9 -4.55
Safety measures 
∆ Weight (kg) -0.85 -0.24 +0.52 +1.18 +2.72 +1.06
%∆ Serum creatinine -0.32 +4.84 +7.16 +13.24 +15.70 +3.18
Edema (# of patients) 3 1 2 6 5 4

The 150µg/day dose of aleglitazar showed similar glycemic effects to pioglitazone as well as significant improvements to patients' lipid profiles. Patients also gained less weight than on pioglitazone. The authors concluded that 150µg aleglitazar yielded equivalent glycemic benefits of pioglitazone, but with a superior lipid profile.

Amylin Sponsored Symposium: Effective Use of Peptide Therapies for Optimal Glucose and Weight Control in Type 2 Diabetes

MULTIHORMONAL REGULATION OF BODY WEIGHT AND THE PATHOPHYSIOLOGY OF OBESITY

Steven R. Smith, MD (Louisiana State University, Baton Rouge, LA)

Dr. Smith provided an overview of the actions of pramlintide (Symlin), a mimetic of the hormone amylin, demonstrating that it decreases liver gluconeogenesis by reducing glucagon secretion from the alpha cell. He ended his talk by reviewing the effects of amylin on satiety and spoke optimistically about a multi-hormonal approach to weight loss.

  • Dr. Smith compared glucose flux after a meal in non-diabetic patients and diabetes patients. In people who don’t have diabetes, glucagon secretion from alpha cells is shut off after a meal, and this turns off glucose production from the liver. However, the normal endocrinology is disturbed in type 2 diabetes; people with type 2 diabetes often have an increase in glucagon secretion that does not shut off after a meal, leading to excessive hepatic glucose production. The glucagon shut off following a meal is largely mediated by the hormone amylin, which is co- secreted with insulin from the beta cell.
  • Both type 1 and type 2 diabetes patients have decreased production of amylin. Often people with type 2 diabetes have basal secretion of amylin, but a blunted postprandial amylin spike (similar to the abnormality initially observed in insulin secretion). Native human amylin makes a poor drug because it forms aggregates when concentrated, but pramlintide is a synthetic amylin analog that does not aggregate. The pharmacokinetic and pharmacodynamic properties of pramlintide are similar to those of the native amylin hormone. Pramlintide reduces postprandial glucagon, thereby reducing postprandial glucose.
  • Pramlintide converges with other peptide hormones such as GLP-1, leptin, and PYY in the brain to control satiety. In particular, the hypothalamus and the hindbrain have receptors for peptide hormones where they control satiety. PYY3-36 binds mostly to the hypothalamus; amylin to the hindbrain (particularly the area postrema, nucleus of the amygdala, and nucleus accumbens); leptin, GLP-1, and oxyntomodulin to both the hindbrain and hypothalamus. Amylin antagonists have the opposite effect of pramlintide – they decrease satiety.
  • The full satiety response to a meal is likely mediated through a symphony of gut- derived satiety signals working synergistically. Many of these satiety signals respond to decreased energy intake; therefore, a multi-hormonal peptide approach may be necessary to produce more significant weight loss. As proof of principle, Dr. Smith showed that in mice, a half- dose of amylin + leptin + PYY 3-36 caused significantly more weight loss than any one or two of those peptides used in a full dose.

ADVANCES IN PHARMACOTHERAPY WITH A FOCUS ON COMBINATION THERAPY

Louis J. Aronne, MD (Weill-Cornell Medical College, New York, NY)

Dr. Aronne, long a champion of combination therapy, spoke optimistically about a multi-hormonal approach to the management of obesity, showing that such an approach can produce better efficacy and lower side effects. Reviewing various obesity drugs in development, Dr. Aronne suggested that there may never be a single magic bullet for obesity, but rather significant weight loss will have to be achieved with a low-dose combination approach. Preclinical data have suggested that a combination of the hormones amylin, leptin, and PYY 3-36 produces as dramatic weight loss as roux-en-Y surgery. We think that combination therapy is a very exciting way of approaching obesity therapy and are closely following leading candidates from Amylin, Vivus, and Orexigen. With a third of the American population obese there is a huge need for medical therapies that can achieve significant weight loss, even if it is not on the same level as that of surgery.

  • The development of leptin resistance may increase a person’s weight set point. When a person’s weight set point is increased, it becomes increasing difficult for that person to lose weight. When they try to lose weight from the new weight set point, the body responds by decreasing energy expenditure through a counter-regulatory mechanism that involves a variety of hormones. Weight lost is almost inevitably gained back because the person becomes leptin- deficient, and the body tries to drive them back to whatever their highest weight set point was.
  • Dr. Aronne reviewed currently approved weight loss drugs. Mean weight change for any of the drugs (sibutramine, phentermine, diethylpropion, and orlistat) was less than 5 kg (11 pounds).
  • Most obesity drugs that are in clinical use often max out in terms of weight loss when used at a set dose. Exenatide once-weekly and Byetta produce similar weight loss, suggesting that we have “maxed out” the GLP-1 system for weight loss. Similarly, low doses of pramlintide produce comparable weight loss to high doses. This suggests that there may ultimately be no magic bullet for obesity, but rather significant weight loss will have to be achieved with a low-dose combination approach. Dr. Aronne suggested that researchers should look into not only combination drug therapies, but also combination drug + surgery.
  • Several combination obesity drugs are in clinical development. One such drug is naltrexone + bupropion (Contrave, Orexigen); another is phentermine + topiramate (Vivus,Qnexa). Dr. Aronne argued that the efficacy of these combination drugs validates the combination approach. In each case, the combination works much more effectively than either agent alone.
  • Dr. Aronne concluded by speaking about multi-hormonal approaches to weight loss. In particular, Dr. Aronne spoke about combining leptin, amylin, and PYY 3-36. Leptin alone is a poor weight-loss drug because its effect is blunted in obesity due to leptin resistance. Fortunately, amylin appears to be a leptin sensitizer and is therefore synergistic with leptin. Dr. Aronne reviewed Amylin’s phase 2 trial of pramlintide + metreleptin, showing that the combination achieved 12.7% weight loss – significantly better than anything else in clinical development, and approaching the 20% weight loss that is achieved with bariatric surgery. Preclinical data has shown that amylin, leptin, and PYY 3-36 combination produces as dramatic weight loss as roux- en-Y surgery.

ADVANCING ISLET HORMONE THERAPY: CLINICAL USE OF AMYLIN AGONISTS IN DIABETES

David M. Kendall, MD (International Diabetes Center, Minneapolis, MN)

Dr. Kendall described the way in which deficiencies in the hormone amylin contribute to the natural history of type 2 diabetes through increases in glucose fluctuations as well as weight gain. He embraced the wider use of pramlintide (Symlin) in the treatment of diabetes and spoke enthusiastically about the currently unapproved use of pramlintide in the absence of mealtime insulin.

  • The hormone amylin may contribute to the natural history of type 2 diabetes. Like insulin, amylin secretion and gut hormone secretion becomes deficient in type 2 diabetes. The consequences of amylin and gut hormone deficiency are multi-factorial and go beyond increased glucose. In particular, these deficiencies may result in weight gain and other lipid abnormalities as well as increased glucose excursions. These glucose fluctuations remain after the introduction of anti-diabetic treatments such as metformin and result in increased hypoglycemia risk, increased oxidative stress, and abnormalities in postprandial lipid metabolism.
  • Pramlintide (Symlin) inhibits postprandial glucagon rise, slows gastric emptying (by about an hour), and promotes satiety while reducing caloric intake. Glucose excursions are profoundly inhibited with pramlintide treatment, which is not seen with any other diabetes drugs. Clinically, pramlintide reduces both fasting and postprandial glucose levels. To reduce the risk of hypoglycemia, clinical guidelines suggest reducing mealtime insulin by 20 to 50% when pramlintide is introduced. Nausea is generally mild to moderate and time limited, and gradual titration is useful. Insulin-induced severe hypoglycemia is more common in type 1 diabetes and the risk is reduced by appropriate patient selection and insulin dose adjustments.
  • Dr. Kendall spoke enthusiastically about the currently unapproved use of pramlintide in the absence of mealtime insulin. When pramlintide is added to basal insulin, glycemic control is improved with the added benefit of weight loss. Last year at ADA, the INSTEAD study was presented that compared the use of pramlintide vs. rapid acting insulin, over a background of basal insulin. At the end of the 24-week study, A1cs were similar between the pramlintide and rapid acting insulin groups. Furthermore, the pramlintide group lost a small amount of weight, whereas the rapid-acting insulin group gained almost 5 kg (11 pounds).

Questions and Answers:

Q: How do we face the increasing expense of drugs used to promote weight loss?

Dr. Aronne: I’d like to point out here a study published by Dr. Anne Wolf about a randomized controlled trial of type 2 diabetics called ICAN – it was a phone-based weight loss program that found it could reduce the amount of medicine used by a patient, saving more than $2,000 per patient. Now the insurance companies are negotiating with Anne to continue this program and finalize its use with other people.

Q: Any comments on the role of weight advantageous therapies in the light of the ACCORD results?

Dr. Aronne: The final results of the post-hoc analysis, as we know, showed intensive therapy increased both mortality and body weight. I think we’ll hear more on this concept later on, as the criticism was post- hoc, and only a relatively small number of people were on exenatide later on.

Takeda Sponsored Symposium: Is Hypoglycemia an Inevitable Pitfall in Early Aggressive Treatment of Type 2 Diabetes?

HYPOGLYCEMIA IN TYPE 2 DIABETES: MORBIDITY AND MORTALITY?

Simon R. Heller, MD, FRCP (University of Sheffield, Sheffield, England)

Dr. Heller opened the Takeda-sponsored symposium by stressing the impact of the termination of the ACCORD trial. As a reminder, the intensive arm of ACCORD concluded early due to statistically significant increases in the risk of death. Along that line, Dr. Heller focused on the epidemiology and pathophysiology of hypoglycemia in type 1 and type 2 diabetes.

  • The causes of hypoglycemia are due to two factors: impaired physiological defenses to hypoglycemia and inappropriate insulin levels. Impaired physiological defenses to hypoglycemia can be further separated into impaired counterregulatory hormone release and hypoglycemia unawareness.
  • Patients with type 2 diabetes were relatively protected from hypoglycemia early after diagnosis. Counterregulatory defenses appeared intact in patients with short duration of type 2 diabetes. In patients diagnosed with diabetes for one month, hormone responses were equivalent to standard non-diabetic individuals. However, increasing duration of type 1 diabetes results in progressively defective endocrine counterregulation. By the end of the fifth year, epinephrine response is normal but glucagon response was approximately a third of prediabetic levels. In patients with prolonged diabetes (14 to 31 years), both epinephrine and glucagon hormone responses had declined to a fraction of pre-diabetic levels.
  • Enhanced sympathoadrenal activity, in the form of epinephrine, appears to compensate for impaired glucagon responses. The mechanism for this protection is unknown.
  • Interestingly, Dr. Heller noted later in the presentation that sympathoadrenal activation is also largely responsible for cardiac effects of acute hypoglycemia. So what exactly caused the additional deaths in ACCORD? Dr. Heller suggested that it could be related to the medication choice, weight gain, and hypoglycemia.

THE LANDSCAPE OF TREATING TYPE 2 DIABETES

Andrew J. Ahmann, MD (University of Portland, Portland, OR)

Dr. Ahmann discussed the logistics of treating type 2 diabetes with the current range of drug treatments. He was against the idea of glipizide as an add-on therapy to metformin, noting pioglitazone produces lower rates of hypoglycemia. Additionally, he predicted that stabilization of beta cells will become more important in the future.

  • With so many products on the market and the range of diabetes knowledge in the audience, Dr. Ahmann assessed some of the most common non-insulin treatments. Sulfonylureas (SU), though inexpensive, are limited by increased risk of hypoglycemia and poor durability. Metformin are also inexpensive and weight neutral but are linked to gastrointestinal side effects and lactic acidosis. Thiazolidinediones (TZDs) are associated with beta cell benefits and some cardiac benefits but patients on TZDs are predisposed to chronic heart failure. Exenatide results in weight reduction with possible beta cell and heart benefits. However, the drug is expensive and can cause nausea and vomiting.
  • Dr. Ahmann was against the idea of glipizide as an add-on therapy to metformin. Although glipizide (10 mg) and sitagliptin (100 mg) were relatively equivalent in mean change in A1c (-0.67% from baseline 7.5%), the two drugs were quite different in the rate of hypoglycemia (4.9% for sitagliptin vs. 32% in glipizide). In a comparison of pioglitazone versus glimepiride, Dr. Ahmann referred to a study that showed that hypoglycemia was 37% and 15.2% with glimepiride (2.9 mg) and pioglitazone (37.4 mg), respectively.
  • Dr. Ahman predicted that beta cell preservation and the interaction between beta cell and diabetic drugs will be the next big area of research. Beta cells treated with GLP- 1 had lower incidence of apoptosis than control cells (p<0.001; Farilla et al. 2002). However, there is little information on durability in humans.

ALTERNATIVE THERAPEUTIC COMBINATIONS FOR TREATMENT OF TYPE 2 DIABETES MINIMIZING WEIGHT GAIN AND HYPOGLYCEMIA

Patrick J. Boyle, MD (New Mexico School of Medicine, Albuquerque, NM)

Dr. Boyle made the interesting point that the data from RECORD may cause us to rethink the absence of rosiglitazone from the 2008 ADA/EASD treatment algorithm. He was also very positive about combination therapy and had particular success in one unique patient who went off insulin due to hypoglycemia and switched to triple combination therapy incorporating metformin, a TZD, and exenatide. Overall, attendance at this symposium was not very high, reflecting, we believe, the community’s familiarity with the TZDs at this point, even with Dr. Steven Nissen’s (Cleveland Clinic) controversy and all.

  • The ADOPT study data shows that 60-70% of patients are inadequately controlled on a single oral agent after three years (Kahn et al., NEJM, 2006). Even with insulin use, Holman et al. (NEJM 2007) showed that only a minority of patients was able to achieve the ADA’s A1c goal of 7%.
  • Weight gain associated with TZDs can be controlled. The Pennington group (Baton Rouge, LA) showed that this was true by putting patients on an isocaloric diet before and after TZD initiation. Additionally, Dr. Boyle noted that Matthews et al. (Diabetes Metab Res Rev, 2005) showed similar weight gain (1.5 kg; 3.3 lbs) when comparing a TZD (pioglitazone, Takeda’s Actos) to a SFU (gliclazide) after one year in patients on a metformin background.
  • He highlighted the absence of rosiglitazone from the ADA/EASD 2008 diabetes treatment algorithm, suggesting that the recently released RECORD data may cause us to rethink this. As a reminder, the RECORD study showed that rosiglitazone did not increase risk of cardiovascular disease or death, though it did increase the risk for heart failure and fractures.
  • Dr. Boyle had praise for comparative studies like the exenatide vs. glargine trial by Barnett et al. (Clini Ther, 2007), which showed identical A1c drops (-1.36%) and rate of A1c drop between both groups – the catch of course being the significant improvement in weight and lack of hypoglycemia in the exenatide arm compared to the glargine arm.
  • He described a very interesting case study with successful use of triple combination therapy, which he suggested was the direction in which therapy was leaning given the undesirable effects of hypoglycemia.
  • He concluded that doctors should be turning to the DPP-4 inhibitors, vildagliptin (Novartis, Galvus) and alogliptin (Takeda), pointing out A1c drops of about 0.8% and 0.6% respectively in newly diagnosed/drug naïve patients, and 1% and 0.8% respectively when used as add-on to pioglitazone.

QUESTIONS AND ANSWERS

Q: Are there differences between DPP-4 inhibitors?

Dr. Boyle: I don’t think so. They probably all reach 100% inhibition pretty easily.

Q: Is there any difference in alpha cell function or mass in type 1 vs. type 2?

Dr. Heller: The glucagon response is diminished but the alpha cell itself is fine in type 1 diabetes. I don’t know about type 2 but I don’t see any reason why it should be different.

Q: How low is too low for blood glucose levels?

A: It depends on the agent being used. If they’re not on sulfonylureas (SFUs)/insulin, there’s no such thing as too low. In new onset patients and those without complications, the potential benefits suggest you can be reasonably aggressive. Anything under 4 mmol/l (72 mg/dl) should be discouraged.

Q: Could you compare long term (five years) efficacy for rosiglitazone and pioglitazone?

Dr: Ahmann: There are no data to that effect. I think they’re both more effective than we think them to be. They’re harder to categorize because we dose them differently.

Q: Why were the glinides and acarbose excluded from algorithm?

Dr. Heller: Acarbose has undesirable gastrointestinal side effects and hasn’t been successful in the UK. The glinides are mild SFUs though there is sparse evidence that they may have slightly less hypoglycemia.

Q: Do you know of any fixed dose triple combinations therapy? Dr. Boyle: No. Takeda is considering mixing alogliptin with pioglitazone. Q: What are your thoughts on NICE-SUGAR?

Dr. Heller: The explanation probably lies in the types of patients and the quality of the glucose control that made up the study.

Novel Drug Therapies

The most exciting advances in novel therapies this year centered around SGLT2 inhibitors, 11βHSD-1 inhibitors, and IL-1ß receptor antagonists. 11βHSD-1 inhibitors were touted for their ability to block glucose production. Dr. John Wilding (University of Liverpool, Liverpool, UK) provided an excellent review of SGLT2 inhibitors and an overview of positive dapagliflozin (BMS/AZ) phase 2b study results. Phase 1 data was also presented on ISIS388626 (ISIS Pharmaceuticals), a SGLT2 inhibitor candidate, as well as early data on JNJ-28431754 (canagliflozin), J&J’s SGLT2 inhibitor in development. Despite the success of dapagliflozin in clinical trials thus far, many physicians noted the need for additional safety data regarding the potential for the SGLT2 inhibitor class to cause urinary tract infections (UTI). We also heard positive phase 1 study results of XOMA 052 (Xoma), an inhibitor of the anti- inflammatory cytokine IL-1β, which produced a sustained decrease in A1c over a three month period. The consensus was that Xoma’s IL-1b antibody has worked well thus far, but the local and systemic processes affected by the drug must be better explored. Salsalate, a safe, inexpensive, and widely used non-steroidal anti-inflammatory drug (NSAID), also garnered a considerable amount of attention for its potential to improve blood glucose levels as well as markers for inflammation. However, physicians expressed concerns regarding any drugs that aim to modulate the immune response. Overall, some very exciting developments to look for in the future.

Novel Drug Therapies Highlights

  • John P.H. Wilding, DM, FRCP (University of Liverpool, Liverpool, UK) described the mode of action of SGLT2 inhibitors and gave an overview of dapagliflozin (BMS/AstraZeneca) data. He presented a study (poster 482-P) that showed significant reductions in A1c with both doses (10 mg and 20 mg) of dapagliflozin from a baseline of 8.5%. Those treated with 10 mg of dapagliflozin had an adjusted mean reduction in A1c of 0.61%, while those treated with 20 mg of dapagliflozin had a reduction of 0.69%. This compares to those on placebo who had an adjusted mean increase in A1c of 0.09%. There were no major adverse events and no urinary tract infections (UTIs).
  • John P.H. Wilding, DM, FRCP (University of Liverpool, Liverpool, UK) presented a study that aimed to investigate the efficacy of the SGLT-2 inhibitor dapagliflozin in combination with metformin and/or TZDs in patients with both type 2 diabetes and insulin resistance. In this 12-week study, patients were instructed to decrease their basal insulin dose by 50%. After 12 weeks, 20 mg dapagliflozin used in combination therapy resulted in a decrease in A1c of 0.7% (baseline A1c = 8.5%), a decrease in fasting plasma glucose (FPG) of 9.6 mg/dl (0.5 mmol/l), and a decrease in weight of 4.3 kg (9.5 lbs). These results indicate that dapagliflozin in combination with metformin and/or TZDs significantly improved glycemic control and lowered weight in insulin resistant patients.
  • Elizabeth Migoya, MD (Merck Research Laboratories, Rahway, NJ) summarized the results of study that investigated the safety, tolerability, and glucose-lowering effects of MK-0599, an orally active allosteric activator of glucokinase (GK). Activation of GK is believed to both enhance glucose uptake in liver and bolster glucose-dependent insulin secretion. MK-0599 administration was able to substantially decrease blood glucose in non-diabetic subjects, indicating it may succeed as a potential treatment for patients with type 2 diabetes in the future. We believe that GK activators are one of the more exciting classes of diabetes drugs in clinical development, and we are excited to learn that Merck is pursuing research in this arena. We note that Merck has several undisclosed diabetes drugs in phase 2, and based on enrollment criteria we believe that one or more may be GK activators.
  • Marc Y. Donath, MD (University of Zurich, Zurich, Switzerland) presented phase 1 data for XOMA 052, an inhibitor of IL-1b that is in development for type 2 diabetes. IL-1b is an inflammatory cytokine that is increased in type 2 diabetes and has been implicated in decreased physiologic insulin secretion. This three-month study randomized 54 patients with type 2 diabetes to different doses of a single injection of XOMA 052 or placebo. As this was a safety/tolerability study, Dr. Donath underscored that the study investigators saw no adverse events with XOMA 052. The drug also produced a predictable PK profile, with a half-life of 22 days for all doses. There was a decrease in A1c of 0.5% at day 60 for the higher doses of the drug, a result that was sustained at the final three-month endpoint. Islet cell production and secretion of insulin was improved out to day 91. We are very interested to see whether higher A1c drops would be seen with longer administration of XOMA 052.
  • Yin Liang, MD, PhD (Johnson & Johnson Pharmaceutical Research & Development, Raritan, NJ) and colleagues presented the results of early research with JNJ- 28431754 (canagliflozin), J&J’s potential SGLT2 inhibitor candidate. Initial results suggest canagliflozin shows selective affinity for SGLT2, with less activity at SGLT1 and no effect on SGLT3. In various animal models, canagliflozin additionally produced an increase in urinary glucose excretion and significant declines in A1c (to about 3% in 100 mg/kg treated mice vs. about 7% in controls) without hypoglycemia. Notably, the compound produced significant weight loss in various animal models as well—we note J&J has previously characterized weight loss as the differentiating factor for canagliflozin within the SGLT2 inhibitor class. We believe that the success of this class hinges on healthcare providers’ comfort with the side effect profile.
  • Brian Roberts, MD (Metabolex, Hayward, CA) discussed GPR119, a G-protein coupled receptor that has recently begun to gain more attention for the treatment of type 2 diabetes. Dr. Roberts described the diverse responses observed from activation of GPR119 in animals, which include enhanced incretin release, suppression of glucagon, and both direct and indirect stimulation of glucose-dependent insulin release, and possibly weight loss. Similar effects were observed in a recent phase 1 trial of Metabolex’s MBX-2982, which bind and activates GPR119. We believe that GPR119 is one of the more exciting classes of drugs in early stage clinical development and several companies are developing drugs that target this receptor.
  • Lina M. Lauffer MD (University of Toronto, Toronto, Canada) presented the hypothesis that the long-chain fatty acid receptor GPR119 but not GPR40 and GPR120 activation improves the survival of L-cells thus increasing GLP-1 secretion. These receptors are present on the L-cells of the intestine. Dr. Lauffer concluded that: 1) GPR119 activation protects both intestinal L-cells and pancreatic beta cells from apoptosis; 2) GPR40 and GPR120 activation induces apoptosis in L-cells but may protect beta cells from apoptosis; 3) GPR119 and GPR40/120 agonists decrease proliferation of cells with less profound effects on beta cells; and 4) GPR119 and possibly GPR40/120 agonists exhibit a favorable profile for future type 2 diabetes therapy with respect to GLP-1 and insulin secretion.
  • Allison B. Goldfine, MD (Joslin Diabetes Center, Boston, MA) provided an update on the development of salsalate for the treatment of type 2 diabetes. Salsalate is a NSAID (non-steroidal anti-inflammatory drug similar to aspirin) that is generic and widely used for the treatment of arthritis. Although the pharmaceutical industry has expressed little interest in developing it as a diabetes drug to its generic status, NIDDK has picked up the tab and is funding its way through clinical development. Dr. Goldfine showed that salsalate improvesglycemia and other metabolic parameters and may be an effective, safe, and inexpensive agent for the treatment of type 2 diabetes. A yearlong “stage 2” efficacy trial is currently enrolling, though we note that some of the toxicities of high-dose NSAIDs – dizziness, bleeding, GI problems – could complicate this mode of therapy.
  • Sanjay Bhanot, MD, PhD (ISIS Pharmaceuticals, Carlsbad, CA) described ISIS 388626 (ISIS Pharmaceuticals), a nucleotide antisense inhibitor of SGLT2 protein synthesis. Like BMS/AZ’s dapagliflozin, it inhibits glucose reabsorption in the kidney, leading to glucosuria (loss of glucose in the urine). Unlike dapagliflozin, it must be injected, but it may be more efficacious; animal studies suggest up to 80% inhibition compared to only 50% with oral inhibitors. Once-weekly ISIS 388626 injection is well tolerated across species (mouse, rat, dog, monkey) with no hypoglycemia, electrolyte changes, or kidney damage. ISIS hopes to move this compound into phase 2 within six to nine months and to investigate both once-weekly and once- monthly administration in type 2 patients. The goal is to exceed the 75 g/day glucose loss that seems to be the limit of small molecule approaches.
  • Robert Henry, MD (University of California at San Diego, La Jolla, CA) and colleagues conducted a double blind, placebo controlled study evaluating the effects of a novel Farnesoid-X receptor agonist on insulin sensitivity in patients with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). 6-ethyl chenodeoxycholic acid (CDCA), INT-747, was used for this trial. Patients were randomized to placebo, 25 mg INT-747, or 50 mg INT-747 groups. Patients were given treatment once daily for six weeks. Improved glucose disposal rate (GDR) and weight loss was seen in both INT-747 groups. Adverse effects were generally mild, which led the authors to conclude that INT-747 is well-tolerated and improves GDR and weight loss in patients with type 2 diabetes and NAFLD.
  • Thomas Mandrup-Poulsen, MD, PhD (University of Copenhagen, Copenhagen, Denmark) explained the use of IL-1 beta-receptor antagonists as a novel treatment for type 2 diabetes. He explained that there is accumulating evidence that IL-1 is involved in the pathogenesis of type 1 and 2 diabetes. For example, IL-1 is implicated in diabetic macroangiopathy and progressive beta cell failure and destruction. Larsen et al. (NEJM, 2007) described one of the main features of IL-1 antagonism as the reduction of low-grade inflammation.
  • Gilbert A. “Zan” Fleming, MD (Kinexum Diabetes, Harper's Ferry, WV) believes that oral insulin fulfills an unmet need for a non-injection approach to insulin delivery. He identified three main approaches to oral insulin (normal insulin combined with an insulin enhancer, chemically modified insulin, or hepatic-targeted insulin), but did not express any preferences for one type over the others. Dr Fleming expects more data in the next two years to provide insight into the potential future of oral insulin therapy.
  • Allison B. Goldfine, MD (Harvard Medical School, Boston, MA) discussed the potential therapeutic benefit of the anti-inflammatory drug, salsalate, in type 2 diabetes. The TINSAL-T2D study is investigating whether salsalate can be used as an effective diabetes treatment. Salsalate is a non-steroidal anti-inflammatory drug (NSAID) originally developed to treat rheumatoid arthritis but has been shown in pilot studies to modestly improve blood glucose levels and markers of inflammation. Dr. Goldfine shared preliminary data from the trial, which suggests salsalate has a positive effect on endothelial function, but noted the need for longer safety studies. She pointed to IL-1 receptor antagonists as the most promising anti- inflammatory agents. We are curious about adherence potential for this drug.
  • Julio Rosenstock, MD (University of Texas Southwestern, Dallas, TX) focused on blocking glucose transporters in the kidney as a method of eliminating excess glucose. Since approximately 90% of renal transporters are sodium-glucose transport protein 2 (SGLT2), recent studies and trials have focus on SGLT2. Before presenting his analysis of dapagliflozin (Bristol-Myers Squibb and AstraZeneca), Dr. Rosenstock argued that SGLT2 inhibitors are safe because individuals with familial renal glycosuria, a rare genetic defect affecting the SGLT2 protein, are commonly asymptomatic.
  • Scherwyn Schwartz, MD (Reata Pharmaceuticals, San Antonio, TX) presented the findings of an open-label phase 2a trial of Reata’s bardoxolone methyl (BARD), an emerging drug aimed at preventing kidney degeneration. Preliminary results suggest that BARD improves kidney function in a severe population of patients with diabetes. These are encouraging results, with BARD providing another option for patients experiencing renal complications. A phase 2b study is currently underway.
  • Sherwyn Schwartz, MD (Reata Pharmaceuticals, San Antonio, TX) explained the vicious cycle by which hyperglycemia promotes diabetic complications through oxidative stress. According to Dr. Schwartz, an important transcription factor Nrf2 produces 250 antioxidant and detoxification enzymes and suppresses reactive oxygen species (ROS) formation and ROS driven inflammation that is commonly associated with diabetes and its complications. Since hyperglycemic pathogenic pathways are inhibited by Nrf2 induced decreases in ROS, this transcription factor may be an important therapeutic target in type 2 diabetes patients. This phase 2a study involved treating type 2 patients of diabetes suffering from chronic kidney disease with Bardoxolone, a novel oral anti-inflammatory agent based on BARD, a potent inducer of Nrf2. The results of this study suggest that Bardoxolone can lower fasting plasma glucose (FPG) levels and improve insulin sensitivity. We look forward to further trials for this drug.
  • Diva de Leon, MD (Children’s Hospital of Philadelphia, Philadelphia, PA) presented the results of a clinical study designed to investigate exenedin-9 as a possible therapy for hyperinsulinemia. Five subjects with KATPHI administered three different dosings of Ex-9 and were measured for blood glucose, insulin, and glucagon levels. All subjects demonstrated significantly higher plasma glucose levels while remaining free of hypoglycemic events. These findings suggest that exendin-(9-39) could be promising in a clinical setting and also presents an interesting route of study for prevention of excess insulin production in early Type 2 diabetes.
  • Matthias H. Tschoep, MD (University of Cincinnati, Cincinnati, OH) reported the results of the combinatorial efficacy of a novel glucagon and GLP-1 co-agonist treatment. The authors of the study found that rodents on the glucagon and GLP-1 co-agonist therapy reduced food intake. Weight loss was observed within a month of treatment. Animals were also reported to have increased energy expenditure. The combination treatment normalized glucose and lipid metabolism in a dose-dependent manner. Dr. Tschoep concluded that their findings provide a novel treatment option for future clinical testing.
  • Matthew E. Bourcier, MPA (Eastern Virginia Medical School, Fairfax, VA) discussed how malignant tumors of the pancreas cause excessive insulin production and hypoglycemia. In his work Dr. Bourcier investigated treatment of such tumors with rapamycin, an mTOR inhibitor known to cause hyperglycemia. The treatment was administered to an 87year-old male with a history of hypoglycemia, intolerant to hyperglycemia agents including diazoxide, HCTZ, phenocytin, and octreocide. After 12 months of treatment, the patient achievedsteady BG of 82 mg/dl (4.6 mmol) and insulin levels between 20 and 30 uIu/mL from an initial glucose level of 43 mg/dl (2.4 mmol) and fasting insulin 60.9 mg/dl. Tumor size held steady. This finding seems promising because it has been proven once clinically, but will need to be repeated and further assessed for long term outcomes.
  • Although beta cell dysfunction occurs after a long period of elevated lipid and glucose levels, Charles Burant MD, PhD (University of Michigan, Ann Arbor, MI) reminded the audience that diabetes is more than just glucose control. He noted that just about every organ in the body respond to overnutrition in a negative manner. He reviewed the causes and effects of lipotoxicity and glucotoxicity, both of which adversely affect beta cells.
  • John E. Gerich, MD (University of Rochester, Rochester, NY) discussed the valuable, yet frequently forgotten, role of the kidney in gluconeogenesis and glucose control. In addition to the liver, kidneys are major sources of endogenous glucose. Along with producing (via gluconeogenesis) and consuming glucose (for cellular maintenance), the kidney also plays an essential role in plasma glucose concentrations by reabsorbing large quantities of glucose from glomerular filtrates.

Symposium: Novel Treatments for Type 2 Diabetes

IL-1ß RECEPTOR ANTAGONIST

Thomas Mandrup-Poulsen, MD, PhD (University of Copenhagen, Denmark)

Dr. Mandrup-Poulsen was charged with explaining the use of IL-1 beta-receptor antagonists as a novel treatment for type 2 diabetes. He explained that there is accumulating evidence that IL-1 is involved in the pathogenesis of type 1 and 2 diabetes. For example, IL-1 is implicated in diabetic macroangiopathy and progressive beta cell failure and destruction. Larsen et al.(NEJM, 2007) described one of the main features of IL-1 antagonism as the reduction of low-grade inflammation.

  • There is accumulating evidence that IL-1 is involved in the pathogenesis of type 1 and 2 diabetes. IL-1 is an adipokine that regulates appetite and body weight homeostasis. There are elevated levels of IL-1 in type 2 diabetes, which drives IL-6 and C-reactive protein levels. IL-1 receptor antagonist activity (predicts development of type 2 diabetes). IL-1 is implicated in diabetic macroangiopathy and progressive beta cell failure and destruction.
  • There are several ways to antagonize IL-1. You can block it by administering antibodies at the binding size, or attach a fusion protein to prevent binding for example.
  • One of the main features of IL-1 antagonism the reduction of low-grade inflammation (Larsen et al. NEJM, 2007). Studies have also shown reduction in beta cell stress as well as a blocking of intra-islet auto-inflammatory processes. In fact, Dr. Mandrup- Poulsen suggested that type 2 diabetes be considered a disease of auto-inflammation.

Questions and Answers

Q: Could you discuss IL-1 receptor specificity for beta cells?

A: It is exquisitely specific for its receptor.

ORAL INSULIN – RATIONALE AND CURRENT THERAPEUTIC APPROACHES

Gilbert A. “Zan” Fleming, MD (Kinexum Diabetes, Harper's Ferry, WV)

Dr. Fleming decided not to go into specifics about different products in development in the field. His approach was more of a holistic one. He believes that oral insulin fills an unmet need for a non-injection approach to insulin delivery. Also, he identified three main approaches to oral insulin (normal insulin combined with an insulin enhancer, chemically modified insulin, or hepatic-targeted insulin), but he did not express any preferences for one type over the others. Dr Fleming expects more data in the next two years to give us a better picture of the field.

  • Dr. Fleming asserted that oral insulin may fill an unmet need. The convenience argument supporting the impetus for a non-injected insulin approach is becoming less important– there has to be some additional clinical benefit for the argument to be truly effective. The clear unmet clinical need is to improve the therapeutic index of insulin. The hope is that absorption of insulin through the GI tract will help control hepatic glucose output and peripheral venous absorption.
  • There have been three main approaches to developing an oral insulin. The earliest approach to oral insulin combined normal insulin with an absorption enhancer (and some manner of protection from digestion). Another approach was to chemically modify it to prevent digestion and possibly affect its properties. There is also the idea of attaching a ligand with high affinity for the liver to create a hepatic-targeting insulin.
  • The development aspect is challenging since we have to figure out if the therapy will be tested as a conventional insulin (must be open label and non inferior to another insulin product) or as an oral agent (double-blind and in comparison to placebo. Safety concerns, in addition to hypoglycemia, include interruption of the GI barrier, which could lead to infection, and local exposure to insulin’s effects as a growth factor.

Questions and Answers

Q: What are the plans for developing the next stage of oral insulin products?

A: There are two programs in the proof of concept stage.

SGLT-2 INHIBITORS – CLINICAL UTILITY

John P.H. Wilding, DM (University of Liverpool and Aintree Hospitals, Liverpool, UK)

Dr. Wilding described the mode of action of SGLT2 inhibitors and gave an overview of dapagliflozin (BMS/AstraZeneca) data presented at ADA 2009. A study presented as poster 482-P showed significant reductions in A1c with both doses of dapagliflozin from baseline. Those treated with dapagliflozin 10 mg had an adjusted mean decrease in A1c of 0.61%, while those treated with dapagliflozin 20 mg had a decrease of 0.69%. This compares to those on placebo who had an adjusted mean increase in A1c of 0.09%. The baseline A1c in the study was 8.5%. There ware no major adverse events and no UTIs.

  • Dr. Wilding stressed that there is still a need for new therapies with a lower risk of weight gain, hypoglycemia, concerns over cardiovascular safety, and of course the natural history of the disease.
  • The kidney plays a major role in glucose metabolism that is often unrecognized. It filters and reabsorbs 180 g of glucose every day. This takes place in the S1 and S2 segments of the proximal tubules. About 90% of this occurs in the proximal tubule by the SGLT-2 transporter, which is almost exclusively expressed in the kidney. In uncontrolled type 2 diabetes we see an up- regulation of glucose reabsorption in the kidney, probably due to increased hyperglycemia.
  • SGLT-2 inhibitors are able to block the glucose transporter and cause a dose- dependent reduction in glucose levels. BMS/AZ has the most advanced SGLT-2 program. There are also compounds in development by Boehringer Ingelheim, JNJ/Mitsubishi, and GSK amongst others. These compounds have been shown to cause dose dependent glycosuria.
  • Concerns with the class include polyuria, electrolyte disturbances due to sodium excretion, and vaginal infections. We also need to keep an eye on potential effects on bone since they have been shown to have a modest impact on magnesium and phosphate levels. However, potential advantages in addition to glycemia lowering include weight loss (75 g glucose= 300 kcal/day). There is a low risk of hypoglycemia and the anti-diuretic effect might lower blood pressure.
  • Dapagliflozin data were presented at ADA 2009 (482-P). The study showed significant A1c reductions with both doses of dapagliflozin from baseline. Those treated with dapagliflozin 10 mg had an adjusted mean decrease in A1c of 0.61%, while those treated with dapagliflozin 20 mg had a decrease of 0.69%. This compares to those on placebo who had an adjusted mean increase in A1c of 0.09%. The baseline A1c in the study was 8.5%. Reductions in body weight were similar to what was seen in previous studies. There ware no major adverse events and no UTIs.

Questions and Answers

Q: What about potassium and calcium levels?

A: There were no changes in potassium levels.

Q: I think you need kidney biopsies in the phase three studies.

A: We’ve had experience with a natural genetic defect in SGLT2, which is a benign condition. There has been no increase in creatinine levels, etc., so we don’t need to do to biopsies.

Q: What’s the next step in SGLT2 inhibitor development?

A: The logical next step would be to see if it could prevent diabetes.

Q: The amount of weight loss seen is similar to orlistat so maybe we could think about it in prediabetes?

A: That is also tempting and worth exploring.

Q: Why did GSK discontinue clinical trials of sergliflozin in phase 2?

A: Sergliflozin was discontinued but they decided to move remigliflozin forward.

ANTI-INFLAMMATORY AGENTS

Allison B. Goldfine, MD (Harvard Medical School, Boston, MA)

Dr. Goldfine discussed the potential therapeutic benefit of the anti-inflammatory drug, salsalate, in type 2 diabetes. The TINSAL-T2D study is investigating whether salsalate can be used as an effective diabetes treatment. Salsalate is an NSAID originally developed to treat rheumatoid arthritis but has been shown in pilot studies to modestly improve blood glucose levels and markers of inflammation. Dr. Goldfine shared that preliminary data from the trial suggest the effect on endothelial function will be positive, but noted the need for longer safety studies. She pointed to IL-1 receptor antagonists as the most promising anti-inflammatory agents.

  • Sub-acute chronic inflammation can precede and predict cardiovascular disease. Glucocorticoids and non-steroidal anti-inflammatory drugs (NSAIDs) are two agents that have been used widely as anti-inflammatory agents. However, glucocorticoids promote insulin resistance.
  • Salsalate is a NSAID originally developed to treat rheumatoid arthritis but it has been shown in pilot studies to modestly improve blood glucose levels and other metabolic parameters. Studies of two doses of salsalate (3.0 g/day and 4.5 g/day) showed improvements in fasting plasma glucose for the 3.0 g/day dose (201 vs. 183 mg/dl) and for the 4.5 g/day dose (112 vs. 92 mg/dl) after two weeks of treatment. Glycated albumin was used instead of glycated hemoglobin as a marker of long-term glycemic control. The glycated albumin decrease in the 3.0 g/day arm was not statistically significant though that for the 4.5 g/day decreased from 13.3% to 10.7%. These changes were obtained without weight gain or hypoglycemia.
  • The drug had beneficial effects on markers of inflammation but caused the side effect of tinnitus (ringing in the ear), an expected side effect of high dose salicylate. C-reactive protein levels were significantly reduced in the 4.5 g/day group (but not the 3.0 g/day group) by 50%. Adiponectin levels increased 40% in the former group and 35% in the latter group.
  • The TINSAL-T2D study is investigating whether salsalate can be used as an effective diabetes treatment. TINSAL-T2D stands for targeting inflammation using salsalate or lifestyle intervention in type 2 diabetes. This multi-center, randomized, placebo-controlled study is being conducted in two phases. It is currently in the second stage, which is dosing 3.5 g/day of salsalate in inadequately controlled type 2s on diet/exercise, metformin, sulfonylurea (SFU), alpha- glucosidase inhibitors, or a low dose combination of the above. Subjects were initially supposed to be followed for 48 weeks but Dr. Goldfine noted that this has been extended to 52 weeks. She added that preliminary data from the trial suggest the effect on endothelial function will be positive.
  • Additional trials are still needed to establish the safety of this drug in a diabetes population. The TINSAL-CVD trial will investigate the effect of salsalate (compared to placebo) on coronary artery plaque volume.
  • There are a number of additional anti-inflammatory drugs under study and Dr. Goldfine believes the most promising agent is an IL-1 receptor antagonist.

Questions and Answers

Q: Explain variability of outcome measures. How did you decide that 3.5 mg was your best dose?

A: We did not want to go forward with increased toxicity with highest dose. So we chose the mid dose.

Q: This drug has been around for a long time. The lack of safety data puts it where CMS can’t find it. Will this provide safety data for the drug?

A: We have found that consumer reports place it at the top of NSAIDS prescribed.

Q: What do you think is the primary mode of action of glycemia lowering?

A: It is difficult to tell. We have seen improvement in glucose utilization in our clamp studies. This dramatic improvement in glucose utilization suggests an effect on insulin sensitivity. That said, beta cell function also likely plays an important role.

Oral Presentations: Novel Drug Therapies

THE GLUCOKINASE (GK) ACTIVATOR MK-0599 LOWERS PLASMA GLUCOSE CONCENTRATIONS IN HEALTHY NON-DIABETIC SUBJECTS

Elizabeth Migoya, MD (Merck Research Laboratories, Rahway, NJ)

In her talk, Dr. Migoya summarized the results of a phase 1 study of MK-0599, an orally active allosteric activator of glucokinase (GK). Activation of GK is believed to both enhance glucose uptake in liver and bolster glucose-dependent insulin secretion. MK-0599 administration was able to substantially decrease blood glucose in non-diabetic subjects, indicating it may succeed as a potential treatment for patients with type 2 diabetes in the future. We believe that GK activators, though early stage, represent an exciting classes of diabetes drugs in clinical development, and we are excited to learn that Merck is pursuing research in this arena. We note that Merck has several undisclosed diabetes drugs in phase 2, and based on enrollment criteria we believe that one or more may be GK activators.

  • MK-0599 is an orally active potent and specific allosteric activator of GK. Activation of GK has been associated with an increase in glucose uptake, metabolism, and glycogen synthesis in the liver as well as a rise in glucose-dependent insulin secretion from the beta cells. The combined effect may result in increased efficacy as compared with existing agents that target a single site.
  • The safety, tolerability, and glucose-lowering ability of MK-0599 were explored in a double blind first-in-man study. Study panels consisting of eight healthy, non-diabetic subjects were randomized to receive MK-0599 or placebo, with MK-0599 administered in either single 0.4 to 160 mg doses or 13 to 100 mg doses three times daily. In order to determine effects on blood glucose levels, MK-0599 was given after an overnight fast, with plasma glucose measurements taken as frequently as every five to 15 minutes.
  • MK-0599 is a potential novel oral glucose-lowering agent. The administration of 50 mg MK-0599 three times daily produced significant decreases in blood glucose throughout the day. Effects were apparent following the administration of the third dose, or 16 to 24 hours after the administration of the first dose. The decrease in mean glucose was dose-dependent in nature. We aren’t sure whether three times daily is required dosing but if so that increases “hassle factor” associated with the drug. Hypoglycemia (see below) is also a clear disadvantage.

Questions and Answers:

Q: Did you observe any cases of hypoglycemia?

A: We did have several values in the hypoglycemic range, which we defined as concentrations of <70 pmol/L with or without symptoms.

XOMA 052, A POTENTIAL DISEASE MODIFYING ANTI-IL-1BETA ANTIBODY, SHOWS SUSTAINED HBA1C REDUCTIONS 3 MONTHS AFTER A SINGLE INJECTION WITH NO INCREASES IN SAFETY PARAMETERS IN SUBJECTS WITH TYPE 2 DIABETES

Marc Y. Donath, MD (University of Zurich, Zurich, Switzerland)

Dr. Donath presented phase 1 data for XOMA 052, an inhibitor of IL-1b that is in development for type 2 diabetes. IL-1b is an inflammatory cytokine that is increased in type 2 diabetes and has been implicated in reduced physiologic insulin secretion. This three-month study randomized 54 patients with type 2 diabetes to different doses of a single injection of XOMA 052 or placebo. As this was a safety/tolerability study, Dr. Donath underscored that the study investigators saw no adverse events with XOMA 052. The drug also produced a predictable PK profile, with a half-life of 22 days for all doses. There was a reduction in A1c of 0.5% at day 60 for the higher doses of the drug, a result that was sustained at the final three-month endpoint. Islet cell production and secretion of insulin was improved out to day 91. We are very interested to see whether higher A1c drops would be seen with longer administration of XOMA 052.

 

MBX-2982, A NOVEL ORAL GPR119 AGONIST FOR THE TREATMENT OF TYPE 2 DIABETES: RESULTS OF SINGLE & MULTIPLE DOSE STUDIES

Brian Roberts, MD (Metabolex, Hayward, Ca, Stanford, Ca)

GPR119 is a G-protein coupled receptor that has recently begun to gain more attention for the treatment of type 2 diabetes. Dr. Roberts described the diverse responses observed from activation of GPR119 in animals, which include enhanced incretin release, suppression of glucagon, and both direct and indirect stimulation of glucose-dependent insulin release, and possibly weight loss. Similar effects were observed in a recent phase 1 trial of Metabolex’s MBX-2982, which bind and activates GPR119. We believe that GPR119 is one of the more exciting classes of drugs in early stage clinical development and several companies are developing drugs that target this receptor.

  • GPR119 is a G-protein coupled receptor that is expressed on both beta cells and L- cells and appears to play an important role in the regulation postprandial glycemia. Activation of GPR119 stimulates the release of incretin hormones (GIP, GLP-1) from the gut, thus enhancing glucose-sensitive insulin secretion. It also thought that GPR119 may play a role in regulating food intake and GI motility. One drug that is in development for the treatment of type 2 diabetes that leverages GPR119 is Metabolex’s MBX-2982. MBX-2982 directly stimulates glucose-sensitive insulin secretion, enhances insulin secretion during hyperglycemic clamps in rats, and acutely lowers glucose excursion and increases plasma GLP-1 and GIP during OGTTs in mice and rats. When combined with sitagliptin (Januvia by Merck), the reduction in glucose excursion during OGTT and increase in active GLP-1 is enhanced. MBX-2982 significantly slows gastric emptying in mice and delays diabetes onset.
  • Dr. Roberts described the phase 1a results as positive overall, with the drug demonstrating good tolerability, pharmacokinetics consistent with once daily dosing, and dose-dependent increases in GLP-1 and reductions in glucose excursion following a meal. A phase 1b study examined the effect of MBX-2982 on a mixed meal tolerance test and graded glucose infusion after three and four days in male patients with impaired fasting glucose (IFG). The results from the study showed that the drug was well tolerated and produced significant reductions in glucose excursion (26-37%; 31-44% in patients with higher baseline fasting glucose (FPG)) and glucagon (17% with 300 mg dose). It also produced evidence of enhanced insulin secretion by Day four (p=0.07), suggesting a direct islet effect.
  • Overall, the preliminary data suggests that synthetic small-molecule GPR119 agonists could be a new method of treatment of type 2 diabetes, capable of improving glucose tolerance through multiple mechanisms, including enhanced incretin release, suppression of glucagon, and both direct and indirect stimulation of glucose-dependent insulin release, and possibly inducing weight loss.

GPR119 BUT NOT GPR40/120 ACTIVATION ENHANCES SURVIVAL OF ENTEROENDOCRINE L CELLS

Lina M. Lauffer, (University of Toronto, Toronto, Canada)

Dr. Lauffer presented the hypothesis that the long-chain fatty acid receptor GPR119 but not GPR40 and GPR120 activation improves the survival of L-cells thus increasing GLP-1 secretion. These receptors are present on the L-cells. Dr. Lauffer concluded that: 1) GPR119 activation protects both intestinal L-cells and pancreatic beta cells from apoptosis; 2) GPR40 and GPR120 activation induce apoptosis in L-cells but may protect beta cells from apoptosis; 3) GPR119 and GPR40/120 agonists decrease proliferation of cells with less profound effects on beta cells; and 4) GPR119 and possibly GPR40/120 agonists exhibit a favorable profile for future type 2 diabetes therapy with respect to GLP-1 and insulin secretion.

Questions and Answers

Q: How did the effects of the GPR agonist compare to GLP-1?

A: We have not yet performed that study.

THE ANTI-INFLAMMATORY DRUG SALSALATE IMPROVES GLYCEMIA IN TYPE 2 DIABETES

Allison B. Goldfine, MD (Joslin Diabetes Center, Boston, MA)

Dr. Goldfine provided an update on the development of salsalate for the treatment of diabetes. Salsalate is a NSAID (non-steroidal anti-inflammatory drug similar to aspirin) that is generic and widely used for the treatment of arthritis. Although the pharmaceutical industry has expressed little interest in developing it as a diabetes drug to its generic status, NIDDK has picked up the tab and is funding its way through clinical development. Dr. Goldfine showed that salsalate improves glycemia and other metabolic parameters and may be an effective, safe, and inexpensive agent for the treatment of type 2 diabetes. A yearlong “phase 2” efficacy trial is currently enrolling, though we note that some of the toxicities of high-dose NSAIDs – dizziness, bleeding, GI problems – could complicate this mode of therapy.

  • Dr. Goldfine discussed the development of a salicylic acid dimer for the treatment of type 2 diabetes. The drug is widely used, generic, and inexpensive. The TINSAL-T2D trial of salsalate has been supported by NIDDK because the pharmaceutical industry has no interest in supporting the development of a generic drug. We aren’t sure who would manufacture the drug were it to be approved or in fact who would take it through the regulatory process.
  • The stage 1 TINSAL-T2D study of salsalate randomized 108 patients to receive 3, 3.5, or 4 grams of salsalate or placebo. Patients were allowed to enter the therapy if treated with lifestyle, metformin, or a combination of metformin and a sulfonylurea – other therapies were exclusionary. At all three intervention doses, A1c was reduced by approximately 0.4% compared to placebo, from a baseline A1c of 7.8% (therefore the A1c reduction with salsalate was not dose- dependent – no explanation for this was provided). There were also placebo corrected changes in fasting glucose of approximately 30 mg/dl (1.7 mmol). The treatment was weight neutral, levels of adiponectin were increased, and safety and tolerability data were favorable.
  • Following the positive results of the stage 1 trial of salsalate, the study investigators have initiated a larger one-year phase 2 trial of the drug. We are interested in learningmore about “hassle factor” associated with the drug; at one point we had heard that it had to be taken three times per day. We aren’t blown away by efficacy though if it is very easy to take, it isn’t bad – SFUs have so much negative baggage currently (weight gain, hypoglycemia, etc.) that it would be great to have another generic.

Q: Have you measured insulin secretion?

A: Not in the stage 1 trial, but we have looked at insulin secretion in other smaller studies. There is improvement in glucose utilization in clamp studies, and improvements in insulin response.

ISIS 388626, AN SGLT2 ANTISENSE DRUG, CAUSES ROBUST AND SUSTAINED GLUCOSURIA IN MULTIPLE SPECIES AND IS SAFE AND WELL-TOLERATED

Sanjay Bhanot, MD, PhD (ISIS Pharmaceuticals, Carlsbad, CA)

ISIS 388626 (ISIS Pharmaceuticals) is a nucleotide antisense inhibitor of SGLT2 protein synthesis. Like BMS/AZ’s dapagliflozin, it inhibits glucose reabsorption in the kidney, leading to glucosuria (loss of glucose in the urine). Unlike dapagliflozin, it must be injected, but it may be more efficacious; animal studies suggest up to 80% inhibition compared to only 50% with oral inhibitors. Once-weekly ISIS 388626 injection is well tolerated across species (mouse, rat, dog, monkey) with no hypoglycemia, electrolyte changes, or kidney damage. ISIS hopes to move this compound into phase 2 within six to nine months and to investigate both once-weekly and once-monthly administration in type 2 patients. The goal is to exceed the 75 g/day glucose loss that seems to be the limit of small molecule approaches.

  • SGLT2 inhibition seems to be safe. People with SGLT2 mutations have primary renal glucosuria with up to 100 g/day loss of glucose. These people (ages 30 to 82 years) are generally asymptomatic. Small molecule inhibition can reduce glucose reabsorption by up to 50% or 55%.
  • ISIS 388626 is a 12-nucleotide long single-stranded antisense molecule that inhibits SGLT2 expression. It localizes preferentially to the kidney because of its small size and binds to SGLT2 mRNA. Because it contains a central DNA-like region, its binding attracts RNase H to cleave the SGLT2 mRNA, preventing SGLT2 protein translation. It has a half-life of eight to 10 days, consistent with once-weekly administration.
  • In mice, rats, dogs, and monkeys, weekly administration of ISIS 388626 safely reduces SGLT2 activity by up to 80%. In 13-week studies, it has been shown to cause dose- dependent glucosuria in normoglycemic mice and monkeys. Even with up to 85% inhibition there has been no evidence of hypoglycemia. Once weekly administration reduced hyperglycemia and improved glucose tolerance in very hyperglycemic db/db mice over 11 weeks of treatment. This effect is maintained for up to five weeks after cessation of therapy. Six-month treatment in the ZDF rat did not affect BUN/Cr ratio, a marker of kidney function.

Questions and Answers:

Q: How much weight are the db/db mice or ZDF rats losing?

A: In leptin-deficient animals when they lose glucose long term they get compensatory hyperinsulinemia so there is no measurable weight loss over the first four to six months. We need to study this in DIO mice, which are a better model.

Q: Did you calculate the fraction of glucose clearance in your animal models?

A: We plan to do this carefully in humans. It’s difficult in mice, but I can tell you it exceeds what has been reported with dapagliflozin.

BARDOXOLONE METHYL SHOWN TO IMPROVE RENAL FUNCTION IN PATIENTS WITH CHRONIC KIDNEY DISEASE AND TYPE 2 DIABETES MELLITUS

Scherwyn Schwartz, MD (Reata Pharmaceuticals, San Antonio, TX)

Dr. Schwartz presented the findings of an open-label phase 2a trial of Reata’s bardoxolone methyl (BARD), an emerging drug aimed at preventing kidney degeneration. Preliminary results suggest that BARD was able to improve kidney function in a severe population of patients with diabetes. While longer-term placebo-controlled studies are on the way, these are encouraging results, with BARD providing another option for patients experiencing renal complications. A phase 2b study is currently underway.

  • BARD belongs to the class of antioxidant inflammation modulators (AIMs) and is the most potent inducer of Nrf2. Nrf2 is a transcription factor that mediates the activation of the phase 2 response, an immune process that incites at least 250 of the body’s antioxidant and detoxification enzymes. Activation of these enzymes serves to repress reactive oxygen species- mediated endothelial dysfunction induced by hyperglycemia.
  • Dr. Schwartz’s open label trial investigated the effects of BARD in patients with extensive type 2 diabetes. Fifty-seven patients with an average duration of diabetes of 20 years received 25, 75, or 150 mg/day of BARD along with standard therapy for 28 days. The primary endpoint for the trial was the change at day 28 in estimated glomerular filtration rate (eGFR), a measure of kidney function. Mean baseline eGFR was 37.3 ml/min/1.73m2 for all patients.
  • BARD significantly improved eGFR at all dosages, indicating it improves kidney function in patients with type 2 diabetes and may delay renal complications. Patients receiving 75 mg/day showed the greatest increase in eGFR, with a mean change of 28.5% (p<0.0001); patients receiving 25 mg/day or 150 mg/day showed a 8.6% increase (p <0.01) and 26.9% increase (p<0.0001) respectively, producing a clear dose-response curve. Creatinine clearance improved following the 75 mg/day administration as well. Stage 4 kidney failure patients, those nearest to dialysis, showed the greatest improvement in renal function. BARD was well tolerated, with eight serious adverse events but none considered related to the drug itself.

BARDOXOLONE, A NOVEL ORAL ANTI-INFLAMMATORY AGENT IMPROVES GLYCEMIC CONTROL IN TYPE 2 DIABETICS WITH CHRONIC KIDNEY DISEASE

Sherwyn Schwartz, MD (Reata Pharmaceuticals, San Antonio, TX)

Dr. Schwartz began by discussing the vicious cycle by which hyperglycemia promotes diabetic complications through oxidative stress. According to Dr. Schwartz, an important transcription factor Nrf2 produces 250 antioxidant and detoxification enzymes and suppresses reactive oxygen species (ROS) formation and ROS driven inflammation that is commonly associated with diabetes and its complications. Since hyperglycemic pathogenic pathways are inhibited by Nrf2 induced decreases in ROS, this transcription factor may be an important therapeutic target in type 2 diabetes patients. This phase 2a study involved treating type 2 patients of diabetes suffering from chronic kidney disease with bardoxolone, a novel oral anti-inflammatory agent based on BARD, a potent inducer of Nrf2. The results of this study suggest that bardoxolone can lower fasting plasma glucose (FPG) levels and improve insulin sensitivity. A one-year phase 2 trial has been initiated and we look forward to further data from future trials for this drug as chronic kidney disease can lead to high blood pressure, cardiovascular disease, anemia (low red blood cell count), and pericarditis (inflammation of the pericardium surrounding the heart).

  • In this Phase 2a study bardoxolone, a potent inducer of the Nrf2 transcription factor, was administered orally for 28 days to 60 patients, at three different dosage levels. Most patients were already on insulin, ACE-inhibitors and/or ARBs, and statins. The activation of Nrf2, believed to be stimulated by bardoxolone, has widespread affects on the production of antioxidant and detoxification enzymes.
  • In patients receiving treatment with bardoxolone, improvements in glucose profiles were observed. FPG decreased across all patients. The most pronounced effects were seen in patients with higher A1c levels at baseline and those with elevated FPG at baseline. A euglycemic clamp study showed improvements in insulin sensitivity. Results do not appear to be dose dependent in this sample size.
  • Outcomes of this study indicate that bardoxolone is a safe and well-tolerated drug. There were generally low percentages of adverse events recorded. Adverse events included: headache, muscle spasms, dizziness, diarrhea, constipation, and nausea. Some hypoglycemia was detected chemically but no patients reported symptoms. None of the serious adverse events recorded in the study were considered related to the study drug but to instead to pre-existing disease.
  • Dr. Schwartz endorsed bardoxolone as a potentially efficacious method for improving glycemic control in patients with long history of type 2 diabetes and numerous co-morbidities. In this study, patients on bardoxolone therapy experienced decreases in A1c and FPG, and improvements in glucose metabolism. A one-year phase 2 trial has been initiated.

Questions and Answers

Q: Did you specify that the pancreatitis was not related to the use of Bardoxolone?

A: The patient with a case of pancreatitis had a history of other related disease; we had good reason to believe it was not the drug.

EXENDIN-(9-39) SUPPRESSES INSULIN SECRETION AND ELEVATES FASTING BLOOD GLUCOSE IN SUBJECTS WITH KATP HYPERINSULINISM

Diva de Leon, MD (Children’s Hospital of Philadelphia, Philadelphia, PA)

Dr. Leon presented the results of a clinical study designed to investigate exenedin-9 as a possible therapy for hyperinsulinemia. Five subjects with KATPHI administered three different dosings of Ex-9 and were measured for blood glucose, insulin, and glucagon levels. All subjects demonstrated significantly higher plasma glucose levels while remaining free of hypoglycemic events. These findings suggest that exendin-(9-39) could be promising in a clinical setting and also presents an interesting route of study for prevention of excess insulin production in early Type 2 diabetes.

  • Congenital hyperinsulinism is characterized by severe hypoglycemia and is caused by mutations in the KATP channels. It is a genetic disorder of beta cell function characterized by an inability to suppress insulin secretion that usually requires pancreatectomy in the first year of life. Outcome is generally poor for patients with 20% developing diabetes mellitus and a majority developing complications.
  • The GLP-1 receptor has been shown to be constitutively active in this disorder. Dr. Leon hypothesized that antagonism of the receptor by exendin-(9-39) could suppress insulin secretion and increase glucagon levels. Antagonism of the GLP receptor by exendin-(9-39) in Sur-1-/- mice (which have a KATP channel loss of function and hyperinsulinemic phenotype) led to decreased BG levels as a result of decreased insulin secretion and correction of fasting hyperinsulinemia. Positive results prompted movement into clinical work.
  • A clinical study was performed on five subjects with KATPHI measuring blood glucose, insulin, and glucagon levels after three different dosings of Ex-9. The initial pilot study was conducted on three females and two males ages 15-44, three of which carried a recessive HI mutation and had received 85-95% pancreatectomies early in life. Patients were given IV infusions of exendin-(9-39) (dosings of 100, 300, and 500 pmol/kg/min) or vehicle in random orders, alternating infusion days for six hours in two infusion days. Blood glucose (primary endpoint), insulin, and glucagon levels were measured.
  • All subjects showed significantly increased blood glucose levels and were not hypoglycemic after an overnight fast. Patients also showed lower mean insulin and higher mean glucagon levels.
  • The study suggests that exendin-9 could be a promising clinical therapy for hyperinsulinemia once more studies are done. It also presents an interesting route of study for prevention of excess insulin production in early type 2 diabetes. It has yet to be determined whether such decrease of insulin production can be safely sustained in patients over a long period of time (avoiding hypoglycemia) and whether reduction of insulin production in type 2 diabetes has clinical benefits or will improve beta cell-preservation.

A NOVEL GLUCAGON/GLP-1 CO-AGONIST ELIMINATES OBESITY IN RODENTS

Matthias H. Tschoep, MD (University of Cincinnati, Cincinnati, Ohio)

Dr. Tschoep reported on the results of the combinatorial efficacy of a novel glucagon and GLP-1 co- agonist treatment. The study authors found that rodents on the glucagon and GLP-1 co-agonist therapy reduced food intake. In fact, weight loss was observed within a month of treatment. Animals were also observed to have increased energy expenditure. The complication treatment also normalized glucose and lipid metabolism in a dose-dependent manner. Dr. Tschoep concluded that their findings provide a novel treatment option for future clinical testing.

 

INHIBITION OF MTOR- A POTENTIAL THERAPY FOR INTRACTABLE HYPOGLYCEMIA DUE TO MALIGNANT INSULIN SECRETION

Matthew E. Bourcier, MPA (Eastern Virginia Medical School, Fairfax, VA)

Dr. Bourcier discussed how malignant tumors of the pancreas cause excessive insulin production and hypoglycemia. In his work Dr. Bourcier investigated treatment of such tumors with rapamycin, an mTOR inhibitor known to cause hyperglycemia. The treatment was administered to an 87 year-old male with a history of hypoglycemia, intolerant to hyperglycemia agents including diazoxide, HCTZ, phenocytin, and octreocide. After 12 months of treatment, the patient achieved steady BG of 82 mg/dl 4.6 mmol) and insulin levels between 20 and 30 uIu/mL from an initial glucose level of 43 mg/dl (2.4 mmol) and fasting insulin 60.9 mg/dl. Tumor size held steady. This finding seems promising because ithas been proven once clinically, but will need to be repeated and further assessed for long term outcomes.

Poster Presentations: Novel Drug Therapies

(482-P) DAPAGLIFLOZIN PILOT STUDY IN INSULIN-RESISTANT T2DM PATIENTS

Wilding J, Norwood P, T'joen C, Bastien A, List J, Fiedorek F

The goal of this study was to investigate the efficacy of the SGLT-2 inhibitor dapagliflozin in combination with metformin and/or TZDs in patients with both type 2 diabetes and insulin resistance. In this 12-week study, patients were instructed to decrease their basal insulin dose by 50%. After 12 weeks, 20 mg dapagliflozin used in combination therapy resulted in a decrease in A1c of 0.7% (baseline A1c = 8.5%), a decrease in fasting plasma glucose (FPG) of 9.6 mg/dl (0.5 mmol/l), and a decrease in weight of 4.3 kg (9.5 lbs). These results indicate that dapagliflozin in combination with metformin and/or TZDs significantly improved glycemic control and lowered weight in insulin resistant patients.

  • Dr. Wilding et al. examined the efficacy and safety of dapagliflozin, an SGLT-2 inhibitor under development by BMS. Seventy-four type 2 diabetes patients on insulin therapy of at least 50 units daily received dapagliflozin 10 or 20 mg or placebo for 12 weeks, and were instructed to reduce their basal insulin dose to 50%. The primary outcome of the study was change in A1c at week 12.
  • After 12 weeks, patients in the dapagliflozin groups saw reductions in A1c of about 0.7% compared to placebo. The placebo group’s A1c increased by 0.9% over the treatment period, while the group treated with 10 mg dapagliflozin decreased 0.61% and the 20 mg group decreased 0.69% (from baselines of 8.4%, 8.4%, and 8.5%). The percent of patients achieving the ADA goal of less than 7% A1c was 23% in both dapagliflozin groups, compared to 19% in the placebo group. Body weight decreased by 4.5 kg (9.9 lbs) in the 10 mg dapagliflozin group, decreased 4.3 kg (9.5 lbs) in the 20 mg dapagliflozin group, and decreased 1.88 kg (4.2 lbs) with placebo. Baseline FPG was 165.9 mg/dl (9.2 mmol/l), 156.0 mg/dl (8.7 mmol/l), and 161.6 mg/dl(8.9 mmol/l) for the dapagliflozin 10 mg, 20 mg, and placebo. At 12 weeks, there were changes of+2.4 mg/dl (0.1 mmol/l), -9.6 mg/dl (-0.5 mmol/l), and +17.8 mg/dl (+1.0 mmol/l) for the same groups, respectively.
  • The drug was well-tolerated, overall. The most common AEs were polyuria (excessive urination), back pain, nausea, nasopharyngitis, headache, and respiratory tract infection. One subject in each group discontinued treatment due to an adverse event. One urinary tract infection was seen in the 20 mg dapagliflozin group, compared to none in the other two treatment groups. More hypoglycemia was seen in the dapagliflozin groups, with seven subjects in the 10 mg group and six in the 20 mg group reporting hypo compared to three in the placebo group.

(534-P) JNJ-28431754/TA-7284, AN SGLT INHIBITOR, LOWERS BLOOD GLUCOSE AND REDUCES BODY WEIGHT IN OBESE AND TYPE 2 DIABETIC ANIMAL MODELS

Liang Y, Arakawa K, Martin T, Du F, Zhi Xu J, Liu Y, Finley M, Minor L, Lenhard J, Demarest K

Liang et al. presented the results of early research with JNJ-28431754 (canagliflozin), J&J’s potential SGLT2 inhibitor candidate. Initial results suggest canagliflozin shows selective affinity for SGLT2, with less activity at SGLT1 and no effect on SGLT3. In various animal models, canagliflozin additionally produced an increase in urinary glucose excretion and significant declines in A1c (to about 3% in 100 mg/kg treated mice vs. about 7% in controls) without hypoglycemia. Notably, the compound produced significant weight loss in various animal models as well—we note J&J has previously characterized weight loss as the differentiating factor for canagliflozin within the SGLT2 inhibitor class. We believe that the success of this class hinges on healthcare providers’ comfort with the side effect profile.

  • SGLT is a sodium-dependent glucose cotransporter predominantly found in the kidneys. Under normal circumstances, glucose is reabsorbed by SGLT1 and SGLT2 transporters in the distal (S3) and proximal (S1) tubules of the kidney respectively. The SGLT2 is a high capacity, low affinity transporter which is the first line of glucose absorption in the kidney. The SGLT1 transporter is a low capacity, high affinity transporter that transports any residual glucose into cells so that no glucose is excreted in urine.
  • This study looked at glycemic control and weight loss in six animal models for a number of different doses of JNJ-28431754 (canagliflozin).
  • Canagliflozin showed selective affinity for SGLT2. In cells overexpressing human SGLT2 or SGLT1, canagliflozin more selectively inhibited SGLT2 with a half maximal inhibitory concentration (IC50) of 4.1 nM. IC50 is a measrure of affinitiy for inhibiting SGLT2 with a lower concentration meaning higher affinity. Canagliflozin was about 200 times less potent on SGLT1 inhibition (IC50 = 664 nM) and showed no interaction with rat skeletal muscle GLUT1 transporters (IC50 >1000 nM) or human SGLT3 transporters (no measurable effect).
  • In various animal models, canagliflozin increased urinary glucose excretion (UGE) and significantly reduced hyperglycemia. A single oral dose of canagliflozin improved oral glucose tolerance tests (OGTTs) in normal Sprague-Dawley rats, Zucker diabetic fatty (ZDF) rats (insulin resistant), and normal dogs, increasing UGE and decreasing blood glucose levels in a dose-dependent manner. In studies with ZDF rats and diabetic (db/db) mice, four weeks of treatment with canagliflozin produced significant dose-dependent declines in A1c without hypoglycemia. In the ZDF rats, treatment additionally increased plasma insulin levels, suggestive of an improvement in beta cell function.
  • Canagliflozin produces significant weight loss in various rodent models and may alter the energy metabolism profile. In diet-induced obese mice, treatment with 30 mg/kg canagliflozin for four weeks significantly decreased body weight gain (treated mice gained 4.8 g as compared to 9.12 g in controls) without declines in food intake – note that the compound didn’t cause weight gain; the study was designed to monitor reduction in weight gain. In ZDF rats (insulin resistant), four weeks of 10 mg/kg canagliflozin treatment produced similar decreases in weight gain, with a significant decline in plasma free fatty acid levels (0.19 meq/L as compared with 0.54 meq/L in the controls). A substantial increase in oxygen consumption and significant decrease in respiratory exchange ratio were observed as well, indicative of a modified metabolic profile. We note J&J has previously characterized weight loss as the differentiating factor for canagliflozin within the SGLT2 inhibitor class. We believe that the success of this class hinges on healthcare providers’ comfort with the side effect profile.
  • The authors concluded that these results support the further study of canagliflozin as a potential therapy for type 2 diabetes and obesity. J&J hopes to enter the compound into phase 3 trials for the treatment of type 2 diabetes by the end of 2009.

(13-LB) FARNESOID-X RECEPTOR AGONISTS: A NEW THERAPEUTIC CLASS FOR DIABETES AND FATTY LIVER DISEASE? THE FIRST FXR THERAPEUTIC STUDY IN DIABETES

Henry R, Mudaliar S, Morrow D, Hompesch M, Kipnes M, Sanyal A, Clopton P, Bohm O, Sciacca C, Mavian A, Pruzanski M, Shapiro D

The authors of this study conducted a double blind, placebo controlled study evaluating the effects of a novel Farnesoid-X receptor agonist on insulin sensitivity in patients with type 2 diabetes and non- alcoholic fatty liver disease (NAFLD). 6-ethyl chenodeoxycholic acid (CDCA), INT-747, was used for this trial. Patients were randomized to placebo, 25 mg INT-747, or 50 mg INT-747 groups. Patients were given treatment once daily for six weeks. Improved glucose disposal rate (GDR) and weight loss was seen in both INT-747 groups. Adverse effects were generally mild, which led the authors to conclude that INT-747 is well-tolerated and improves GDR and weight loss in patients with type 2 diabetes and NAFLD.

  • 6-ethyl chenodeoxycholic acid (CDCA), INT-747, is a novel derivative of the primary human bile acid CDCA. CDCA is the natural ligand for the Farnesoid-X receptor (FXR), which is a nuclear hormone receptor. INT-747 is approximately 100 times more potent as an FXR agonist than CDCA, and in vitro increases insulin secretion by human pancreatic islets, enhances adipocyte lipid store, and improves secretion of adiponectin and leptin.
  • The authors conducted a double blind, placebo controlled study evaluating the effects of INT-747 on insulin sensitivity using a two-stage euglycemic insulin clamp. Patients (n = 64) with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) were randomized to receive placebo, INT-747 25 mg, or INT-747 50 mg once daily for six weeks. The authors determined the glucose disposal rate (GDR) after steady state was achieved with low and high dose insulin infusions (60 and 120 mU x m2 body surface area/min).
  • Patients in both INT-747 groups demonstrated increased GDR with both low and high dose insulin clamps as well as improved weight loss compared to patients on placebo. Patients in the 25 mg group demonstrated higher percent change from baseline in GDR compared to those in the 50 mg group (Low Dose: ~30% vs ~20%; High Dose: ~20% vs ~10%, respectively). However, patients in the 50 mg group demonstrated nearly 2% decrease in body weight compared to less than 1% in the 25 mg group. The authors noted that the greatest responses appeared to occur in patients with BMI<40 kg/m2 and A1c >7%. Minor increases in LDL and decreases in HDL and triglycerides were seen.
  • Adverse experiences were generally mild/moderate and not clearly differentiated across groups. Constipation seemed to be the most common (19% in the 50 mg group).
  • The authors concluded that INT-747 was well-tolerated and improved GDR and weight loss in patients with type 2 diabetes with NAFLD.

Bristol-Myers Squibb Company/AstraZeneca Pharmaceuticals Sponsored Symposium: Type 2 Diabetes Today: Exploring Etiology and Emerging Therapies

GLUCOLIPOTOXICITY AND BETA CELL DYSFUNCTION

Charles Burant MD, PhD (University of Michigan, Ann Arbor, Michigan)

Although beta cell dysfunction occurs after a long period of elevated lipid and glucose levels, Dr. Burant reminded the audience that diabetes is more than just glucose control. He noted that just about every organ in the body respond to overnutrition in a negative manner. He reviewed the causes and effects of lipotoxicity and glucotoxicity, both of which adversely affect beta cells.

  • Lipotoxicity occurs when the influx of glucose exceeds the body’s need for glucose. Excess food results in an increased flux of free fatty acids into tissues. When this occurs, fatty acids can be oxidized, stored as triglycerides or transformed into biologically active lipid moieties. Dr. Burant stressed that this process is the normal response to having nutrient coming into the tissue, however, the problem occurs when there’s an overload of lipids and the fatty acid processing is constantly activated. Excess glucose and nutrient in the diet can also cause endoplasmic reticulum stress.
  • Glucotoxicity is caused by glucose desensitization and beta cell exhaustion after prolonged exposure to elevated glucose results. When glucose intake exceeds the oxidation of glucose, the excess glucose is diverted to fatty acid synthesis. The implications are quite significant. In a high carbohydrate, high fat diet, rat showed alterations in metabolite flux in their islets after only two days. Dr. Burant noted the high levels of glycolic intermediates found in the islets.
  • Dr. Burant determined that there is ample evidence for beta cell glucolipotoxicity in humans. In human islets incubated for 48 hours with free fatty acid (oleate and palmitate), free fatty acids increased islet triglyceride and decreased insulin content, insulin secretion and glucose utilization. There appears to be a large genetic factor, although the extent of this effect is still not well understood. However, beta cell damage appears to be salvageable in the short term. Past studies have shown improved insulin secretion after subcutaneous insulin infusions.
  • Dr. Burant concluded by noting the severity of beta cell degeneration. As beta cell function begins to deteriorate, the remaining beta cells must work harder which increases their potential for damage.

Questions and Answers:

Q: Which is more toxic to beta cells: increase glucose or increase fatty acids?

A: All of the above… Really, we don’t know enough about the genetic defects that cause beta cell failure to choose between the two. But having both is obviously bad. I think this needs to be evaluated on an individual basis.

Q: I think the way I would think about it is that low carbohydrate diets result in less glucose and you also lose weight…

A: Sure but we know that amino acid acids are important too. We might be hearing soon how high flux of amino acids can also cause dysfunction.

RENAL GLUCOSE TRANSPORT IN NORMOGLYCEMIA AND HYPERGLYCEMIA

John E. Gerich, MD (University of Rochester, Rochester, New York)

In addition to the liver, kidneys are major sources of endogenous glucose. Along with producing (via gluconeogenesis) and consuming glucose (for cellular maintenance), the kidney also plays an essential role in plasma glucose concentrations by reabsorbing large quantities of glucose from glomerular filtrates. Dr. Gerich discussed the valuable, yet frequently forgotten, role of the kidney in gluconeogenesis and glucose control.

  • The kidney is a major source of endogenous glucose. The liver and the kidney are the only two organs that are capable of releasing glucose by gluconeogenesis. Until recently, the liver was thought to be the organ most responsible for producing glucose. However, a study in 2000showed that liver transplant volunteers who had no liver for approximately an hour between transplant surgeries were still producing high levels of endogenous glucose. This indicated that an organ other than the liver was responsible for some endogenous glucose production. A later study verified that this glucose release was indeed from the kidney.
  • Glucose production and reabsorption in the kidney exceeds glucose utilization. On adaily basis, glucose production is approximately 60 grams per day, glucose utilization by the kidney is approximately 30 grams per day and glucose reabsorption from glomerular filtrate is approximately 180 grams per day. Moreover, after a meal, glucose release is more substantial in the kidney than the liver.
  • The kidney overproduces glucose in patients with type 2 diabetes. Systemic release ofglucose was 1.5 times higher in diabetics than non-diabetics. Postprandial tissue glucose uptake was higher in the kidney for patients with type 2 diabetes. This coincides with increased cellular and renal glucose transporters (SGLT2 and GLUT4) expression.
  • Dr. Gerich hypothesized that the inhibition of the glucose transporter in the kidney can lower hyperglycemia in patients with diabetes. In a healthy individual, the majority of filtered glucose is reabsorbed by the kidney. There are two main transporters in the kidney responsible for glucose reabsorption: sodium-glucose transport protein 1 and 2 (SGLT1 and SGLT2). Of the two transport proteins, SGLT2 is found exclusively in the kidney. Inhibition of SGLT2 would address the three major abnormalities of renal glucose handling in patients with diabetes, which includes increased glucose production, increased glucose utilization and increased glucose reabsorption from glomerular filtrates.

Questions and Answers:

Q: What happens to SGLT2 in situation of CFR?

A: I don’t know of measurements of protein under these condition… but the reabsorption of glucose is based on filtered load.

TAKING CONCEPT TO THE CLINIC: SGLT2 INHIBITION IN TYPE 2 DIABETES?

Julio Rosenstock, MD (University of Texas Southwestern, Dallas, TX)

Dr. Rosenstock focused on blocking glucose transporters in the kidney as a method of eliminating excess glucose. Since approximately 90% of renal transporters are sodium-glucose transport protein 2 (SGLT2), recent studies and trials have focus on SGLT2. Before presenting his analysis of dapagliflozin (Bristol-Myers Squibb and AstraZeneca), Dr. Rosenstock argued that SGLT2 inhibitors are safe because individuals with familial renal glycosuria, a rare genetic defect affecting the SGLT2 protein, are commonly asymptomatic.

  • Dr. Rosenstock suggested that SGLT2 inhibition can be safe and effective for patients with type 2 diabetes. He argued his case by referring to the asymptomatic nature of familial renal glycosuria. Familial renal glycosuria is a rare autosomal recessive mutation affecting the SGLT2 gene. In the majority of individuals with familial renal glycosuria, there is no evidence of renal tubular dysfunction. Moreover, patients are rarely, if ever, hypoglycemic or hypovolemic (low blood volume). Diabetes and obesity is also rare in this population. Given these observations, Dr. Rosenstock believes that in a patient with type 2 diabetes, blocking the SGLT2 transporter would lower the reabsorption of glucose, independent of insulin resistance or the degree of beta cell dysfunction.
  • Dr. Rosenstock devoted the remainder of his presentation to an analysis of dapagliflozin, an experimental SGLT2 inhibitor in development with Bristol-Myers Squibb(BMS) and AstraZeneca. It certainly didn’t escape anyone’s notice that Dr. Rosenstock happened to be giving his presentation in a symposium sponsored BMS and AstraZeneca. Not surprisingly, he spoke highly of the early results on dapagliflozin, noting that dapagliflozin is “as good as GLP-1 analogs” on a number of measures. Fasting plasma glucose declined significant with dapagliflozin treatment, as did mean weight (-5.0 lbs) and postprandial blood glucose. In fact, fasting plasma glucose was significantly reduced by the end of the first week of treatment. The reduction in weight is consistent with the loss of calories (via glucose) since SGLT2 is not longer reabsorbing glucose across the nephron.
  • Dapagliflozin was well tolerated and Dr. Rosenstock noted that there were no incidences ofdehydration. There were also no differences in adverse events between the control, dapagliflozin, and metformin arms, with the notable exception that patients in the dapagliflozin had a significantly higher rate of genital infection (7%). Dr. Rosenstock commented that the number of infections needs to be closely monitored.

Questions and Answers:

Q: What transporters mediate glucose release from the cell during gluconeogenesis?

A: GLUT2 but interestingly if you knockout GLUT2 out of animal, you don’t decrease gluconeogenesis.

Continuous Glucose Monitoring and Closing the Loop

Continuous glucose monitoring was a hot topic throughout ADA, playing the star role in many blockbuster talks and symposia. Of particular note, Bruce Bode, MD (Atlanta Diabetes Associates, Atlanta, GA) delivered an eagerly anticipated presentation on the extended JDRF CGM trial, documenting the sustained efficacy of CGM over 52 weeks in adults and the success of CGM use in improving glycemic profiles of children who use the device consistently for a one-year period. Other talks discussed the use of CGM in the hospital, in nutritional therapy, and in patients with type 2 diabetes (which we feel still needs quite a bit more attention and clinical research). We found the talk on integrating CGM into clinical practice given by Irl B. Hirsch, MD (University of Washington, Seattle, WA) at the Medtronic sponsored symposium very moving—he emphasized how important it is for healthcare providers to understand how to optimally use the wealth of information provided by CGM to the fullest and to be willing and able to teach their patients how to use the device properly. The consensus of most of the talks delivered was that when used consistently, CGM can provide an improvement in glycemic control, and, importantly, do so safely while significantly reducing the risk of hypoglycemia.

Throughout the conference, consistency of use emerged as the key factor in determining the success of CGM. Not surprisingly, a question repeated many times during the conference was, “for which patients is CGM most appropriate?” The resounding answer seemed to be that until CGM technology is advanced and made more user-friendly, the best users are those who are highly motivated and willing to be very active in their disease management. We were happy to see open discussion of the limitations and barriers to widespread commercial use of CGM share the limelight with praise of the technology and agree with Howard A. Wolpert, MD (Joslin Diabetes Center, Boston, MA) that wider adoption of CGM will depend on improved technology.

Ultimately, what we are most excited about is the role that CGM could ultimately play in closing the loop. In the opinion of many expert voices at ADA, CGM represents an important step towards a closed- loop system. Efforts need to be focused on refining CGM technology while we wait for an ultra-rapid acting insulin, improved algorithms, and better safety measures that can bring us closer to the artificial pancreas.

Continuous Glucose Monitoring and Closing the Loop Highlights

  • Bruce Bode, MD (Atlanta Diabetes Associates, Atlanta, GA) presented very exciting one-year data from the JDRF CGM trial - an independent study looking into the efficacy of CGM in patients with type 1 diabetes over a year long period in three different age cohorts. The primary goal of this study was to determine if improvements in glycemic control, including avoidance of hypoglycemia, could be sustained during a full year of CGM use. The previously published (and now considered landmark, published in NEJM) six- month results showed that CGM improves both A1c and hypoglycemia for patients over 25 years, and for all patients who used the device frequently. At the one-year mark, initial benefits in A1c were sustained over the year in both the greater than 7% (≥7%) A1c at baseline cohort and the less than 7% (<7%) A1c at baseline cohort. In particular, children aged eight to fourteen years old in the >7% cohort demonstrated an A1c improvement, which hadn’t been statistically significant in the first 26 weeks. As before, adolescents failed to show a benefit unless they used the device consistently. A major highlight of this data was that A1c gains were sustained in the next six months following the initial six months and the rates of hypoglycemia continued to fall significantly for both groups. Incredibly, adults in the <7% group experienced zero (zero!) severe hypoglycemia. Children in the <7% group experienced an A1c increase of 0.4%, which was significant. Although this seems counterintuitive, we assume that due to lower hypoglycemia and reduced glycemic variability contributed to the A1c increase. Presenters said that because the children were still well controlled, the trade-off (higher A1c) was worth it. It wasn’t discussed, but we believe these results reinforce that teens are very hard to treat; absent from the conversation, however, was the fact that CGM adherence will improve when the devices become easier to use. As a reminder, many in the trial had first-generation devices that now have advanced to later generations that are considerably more user-friendly
  • Bruce Buckingham, MD (Stanford University, Stanford, CA) discussed the use of an algorithm to shut off insulin delivery and avoid hypoglycemia. The algorithm uses a more sophisticated ‘voting system’ in which five prediction algorithms contribute to the insulin shutoff decision-making process. In a trial of 14 patients, 84% of all nighttime hypoglycemia events were avoided. WHEW! This is a very impressive result, and takes ‘Low Glucose Suspend’ a step further into the prevention realm. Note that at no time does this algorithm dose insulin – it’s all about improving patient safety. It’s hard to imagine a rationale that would not advocate reducing nocturnal hypoglycemia by 84%. But as we understand it, there’s a much higher bar to get this cleared in the US than there is in the EU.
  • Notably, Dr. Buckingham showed an interesting picture of the ‘Florence’ system, consisting of an Abbott Navigator sensor/transmitter, the Abbott Aviator insulin pump (not commercially available), a Companion handheld combined controller, and a control algorithm device (CAD). No more details were available at this stage, but it looks like Abbott’s artificial pancreas research system. It’s compact and we assumed that it would be used for the outpatient trials, although this wasn’t clear.
  • For the CGM symposium, Howard A. Wolpert, MD (Joslin Diabetes Center, Boston, MA) presented an overview of the impact of CGM on self-care behavior and advances in CGM technology. The big challenge with CGM is that it puts an extra burden on people with diabetes due to hardware hassles, information overload, and alarm fatigue. For many people these become barriers to sustained use of CGM. Additionally, potential causes of sensor inaccuracy and instability include: biofouling, mechanical obstruction of sensor membrane, calibration procedure, signal processing delays, and interfering substances. Overall, although improvements in CGM technology have set the stage for a paradigm shift in diabetes care, there are limitations in the point accuracy of current CGM devices, patients need further education, and wider adoption of CGM will depend on improved technology.
  • Boris Kovatchev, PhD (University of Virginia, Charlottesville, VA) reported the exciting results of a JDRF-funded closed loop study. Twenty type 1 diabetes patients, wearing FreeStyle Navigator CGM and Insulet OmniPod, were admitted to the clinic twice for overnight glucose control – first with an open-loop, physician-supervised control and then using a model-predictive control (MPC) closed-loop algorithm. The MPC algorithm uses a model that can predict future glucose levels, based on an insulin-dosing plan. This approach is generally more successful than the earlier generation of proportional-integral-derivative (PID) algorithms, which react to historic glucose levels. When on MPC closed-loop, patients spent more time within a glucose range of 70-14o mg/dl (78%) compared with open loop (68%). Furthermore, hypoglycemia was five times more likely on open loop than closed - 23 episodes against four! Nowthis is progress…. to boot, this study set a precedent by skipping animal studies by using an “in silico” trial as an alternative to animal trials.
  • Bruce Buckingham, MD (Stanford Medical Center, Stanford, CA) and the JDRF CGM study group examined the factors that determined adherence to CGM. The study found that age, self-reported number of daily home glucose meter measurements, and percentage of time in zone (71-180 mg/dl) during a week of blinded CGM use were factors predictive of adherence (at least six days/week).
  • David Rodbard, MD (Hahnemann Medical College and Hospital, Philadelphia, PA) studied the impact of continuous glucose monitoring on glycemic control and glycemic variability in 64 patients with type 1 diabetes either on multiple daily injections or using an insulin pump. Following the three-week study, time in target zone (80-140 mg/dl; 4.4-7.8 mmol/l) increased 19% (MDI) and 17% (CSII) compared to (self) controls. There was significant improvement in glycemic variability with the use of CGM in both groups.
  • Richard Weinstein, MD (Diablo Clinical Research, Inc., Walnut Creek, CA) and colleagues studied Abbott’s Navigator CGM augmented with an algorithm that enables the device to report glucose readings one hour after insertion – as opposed to 10 hours as currently commercially available. The algorithm is called the TRUstart algorithm and if approved, could make up for a part of the competitive advantage that the DexCom and Medtronic systems hold over Abbott in the CGM arena – it only takes two hours for the current iterations of DexCom’s SEVEN PLUS and Medtronic’s Paradigm to start delivering readings. Accuracy measured by absolute relative difference (vs. YSI) was not compromised with the use of one-hour startup time. Mean and median absolute relative difference between Navigator readings and YSI readings were 14.5% and 10.7% respectively. Accuracy measured by Clarke Error Grid performance was likewise not compromised using the shorter startup time. The study reported 77.1% of the data pairs (CGM vs. YSI) in Zone A (clinically relevant/very accurate). This study could potentially mean that Abbott may be headed back to the FDA to try to obtain an indication that does not call for a 10-hour warm-up time
  • Timothy Bailey, MD (University of California at San Diego, La Jolla, CA) and colleagues studied the performance of the recently released DexCom SEVEN PLUS CGM in 53 subjects enrolled at three centers. The overall mean absolute relative difference (MARD) between CGM and YSI readings was 13.0%. Median ARD compared to SMBG was 12.1%. Clarke Error Grid analysis showed 73.8% of CGM/YSI data pairs in zone A, and 22.1% in zone B. The authors note that the data loss was much less with the SEVEN PLUS compared to the SEVEN.
  • Howard Zisser, MD (Sansum Diabetes Research Institute, Santa Barbara, CA) and colleagues investigated the accuracy of the GluCath (GluMetrics) intravascular continuous glucose monitoring system. The sensor met ISO-15197 standards for accuracy. Impressively, 100% of all values below 75 mg/dl were within 15 mg/dl of the reference value and 94.5% of all values above 75 mg/dl were within 20 mg/dl of the reference value. Clarke Error Grid analysis showed 95% of data pairs in Zone A, and the remaining 5% in Zone B. There were no adverse events reported.
  • Irl B. Hirsch, MD (University of Washington, Seattle, WA) reviewed recent advances in clinical trials testing the effectiveness of continuous glucose monitors (CGM). He addressed major pitfalls in the design of CGM trials and the interpretation of results. Most importantly, he provided the audience with valuable insight regarding the implications of these trials on the future of CGM technology. Dr. Hirsch concluded the lecture by explaining the complexities of type 1 diabetes and that more research addressing the behavioral issues associated with using a CGM device is required.
  • Denis Raccah, MD (University Hospital Sainte Marguerite, Marseille, France), presented Medtronic’s RealTrend study, which examined the effectiveness of continuous glucose monitor (CGM) versus self-monitoring of blood glucose (SMBG) in managing insulin doses administered with an insulin pump. One hundred and thirty two subjects with type 1 diabetes who were poorly controlled on multiple daily injections (MDI) were randomized to either the Medtronic Paradigm pump with integrated CGM or traditional pump treatment with SBMG. After six months, subjects in the Paradigm (PRT) group had an average A1c decrease of 0.81%, compared to 0.57% in the CSII group, although (surprisingly to us) this difference was not significant. In the subset of patients using their sensors more than 70% of the time, there was an A1c reduction of 0.96%, and this was significant versus the control group. The results are promising for CGM, and potentially could be interpreted as positive for the Paradigm system in particular – it remains, for now, the only integrated pump/continuous glucose monitor.
  • A talk by Roman Hovorka, PhD (University of Cambridge, Cambridge, UK) on closed-loop control focused on the use of an artificial pancreas system consisting of a CGM sensor, control algorithm, and insulin pump used in a small study in young subjects with type 1 diabetes. The primary goal of this ambitious study was to determine if such a closed loop system could maintain stable glucose levels overnight after three types of stress: small carbohydrate meal, large carbohydrate meal, and exercise. The closed loop system was evaluated against continuous subcutaneous insulin infusion therapy. As a consequence of the design, the study also evaluated the efficacy of the control algorithm developed. After the small meal, 61% of the closed loop patients remained in the target glucose range compared to 38% in the CSII group. This is a quite notable result in our view. After the large meal, the closed loop system performed comparable to CSII. The standard deviation of overnight glucose was slightly higher in the CSII group. Data from the exercise condition was not discussed in depth. There was a significant reduction (eight-fold) in the percentage of time spent in hypoglycemia in the closed loop group. Dr. Hovorka suggested his data shows that such a closed loop system could be a viable option for reducing the risk of nocturnal hypoglycemia. These results are intriguing, and we hope to see more work using closed loop systems, especially in situations in which the algorithm must address active changes in glucose levels. From a patient perspective, we appreciated the closing note of the talk, in Q&A: “Closed loop is not about perfection it is about improvement.”
  • Maggie Powers, PhD (International Diabetes Center, Minneapolis, MN) compared the glycemic impact of meals with varying carbohydrate content using continuous glucose monitoring technology (CGM, specifically Abbott’s Freestyle Navigator). Subjects with type 2 diabetes were fed four lunches, two moderate (45 g – wow we don’t necessarily think of that as moderate) and two high (90 g) in carbohydrate content, and were measured using CGM for four hours beginning at the start of the meal. She found significantly elevated peak glucose (+20 mg/dl), time to return to baseline (+38.1 minutes), four hour AUC, and four hour mean glucose. Given these findings, she concluded that significant differences exist in glycemic response to 45 gram lunch and 90 gram lunch, that relationships between quantity of carbohydrates and glycemic response are not linear, and CGM provides a more complete picture of glycemic response. She suggested that CGM could be a useful tool in nutritional therapy and noted that it could be particularly useful for type 2 diabetes patients with poor post-prandial glucose control.
  • Jessica R. Castle, MD (Oregon Health and Science University, Portland, OR), presented a study investigating the use of subcutaneous glucagon infusion during closed-loop control. Her study randomized subjects to either aspart (Novo Nordisk’s NovoLog) insulin alone or insulin plus glucagon. Subjects all had type 1 diabetes, and were controlled for nine hours surrounding a meal using a closed-loop system utilizing the Fading Memory Proportional Derivative (FMPD) algorithm. Results showed a trend toward increased time in zone and decreased time in hypo and hyperglycemia with glucagon treatment, none of which were significant. Nevertheless, these results provide a suggestion in humans that the use of glucagon in closed-loop systems could help avoid glycemic excursions.
  • Alicia Jenkins, MD (University of Melbourne, Melbourne, Australia), presented a study that examined the use of an algorithm to suggest treatment recommendations based on continuous glucose monitor (CGM) readings in patients newly initiated on CGM. The algorithm was accessed on a mobile phone, and gave patients suggestions based on their CGM’s glycemic zone and trend arrows, as well as the time of day. At 16 weeks, the subjects crossed over to the opposite arm and remained there until 32 weeks. The results showed an initial reduction in A1c in those subjects initially given the algorithm, which then disappeared when they discontinued its use. Interestingly, however, subjects who crossed over to algorithm use at 16 weeks did not realize any A1c benefit. Dr. Jenkins speculated that those subjects had already developed a system for interpreting their CGM readings and did not adapt to use of the new algorithm.
  • Steven J. Russell, MD (Boston University, Boston, MA) discussed a trial that tested a bi-hormonal (insulin and glucagon) closed-loop system in ten patients with type 1 diabetes over 27 hours, including three standardized meals. The system used venous BG measurements every five minutes and a model-predictive-control (MPC) algorithm to calculate infusion rates of lispro (Humalog by Lilly) and glucagon. The system maintained more stable glucose control between meals than open-loop control, with a mean glucose value of 143 mg/dl(8.5 mmol). Hypoglycemia was largely avoided in patients with normal lispro kinetics (five-eight hrs duration) but occurred frequently in patients who had abnormally slow lispro kinetics (nine- 24 hrs duration) because there was more insulin on board than the algorithm predicted. We think this illustrates the need for more rapid-acting insulin analogs with more consistent kinetics as research toward the artificial pancreas continues. We’re interested to see more work on this particular closed loop, particularly using subcutaneous CGM rather than venous BG measurements.
  • A “standard CGM” study, presented by Stuart A. Weinzimer, MD (Yale University, New Haven, CT), examined continuous glucose monitor’s (CGM) effects on A1c and hypoglycemia without additional support intervention. While subjects in recent trials have typically followed an intensive clinical management program, it is unknown how effective CGM can be when used in a setting more closely approximating normal clinical practice. This presentation focused only on the crossover period of the study, during which subjects previously on SMBG were switched to CGM for a period of six months. There was a significant 0.3% decrease in A1c in the adult group of the study only with a baseline A1c of 7.6%, and reductions of hypoglycemia in all groups. These results help to confirm that CGM can be helpful in a real-world setting, although we look forward to more complete data on this subject (and more clinical experience!).
  • David Rodbard, MD (Hahnemann Medical College and Hospital, Philadelphia, PA) discussed a valuable study exploring the challenge of how best to utilize statistical tools in order to evaluate CGM. Dr. Rodbard analyzed retrospective data looking at a variety of measures to evaluate quality and variability of glucose control. The data considered was masked for week one and unmasked for weeks two and three. Each subject served as their own control. There were dramatic statistical reductions in hyperglycemia and a reduction of variability of glucose levels on CGM. Dr. Rodbard concluded that the use of CGM, even for a short period of time, results in improvement in quality of glycemic control. He emphasized that there are several measures that are sensitive and reliable in evaluating CGM efficacy.
  • Martin Haluzik, MD (Charles University and General Teaching Hospital, Prague, Czech Republic) delivered a talk on the importance of glycemic control in critically ill patients and discussed a study exploring the use of CGM combined with a computer based eMPC algorithm in post cardiac surgery patients. The efficacy of ePMC-CGM was compared against standard protocols for intensive insulin therapy. According to Dr. Haluzik, the eMPC CGM group had lower blood glucose levels and there were no hypoglycemic events in the eMPC CGM group. He emphasized that the system showed reasonable accuracy and reliability and he believes it could represent an improvement in safety compared to the standard protocol for insulin therapy. He suggested that this is a promising step closer towards a fully automated closed loop system. We agree with Dr. Haluzik that these results are compelling and that further study needs to be done in larger trials and perhaps additional patient populations.
  • William H. Polonsky, PhD (Behavioral Diabetes Institute, San Diego, CA) listed five key psychosocial issues with CGM that need to be addressed: behavior, perceived benefits, perceived disadvantages, selection criteria, and innovative uses. The behavior issue addresses whether current CGM users are making appropriate use of their device, specifically how often and when the device is worn, and reaction to the data. The perceived benefits/disadvantages of CGM focus on the patients’ view of their devices. The selection criteria issue focuses on what types of patients will make good CGM users. The innovative uses issue addresses how CGM can be better used to enhance self-care and quality of life. Three other critical psychosocial issues need to be explored more: confidence, perceived treatment efficacy, and mistrust (how much to trust a CGM).
  • Neesha Ramchandani, APRN, PNP, CDE (Maimonides Medical Center and Children’s Hospital of Brooklyn, Brooklyn, NY) gave a very crisp, clear, and concise overview of real-time continuous glucose monitoring (RT-CGM). In addition to reviewing details of the technology, she pointed out the specific advantages of RT-CGM vs. blood glucose monitoring in pediatric type 1 patients: the ability for families and clinicians to see trends and make changes accordingly, decreased fear of hypoglycemia, and improved glucose control with increased sensor use. Limitations include problems with insurance, the need for a second insertion site for pumpers, and accuracy issues (±20%) – though CGM today is actually more accurate than the first blood glucose meters. Overall, she said that CGM has been embraced in her practice.
  • Donna M. Tomky, MSN, RN-C, CDE (ABQ Health Partners, Albuquerque, NM) advocated individualized glucose targets with less aggressive goals for individuals with frequent hypoglycemia or hypoglycemia unawareness. She mentioned that continuous glucose monitoring (CGM) offers a better picture of overall trends and briefly showed a graph of data from Garg et al., Diabetes Care, suggesting that use of CGM improves glucose trends. Most of her talk was devoted to interpreting meter data, however. Some of her tips included: organize the numbers into columns, color code numbers as fasting or postprandial, evaluate whether the A1c is consistent with logbook numbers, identify outlier numbers, and discuss these with the patient to identify problems and strategies for improvement.
  • The big takeaway from Esther Wei, MSN, ANP, CDE (NYP-Weill Cornell Medical Center, New York City, NY), who discussed pattern management in type 2 diabetes patients, was that regular self-monitoring of blood glucose (SMBG) is useful even in patients not on insulin. Several days of fasting and postprandial SMBG values are needed in order to identify trends and make changes. She said that unfortunately, most type 2 patients do not perform regular SMBG, either by preference or due to reimbursement issues. We were impressed with Ms. Wei’s work with patients; unfortunately most primary care offices do not have the resources to regularly review SMBG values, which is clearly essential for obtaining the most benefit out of patient self-monitoring.
  • During the Q&A on pattern management several attendees brought up the issue of using logbook data vs. downloading meter data using data management software in the office. The CDE speakers and attendees had various perspectives on this. Some argued that data management software allows for more accurate and efficient evaluation of trends in the office and that patients also benefit from being able to play with their own data. Others, who work only with older patients without computer experience, preferred logbooks and felt that they were a useful way of involving the patient in self-care. About two-thirds of the audience had used data management software before. Regarding trying out CGM sensors before buying them, Ms. Ramchandani praised Medtronic for making that possible while Ms. Tomky praised DexCom, which sponsors clinics at her hospital allowing patients to try out the sensor for a week before buying. The Navigator is not yet approved in pediatric patients.
  • Heather Lamar, RD, CDE (Diabetes Management Consultants, Las Vegas, NV), an educator and a CGM user, discussed the benefits of CGM and the use of retrospective data as well as provided suggestions for successful CGM use. She characterized standard deviation as an effective way of measuring glycemic variability in the clinic. A lower standard deviation allows for more effective recommendations because it’s easier to spot anomalies. Unfortunately, she said, there are no standards for standard deviation targets. Her initial target for standard deviation is <50% of optimal glucose with a final goal of <30%. She discussed case studies with glycemic control improvement from simply observing CGM tracings without additional input from a clinician. Another case study suggested that CGM gave a type 2 patient confidence in diabetes self-management and resulted in an A1c drop from 8.1% to 6.4%! We would like to see considerably more CGM study done in patients with type 2 diabetes to demonstrate whether improvements like this are the exception or the rule – we believe with proper education it is more likely they are the rule. Notably, in this talk, Ms. Lamar expressed a major desire for faster insulins.
  • Tim Wysocki, PhD (Nemours Children’s Clinic, Jacksonville, FL) opened his talk by recalling previous instances when people have confronted him after delivering this presentation for speaking negatively about CGM. He emphasized that his intention is to speak realistically about CGM. Dr. Wysocki explained that CGM use occurs in a psychosocial context and that behavioral, cognitive and affective factors can influence the frequency of use and benefit gained from CGM. Dr. Wysocki described a number of unsuccessful case studies from the JDRF CGM trial. These cases were categorized into three variables of psychological barriers: pain/discomfort/inconvenience, social complications such as family conflict, and lack of appropriate expectations. Historically, we have been among Dr. Wysocki’s critics, because we don’t think he talks (particularly the one in 2008 before the NIH) have had the appropriate constructive context, but we were impressed by this presentation and strongly agree that psychological barriers need to be addressed, not ignored. From our view, each generation of continuous monitor has significantly improved ease of use – it is inevitable that “hassle factor” is high with early generations and we felt it would have been helpful for Dr. Wysocki to discuss the impact of technological progress from generation to generation.
  • Irl Hirsch, MD (University of Washington, Seattle, WA) appeared at the Medtronic/LifeScan symposium to speak about the power and limitations of using CGM to help patients mimic normal glycemic patterns. The major theme of his talk centered on encouraging HCP and patients to learn how to utilize the wealth of information provided by CGM to the fullest. In order to realize the full benefits of CGM, a patient not only needs to understand how to use the information CGM provides, but how to make appropriate decisions based on this data in dosing insulin. Dr. Hirsch encouraged companies to incorporate glucose trend data into “bolus wizards”; he also mentioned upside for CGM in use for both MDI (multiple daily injectors’) as well as pump users. We believe we’ll be starting to hear much more about use in the first population.
  • Suzanne Ghiloni, BSN, RN, CDE (Joslin Diabetes Center, Boston, MA) covered realistic expectations, requisite knowledge base, and downloading in her presentation on the practical issues surrounding CGM use. She stressed the need for cumulative and repetitive learning with emphasis on hands-on training, and proactive (looking at downloads) and reactive (looking at the real-time display frequently) diabetes management. It is rewarding to start patients on this hopeful and productive journey. She quoted one patient as saying, “For the first time in my 15 years with diabetes, I can relax.”
  • Howard A. Wolpert, MD (Joslin Diabetes Center, Boston, MA) focused much of his presentation on optimizing CGM alarms. He described a set of steps that could be used in setting appropriate thresholds. Initially, wider target ranges are used and high and low thresholds are optimized separately. He noted his view that the lag between interstitial glucose and blood glucose makes CGM inappropriate to assess the response to treatment of hypoglycemia.
  • Ulrike Klueh, PhD (University of Connecticut, Storrs, CT) discussed the role of mast cells in biofouling, the process of pronounced degradation that has frustrated attempts to create a long-term implantable glucose sensor. Using a modified continuous glucose monitor (CGM) sensor implanted in wild-type mice and those genetically lacking mast cells, she was able to show that mast cells are responsible (at least in part) for the degradation of the sensor’s accuracy over a period of several weeks. In addition, the injection of mast cells into these genetically modified mice produced some sensor degradation. Since mast cells are critical for proper immune function, the translation of this research into a clinically applicable solution to the problem of biofouling is complicated.
  • Youqing Wang, PhD (University of California, Santa Barbara, CA) argued that because of delays in continuous glucose monitoring (CGM) systems and insulin action, it is too late to change basal insulin dosing once glucose values cross the hyper- or hypoglycemic thresholds. His group’s algorithm depends on both absolute glucose levels and rates of change to determine a ‘basal gain’. In the algorithm, rate of change (ROC) was taken into account between the values of 80 mg/dl (4.4 mmol/l) and 140 mg/dl (7.8 mmol/l), and was solely dependent on the glucose value below 80 mg/dl and above 140 mg/dl. Patients’ ROC would be re-estimated every thirty minutes. Adjustment of basal rate would be based on these measurements. The algorithm was tested in the UVA/Padova diabetes simulator, and was shown to increase amount of time spent in the target zones and particularly reduced hypoglycemia compared with a fixed basal insulin. Dr. Wang noted that clinical trials are needed to verify these results.
  • Hung T. Nguyen, AM, PhD (Timothy Jones University of Technology, Sydney, Australia) presented an impressive non-invasive continuous hypoglycemia-monitoring device, HypoMon, being developed by AIMedics, a company of which he is a senior member. HypoMon depends on signals that can be captured from the skin such as sweating and electrocardiogram (ECG) changes, including heart rate and QT interval. The presence of hypoglycemia is calculated by Bayesian neural networks, which concentrate on minimizing error. We believe many limitations exist with this study including a lack of calculation of false positives, a comparison with other continuous glucose monitoring (CGM) devices, and the absence of acknowledging the difficulty associated with detecting symptoms during hypoglycemia unawareness.
  • Frank L. Schwartz, MD (Department of Specialty, Ohio University, Athens, OH) presented a study (n = 1553) he performed in hospital settings to assess the effectiveness of using Glucotech’s G+ system, a computer directed algorithm for calculating intravenous (IV) insulin administration. The average time required for patients to achieve target ranges (107 mg/dl [6 mmol/l]) from an initial blood glucose of, on average, 260 mg/dl (14 mmol/l) was 2.5 hours. In conclusion, Dr. Schwartz asserted the data show that the G+ system is safe and effective in controlling blood glucose.
  • Lois Jovanovic, MD (Sansum Diabetes Research Institute, Santa Barbara, CA) summarized the mechanisms and risks associated with gestational diabetes. She explained the cause for particular birth defects with early hyperglycemia during pregnancy and provided data relating the use of continuous glucose monitoring (CGM) and macrosomia (birth weight > 90th percentile). She concluded that the frequency of blood glucose measurements trumps accuracy and that CGM devices are instrumental in identifying fluctuations in glucose measurements.
  • Jothydev Kesavadev, MD (Jothydeva Diabetes Research Center Trivandrum, Kerala, India) reviewed a small study (n=20) he conducted to summarize patient reactions to continuous glucose monitoring (CGM) and continuous subcutaneous insulin infusion (CSII) in a population of pre-selected highly motivated individuals. His practice found that highly motivated patients who exhibited impressive self-learning skills greatly benefited from the use of these devices, as evidenced by an increase in their quality of life (QOL).
  • Michael Riddell, PhD (York University, Toronto, Canada), a type 1 patient himself, discussed the role of exercise in diabetes. He explained why the improvement in glycemic control seen by type 2 diabetes patients is more difficult to replicate in type 1 diabetes patients using athletes as a case study. Athletes with type 1 diabetes do not necessarily have good metabolic control and often fear hypoglycemia. Iscoe et al. (DT&T, 2006) showed that exercise-induced hypoglycemia has both an acute and a delayed component, which makes it particularly dangerous. An unpublished study from Dr. Riddell’s group showed that continuous types of exercise reduce glucose levels while short intermittent exercise tends to cause hyperglycemia. We have heard much frustration from patients over the years in trying to understand and prevent this. We would like to know more about the role of CGM in exercise.

Symposium: Continuous Glucose Monitoring – Clinical Update

ADVANCES IN THE TECHNOLOGY OF CONTINUOUS GLUCOSE MONITORING

Howard A. Wolpert, MD (Joslin Diabetes Center, Boston, MA)

Dr. Wolpert presented an overview of the historical perspectives on technology in diabetes care, the impact of CGM on self-care behavior, and the advances in CGM technology. The big challenge with CGM is that it puts an extra burden on people with diabetes due to hardware hassles, information overload, and alarm fatigue. For many people these become barriers to sustained use of CGM. Additionally, potential causes of sensor inaccuracy and instability include: biofouling, mechanical obstruction of sensor membrane, calibration procedure, signal processing delays, and interfering substances. Overall, although improvements in CGM technology have set the stage for a paradigm shift in diabetes care, there are limitations in the point accuracy of current CGM devices, patients need further education, and wider adoption of CGM will depend on improved technology.

  • Dr. Wolpert presented an overview of the impact of CGM on self-care behavior and advances in CGM technology. Glucose monitoring technology has been an important part of improving diabetes care starting from urine testing to intermittent capillary testing, which led to changes in how diabetes patients manage insulin therapy and finally CGM. One of the problems is that there is an inverse relationship between A1c and the risk of hypoglycemia. The hope is that with CGM technology people with diabetes will be able to lower their A1c without the same risk for hypoglycemia. CGM also provides a more complete picture of glucose levels. The current CGM devices include: the Abbott Navigator, the DexCom Seven/SevenPLUS, and the Medtronic Paradigm 722/Guardian. Current research does not have strong conclusions regarding which CGM device is the most accurate.
  • The big challenge with CGM is that it puts an extra burden on people with diabetes due to hardware hassles, information overload, and alarm fatigue. For many patients these become barriers to sustained use of CGM. In order to lessen the hurdles there needs to be improvements in the technology focusing on the risk for sensor burnout. Overall, improvements with technology are associated with better adherence. Studies have shown that there are some key differences between responders and non-responders to CGM including that responders have a greater capacity to shift and have a more self-controlled coping style. Shifting is defined as the ability to problem-solve flexibly, switch or alternate attention, and change focus from one mindset topic to another.
  • Potential causes of sensor inaccuracy and instability include: biofouling (inflammatory response, protein deposition on membrane), mechanical obstruction of sensor membrane, calibration procedure, signal processing delays, and interfering substances. Sensor inaccuracy in current CGM devices affects the sensitivity and specificity of the CGM alarms which leads to a clinical conundrum when setting the alarm threshold as doctors want to lesson alarm fatigue while at the same time accurately alerting patients.
  • Dr. Wolpert discussed a number of interesting avenues for improvement. Improvements that can help lessen alarm fatigue include enhanced alarm functionality such that a patient can have different alarms for different times of the day and as well as an adjustable alarm snooze function. Other improvements will include various algorithms for meal detection and pump suspension, which will ultimately help prevent hypoglycemia.
  • Overall, while improvements in CGM technology have set the stage for a paradigm shift in diabetes care, there are limitations in the point accuracy of current CGM devices, patients need further education, and wider adoption of CGM will depend on improved technology.

Questions and Answers

Q: One of the problems with starting patients on CGM is patients’ tendency to overreact. How do you train patients not to expect things to happen so fast so they do not overreact and thus over bolus?

A: You highlight a key important issue. Patients need a lot of training in terms of bolus and they need to understand the glycemic index so that they better understand their postprandial glucose profiles. People can have more incidence of hypoglycemia because they tend to over bolus.

REVIEW AND UPDATE OF RECENT CONTINUOUS GLUCOSE MONITORING TRIAL RESULTS

Irl B. Hirsch, MD (University of Washington, Seattle, WA)

Dr. Hirsch reviewed recent advances in clinical trials testing the effectiveness of continuous glucose monitors (CGM). He addressed major pitfalls in the design of CGM trials and the interpretation of results. Most importantly, he provided the audience with valuable insight regarding the implications of these trials on the future of CGM technology. Dr. Hirsch concluded the lecture by explaining the complexities of type 1 diabetes and that more research addressing the behavioral issues associated with using a CGM device is required.

  • Dr. Hirsch briefly discussed his interpretation of the results of the DCCT and STAR1 trials. He claimed that the DCCT trial did not test the efficacy of self-monitoring blood glucose (SMBG) although it is often interpreted in such a manner. He also expressed interest in the STAR1 trials, despite the results showing no difference in A1c levels between patients using CGM and patients using SBMG. He believes STAR1 taught the industry how to better design CGM trials, use CGM, and select appropriate candidates who will actually use the device.
  • Dr. Hirsch emphasized the importance of patient willingness to use the CGM device, which he argued is a key component to achieving glucose control.
  • Dr. Hirsch explained the desperate need for a better gold standard for the assessment of glycemic variability with CGM. He urged physicians to understand that type 1 diabetes is more complicated than taking a daily pill or injection and that handing a patient a CGM device or SMBG meter will not magically control blood glucose. He believes that we need more research addressing behavioral and mental issues associated with CGM use, especially in teens.

PSYCHOLOGICAL ASPECTS OF CONTINUOUS GLUCOSE MONITORING

William H. Polonsky, PhD (Behavioral Diabetes Institute, San Diego, CA)

The behavior issue addresses whether current CGM users are making appropriate use of their device, specifically how often and when the device is worn, and reaction to the data. The perceived benefits/disadvantages of CGM focus on the patients’ view of their devices. The selection criteria issue focuses on what types of patients will make good CGM users. The innovative uses issue addresses how CGM can be better used to enhance self-care and quality of life. Three other critical psychosocial issues need to be explored more: confidence, perceived treatment efficacy, and mistrust (how much to trust a CGM and how to deal with a device that one can only trust conditionally).

  • Dr. Polonsky started by emphasizing that the psychosocial issues with CGM need to be conceptualized and that right now we do not know very much. There are five key critical issues that need to be addressed: behavior, perceived benefits, perceived disadvantages, selection criteria, and innovation uses.
  • The behavior issue addresses whether current CGM patients are making “appropriate” use of their device, specifically how often and when the device is worn, and reaction to the data. Informal surveys have shown that intermittent use is the most common approach to CGM due to cost, aggravation, and the need for a “diabetes vacation.” Dr. Polonsky reminded everyone that the dirty secret is that everyone takes time off from his or her diabetes. There is no research available showing how patients use the data from CGM and if they are using it well. Oftentimes the manner in which people think about their device determines how they use the data and often the most successful patients with CGM are those who view the device as a compass rather than as a GPS. It is quite common for patients to overreact to the data as they do not fully understand that there is a lag time between interstitial glucose and blood glucose. There is general mistrust of the CGM data as well, which is an additional issue.
  • The perceived benefit of CGM focuses on what patients value about their devices. Dr. Polonsky spoke about his real world observations where patients often say that CGM gives them “piece of mind” and it reduces their fear of hypoglycemia; they “feel more confident when [they are] out and about.” Additionally, individual blood glucose values are less emotionally-laden and patients feel more in control of their diabetes. Spouses and parents also feel more comfortable both during the day and at night since they can allay any fears by looking at the device. Ultimately, the key point is that the device is enhancing people’s confidence.
  • Perceived disadvantages of CGM include negatives patients see in the devices. The main reasons Dr. Polonsky gave for patients quitting CGM are cost, disappointing results, adhesive problems, bulkiness, and alarms. Often spouses will wake up to the CGM alarms (and users/patients do not) creating frustration and tension between spouses. Another problem is the question of how much the user can trust the device. Ultimately, there is a love-hate relationship between patients and their CGM.
  • The selection criteria issue focuses on what types of patients will make good CGM users. Characteristics that predispose patients towards wearing the CGM at least 50% of the time include: appropriate expectations (not a cure, perfection not probable, self-care still needed), an obsessive nature, and having an engineering or scientific degree (high level numeracy and problem solving skills). Unfavorable characteristics include: teens (especially those without effective parental support), innumeracy, and hyperglycemic fear syndrome. The next step is to design instructions on how to assess whether a patient will make a good CGM user.
  • The innovative uses issue addresses how CGM can be better used to enhance self- care and quality of life. Dr. Polonsky suggested potential uses such as addressing fear of hypoglycemia, new approaches to diabetes education, and promoting patient activation and motivation.
  • Overall, Dr. Polonsky emphasized that three critical psychosocial issues relating to CGM need to be explored: confidence, perceived treatment efficacy, and mistrust (how much to trust a CGM and how to deal with a device that one can only trust conditionally). For now, intermittent use is and will be the norm and training programs need to be developed to support such intermittent use.

Questions and Answers

Q: I know that there is no data but there is a lot of depression in diabetes. Can technology play a role in reducing depression?

A: If you think about real major depressive disorder, then probably not but if you think about moderate depression related to diabetes then the answer is yes indeed.

THE UTILITY OF CONTINUOUS GLUCOSE MONITORING IN PREGNANCY

Lois Jovanovic, MD (Sansum Diabetes Research Institute, Santa Barbara, California)

Dr. Jovanovic summarized the mechanisms and risks associated with gestational diabetes. She explained the cause for particular birth defects with early hyperglycemia during pregnancy and provided data relating the use of continuous glucose monitoring (CGM) and macrosomia (birth weight > 90th percentile). She concluded that the frequency of blood glucose measurements trumps accuracy and that CGM devices are instrumental in identifying fluctuations in glucose measurements.

  • Dr. Jovanovic presented data linking hypoglycemia with spontaneous abortion. She noted that the prevalence of spontaneous abortion rose exponentially with the presence of hypoglycemia, especially in the first trimester. She presented the alarming statistic that women with type 2 diabetes are 13% more likely of having a child with a birth defect. Malformations are related to glucose concentrations, not the type of insulin. Dr. Jovanovic pointed to studies by Wyatt et al. that reported 27 malformations in 500 observed pregnancies. All 27 malformations occurred when the mother’s A1c was two standard deviations above the mean A1c. No other congenital defects were observed out of the 500 observed pregnancies.
  • Dr. Jovanovic urged against the use of oral agents, such as metformin, which are known to cross the placenta. Dr. Jovanovic explained that while maternal glucose crosses the placenta, exogenous insulin does not. Therefore, the fetus responds to hypoglycemic stimulus by secreting large amounts of insulin. She warned that if the fetus has inherited a genetic susceptibility for type 2 diabetes, the hyperinsulinemia could cause insulin resistance.
  • Macrosomia results in visceral adiposity. Dr. Jovanovic reported an association between peak post-prandial response greater than 120 mg/dl (6.7 mmol) and increased risk of giving birth to a child with macrosomia. In conclusion, Dr. Jovanovic stressed the importance of glycemic control in minimizing fetal risks.

Symposium: Pattern Management – The GPS for Blood Glucose Control

PATTERN MANAGEMENT IN TYPE 1 DIABETES IN ADULTS

Donna M. Tomky, MSN, RN-C, CDE (ABQ Health Partners, Albuquerque, NM)

Ms. Tomky advocated individualized glucose targets with less aggressive goals for individuals with frequent hypoglycemia or hypoglycemia unawareness. She mentioned that continuous glucose monitoring (CGM) offers a better picture of overall trends and briefly showed a graph of data from Garg et al., Diabetes Care, suggesting that use of CGM improves glucose trends. Most of her talk was devoted to interpreting meter data, however. Some of her tips included: organize the numbers into columns, color code numbers as fasting or postprandial, evaluate whether the A1c is consistent with logbook numbers, identify outlier numbers, and discuss these with the patient to identify problems and strategies for improvement.

  • Ms. Tomky emphasized that diabetes educators need to understand what their patients are doing and their blood glucose records; often insulin adjustments are made without asking the right questions. Pattern management is defined as a system for organizing, sorting and processing glucose data that links to patient self-care behaviors and reveals trends or patterns with the ultimate goal of bringing a patient back into glycemic control. Pattern management concerns include: approaches for organizing data to best identify glucose trends or patterns, improving self-care behaviors for patients, and asking the right questions to discover what patients are doing to affect their glucose control.
  • Steps in pattern management include: 1) consider guidelines and establish individual targets; 2) gather and organize glucose data; 3) find patterns through data analysis; 4) identify desired changes and strategies to bring glucose back to target ranges; 5) develop a plan of action; and 6) evaluate the response to the plan and revise the plan if necessary.
  • She suggested four key questions for healthcare providers to ask themselves when interpreting blood glucose results: 1) What does the A1c level tell you? 2) What does the history tell you? 3) What do the BGM records tell you? 4) What is your approach? Overall, diabetes self-management is complex and diabetes educators need accurate and sufficient data to determine a plan of action and develop problem solving.

PATTERN MANAGEMENT FOR TYPE 2 DIABETES IN PRIMARY CARE—CAN IT BE DONE?

Esther Wei, MSN, ANP, CDE (NYP-Weill Cornell Medical Center, New York City, NY)

Ms. Wei’s talk on pattern management in type 2 diabetes patients showed that regular self-monitoring of blood glucose (SMBG) is necessary in order for patterns to emerge, and is useful even in patients not on insulin. Several days of fasting and postprandial values are needed in order to identify trends and make changes. She said that unfortunately most type 2 patients do not perform regular SMBG, either by preference or due to reimbursement issues. We were impressed with Ms. Wei’s work with patients; unfortunately most primary care offices do not have the resources to regularly review SMBG values, which is clearly essential for obtaining the most benefit out of patient self-monitoring.

  • Regular self-monitoring of blood glucose (SMBG) is useful for optimizing control in type 2 diabetes – though unfortunately most type 2 patients do not perform regular SMBG, either by preference or due to reimbursement issues. One of Ms. Wei’s case studies was an obese type 2 who had lost 20 lb on exenatide (Amylin’s Byetta) but whose A1c values were still creeping up; after examination of her 4x/day logbook values, Ms. Wei was able to find the source of the problem.
  • The basic steps for the clinician are: 1) know the target; 2) gather data; 3) look for patterns; 4) assess for influencing factors; and 5) take action. Ms. Wei’s practice follows the ADA’s target recommendations for glucose goals. Several days of consistent 4x/day logbook data are necessary in order to find patterns. Three days of elevated numbers or two days of depressed numbers should be cause for medication adjustment.
  • Insulin should be added when oral medications are insufficient. Ms. Wei pointed out that there is huge inertia to insulin initiation. She showed data that type 2s spend on average five years with A1c >8% and 10 years wit A1c >9%. Basal and oral meds are good for high fasting values. For patients with elevated values throughout the day, premixed insulin is good if they eat consistent meals while basal/bolus is the most flexible.

PATTERN MANAGEMENT FOR CHILDREN AND PARENTS

Neesha Ramchandani, APRN, PNP, CDE (Maimonides Medical Center and Children’s Hospital of Brooklyn, Brooklyn, NY)

Ms. Ramchandani gave a very crisp, clear and concise overview of real-time continuous glucose monitoring (RT-CGM). In addition to reviewing details of the technology, she pointed out the specific advantages of RT-CGM vs. blood glucose monitoring in pediatric type 1 patients: the ability for families and clinicians to see trends and make changes accordingly, decreased fear of hypoglycemia, and improved glucose control with increased sensor use. Limitations include problems with insurance, the need for a second insertion site for pumpers, and accuracy issues (±20%) – though CGM today is actually more accurate than the first blood glucose meters. Overall, she said that CGM has been embraced in her practice.

  • Ms. Ramchandani gave a very clear and concise overview of real-time continuous glucose monitoring (CGM). CGM can be customized to each individual patient including out-of-range alarms, target blood glucose values, and predictive alarms. However, the CGM is not 100% accurate and thus highs and lows need to be confirmed with a meter. In her practice every child is an appropriate candidate for CGM; however, the child must be willing to wear the device or convinced to wear the device and the child’s family must be able to afford the CGM ($35 to $80 per sensor after the starter cost). She said that while the sensors last from three to seven days, patients usually use them for twice as long.
  • The advantages of CGM in children with type 1 diabetes include: helping parents sleep through the night by decreasing anxiety about hypoglycemia, better correction of overnight doses, better understanding of glucose variability during school, exercise, and post exercise, and helping children when they are out with friends, at sleepovers, etc. CGM has a large impact on children and their parents as the child and family is alerted to low and high blood sugars as they happen. Also, there is a decreased fear of hypoglycemia, increased security (parents can sleep through the night without worry), fewer fingersticks, and more autonomy for the patient and their family.
  • The limitations of CGM include: accuracy (±20%), lag time (10-12 minutes, can be up to 20 min), insurance coverage, and the need for two insertion sites in patients using both CGM and an insulin pump.
  • CGM makes it possible to see what is happening in between fingersticks. This allows for better decision making when making adjustments, which has led to a decrease in A1c and glycemic variability. This is because patients get up to 288 readings per day from CGM vs. four to 10 readings per day from a meter. She reviewed a few case studies of patients who went on various different CGM monitors and were able to improve their BG control due to better knowledge of trends. Overall, she said that CGM has been embraced in her practice.

CLINICAL VALUE PANEL DISCUSSION

During the Q&A on pattern management the various attendees brought up the issue of using logbook data vs. downloading meter data using data management software in the office. The CDE speakers and attendees had various perspectives on this. Some argued that data management software allows for more accurate and efficient evaluation of trends in the office and that patients also benefit from being able to play with their own data. Others, who work only with older patients without computer experience, preferred logbooks and felt that they were a useful way of involving the patient in self-care. About two-thirds of the audience had used data management software before. Regarding trying out CGM sensors before buying them, Ms. Ramchandani praised Medtronic for making that possible for that while Ms. Tomky praised DexCom, which sponsors clinics allowing patients to try out the sensor for a week before buying. The Navigator is not yet approved in pediatric patients.

Q: When patients need to test more often and Medicare only allows one test per day because they’re on oral agents, how do you get more information on trends?

Ms. Wei: It depends on what medication they are on. I might have them alternate what time they check on different days.

Q: Good job, Esther, on getting POC A1c testing in the primary care setting.

Ms. Wei: Yes. We did an abbreviated study of the effect of POC testing by looking at what providers did when the A1c was >7%. We had to set up an elaborate system to make sure the patients got their A1c values checked before they saw their doctor. The data were really impressive: 60% of the patients with A1c >7% had a medication change made and the remainder had some other change made, i.e., referral to dietician, change in daily habit, etc.

Comment: Logging into the logbook can take a long time for patients. OneTouch UltraSmart is really good for correlating information with meals.

Q: How do you tell when patients are fabricating numbers?

Ms. Ramchandani: My pediatric patients almost never log numbers anymore. I usually write down the meter average at every visit and that can give me information if they are logging and are fabricating. I tell parents not to use the words “cheating” or “sneaking”.

Comment: I think an emphasis on eliminating hypoglycemia is more important than chasing the highs. I try to tell my patients to be ‘hypoglycemia detectives’.

Comment: I find copies of logbooks worthless. We looked for a better way of recording it called the GlucoGraph. It makes it a lot easier to look at profiles.

Comment: I like data management better than logbooks. I download all of the meter data and the pump data. It is so time efficient that I can spend my time looking over the patterns with my patient, which I wouldn’t be able to if I were looking over 30 pages of logbook. And I don’t have to worry about made-up numbers.

Q: How do you feel about download programs?

Ms. Tomky: Clinicians find their own preferred software. I think the graphs and pictures are useful for patients.

Survey: How many of you have used data management software? [About 2/3 raised their hands]

Comment: We have found that patients who want to lose weight are hungrier on Lantus and less hungry on Levemir or NPH.

Comment: A lot of us think data management is the be-all and end-all, but not all of our patients have the ability to use the data management at home. Using some type of logbook at home can help with that. I work with a lot of elderly patients who don’t understand technology.

Ms. Wei: I agree. Most of my patients do not have computers.

Q: What is your experience with patients trying out CGM or pumps?

Ms. Ramchandani: Medtronic has the easiest way for patients to try out the sensor for a week. Navigator is not approved for children yet.

Ms. Tomky: DexCom sponsors clinics in which our patients can try the sensor for a week. Comment: DexCom gives a 30-day guarantee.

Case Study: Continuous Glucose Monitoring – Translating Sensor Data into Practice

BASAL INSULIN/MEAL ADJUSTMENTS

Heather Lamar, RD, CDE, (Diabetes Management Consultants, Las Vegas, NV)

Heather Lamar, an educator and a CGM user, discussed the benefits of CGM and the use of retrospective data as well as provided suggestions for successful CGM use. She characterized standard deviation as an effective way of measuring glycemic variability in the clinic. A lower standard deviation allows for more effective recommendations because it’s easier to spot anomalies. Unfortunately, she said, there are no standards for standard deviation targets. Her initial target for standard deviation is <50% of optimal glucose with a final goal of <30%. She discussed case studies with glycemic control improvement from simply observing CGM tracings without additional input from a clinician. Another case study suggested that CGM gave a type 2 patient confidence in diabetes self-management and resulted in an A1c drop from 8.1% to 6.4%! We would like to see considerably more CGM study done in patients with type 2 diabetes to demonstrate whether improvements like this are the exception or the rule – we believe with proper education it is more likely they are the rule. Notably, in this talk, Ms. Lamar expressed a major desire for faster insulins.

  • At Diabetes Management Consultants, CGM training is 1-on-1 and lasts about an hour. Education is focused on how to analyze trends with a one-week follow-up for hands on data analysis. Most importantly, it is important to keep diabetes management coaching concepts as simple as possible. She repeatedly stressed the need for patient empowerment.
  • Ms. Lamar noted that patients have an additional focus on quality of life as well as optimal glucose control with less hypoglycemia – for clinicians, the focus primarily tends to be on just optimal control. She asserted the need for a paradigm shift in patient understanding of diabetes to teaching patients the value of the trend.
  • There is no “best” retrospective data to observe. Different data reports provide different types of information. She did express a bias towards hourly statistical charts.
  • Standard deviation is an effective way of measuring and explaining glycemic variability in the clinic. A lower standard deviation allows for more effective recommendations because it’s easier to spot anomalies. Unfortunately there are no standards for standard deviation targets. Her initial standard deviation target is <50% of optimal glucose with a final goal of <30%.
  • She was insistent that current insulins are not fast enough and expressed anticipation for faster acting insulin.
  • During her case study presentation, she described marked improvements in time spent within target zones in patients who were simply instructed to observe the CGM i.e., they were not given any therapy adjustments but they were independently able to improve their glucose numbers. There was another case study, in which CGM helped her figureout whether a patient’s daytime hyperglycemia was due to improper bolusing or basal insulin levels. CGM helped them determine that the problem was associated with carb-counting, since glycemia improved when the patient ate foods with easily available nutritional information.
  • She has also had success with type 2 diabetes patients on CGM. She found the device gave the patient more confidence about diabetes management and discussed one case in which a patient’s A1c dropped from 8.1% to 6.4%. A similar confidence boost was seen in a type 1 patient who were afraid of hypoglycemia. She taught the patient to use CGM in order to give her enough confidence not to eat when her glucose levels were stable.

PHYSICAL ACTIVITY ADJUSTMENTS

Michael Riddell, PhD (York University, Toronto, Canada)

Dr. Riddell, a type 1 patient himself, discussed the role of exercise in diabetes. He explained why the improvement in glycemic control seen by type 2 diabetes patients is more difficult to replicate in type 1 diabetes patients using athletes as a case study. Athletes with type 1 diabetes do not necessarily have good metabolic control and often fear hypoglycemia. Iscoe et al. (DT&T, 2006) showed that exercise- induced hypoglycemia has both an acute and a delayed component, which makes it particularly dangerous. An unpublished study from Dr. Riddell’s group showed that continuous types of exercise reduce glucose levels while short intermittent exercise tends to cause hyperglycemia. We have heard much frustration from patients over the years in trying to understand and prevent this. We would like to know more about the role of CGM in exercise. A possible explanation is that glucose levels rise since heart rate, VO2, respiration exchange rate, and ventilation rates are continually rising over the course of intermittent exercise. It is possible that performing sprints after continuous exercise may prevent delayed hypoglycemia; however this needs to be validated in additional studies.

  • Exercise improves cardiovascular (CV) risk, delays micro- and macrovascular diseases, enhances psychosocial development, improves fitness and body composition and can enhance glycemic control in type 2 diabetes.
  • Athletes with type 1 diabetes do not necessarily have good metabolic control and often fear hypoglycemia. Exercise increases glucose turnover 2-10 fold and actually decreases neuroendocrine and autonomic nervous system counterregulation dysfunction during hypoglycemia.
  • Iscoe et al. (DT&T, 2006) showed that exercise-induced hypoglycemia has both an acute and a delayed component, which makes it particularly dangerous. This is why physicians recommend waking up in the middle of the night to test blood glucose after a day involving exercise. Going to bed with a high blood sugar level does not protect from exercise- induced hypoglycemia. In type 1 diabetes, (exogenous) insulin levels do not decrease after exercise (as in non diabetes patients) and the glucagon response is impaired.
  • CGM glucose values lag behind blood glucose values which becomes very pertinent during times of exercise and emphasizes the importance of differentiating between the trending value of CGM versus the point glucose estimates.
  • An unpublished study from Dr. Riddell’s group showed that continuous types of exercise decrease glucose levels while short intermittent exercise tends to cause hyperglycemia. A possible explanation of this phenomenon is that glucose levels rise since heart rate, VO2, respiration exchange rate, and ventilation rates are continually rising over the course of intermittent exercise.
  • It is possible that performing sprints after continuous exercise may prevent delayed hypoglycemia but this needs to be validated in additional studies.

BEHAVIORAL MEDICINE ISSUES

Tim Wysocki, PhD (Nemours Children’s Clinic, Jacksonville, FL)

Dr. Wysocki opened his talk by recalling previous instances when people have confronted him after delivering this presentation for speaking negatively about CGM. He emphasized that his intention is to speak realistically about CGM. Dr. Wysocki explained that CGM use occurs in a psychosocial context and that behavioral, cognitive and affective factors can influence the frequency of use and benefit gained from CGM. Dr. Wysocki described a number of unsuccessful case studies from the JDRF CGM trial. These cases were categorized into three variables of psychological barriers: pain/discomfort/inconvenience, social complications such as family conflict, and lack of appropriate expectations. Historically, we have been among Dr. Wysocki’s critics, because we don’t think he talks (particularly the one in 2008 before the NIH) have had the appropriate constructive context, but we were impressed by this presentation and strongly agree that psychological barriers need to be addressed, not ignored. From our view, each generation of continuous monitor has significantly improved ease of use – it is inevitable that “hassle factor” is high with early generations and we felt it would have been helpful for Dr. Wysocki to discuss the impact of technological progress from generation to generation.

  • It is reasonable to think that pediatric patients may achieve glycemic benefit via CGM. CGM does not appear to have adverse effects on quality of life.
  • The JDRF CGM trial had a strongly statistically significant interaction between treatment effect and age. Those of age 25 years and over had significant A1c improvement but those below 25 years of age did not. Adults were much more likely to use the device six or more days per week. Patients who used the device six or more days a week had marked glycemic benefits independent of age.
  • He described some unsuccessful cases from the JDRF CGM study. One case involved a mother who was overbearing about her daughter’s glucose resulting in the child’s rebellion. Another case described an adolescent who refused to wear sensors because of discomfort and incessant questions from peers (after finagling an iPhone from his parents in exchange for participating in the study). One more case involved a child who turned off the alarms to avoid having to take additional necessary boluses.
  • He pointed out the importance of being realistic about the potential advantages of CGM and the significant amount of effort required for effective usage. He also urged healthcare providers to be positive when discussing data. Patients should use the device often enough to benefit from the experience and leave alarms on whenever possible. They should be ready to cope with the increased volume of information and additional hassle required to use the technology.
  • In conclusion, CGM use occurs in a psychosocial context and behavioral, cognitive, and affective factors can influence the frequency, use, and benefit of CGM. Dr. Wysocki categorized three variables of issue: pain/discomfort/inconvenience, social complications such as family conflict, and lack of appropriate expectations. These issues affect the frequency of CGM and this has a negative effect on active self-regulation. Dr. Wysocki believes that variability in glycemia, and notably in diabetes self-management, will be an important moderator of the link between active self-regulation and glycemic control. From our view, each generation of continuous monitor has significantly improved ease of use – it is inevitable that “hassle factor” is high with early generations and we felt it would have been helpful for Dr. Wysocki to discuss the impact of technological progress from generation to generation.

Questions and Answers

Q: How effective is the IOB feature when paired with CGM?

Heather Lamar: I think it is a good tool but I’ve lost some faith in it after cross-referencing CGM data with IOB data. The problem is that pumps cannot take into account the glucose trend when giving bolus-dosing recommendations.

Q: How would you help a pregnant lady whose obstetrics team tells her not to exceed 7.0 mmol/l (126 mg/dl) resulting in hypoglycemic events four to five times a day?

Heather Lamar: I think the focus needs to be on teaching appropriate carb-counting. You should also determine if the mother is using the trend data appropriately.

Comment: We should be thinking more about basal insulin adjustments and exercise.

Q: Can you comment on the lack of independence of children with technological improvement?

Dr. Wysocki: Data shows that families that maintain healthy parent-youth collaboration do better. The issue is that the kind of involvement of the parent should evolve with the child’s maturity. In children, parents are basically the monitors. In middle-youth, parents are executives and in adolescence, parents are basically consultants.

Comment: With kids, we should pay attention to being positive when discussing management in order to gain effective results. We should also be ready to commend good numbers.

Q: Can you predict which patients will do well on CGM?

Dr. Wysocki: No. But I’m optimistic that kind of a profile may be created eventually. We should think as much about using this technology in patients who are not achieving their goals even though they are trying as opposed to just putting it on our best-motivated patients. I don’t think it is likely we will find a CGM personality type.

Q: In non-athletes, is it possible to use it intermittently and maintain the benefit?

Heather Lamar: I think it helps motivate patients especially with the exercise. One of the biggest complaints I get is that I feel like I have to eat before exercise so I don’t go into hypoglycemia, which defeats the purpose of exercise. CGM helps them see whether they actually need to eat.

Q: What is the best snack to prevent nocturnal hypoglycemia?

Dr. Riddell: The best bedtime snack to prevent nocturnal hypoglycemia seems to be a slow release carbohydrate (or something that has fiber and is a protein source).

Oral Presentations: Continuous Glucose Monitoring and Closing the Loop

SUSTAINED BENEFITS OF CONTINUOUS GLUCOSE MONITORING THROUGH 12 MONTHS OF SENSOR USE IN THE JDRF CGM RANDOMIZED CLINICAL TRIAL

Bruce Bode, MD (Atlanta Diabetes Associates, Atlanta, GA)

Dr. Bode presented very exciting one-year data from the JDRF CGM trial – an independent study looking into the efficacy of CGM in patients with type 1 diabetes over a year long period in three different age cohorts. The primary goal of this study was to determine if improvements in glycemic control, including avoidance of hypoglycemia, could be sustained during a full year of CGM use. The previously published (and now considered landmark, published in NEJM) six-month results showed that CGM improves both A1c and hypoglycemia for patients over 25 years, and for all patients who used the device frequently.

At the one-year mark, initial benefits in A1c were sustained over the year in both the greater than 7% (≥7%) A1c at baseline cohort and the less than 7% (<7%) A1c at baseline cohort. In particular, children aged eight to fourteen years old in the >7% cohort demonstrated an A1c improvement, which hadn’t been statistically significant in the first 26 weeks. As before, adolescents failed to show a benefit unless they used the device consistently.

A major highlight of this data was that A1c gains were sustained in the next six months following the initial six months and the rates of hypoglycemia continued to fall significantly for both groups. Incredibly, adults in the <7% group experienced zero (zero!) severe hypoglycemia. Children in the <7% group experienced an A1c increase of 0.4% (which was significant). Although this seems counterintuitive, we assume that due to lower hypoglycemia and reduced glycemic variability contributed to the A1c increase. Presenters said that because the children were still well controlled, the trade-off (higher A1c) was worth it. It wasn’t discussed, but we believe these results reinforce that teens are very hard to treat; absent from the conversation, however, was the fact that CGM adherence will improve when the devices become easier to use. As a reminder, many in the trial had first-generation devices that now have advanced to later generations that are considerably more user-friendly.

  • This independent study examined the efficacy of CGM use in three age cohorts over a 12-month period. The study included 322 subjects in three age groups: children age eight to fourteen years old, adolescents age 14-25, and adults above age 25. There were 10 clinical sites involved in the study and patients were grouped into cohorts who had A1c≥7% at baseline and those with A1c<7% at baseline. Completion rate was exceptional, with 95% of the A1c≥7% patients completing the study and 100% of A1c<7% completing the program.
  • In the first six months (previously reported), all subjects with CGM use of greater than six days/week showed downward trends in A1c with the adult group experiencing a clinically significant drop in A1c of 0.5%. The control group showed a rising trend in A1c levels.
  • After twelve months, there was a slight trend in decreasing device use in the A1c≥7% group that was not seen in the A1c<7% group.
  • In the A1c7% cohort, after one-year, the improvement in adult A1c was sustained, the child cohort attained clinically significant reductions in A1c, and the adolescent group A1c showed a non-significant downward trend. The adults maintained the significantly reduced A1c levels obtained in the first six months compared to baseline while the child age group reached A1c reductions that were finally clinically significant after one-year. The adolescent group did not obtain significantly reduced A1c levels, but did show downward trends. From our view, this reinforces that teens are very hard to treat; we believe more will use CGMwhen the devices improve. As a reminder, many in the trial had first-generation devices that now have advanced to later generations that are considerably easier to use.
  • In the A1c<7% cohort, after one-year, the adults maintained low A1c levels, adolescent A1c did not differ significantly from baseline, and the users in the child age group showed a statistically significant increase in A1c levels from 6.2% to 6.6%. This increase was surprising, but Dr. Bode did not comment or speculate as to its cause. We suspect that it is due to the elimination of hypoglycemia (see below).
  • Hypoglycemia fell for all groups over the one-year period. Most impressively, in the A1c<7% cohort hypoglycemia rates fell in the adolescent group and dropped to zero in both the adult and children groups.
  • Dr. Bode emphasized that CGM can be effective in helping patients sustain improved glucose control while reducing the risk of hypoglycemia over time. He showed a great graphic of the original DCCT A1c/hypoglycemia trade-off with the JDRF data overlaid, showing a far superior trade-off. As before, it is important for patients to use the device consistently to obtain optimal results.

Questions and Answers

Q: In the child group of A1c<7% where A1c rose, was there a correlation in the amount of insulin the subjects used?

A: Insulin use remained the same overall in the study; however, we do know that individuals did change their insulin dosage. In the children where A1c levels increased we do not have a separate analysis on insulin dosing.

Q: If you look at sensing in the adult group, if people with diminished use less than six days in the second half, does that correlate with diminished success in A1c?

A: There isn’t a slight rise in adults, only in children. There is a learning curve, the more you wear it, the better you do. The rates of hypoglycemia approached zero, which shows that they have to learn how to use their sensor and alarms system.

PREVENTING NOCTURNAL HYPOGLYCEMIA USING PREDICTIVE ALGORITHMS AND PUMP SUSPENSION

Bruce Buckingham, MD (Stanford University, Stanford, CA)

Dr. Buckingham discussed the use of an algorithm to shut off insulin delivery and avoid hypoglycemia. The algorithm uses a more sophisticated ‘voting system’ in which five prediction algorithms contribute to the insulin shutoff decision-making process. In a trial of 14 patients, 84% of all nighttime hypoglycemia events were avoided. WHEW! This is a very impressive result, and takes ‘Low Glucose Suspend’ a step further into the prevention realm. Note that at no time does this algorithm dose insulin – it’s all about improving patient safety. It’s hard to imagine a rationale that would not advocate reducing nocturnal hypoglycemia by 84%. But as we understand it, there’s a much higher bar to get this cleared in the US than there is in the EU.

  • Dr. Buckingham described the prediction system, which uses five-way voting. Five prediction algorithms (statistical linear prediction, Kalman filter, hybrid infinite impulse, numerical logical algorithm, linear projection) ran independently. As blood glucose decreases,more of these alarms go off. The overall system was triggered when any three out of five algorithms were predicting impending hypoglycemia.
  • In order to induce hypoglycemia at night, basal rates were increased 5% to 25% every 90 minutes based on current glucose and glucose rate of change. The idea was to create consistent lows in order to find out if they could be prevented. The goal was to prevent hypoglycemia 80% of the time. Hypoglycemia was obtained in >80% of study nights. Ninety- minute adjustments were chosen since it takes 60 minutes to see a meaningful glucose change after changing the basal levels and then 30 more minutes to reach a stable value.
  • In trials with 14 patients, 84% of all nighttime hypoglycemia events were avoided, or in 75% of the subjects. This is quite a significant result. Some nights there was more than one basal shut off. There was a 30 minute mandatory basal restoration after the 90 minute shut off, but it appears that in some cases, it would have been better to have a two hour shut off if blood glucose were still low or declining.
  • The congruence of the Navigator glucose readings and the YSI reference blood glucose levels was a statistically significant indicator of prediction success. This makes sense since if the CGM is reading high or low, it will base its hypoglycemia predictions on erroneous data, which will reduce the accuracy of its predictive ability.
  • Notably, the rate of change was not a statistically significant indicator of prediction success. This is a good reinforcement of the trending accuracy of the Navigator.
  • Notably, Dr. Buckingham showed an interesting picture of the ‘Florence’ system, consisting of an Abbott Navigator sensor/transmitter, the Abbott Aviator insulin pump (not commercially available), a Companion handheld combined controller, and a control algorithm device (CAD). No more details were available at this stage, but it looks like Abbott’s artificial pancreas research system. It’s compact and we assumed that it would be used for the outpatient trials, although this wasn’t clear.

Questions and Answers

Q: Is the hypoglycemia inducing protocol too stringent?

A: We get a larger rate of change than would likely normally occur - but people do exercise before bed sometimes.

Q: Can you look at the different algorithms in the scheme to see which is working better/ is more active?

A: The linear prediction is the least sensitive and is only involved in predicting about 10% of events. This is what’s used in commercial sensors. The two others used for prediction accounted for between 40-60%.

Q: Given the method of hypoglycemia induction, you are probably underestimating the positive effect you are seeing from the algorithm.

A: I agree – we were trying to be quick and dirty in simulating a high incidence of hypoglycemia.

PERSONALIZED SUBCUTANEOUS MODEL-PREDICTIVE CLOSED-LOOP CONTROL OF T1DM: PILOT STUDIES IN THE USA AND ITALY

Boris Kovatchev, PhD (University of Virginia, Charlottesville, VA)

In this JDRF-funded study, patients in Virginia, Padova, Italy, and Montpelier, France (n=20), wearing FreeStyle Navigator CGM and Insulet OmniPod, were admitted to the clinic twice for overnight glucose control – first with an open-loop, physician-supervised control and then using a model-predictive control (MPC) closed-loop algorithm. The MPC algorithm uses a model that can predict future glucose levels, based on an insulin-dosing plan. This approach is generally more successful than the earlier generation of proportional-integral-derivative (PID) algorithms, which react to historic glucose levels. When on MPC closed-loop, patients spent more time within a glucose range of 70-14o mg/dl (78%) compared with open loop (68%). Furthermore, hypoglycemia was five times more likely on open loop than closed - 23 episodes against four)! Now this is progress….to boot, this study set a precedent by skipping animal studies by using an “in silico” trial as an alternative to animal trials.

  • The MPC algorithm is personalized to the patient at the time of his first admission. Factors like age, daily insulin use, body weight, basal rate, and insulin sensitivity are used to ‘tune’ the model to the patient. The model can predict potential future blood glucose based on an insulin plan. The algorithm sets up an insulin plan that allows glucose to reach target. Every 15 minutes, a new data point from CGM sensor is used to update the glucose curve and a modified insulin plan is created. MPC is an alternative to the PID algorithm, which can only recommend insulin dosing by reacting to past glucose values.
  • Dr. Kovatchev felt this study set a precedent by skipping animal studies. This study was approved for the clinic via an FDA computer simulation, called an “in silico” trial, as an alternative to an animal trial. It is one of the first trials to have done so and has saved years of time.
  • Closed-loop was successful for overnight glucose control, but needs some improvement for mealtime periods. Overnight, the closed loop controlled glucose better and offered an exciting five-fold reduction in hypoglycemic episodes (from 23 events to four). Patients on the closed loop spent 78% of time within the target range (70-140 mg/dl) versus 68% of the time on open loop. During breakfast time, however, closed loop provided slightly worse control than open loop, though the difference was not significant.

THE REALTREND STUDY: EFFECT ON METABOLIC CONTROL IN POORLY CONTROLLED TYPE 1 DIABETES USING PROPERLY THE PARADIGM REAL-TIME SYSTEM VS. CONVENTIONAL BLOOD GLUCOSE SELF-MONITORING AND CONTINUOUS SUBCUTANEOUS INSULIN INFUSION

Denis Raccah, MD (University Hospital Sainte Marguerite, Marseille, France)

The RealTrend study examined the effectiveness of continuous glucose monitor (CGM) versus self- monitoring of blood glucose (SMBG) in managing insulin doses administered with an insulin pump. One hundred and thirty two subjects with type 1 diabetes who were poorly controlled on multiple daily injections (MDI) were randomized to either the Medtronic Paradigm pump with integrated CGM or traditional pump treatment with SBMG. After six months, subjects in the Paradigm (PRT) group had an average A1c decrease of 0.81%, compared to 0.57% in the CSII group, although (surprisingly to us) this difference was not significant. In the subset of patients using their sensors more than 70% of the time, there was an impressive A1c reduction of 0.96%, and this was significant versus the control group. In our view, the reductions in A1c will become more significant in the CGM group the more user-friendly the devices become. The results are promising for CGM, and potentially could be interpreted as positive for the Paradigm system in particular – it remains, for now, the only integrated pump/ continuous glucose monitor.

  • In the study, adults and children with inadequate glycemic control on MDI (A1c greater than 8%) were assigned to insulin treatment with either the Medtronic Paradigm pump and CGM or traditional pump treatment (on the paradigm 512/712) with SMBG. The trial enrolled 132 subjects, all of whom performed SMBG at least three times daily. Treatment lasted for six months. The baseline A1c was about 9% in all groups. The primary endpoint was change in A1c. Secondary endpoints included the CGM-derived parameters: average glucose, time spent above and below glycemic limits, and number of excursions out of range. These outcomes were determined through the use of a blinded CGM before and after the main phase of the study.
  • The results suggested that the A1c improvement was larger in the CGM group. Patients in the Paradigm (PRT) group saw an A1c decease of 0.81%, compared to a decrease of 0.57% in the CSII group, but this difference was not significant (p=0.087). The difference between A1c from screening to the end of the study in the PRT group was 1.14%, giving a significant difference between the two groups. In the subset of patients who wore their sensors over 70% of the time (n=1), there was an A1c decrease of 0.96%, and this was significant compared to the CSII group (p=0.004). In this population, the 1c drop was decreased during the training period as well. In the PRT group, hyperglycemia parameters decreased in line with A1. There was no difference in hypoglycemia. 20% of the subjects in the PRT group used the device to change their lifestyle, versus 10% of the control group. Two out of three in the PRT group used the device to change the way they treat glycemic excursions. In our view, the reductions in A1c will become more significant in the CGM group the more user-friendly the devices become.

Questions and Answers:

Q: Did patients know their group during the nine-day training period?

A: Yes, they knew during the training phase. We didn’t expect that this period would have such an impact on A1c.

Q: Were there any differences in patient contacts to the healthcare team?

A: We had some dropout at the beginning of the study particularly in the PRT group. It was due to technical problems and patients feeling like it was too difficult and too cumbersome to wear over the six month period. When the care team became more familiar with the system, we had fewer problems.

Q: What were your glucose targets?

A: The patients included were very poorly controlled even with a basal/bolus regimen. They were not very compliant. Even in these patients, we have obtained significant improvement. The targets were individualized at each study visit, and we trained them on the use of the device to improve control.

Comment from Dr. Bruce Buckingham: I would caution against your first conclusion. In the STAR-1 study, we saw the same drop. I think that the education you provided may have caused a study effect apart from the switch from MDI.

Q: Were the subjects pump-naïve?

A: Yes, they had no experience with insulin pumps before the study.

OVERNIGHT CLOSED-LOOP (CL) INSULIN DELIVERY IN CHILDREN AND ADOLESCENTS WITH TYPE 1 DIABETES (T1D): TOWARDS HOME TESTING

Roman Hovorka, PhD (University of Cambridge, Cambridge, UK)

This interesting talk by Dr. Hovorka focused on the use of an artificial pancreas system consisting of a CGM sensor, control algorithm, and insulin pump used in a small study in young subjects with type 1 diabetes. The primary goal of this ambitious study was to determine if such a closed loop system could maintain stable glucose levels overnight after three types of stress: small carbohydrate meal, large carbohydrate meal, and exercise. The closed loop system was evaluated against continuous subcutaneous insulin infusion therapy. As a consequence of the design, the study also evaluated the efficacy of the control algorithm developed. After the small meal, 61% of the closed loop patients remained in the target glucose range compared to 38% in the CSII group. This is a quite notable result in our view. After the large meal, the closed loop system performed comparable to CSII. The standard deviation of overnight glucose was slightly higher in the CSII group. Data from the exercise condition was not discussed in depth. There was a significant reduction (eight-fold) in the percentage of time spent in hypoglycemia in the closed loop group. Dr Hovorka suggested his data shows that such a closed loop system could be a viable option for reducing the risk of nocturnal hypoglycemia. These results are intriguing, and we hope to see more work using closed loop systems, especially in situations in which the algorithm must address active changes in glucose levels. From a patient perspective, we appreciated the closing note of the talk, in Q&A: “Closed loop is not about perfection it is about improvement.”

  • This small study explored the efficacy of a closed-loop system in young type 1 diabetes patients. Seventeen patients with type 1 diabetes aged five to eighteen participated in this study.
  • The closed loop system was used for 12 hours overnight after patients were exposed to either a small carbohydrate meal, a large carbohydrate meal, or exercise. Patients were fed a 67 g or 130 g carbohydrate meal or exercised for 40 minutes before they were put on the closed loop system for 12 hours.
  • The algorithm used a model predictive control, a Kalman filter with interacting multiple model strategy, and safety rules to limit insulin overdosing.
  • Lower plasma glucose levels were achieved in the closed loop group compared to the CSII group.
  • After the small meal, 61% of the closed loop patients remained in the target glucose range compared to 38% in the CSII group. This is a quite notable result in our view.
  • After the large meal, the closed loop system performed comparable to CSII. The standard deviation of overnight glucose was slightly higher in the CSII group. Data from the exercise condition was not discussed in depth.
  • There was a significant reduction (eight-fold) in the percentage of time spent in hypoglycemia in the closed loop group.
  • Dr. Hovorka concluded by suggesting this data supports the use of closed loop systems in reducing the risk of nocturnal hypoglycemia and improving glucose control in children and adults. We think this study is interesting, and look forward to more work done in this area. We noted that the closed loop system was not used until two hours after eating the meals or exercising and it took four hours for the closed loop system to become fully effective. We wonder if a closed loop system could hold the minute-to-minute changes associated with changes in diet and exercise. We also wonder what the impact of a faster insulin would have been, particularly with the large meal.

Questions and Answers

Q: In terms of insulin distribution, how did it change?

A: On average they were on the same amount of insulin, took more insulin when it was needed, redistribution of insulin during the night (spread out in closed loop) instead of one huge dose after a meal.

Q: It seems that there was some variability of the efficacy in your patients with closed loop especially with hypoglycemia. Did you identify the causes for this, and could you improve it to minimize this error?

A: The subject experienced sensor error. Even with sensor error he still did better than without CGM. Closed loop is not about perfection it is about improvement.

Q: You said that you started the closed loop system at 8pm, at the peak of post-prandial glucose level. Would you see a difference if you start it at a lower glucose level?

A: We did not do any formal analysis on the glucose effect.

Q: You are using just one sensor, what happens when it might not be working, how often do you recalibrate?

A: All these studies are designed with home use in mind. In principle, if we knew a sensor was not performing well, we would move on. We don’t want to force calibration because we want to mimic what we would see in the home.

CONTINUOUS GLUCOSE MONITORING ELUCIDATES THE GLYCEMIC IMPACT OF FOOD

Maggie Powers, PhD, RD, CDE (International Diabetes Center, Minneapolis, MN)

Dr. Powers compared the glycemic impact of meals with varying carbohydrate content using continuous glucose monitoring technology (CGM, specifically Abbott’s Freestyle Navigator). Subjects with type 2 diabetes were fed four lunches, two moderate (45 g – wow we don’t necessarily think of that as moderate) and two high (90 g) in carbohydrate content, and were measured using CGM for four hours beginning at the start of the meal. She found significantly elevated peak glucose (+20 mg/dl), time to return to baseline (+38.1 minutes), four hour AUC, and four hour mean glucose. Given these findings, she concluded that significant differences exist in glycemic response to 45 gram lunch and 90 gram lunch, that relationships between quantity of carbohydrates and glycemic response are not linear, and CGM provides a more complete picture of glycemic response. She suggested that CGM could be a useful tool in nutritional therapy and noted that it could be particularly useful for type 2 diabetes patients with poor post-prandial glucose control.

  • Subjects with type 2 diabetes were fed four lunches—two moderate and two high in carbohydrates—and had glycemic responses measured by a continuous glucose monitor. Other aspects of the meal, such as fat and protein (among others), were kept constant. Moderate meals contained 45 grams of carbohydrates while high carbohydrate meals contained 90 grams. The order of the lunches was randomized for each patient individually. The population of patients with type 2 diabetes used in this study had mean age of 65 years and duration of 4.8 years, 28.8 BMI, and an A1c of 8%.
  • Using the data from CGM analysis, the authors found significantly elevated peak glucose (+20 mg/dl), time to return to baseline (+38.1 minutes), four hour AUC, and four hour mean glucose in the high carbohydrate diet compared to the moderate diet.
  • There was a significant difference in the glycemic response to different amounts of carbohydrates, but the relationship was not linear. Given these findings, she claimed theCGM provides a more complete picture of glycemic response, and suggested that it may be a useful tool for nutrition therapy.
  • She emphasized the need for further study. She specifically noted the need for trials with a larger cohort, using participants on different medication regimen, designed to answer questions related to nutritional component of meals, and investigating the use of CGM in type 2 diabetes to refine nutrition recommendations and increase adherence to food plans in patients with type 2 diabetes.

Questions and Answers:

Q: Subjects had A1c scores between six and nine percent. Have you looked at the data and examined those close to 7% separately from those close to 9%?

A: We did not analyze these data.

Q: Did you notice any difference on the first day compared to second or third day?

A: Meals were randomized, and they were not all in one group. We had three different time periods when the meals came. Each time, the meals were randomized. We did not examine looking at those that had, for instance, high carbohydrate meal on day one versus those that had the high carbohydrate meal on day four.

Q: How have you determined the glycemic index of these meals?

A: We used a standard formula, actually calculating the glucose content of each food.

Q: Care to comment on managed care coverage for type 2 diabetes?

A: Some new guidelines have made it easier to obtain coverage for CGM.

THE EFFECT OF AUTOMATED GLUCAGON DELIVERY ON HYPOGLYCEMIA DURING CLOSED LOOP GLYCEMIC CONTROL IN TYPE 1 DIABETES

Jessica R. Castle, MD (Oregon Health and Science University, Portland, OR)

Dr. Castle presented a study investigating the use of subcutaneous glucagon infusion during closed-loop control. Her study randomized subjects to either aspart (Novo Nordisk’s NovoLog) insulin alone or insulin plus glucagon. Subjects all had type 1 diabetes, and were controlled for nine hours surrounding a meal using a closed-loop system utilizing the Fading Memory Proportional Derivative (FMPD) algorithm. Results showed a trend toward increased time in zone and decreased time in hypo and hyperglycemia with glucagon treatment, none of which were significant. Nevertheless, these results provide a suggestion in humans that the use of glucagon in closed-loop systems could help avoid glycemic excursions.

  • Dr. Castle’s study randomized subjects to either aspart insulin alone or insulin plus glucagon. Nine subjects have participated so far, with a goal enrollment of 18 subjects. The study included six data sets, each with a different sensor. Subjects all had type 1 diabetes, and were controlled for nine hours using a closed-loop system utilizing the Fading Memory Proportional Derivative (FMPD) algorithm. This algorithm determines rates of insulin and glucose based on proportional error (the difference between glucose and the target level) and derivative error (glucose rate of change). Two glucagon infusion styles (GGIRs) were compared— it was given either as a low gain, prolonged infusion, or a high-gain, brief infusion including a refractory period. Glucose was measured every ten minutes with dual sensors. Patients were givenpre-meal insulin boluses equivalent to 40-75% of their typical dose. Insulin on board was calculated on an ongoing basis.
  • Results showed a trend toward improvement in time in target range (70-170 mg/dl), with target achievement in 75% in the front-loaded glucagon group, 66% in the low gain group, and 63% in the group with no glucagon, but this was not significant. Hyperglycemia was seen during 24.4% of the time in front-loaded subjects, 31% in the low-gain group and 30% in the no glucagon group (this finding was not significant). Hypoglycemia was not seen in the front-loaded subjects, was seen in 2.4% in the low-gain, and 6.5% with no glucagon (p=0.06). Threats of hypoglycemia were 13 in front-loaded, 22 in low-gain glucagon, and 19 in no glucagon, with a significant difference between front-loaded subjects and both other groups.
  • These results suggest that front-loaded glucagon reduces the risk of glycemic excursions. Future trials will look at any potential risk of repeated glucagon, potential for depletion of glycogen stores, glucagon stability, dose-effect relationship, and use of ultra-rapid- acting insulin in closed loop systems.

Q: What side effects did you observe?

A: We had one patient who had nausea and vomiting.

Q: Do you know if the quality of meal might have made a difference?

A: We matched the meals between the studies for the number of carbs, but we didn’t match the GI. We’re looking to do a study comparing low GI and high GI.

Q: How long did you stop insulin delivery in those you discontinued?

A: It was variable—when we reached a certain threshold, we would turn off insulin until they fell below that level. We used that same threshold for all patients.

REDUCED GLYCEMIC VARIABILITY WITH THE USE OF REAL-TIME CONTINUOUS GLUCOSE MONITORING

David Rodbard, MD, Hahnemann Medical College and Hospital

This study explored the challenge of how best to utilize statistical tools in order to evaluate CGM. Dr. Rodbard analyzed retrospective data looking at a variety of measures to evaluate quality and variability of glucose control. The data considered was masked for week one and unmasked for weeks two and three. Each subject served as their own control. There were dramatic statistical reductions in hyperglycemia and a reduction of variability of glucose levels on CGM. Dr. Rodbard concluded that the use of CGM, even for a short period of time, results in improvement in quality of glycemic control. He emphasized that there are several measures that are sensitive and reliable in evaluating CGM efficacy.

  • Using retrospective data of patients beginning CGM therapy, Dr. Rodbard explored a number of different statistical measures in evaluating the quality of glucose control and variability of glucose control when using CGM.
  • Dr. Rodbard concluded that the statistical analysis showed that CGM offers improvements in quality of glycemic control and in reducing variability of glucose levels.
  • According to Dr. Rodbard, there were a number of measures of quality of glycemic control that proved useful in this study. Percent within target range, percent withhypoglycemia, percent with hyperglycemia, mean glucose, M100, J index, GRADE, and IGC (the index of glycemic control developed by Dr. Rodbard) were all shown to be sensitive in predicting CGM efficacy.
  • There are a number of statistical measures that are useful in evaluating glucose variability. Standard deviation for one week, standard deviation between days, standard deviation of daily means, MAGE, and MODD were highlighted as successful measures of glycemic variability.

Q: In some of your measurements of standard deviation, it looked like measurements were better at the end of the first week and that they began to slip back at end of the second week.

A: I don’t yet have an explanation for this.

Q: If the mean goes down, does the standard deviation go down? Would we do a coefficient of variation?

A: The coefficient of variation remained constant. The mean went down, the standard of deviation went down.

Q: We did not see similar changes in glucose variability in the JDRF trial, is it because we were dealing with different mean blood glucose levels?

A: The key is to analyze the data within each variable. If you pool the data over all the subjects, the between-subject variability will wash out any of the change within subject variability.

Q: If you are to choose a few metrics what would they be and why?

A: For quality of glycemic control: percentage within a specified target range. In terms of overall variability – overall standard deviation works very well. But all the others I’ve discussed correlate very well.

Q: From a data mining perspective do you have any recommendations on data mining for SMBG data, which is a much lower density?

A: Use the same criteria and look at standard deviation for each time point for SMBG.

A CLINICAL FEASIBILITY TRIAL OF BI-HORMONAL CLOSED-LOOP BLOOD GLUCOSE CONTROL FOR TYPE 1 DIABETES

Steven J. Russell, MD (Boston University, Boston, MA)

This trial tested a bi-hormonal (insulin and glucagon) closed-loop system in ten patients with type 1 diabetes over 27 hours, including three standardized meals. The system used venous BG measurements every five minutes and a model-predictive-control (MPC) algorithm to calculate infusion rates of lispro (Eli Lilly’s Humalog) and glucagon. The system maintained more stable glucose control between meals than open-loop control, with a mean glucose value of 143 mg/dl (8.5 mmol). Hypoglycemia was largely avoided in patients with normal lispro kinetics (five-eight hrs duration) but occurred frequently in patients who had abnormally slow lispro kinetics (nine -24 hrs duration) because there was more insulin on board than the algorithm predicted. We think this illustrates the need for more rapid-acting insulin analogs with more consistent kinetics as research toward the artificial pancreas continues. We’re interested to see more work on this particular closed loop, particularly using subcutaneous CGM rather than venous BG measurements.

  • This feasibility trial tested a bi-hormonal (insulin and glucagon) closed-loop system in ten patients with type 1 diabetes. The system uses the weight of the patient as an initial parameter and used venous blood glucose values sampled every five minutes in order to predict necessary infusion rates of SC insulin lispro or glucagon using a model predictive control algorithm. It delivered a basal amount of insulin in microboluses when the algorithm predicted that the subject was in homeostasis. The authors measured plasma lispro and glucagon every 10 minutes in order to assess the pharmacokinetics of lispro infusion. Each patient was followed for 27 hours on the closed loop system, during which time they ate three standardized meals.
  • In six patients who had normal lispro duration of action, the closed-loop system maintained a mean glucose of 143 mg/dl with only one hypoglycemic event of 66 mg/dl and no need for rescue carbs. In these patients, duration of action of lispro (Lilly’s Humalog) was on the order of five to eight hours (compared to the manufacturer’s reported duration of ~five hrs).
  • However, there was much more hypoglycemia in the four patients for whom lispro duration was prolonged (nine-24 hrs) because there was more insulin on board than the algorithm predicted. In these four patients there were a total of 15 hypoglycemic events over 92 total hours of control (compared to one event in 151 hours for the other six patients) and all four required rescue carbs at least once. Per the study protocol, rescue carbs were indicated if the patients had BG <60 mg/dl with symptoms or BG <60 mg/dl x 20 min or BG<50 mg/dl x 10 min without symptoms.
  • The closed-loop maintained more stable glucose control between meals than open- loop control. Dr. Russell concluded that this bi-hormonal closed-loop system provides good control with normal lispro kinetics but would need to be adjusted for patients with longer lispro kinetics. We think this is a good example of the continued need for even more rapid-acting insulin analogs in order to advance the research toward the artificial pancreas.

Questions and Answers

Q: Were there any clinical characteristics that could predict which patients had extended lispro kinetics?

A: We pre-specified that we would look for anti-insulin antibodies in our patients. While our assay was for anti-regular insulin antibodies, not anti-lispro antibodies, there was a nonsignificant trend toward slower lispro pharmacokinetics. There is evidence in the literature that high-affinity low-titer antibodies are correlated with slower insulin kinetics; these were more common when beef or pork insulin was widely used. I would point out that insulin lispro, aspart, and glulisine have similar numbers of amino acid changes as bovine or porcine insulin. However, we have no assay to look specifically for high-affinity low- titer antibodies and there is also no commercially available assay for anti-lispro antibodies.

Q: Some of the CGM monitors are looking at IV sensors. Do you think the pharmacokinetics would be more predictable if you could use intravenous insulin?

A: This is probably true, but we haven’t pursued this because of the impracticality of using long-term indwelling intravenous catheters in free-living type 1 diabetes patients who would then be at risk for blood infections. Personally I would be interested in insulins with more rapid kinetics.

FOLLOW UP OF TYPE 1 DIABETIC SUBJECTS ON CSII IN THE ALG-OS STUDY EVALUATING AN ALGORITHM INFORMING PATIENT RESPONSES TO REAL TIME- CONTINUOUS GLUCOSE MONITORING

Alicia Jenkins, MD (University of Melbourne, Melbourne, Australia)

This study examined the use of an algorithm to suggest treatment recommendations based on continuous glucose monitor (CGM) readings in patients newly initiated on CGM. The algorithm was accessed on a mobile phone, and gave patients suggestions based on their CGM’s glycemic zone and trend arrows, as well as the time of day. At 16 weeks, the subjects crossed over to the opposite arm and remained there until 32 weeks. The results showed an initial reduction in A1c in those subjects initially given the algorithm, which then disappeared when they discontinued its use. Interestingly, however, subjects who crossed over to algorithm use at 16 weeks did not realize any A1c benefit. Dr. Jenkins speculated that those subjects had already developed a system for interpreting their CGM readings and did not adapt to use of the new algorithm.

  • The ALGOS study investigated the efficacy of using an algorithm to help patients make treatment decisions based on their CGM devices. The study enrolled 60 subjects (38 adults and 24 adolescents), recruited in A1c, age, and gender-matched pairs, who were educated on the Paradigm REAL-Time system and randomized to the use of a treatment algorithm or care without an algorithm. The mean A1c of participants was about 8%. The algorithm, accessed on a mobile phone, suggested treatment responses depending on glucose zone, trend arrows, and time of day. At 16 weeks, the results were evaluated (these results were released at EASD 2008), and then subjects crossed over the opposite arm. Fifty of the subjects completed a full 32 weeks.
  • The results showed that in those adults utilizing the algorithm from the beginning of the study to 16 weeks, the benefits were lost once they switched away from the algorithm (A1c was 7.54% at baseline, 6.9% at 16 weeks, and 7.5% at 32 weeks). In those adults receiving the algorithm at 16 weeks, A1c did not change (7.5%, 7.3%, and 7.4%, respectively). Adolescent groups saw no clear effect of the algorithm, but algorithm use was reportedly more frequent in the adult population than in the adolescent. Less than 2% of algorithm recommendations were rejected by subjects. Handset use was correlated with lowered levels of A1c.
  • These results suggest that this algorithm can be useful in adults if it is initiated along with CGM/CSII therapy, but not if it is delayed.

Questions and Answers:

Q: Why do you think that patients given the algorithm later didn’t show improvements?

A: It was the same algorithm—we suspect that they develop their own way of dealing with information from the CGM, and then don’t re-adapt.

THE USE OF CONTINUOUS GLUCOSE MONITORING COMBINED WITH COMPUTER- BASED EMPC ALGORITHM FOR TIGHT GLUCOSE CONTROL IN CARDIOSURGICAL ICU: A FEASIBILITY STUDY

Martin Haluzik, MD (Charles University and General Teaching Hospital Prague, Czech Republic)

Dr. Haluzik delivered a talk on the importance of glycemic control in critically ill patients and discussed a study exploring the use of CGM combined with a computer based eMPC algorithm in post cardiac surgery patients. The efficacy of ePMC-CGM was compared against standard protocols for intensive insulin therapy. According to Dr. Haluzik, the eMPC CGM group had lower blood glucose levels and there were no hypoglycemic events in the eMPC CGM group. He emphasized that the system showed reasonable accuracy and reliability and he believes it could represent an improvement in safety compared to the standard protocol for insulin therapy. He suggested that this is a promising step closer towards a fully automated closed loop system. We agree with Dr. Haluzik that these results are compelling interesting and that further study needs to be done in larger trials and perhaps additional different patient populations.

  • In a small study on the use of eMPC-CGM in post cardiac surgery patients, the eMPC-CGM group had better average blood glucose levels compared to patients following the standard protocol for intensive insulin therapy. Average blood glucose was better in the ePMC-CGM group. The time spent above the target range (80-100 mg/dl) was lower in the ePMC-CGM group as well.
  • While time spent below the lower boundary of the target range (80 mg/dl) was higher in the eMPC-CGM group, there were no hypoglycemic events in this group.
  • Dr. Haluzik suggests that eMPC-CGM is reasonably accurate and reliable and improves safety compared to standard protocol for insulin therapy.

Questions and Answers

Q: What was the health care provider interaction involved?

A: Nurses devoted to this study were available for manually putting in values and making sure it was acceptable and working.

Q: There was increased time spent below target but no hypoglycemia, please explain that?

A: We defined hypoglycemia below 52 mg/dl, while the target range started at 80. So we got more time in this range, but the algorithm was safe enough so that it did not go below 52 mg/dl.

Q: In terms of you taking hourly glucose levels, how often was the guardian being calibrated, what is your methodology of the glucose measure?

A: Calibrated guardian based on recommendations every 12 hours. In four patients we didn’t have to perform any additional recalibration. We measured arterial glucose and used a radiometer.

Q: You felt more populations needed to be studied. Do you have ideas about who would not be a good candidate for closed loop?

A: Cardiac surgery patients probably benefit the most based on studies already done. In general, most of the critically ill patients could benefit from some level of glucose control. Another patient group that could benefit is myocardial infarction.

CONTINUOUS GLUCOSE MONITORING (CGM) USING A STANDARD CARE MANAGEMENT APPROACH

Stuart A. Weinzimer, MD (Yale University, New Haven, CT)

While subjects in recent continuous glucose monitor (CGM) trials have typically followed an intensive clinical management program, it is unknown how effective CGM can be when used in a setting more closely approximating normal clinical practice. This study examined CGM’s effects on A1c and hypoglycemia without additional support intervention. This presentation focused only on the crossover period of the study, during which subjects previously on SMBG were switched to CGM for a period of six months. There was a significant 0.3% decrease in A1c in the adult group of the study only, with a baseline A1c of 7.6%, and reductions of hypoglycemia in all groups. These results help to confirm that CGM can be helpful in a real-world setting, although we look forward to more complete data on this subject (and more clinical experience!).

  • Subjects in recent CGM trials have typically followed an intensive clinical management program. It is unknown how effective CGM can be when used in a setting more closely approximating normal clinical practice. This study examined CGM’s effects on A1c and hypoglycemia.
  • Subjects were older than eight years and were naïve to CGM. They were randomized to six months of CGM versus SMBG, at which point the control group crossed over to CGM. This presentation discussed the crossover period. The majority of patients were using pumps.
  • In the primary cohort, there was a significant A1c decrease from 7.6% to 7.3% in adults but not in other groups after 26 weeks. The change in glycemic control was significantly related to frequency of device use. Severe hypoglycemia was reduced in all subjects, and all groups saw decreases in duration of hypoglycemia (significant in the adult age groups). Scores on a feedback survey showed overall positive feelings toward CGM, and the devices were felt to be useful. Negative feelings toward included “bugs” and unnecessary alarms. As in other studies, we continue to think results will improve further with more user-friendly devices.
  • This data confirms that CGM use can benefit people with diabetes in maintaining or lowering glycemic levels, even in the setting of typical clinical practice.

Questions and Answers:

Q: Was there any difference in satisfaction between the different CGM systems?

A: We didn’t compare the different sensors. The choice was made by the subject and clinician.

ADAPTIVE BASAL INSULIN PROFILE BASED ON GLUCOSE VALUE AND ITS RATE OF CHANGE

Youqing Wang, PhD (University of California, Santa Barbara, CA)

Dr. Wang argued that because of delays in CGM and insulin action, it is too late to change basal insulin dosing once glucose values cross the hyper- or hypoglycemic thresholds. His group’s algorithm depends on both absolute glucose level and rate of change to determine a ‘basal gain’. In the algorithm, rate of change (ROC) was taken into account between the values of 80 mg/dl (4.4 mmol/l) and 140 mg/dl (7.7 mmol/l), and was solely dependent on the glucose value below 80 mg/dl (4.4 mmol/l) and above 140 mg/dl (4.4 mmol/l). Patients’ ROC would be re-estimated every thirty minutes. Adjustment of basal rate would be based on these measurements. The algorithm was tested in the UVA/Padova diabetes simulator, and was shown to increase time in zone and particularly reduce hypoglycemia compared to a fixed basal. Dr. Wang noted that clinical trials are needed.

Questions and Answers:

Q: How do you account for the time-lag before the insulin action?

A: That’s why we’re using the rate of change. For this method, we’re adjusting the basal rate with enough time to match glucose changes.

Q: Does the gain distribution adapt over time?

A: Not really. If you have the same glucose value and rate of change you’ll always have the same gain.

KEY ROLE OF MAST CELLS IN CONTROLLING GLUCOSE SENSOR FUNCTION IN VIVO

Ulrike Klueh, PhD (University of Connecticut, Storrs, CT)

Dr. Klueh discussed the role of mast cells in biofouling, the process of pronounced degradation that has frustrated attempts to create a long-term implantable glucose sensor. Using a modified CGM sensor implanted in wild-type mice and those genetically lacking mast cells, she was able to show that mast cells are responsible (at least in part) for degradation of the sensor’s accuracy over a period of several weeks. In addition, the injection of mast cells into these genetically-modified mice produced some sensor degradation. This research is intriguing but still somewhat early stage. Because mast cells are critical for proper immune function; the translation of this research into a clinically applicable solution to the problem of biofouling is not straightforward.

  • Dr. Klueh is interested in eliminating barriers to long-term implantable sensors. Previous attempts to develop an implantable sensor have met with limited success due to biofouling. Tissue response to a sensor may include inflammation, neovascularization, and fibrosis, destroying the effectiveness of the sensor. The study of mast cells, which function in innate and acquired immunity, may hold the key to reducing biofouling, as they are responsible for some of the processes underlying biofouling.
  • Dr. Klueh used a mouse model of CGM to study this issue, using both wild-type and mast cell-deficient mice. A CGM sensor (a modified Navigator sensor) was implanted in the mouse and connected to a computer.
  • In wild-type mice, CGM readings degrade significantly beyond seven days. Her group has seen a maximum sensor life of about 28 days. By contrast, the sensor did not degrade over the 28-day period in mast cell-deficient mice. This difference was paralleled by decreased inflammation and fibrosis in mast cell-deficient mice, as well as by a decrease in mast cells in the area of the sensor (not surprisingly). The injection of mast cells into the site of sensor implantation degraded sensor function but did not completely prevent it from functioning.

Questions and Answers:

Q: What are the clinical implications of this research?

A: The clinical relevance is not fully formed—we are just dissecting the problem at this point.

Q: There was a clear drop after day eight in mast cell positive mice, but then it came back. Why?

A: Yes, you have sporadic up and downs in the control group. We believe that the cycle of inflammation is never concluded, and any further movement of the sensor triggers another acute reaction.

Q: Could we coat these sensors to prevent the reaction?

A: Yes, that should be studied in the future. We are only targeting a very small, specific area, so we need to find a way to diminish the mast cell reaction locally.

REAL-TIME BAYESIAN NEURAL-NETWORK DETECTION OF NOCTURNAL HYPOGLYCEMIA IN CHILDREN WITH TYPE 1 DIABETES USING A NOVEL NON- INVASIVE HYPOGLYCEMIA MONITOR

Hung T. Nguyen, AM, PhD (Timothy Jones University of Technology, Sydney, Australia)

Dr. Nguyen presented an impressive non-invasive continuous hypoglycemia-monitoring device, HypoMon, being developed by AIMedics, a company of which he is a senior member. HypoMon depends on signals that can be captured from the skin such as sweating and ECG changes such as heart rate and QT interval. The presence of hypoglycemia is calculated by Bayesian neural networks, which concentrate on minimizing error. We believe many limitations exist with this study including a lack of calculation of false positives, a comparison with other CGM devices, and the absence of acknowledging the complications that arise in detecting symptoms during hypoglycemia unawareness.

  • The aim of this study was to evaluate effectiveness of a novel non-invasive, continuous hypoglycemia-monitoring device (HypoMon from AIMedics). Symptoms of hypoglycemia arise from activation of the autonomous central nervous system from reduced cerebral glucose consumption. There has been a limited number of non-invasive and minimal invasiveness devices. HypoMon measure skin impedance (sweating) and ECG changes (heart rate and QT interval) to provide early detection of hypoglycemia. The device consists of a chest belt transmitter with four skin surface biosensor electrodes as well as a wireless hand help microcomputer. A picture of the device was displayed and resembles the size of a small calculator. AIMedics filed a patent for this technology in November of 2008.
  • After applying an evidence framework for Bayesian inference, blood glucose profiles were significantly correlated with the detection of hypoglycemia by HypoMon. In order to detect hypoglycemia, Bayesian neural networks were used to calculate hypoglycemic episodes. Twenty-four children with type 1 diabetes (with an average duration of 14.4 +/- 1.6 years) volunteered for experiencing a 10-hour overnight hypoglycemia. HypoMon was used to measure physiological parameters and compared with actual blood glucose levels collected for reference. HypoMon was able to detect hypoglycemic episodes in children (<60 mg/dl) using normalized values: both heart rate and corrected QT intervals increased significantly. Overall data was organized into a training set (12 patients) and a test set (another 12 patients) which were randomly selected. After applying an evidence framework for Bayesian inference, blood glucose profiles were significantly correlated with the detection of hypoglycemia by HypoMon.
  • We believe many limitations exist with this study including a lack of calculation of false positives, a comparison with other CGM devices, and the absence of acknowledging the complications that arise in detecting symptoms during hypoglycemia unawareness.

Questions and Answers

Q: What distribution did you use for your calculations?

A: We used a Gaussian distribution. This distribution gives us some idea of the optimal number of hidden nodes in the neural network.

Q: Correlation is not a terribly helpful statistic. What are the true false positives?

A: It is very hard to get true value with sensitivity and specificity. Indication is sensitivity will be >85%.

Q: Did any patients have hypoglycemia unawareness?

A: Roughly 10% showed signs of hypoglycemia unawareness. We are looking more into this aspect of HypoMon.

Q: Did you see any changes in hypoglycemia response depending on the duration of diabetes?

A: I don’t believe so. We developed a system to develop this in a whole cross section of people.

Q: Will it give a warning before hypoglycemia will occur or just alert once hypoglycemia has already been detected?

A: We should be able to detect 70, 60, and 50 mg/dl. We will report this information in the future.

Q: You did comparison with one-time glucose values. Have you looked at the rate of change of glucose with real time sensors?

A: Last year we performed studies with glucose clamp structure. We not only looked at heart rate and QT but also variations in blood glucose.

USE OF THE G+™ SYSTEM COMPUTERIZED IV INSULIN ALGORITHM IN COMMUNITY HOSPITAL SETTING

Frank L. Schwartz, MD (Department of Specialty, Ohio University, Athens, OH)

Dr. Schwartz explained a study (n = 1553) he performed in hospital settings to assess the effectiveness of using Glucotech’s G+ system, a computer directed algorithm software for calculating intravenous (IV) insulin administration. He continued to remark on the time spent within target ranges and the frequency of hypoglycemia for patients who used the G+ system.

  • Dr. Schwartz cited the NICE-SUGAR as shifting the paradigm from prevention of adverse effects to the prevention of hypoglycemia. This study showed that hypoglycemia was the major factor that resulted in an increased risk for death in the intensively controlled group versus the conventional control group.
  • Dr. Schwartz described the specific characteristics of the G+ system. The G+ system was licensed by Glucotech, Inc. and is a computer-directed algorithm software program that has been refined over many years. The three different hospitals that participated in this study were quite different in character. Intravenous (IV) fluids were supplemented until blood glucose was>250 mg/dl. Insulin infusion with a target glucose of 90-120 mg/dl had an initial multiplier set to0.05. The multiplier represents the amount by subtracting 60 mg/dl from the initial blood glucose level and subsequently multiplied by multiplier.
  • Blinded data from 1553 patients (55,018 insulin runs) concluded that the G+ system was a safe and effective algorithm for computerized IV insulin. Non-linear regression was used to analyze the data. Patients were monitored for an average of 51 hours, starting with an initial blood glucose of approximately 260 mg/dl. The time required for patients to achieve target ranges was, on average, 2.5 hours. Separation of time-to-target data between surgical pathways and acute illness has not been performed. Average glucose concentrations once patients reached target was 107 mg/dl. Insulin-induced hypoglycemia was the most important factor analyzed– 27% of patients experienced blood glucose concentrations of less than 60 mg/dl and out of all insulin runs (12,989), 1% experienced a blood glucose of less than 40 mg/dl. In conclusion, the G+ system was shown to be safe and effective in controlling blood glucose.

Questions and Answers

Q: Why was the variability different in different hospitals?

A: Certain hospitals had very sick patients and depending on the hospital, different percentages of the patients who went on the system had not even been diagnosed with diabetes.

Q: Do you have access to complications data?

A: We are going to work on that for the paper – we will outline diagnoses, outcomes, and calculate glucose variability.

Q: Any thoughts on optimal level for glucose ranges to avoid hypoglycemia?

A: This is a loaded question and if you put two physicians in a room, you will get four opinions. I have a feeling we will find that optimal target ranges will depend on other diseases of the patient and there will be an optimal target. When it comes to an absolute low, I become real uncomfortable below 60.

ROLE OF CGM IN MODIFYING DIET AND LIFESTYLES IN DIABETES SUBJECT

Jothydev Kesavadev, MD (Jothydeva Diabetes Research Center Trivandrum, Kerala, India)

Dr. Kesavadev reviewed a small study (n=20) he conducted to document the reaction by patients to continuous glucose monitoring (CGM) and continuous subcutaneous insulin infusion (CSII) in a population of pre-selected highly motivated individuals. His practice found that highly motivated patients who exhibited impressive self-learning skills greatly benefited from the use of these devices, as evidenced by an increase in their quality of life (QOL).

  • Dr. Kesavadev screened patients for specific qualities hypothesized to be associated with successful usage of CGM and CSII devices. Ten type 2 diabetes patients were assigned the Medtronic insulin pump paradigm 715 and the other ten type 2 diabetes patients were assigned RealTime-Paradigm. Highly motivated patients were screened for exhibiting excellent self-learning skills.
  • Despite initially causing stress and anxiety, RT-CGM was found to greatly increase patient’s quality of life (QOL). Patients were provided with a diabetes telemanagement system (DTMS), which consisted of a diabetes team of physicians, pharmacists, telephone and email contact, as well as various appropriate treatments suggested by physicians. After two years, QOL improved significantly as measured by an interview performed on patients. Lastly, Dr. Kesavadev outlined major barriers to CGM and insulin pumps including widespread lack of reimbursement (in India), time of use, motivation, and technical failures, which are infrequent but do occur.

Questions and Answers

Q: Were there any difference in timing of bolus treatments?

A: The time when patients were instructed to take bolus was kept static; only changed timing of the exercise. We did not change the time of bolus.

Q: Was weight affected?

A: Patients either maintained body weight or lost body weight. Total dose of insulin remained the same.

Poster Presentations: Continuous Glucose Monitoring and Closing the Loop

(1866-P) FACTORS PREDICTIVE OF CONTINUOUS GLUCOSE MONITORING (CGM) USE AND BENEFIT IN THE JDRF CGM RCT

Buckingham B, Tanner J, The Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group

The JDRF CGM study group examined the factors that determined adherence to CGM. The study found that age, self-reported number of daily home glucose meter measurements, and percentage of time in zone (71-180 mg/dl) during a week of blinded CGM use were factors predictive of adherence (at least six days/week).

  • The JDRF CGM study group examined the factors that determined adherence to CGM. As a reminder, the original JDRF CGM trial showed an improvement in A1c after six months of use in type 1 patients aged ≥ 25 years. In a simultaneous trial of 129 type people with well-controlled (A1c <7%) type 1 diabetes, there was no difference between groups in A1c levels, though CGM use did vary by age range. The investigators examined the factors contributing to CGM adherence and improvements in glycemic control (in addition to age).
  • Age, self-reported number of daily home glucose meter measurements, and percentage of time in zone (71-180 mg/dl; 3.9-10 mmol/l) during a week of blinded CGM use were factors predictive of adherence (at least six days/week). CGM use in the first month was predictive of use after six months. It was surprising to note that baseline A1c was not predictive of adherence. This goes a long way to separate out whether it is poorly controlled vs. poorly motivated patients who are judged (a priori) to have poor adherence. Education level, gender, race, and length and type of therapy (pump/MDI) were also not predictive of good adherence.

(2-LB) IMPACT OF CONTINUOUS GLUCOSE MONITORING (CGM) ON GLYCEMIC VARIABILITY AND CONTROL IN SUBJECTS WITH TYPE 1 DIABETES USING MULTIPLE DAILY INJECTIONS (MDI) VS INSULIN PUMP

Rodbard D, Jovanovic L, Garg S

Rodbard et al. studied the impact of continuous glucose monitoring on glycemic control and glycemic variability in 64 patients with type 1 diabetes either on multiple daily injections or using an insulin pump. Following the three-week study, time in target zone (80-140 mg/dl; 4.4-7.8 mmol/l) increased 19% (MDI) and 17% (CSII) compared to (self) controls. There was significant improvement in glycemic variability with the use of CGM in both groups.

  • Rodbard et al. studied the impact of continuous glucose monitoring on glycemic control and glycemic variability in 64 type 1 patients over three weeks. Subjects were blinded to CGM data during the first week, but could access the data for the rest of the study. They were either delivering insulin via multiple daily injections (MDI) or an insulin pump (CSII).
  • Outcome measures described both the “quantity” and “quality” of glycemic control obtained. Basically this means that the investigators were looking at overall glucose lowering (quantity) as well as the variability in glycemia required to attain this lowering.
  • Time in target zone (80-140 mg/dl; 4.4-7.8 mmol/l) increased 19% (MDI) and 17% (CSII) compared to (self) controls. There were significant reductions in mean glucose, overall standard deviation, standard deviation between daily means (SDdm), mean amplitude of glycemic excursion (MAGE), mean of daily differences (MODD), improvements in quality of glycemic control (Schlichtkrull''s M100, Hill’s GRADE, and Hyperglycemia Index or Kovatchev's High Blood Glucose Index (HBGI)).
  • There were no significant differences in glycemic control and glycemic variability measures between the MDI and CSII groups. This is a counter-intuitive result since we would expect insulin pumps to provide more physiologic insulin delivery resulting in greater improvements in glycemic variability.
  • The data are summarized in the chart below which was obtained from Poster 2-LB presented at ADA 2009.

(413-P) PERFORMANCE OF THE FREESTYLE NAVIGATOR CONTINUOUS GLUCOSE MONITORING SYSTEM WITH THE TRUSTART ALGORITHM

Weinstein R, Brazg R

Weinstein et al. studied Abbott’s Navigator CGM augmented with an algorithm that enables the device to report glucose readings one hour after insertion – as opposed to 10 hours as currently commercially available. The algorithm is called the TRUstart algorithm and if approved, could make up for a part of the competitive advantage that the DexCom and Medtronic systems hold over Abbott in the CGM arena it only takes two hours for the current iterations of DexCom’s SEVEN PLUS and Medtronic’s Paradigm to start delivering readings. Accuracy measured by absolute relative difference (vs. YSI) was not compromised with the use of one-hour startup time. Mean and median absolute relative difference between Navigator readings and YSI readings were 14.5% and 10.7% respectively. Accuracy measured by Clarke Error Grid performance was likewise not compromised using the shorter startup time. The study reported 77.1% of the data pairs (CGM vs. YSI) in Zone A (clinically relevant/very accurate). This study could potentially mean that Abbott may be headed back to the FDA to try to obtain an indication that does not call for a 10-hour warm-up time.

  • Weinstein et al. studied Abbott’s Navigator CGM augmented with an algorithm that enables the device to report glucose readings one hour after insertion – as opposed to 10 hours as currently commercially available. The algorithm is called the TRUstart algorithm and, if approved, could make up for a part of the competitive advantage that the DexCom and Medtronic systems hold over Abbott in the CGM arena – it only takes two hours for the current iterations of DexCom’s SEVEN PLUS and Medtronic’s Paradigm to start delivering readings.
  • The study was performed in 47 subjects aged 19 to 66 years, at two different centers. Each subject wore two sensors, from which data were collected starting one hour after insertion. Comparison data were obtained from lab blood glucose measurements (YSI) every 15 minutes for 26 hours. The sensors were used for five days.
  • Accuracy measured by absolute relative difference (vs. YSI) was not compromised with the use of one-hour startup time. Mean and median absolute relative difference between Navigator readings and YSI readings were 14.5% and 10.7% respectively. For some context, this compares to 16.1% and 10.4% respectively in a prior study by Smith et al. in the November, 2009 issue of Diabetes Technology & Therapeutics. We would hesitate to draw conclusions regarding whether accuracy was actually improved with the TRUstart algorithm since this was not a head-to-head study.
  • Accuracy measured by Clarke Error Grid performance was likewise not compromised using the shorter startup time. The study reported 77.1% of the data pairs (CGM vs. YSI) in Zone A (clinically relevant/very accurate). Again for context, the paper by Smith et al. in the November, 2009 issue of Diabetes Technology & Therapeutics, showed 77.5% of data pairs in Zone A. Hypoglycemia (≤70 mg/dl; 3.8 mmol/l) was detected 91.6% of the time while the detection rate for hyperglycemia (≥240 mg/dl; 13.3 mmol/l) was 97.2%. The false alarm rates for hypoglycemia (<70 mg/dl; 3.8 mmol/l) and hyperglycemia (>240 mg/dl; 13.3 mmol/l) werereported at 25.2% and 21.2% respectively.
  • This study could potentially mean that Abbott may be headed back to the FDA to try to obtain an indication that does not call for a 10-hour warm-up time. This is one of the first prominent outward signs of iterative progress in the Abbott CGM franchise.

(410-P) NEW FEATURES AND PERFORMANCE OF A NEXT GENERATION SEVEN DAY CONTINUOUS GLUCOSE MONITORING SYSTEM WITH APPARENT SHORT LAG TIME

Bailey T, Zisser H, Chang A

Bailey et al. studied the performance of the recently released DexCom SEVEN PLUS CGM in 53 subjects enrolled at three centers. The overall mean absolute relative difference (MARD) between CGM and YSI readings was 13.0%. Median ARD compared to SMBG was 12.1%. Clarke Error Grid analysis showed 73.8% of CGM/YSI data pairs in zone A, and 22.1% in zone B. The authors note that the data loss was much less with the SEVEN PLUS compared to the SEVEN.

  • Bailey et al. studied the performance of the recently released DexCom SEVEN PLUS CGM in 53 subjects enrolled at three centers. This was a non-randomized, single-arm study. The cohort was 81% type 1 and 19% type 2. The study compared CGM readings to SMBG and YSI blood glucose readings in an eight-hour clinic session on the first, fourth, or seventh day of the seven-day study. A subgroup of 18 patients wore an additional blinded SEVEN PLUS sensor to measure device precision.
  • The overall mean absolute relative difference (MARD) between CGM and YSI readings was 13.0%. Median ARD compared to SMBG was 12.1%.
  • Clarke Error Grid analysis showed 73.8% of CGM/YSI data pairs in zone A, and 22.1% in zone B. The median time lag between CGM and YSI readings was estimated at five minutes (IQR = 10 minutes). No serious adverse events were reported.
  • The authors note that the data loss was much less with the SEVEN PLUS compared to the SEVEN. Data capture rate in this study was reported to have been improved with the SEVEN PLUS. In terms of sensor life, 86% of the sensor lasted for seven days as indicated.

(1-LB) ACCURACY OF A NOVEL INTRAVASCULAR FLUORESCENT CONTINUOUS GLUCOSE SENSOR

Zisser H, Jovanovic L, Khan U, Peyser T, Gamsey S, Romey M, Spencer H

Zisser et al. investigated the accuracy of the GluCath (GluMetrics) intravascular continuous glucose monitoring system. The sensor met ISO-15197 standards for accuracy. Impressively, 100% of all values below 75 mg/dl were within 15 mg/dl of the reference value and 94.5% of all values above 75 mg/dl were within 20 mg/dl of the reference value. Clarke Error Grid analysis showed 95% of data pairs in Zone A, and the remaining 5% in Zone B. There were no adverse events reported.

  • Zisser et al. investigated the accuracy of the GluCath (GluMetrics) intravascular continuous glucose monitoring system. The system was tested in five type 1 patients over eight hours. Blood glucose data were collected using the GluCath CGM every minute compared to hospital and lab blood glucose measurements (taken every 15 minutes).
  • The sensor met ISO-15197 standards for accuracy. Impressively, 100% of all values below 75 mg/dl were within 15 mg/dl of the reference value and 94.5% of all values above 75 mg/dl were within 20 mg/dl of the reference value.
  • Clarke Error Grid analysis showed 95% of data pairs in Zone A, and the remaining 5% in Zone B. There were no adverse events reported.
  • The GluCath system works via a different mechanism from the regular electrochemical enzymatic sensors. The measurement is based on glucose-specific fluorescent chemistry. The sensor chemistry is equilibrium-based, non-enzymatic, and has been tailored to optimize resolution in the hypoglycemic range. The technology works by sending light down a small (0.017 inch) fiber optic cable placed in a blood vessel. In the presence of glucose, the blue light sent down the optical fiber results in green fluorescent light being returned up the optical fiber. The amount of fluorescent green signal is proportional to the local glucose concentration surrounding the sensor.

Medtronic/LifeScan Sponsored Symposium: Integrating Continuous Glucose Monitoring into Clinical Practice: Practical Perspectives

MIMICKING NORMAL GLYCEMIC PATTERNS USING CONTINUOUS GLUCOSE MONITORING (CGM)

Irl Hirsch, MD, University of Washington, Seattle, WA

The major theme of Dr. Hirsch’s talk centered on encouraging healthcare providers and patients to learn how to utilize the wealth of information provided by CGM to its fullest potential. In order to realize the full benefits of CGM, a patient not only needs to understand how to use the information CGM provides, but how to make appropriate decisions based on this data in dosing insulin. Dr. Hirsch mentioned upside in use for both MDI (multiple daily injectors’) as well as pump users; we believe we’ll be starting to hear much more about use in the first population.

  • Dr Hirsch emphasized the need to standardize nomenclature with regards to insulin. He lamented the lack of consensus on nomenclature and implied that the problem is that the nomenclature is not currently evidenced-based. We agree and think that it is not only important for healthcare providers to come to a consensus on language, but to make sure that their patients have a shared understanding of the nomenclature.
  • An important consideration in using CGM is using it in the correct populations. While CGM could potentially be used by a broad population of patients, Dr. Hirsch emphasized that it is important to realize that CGM is not appropriate for all patients. Successful CGM patients have to be motivated and willing to make changes to their behavior based on data they obtain from the device.
  • The golden rule to teach patients learning how to use CGM is that the “trend trumps insulin-on board.” Patients new to CGM and unfamiliar with how to utilize the trend data provided by the device are prone to making bolus-dosing decisions based on blood glucose and insulin on board alone. This technique produces sub-optimal control because the patient is then likely to under- or over-dose if they disregard the direction of the glycemic trend. This kind of issue can be solved by retrospective review and guidance of HCP.
  • He suggested that next generation “bolus wizard’s” should take glucose trend information into account. Pointing to the table where Chris O’Connell, President of Medtronic Diabetes unit, was sitting, Dr. Hirsch said, “I see some heads nodding.”
  • Health care providers can use the data provided by software systems like Medtronic’s CareLink Professional to help them understand how the patient thinks. The data output of CGM can give healthcare providers a “bird’s eye view” of a patient’s diet choices and basal/bolus dosing patterns. This kind of data can help a them learn how a patient thinks and decide when and how much to bolus. Dr. Hirsch implied that this can be a valuable exercise as it allows healthcare providers to more accurately adjust a patient’s basal/bolus regimen and to teach them how to make the right choices when blousing.
  • Even for patients who have achieved target glycemic profiles, CGM can help its users avoid hypoglycemia. CGM is useful for patients with type 1 diabetes who have already achieved good glycemic control with A1c<7% because it offers them more protection against hypoglycemia than SMBG devices alone.
  • Dr. Hirsch concluded by remarking that we still have much to learn about how to best utilize this therapy. CGM can be useful for both multiple daily injection users and continuous subcutaneous insulin infusion users, but there is much to be learned about optimizing care. Educating patients how to make good use of the data provided by CGM will be critical in allowing patients to have success with this device.

PRACTICAL ISSUES IN THE USE OF CGM (MEDTRONIC/LIFESCAN)

Suzanne Ghiloni, BSN, RN, CDE (Joslin Diabetes Center, Boston, MA)

Suzanne Ghiloni covered realistic expectations, requisite knowledge base, and downloading in her presentation on the practical issues surrounding CGM use. She stressed the need for cumulative and repetitive learning with emphasis on hands-on training, and proactive (looking at downloads) and reactive (looking at the real-time display frequently) diabetes management. It is rewarding to start patients on this hopeful and productive journey. She quoted one patient as saying, “For the first time in my 15 years with diabetes, I can relax.”

  • Suzanne Ghiloni shared insights on how to optimize the CGM experience. She stressed the need for cumulative and repetitive learning with emphasis on hands-on training. Users must be motivated and emotionally ready to accept the data. They must understand the interrelationship between all the different parts of the glycemic control puzzle.
  • CGM users must develop goals with their healthcare providers – success is tied to active participation.
  • Healthcare providers must provide support as well as expertise. They must recognize and react to the ongoing learning curve for both themselves and their patients.
  • The issue of lag is physiologically normal – even if it is not desirable in terms of precision compared to blood glucose. Patients must understand this connection to minimize frustration with the technology and the need to perform fingersticks – the number one consideration in sensor accuracy. She stressed the need for proper calibration during the steady state though this can be challenging for patients if they have to delay meals for proper calibration.
  • Ghiloni advocated the use of wider alarm thresholds to prevent alarm burnout especially early on during CGM initiation. She acknowledged that there are trade-offs when thresholds are set too wide or too narrow. At least initially, it is a priority to ensure against patient burnout caused by false alarms.
  • The incorporation of arrows in CGM data give extra information to allow for better dosing decisions. Arrows indicate rate of change in glucose levels, so patients can better gauge how quickly their blood glucose levels are changing.
  • “I used to worry about my diabetes five times a day; now I worry about it every five minutes.” Ghiloni advocated the use of mental checklists before taking actions after interacting with CGM and performing confirmatory fingersticks. These checklists ensure the user is thinking holistically about what is going on with his/her glucose levels before making a decision.
  • She was very positive on the impact of a diabetes educator and advocated clinical specialists as useful resources.

FOLLOW-UP CARE OF THE PATIENT USING CGM

Howard A. Wolpert, MD (Joslin Diabetes Center, Boston, MA)

Dr. Wolpert focused much of his presentation on optimizing CGM alarms. He described a set of steps that could be used in setting appropriate thresholds. Initially, wider target ranges are used and high and low thresholds are optimized separately. He noted his view that the lag between interstitial glucose and blood glucose makes CGM inappropriate to assess the response to treatment of hypoglycemia.

  • Dr. Wolpert discussed the trade-offs in setting different alarm thresholds. If the target is for “ideal” narrow target ranges, patients will be alerted to the majority of lows and highs. However, there will be frequent false alarms resulting in sleep disruption, frustration, and alarm burnout leading to reduced sensor use.
  • He suggested one set of techniques to set and “titrate” alarm thresholds. One idea is to set the target range to be fairly wide (55 to 250 mg/dl; 3.1 to 14 mmol for example). During this initial phase, the patient is using the sensor to normalize his/her glucose patterns. During the follow-up step, the healthcare provider works with the patient to see if the high and low alarms are being set off appropriately. If the high alarm is sounding erroneously, then the high threshold can be increased. If on the other hand, the patient is awaking frequently with hyperglycemia but without a high alarm, the patient should check to ensure that they are detecting the alarm when it sounds, and/or decrease the high alarm threshold.
  • He pointed to the “Quick View Summary” on the Medtronic CareLink pump download as one he frequently looks at first. He noted that downloads have elucidated to physicians the notion that patients often reduce their basal rates when they start going low, resulting in glucose spikes after periods of hypoglycemia.
  • Patients should not rely on sensor glucose to assess treatment response to hypoglycemia. The lag between interstitial fluid glucose and blood glucose means that the treatment effect is not reflected on CGM. If the user relies only on CGM readings, he/she might take additional rescue carbohydrates when their glucose trend is rising, leading to rebound hyperglycemia.
  • He emphasized the importance of proper carbohydrate counting, advocating the use of registered dietitians for proper instruction. Studies of carbohydrate counting in pump patients have shown marked variations in responses when people were asked carbohydrate contents of various foods.

QUESTIONS AND ANSWERS

Q: Given the lag between interstitial fluid glucose and blood glucose, why would I set my initial hypoglycemia alarm threshold at 60 mg/dl? Shouldn’t I set it higher?

Dr. Wolpert: The fingerstick reading is going to be higher than the sensor when the glycemic trend is on the rise. You want to try to minimize the number of false alarms that people are going to be getting. If you set the alarms at higher than 70 mg/dl people are going to get more false alarms. If they get too many alarms we found in STAR-1 that patients start removing devices or turning off alarms. Its not a question of the optimal ranges, but how to prevent burnout.

Q: Are you getting many hypoglycemia readings? If yes, then maybe set it lower?

Dr. Hirsch: It depends on the patient’s initial A1c. We can usually predict the low and high targets from the baseline A1c levels. The problem in practice is that we start people with relatively broad low and high targets, but then the patient doesn’t follow up until three months later and their target has been inappropriate for some time. You need to change these targets soon after the patient learns how to use the device for them to be able to get the full benefit of the device.

Q: What guidelines do you give for bolusing?

Dr. Hirsch: The field is not currently in agreement on what to do in-between meals. Disagreements between pediatricians and internal medicine docs are the most obvious. I want people to start additional bolusing an hour after the first bolus because if you misjudged the initial dose, you need to take care of the rising glycemic trend. However, pediatricians say one hour is too soon to give additional insulin. The

biggest behavioral change in patients learning to use CGM is that they have to learn to give the insulin time to get in and act because that “rapid acting insulin is actually not that rapid.

Dr. Wolpert: The important issue here is the impact of carbohydrates and diet on postprandial glucose levels. Telling people to actually factor in what kind of carbohydrate load they have eaten so that they can have an idea of what kind of glucose is still coming into their system is key. We caution people to wait to give an additional bolus after two hours of initial blousing when they’ve had a high glycemic index meal because they may otherwise choose to administer insulin when most of the carbohydrate has already been absorbed. If someone is running high after two hours and it’s a low glycemic index meal and they think more glucose will still be coming into their system the bolus is the think to do. The point you raise is to really caution people against over-bolusing.

Q: To follow up on that, do you ever actually set limits on the amount of carbohydrates at one bolus event?

Dr. Wolpert: In principle that would be a great idea. The practical issue really comes down to who the patient is. What is their level of motivation and what can we realistically expect them to do? Ideally, the suggestion would be to be prudent with carbohydrate intake.

Dr. Hirsch: I will comment that perhaps I’m alone in this observation but I have a large percentage of patients who just cannot figure out carbohydrate values so they don’t get the potential benefit that they could from using a bolus wizard. People like this are the ones that do the best with CGM, they can’t get improvements in glycemic profiles with the bolus wizard, but they can follow their trends on the CGM.

Q: What is biggest hurdle for the closed loop? The algorithms?

Dr. Wolpert: There are things that will be overcome in time that are practical issues, which necessitate a stepwise approach. Dealing with lags in sensing and also in insulin action is the real challenge right now. We don’t have a reaction time that is rapid enough and fully functional for keeping up with activity. A lot of progress in terms of alarm systems, integrating algorithms into the CGM device so they are more intelligent is the next step and will be of enormous promise.

Dr. Hirsch: We were told these were smart pumps with the bolus wizard but there not quite as smart as we would like them yet. We have to make them smarter. Hurtles of accuracy and rapidity of the insulin. That is changing, the incremental benefits will be pump suspension and getting the bolus wizard to give better recommendations based on the trend at the time. This will get us closer.

Q: Carbohydrate counting and motivation is a large component in management, and the iPhone has an application for carbohydrate counting. Several college age patients are utilizing that to get pretty good at their carbohydrate intake. If a technology can motivate them is that what’s important?

Dr. Hirsch: My only concerns about that is whenever we have a new technology, whether it’s a pen or a pump, is whether that initial motivation is still going to be there in six, 12, 18 months later? We see excitement early on, but will it be sustained?

Q: What have you found with gastroparesis?

Dr. Wolpert: There may be a form of delayed gastric emptying that we see in CGM profiles of younger patients. A lot of what we see in the variability is the age issue and it’s the other macronutrients, which are delaying stomach emptying.

Dr. Hirsch: A lot of kids are getting labeled with gastroparesis and then we see CGM and we figure out they actually have celiac disease.

Comment: In the UK we have the Medtronic Paradigm Veo and we are really excited about this being started in the UK, its just very exciting and great that we had a product release before the US markets. In the UK, I have been using a Swedish telecommunications company so that a patient in Calcutta using CGM can plug in their home sender, all they need to have is electricity, and I can see their data. Medtronic is not even playing in the same sand pit as companies like this. I can phone in and do a telephone consultation, possibly saving this patients life, or telling her how to alter her plan of management. Telecommunications is a method that you can do without any other software and all insulin pumps and CGM need to get to this point. Medtronic, please start playing the game.

Developments in Insulin Delivery

Patch pumps and MannKind’s inhalable insulin Afresa dominated the insulin delivery discussions for most of the five days of ADA 2009. There were brief mentions of the development of oral insulin on the horizon, but it was not a significant focus.

We, of course, were excited to see patch pumps get so much coverage as we believe they are a new frontier for insulin delivery that is ready to be explored more deeply. In a sensational talk, Nancy Bohannon, MD (St. Luke’s Hospital, San Francisco, CA) mentioned that two unspecified companies are planning to be able to release new patch pumps within the next 12 months. We also like the idea of broadening the patch pump audience: Dr. Bohannon suggested that patch pumps could possibly be used for easy dosing in type 2 patients, which could allow for earlier insulin treatment and the prevention of complications. There will likely be additional concerns with this use, such as larger insulin reservoirs and patient acceptance, but it feels like a step in the right direction.

On the Afresa front, Robert Baughman, PhD (MannKind, Danbury, CT), presented a notable talk comparing MannKind’s candidate inhalable insulin to current popular fast-acting insulins. We were impressed by the kinetics of Afresa highlighted in the study, but continue to be cautious because we suspect the success of the drug will hinge on safety issues and patient acceptance. In any event, despite the challenges Afresa may face entering the market, we do still see a strong unmet need for an alternative to injectable insulin and are confident this is an important area of research.

In addition to all the Afresa and patch pump news, we were happy to see practical talks such as the one delivered by Lutz Heinemann, PhD (Profil Institute for Metabolic Research, Neuss, Germany) concerning the rate of change of steady state insulin/glucose levels in response to changes in basal insulin infusion rate on pumps and a few presentations on the use of pumps in the type 2 diabetes population.

Developments in Insulin Delivery Highlights

  • Robert Baughman, PhD (MannKind, Danbury, CT) presented an open-label, single- dose, three-way crossover study in 18 insulin-dependent type 2 diabetes patients that compared the ability of 45 U Afresa (MannKind), 12 IU insulin lispro, or 4 mg of Exubera (Pfizer) to suppress endogenous glucose production (EGP). All three doses produced equivalent overall suppression of EGP after a single administration; notably, the Afresa dose produced the earliest nadir of suppression (40 min vs. 75 min for Lilly’s lispro [Humalog] and 130 min for Exubera) and suppressed glucose more effectively in the first 60 minutes than the other two insulins. We appreciate the comparison of Afresa to other rapid-acting insulins in this study rather than to regular insulin. While the kinetics look promising, we note that safety is the main factor needed to garner FDA approval and reimbursement and convenience are essential to have any opportunity to enter the market. Still, we did see these results as differentiated. We are curious how fast the insulin action ends.
  • Richard Bergenstal, MD (International Diabetes Center, Minneapolis, MN) described a study that compared Afresa with insulin aspart, both on top on insulin glargine, for a period of one year. After the treatment period, subjects treated with Afresa showed statistically similar A1c changes (although the decrease with Afresa was substantially smaller, the difference was not significant), decreases in FPG and PPG, and a more favorable change in body weight compared to the insulin aspart group. There was a small decrease in hypoglycemia with Afresa treatment. We’re interested to see how Afresa fares—although this datalooks somewhat promising, we anticipate that the product will face significant hurdles based on perceived safety and patient acceptance in the future.
  • The marvelous Nancy Bohannon, MD (St Luke’s Hospital, San Francisco, CA) gave the best presentation we’ve seen to date on the exciting field of patch pumps. In her words: “Pumping is wonderful, but patch pumping offers a whole new dimension… hopefully to those with type 2 as well as type 1.” She cited more than ten companies developing patch pumps – some are mechanical, some electronic, some basal only, some bolus only, and some basal/bolus. All aim to be as small as possible; most can be operated through clothing or via a wireless controller. Some have a multi-part design that allows the minimum amount of material to be thrown away after each cycle. Dr. Bohannon suggested that for type 2 patients, an important need is to keep costs low for easier reimbursement. Companies to watch include Medtronic, Insulet, Calibra, Valeritas, Medingo, Medsolve, CellNOVO, NiliMEDIX, STMicroelectronics/Debiotech and Altea. Some other companies had specifically requested not to be mentioned in her review. In response to a questioner “from Switzerland”, Dr. Bohannon stated that at least two of these pumps in development would be launched within the next 12 months.
  • Lutz Heinemann, PhD (Profil Institute for Metabolic Research, Neuss, Germany) reported the results of a euglycemic clamp study, supported by Roche and Disetronic, that was designed to evaluate the time required to make a change in the basal insulin infusion rate for patients on pump therapy. It included ten males with type 1 diabetes who received various continuous subcutaneous insulin infusion (CSII) rates (0.5, 1.0, and 2.0 U/hr) for four hours each. The authors showed that it takes up to four hours for a new steady state of insulin and glucose levels to occur after basal infusion rates are altered. One must therefore consider this delay in making basal infusion rate changes.
  • Joakim Bragd (Stockholm, Sweden) reported a study in which 15 seasoned pump users with type 1 diabetes were randomized to continue using CSII or to get a morning dose of glargine (Sanofi-Aventis’ Lantus), administered via their pump, along with mealtime boluses as before. Concurrent CGM showed that CSII was associated with lower mean glucose, longer periods of glucose within target, and a lower A1c (6.5% versus 6.8%); baseline A1c was not specified, unfortunately, although criteria to enter the trial required a relatively low baseline A1c of 6-8%. Dr. Bragd was surprised that there was no significant difference in glycemic variability, which is an indication in his clinic for starting CSII – he suggested the study wasn’t sufficiently powered to detect it.
  • Yun-Hee Noh (Chungju, Republic of Korea) found that six months of pump therapy dramatically lowered A1c and improved beta cell function in patients with longstanding type 2 diabetes. Their study was designed to look at whether CSII could impact beta cell function in advanced type 2 patients. The study used insulinogenic index and proinsulin- to-insulin ratio as two ways of evaluating beta cell function. After six months of CSII therapy in 32 type 2 patients with mean duration of diabetes 11.3 years, mean A1c dropped from 9.1% to 6.7%. Notably, significant improvement in insulinogenic index and proinsulin-to-insulin ratio suggested some restoration of beta cell function. We find these results very impressive - they argue strongly for the utility of pump therapy in patients with a long history of type 2 diabetes, who may have as little beta cell function as type 1 patients. Notably, the best responders to CSII were those with higher baseline BMI, Dr. Noh said in Q&A – that was quite interesting from our view and bodes well for greater use of pumps in patients with type 2 diabetes.
  • Andrea Palermo, MD (Rome, Italy) presented a 15-patient open-label phase 2 study looking at the ability of Oral-lyn insulin to suppress postprandial glucose in people with impaired glucose tolerance (IGT). Oral-lyn is an oral insulin spray designed to be absorbed through the mucosa of the cheeks. He found that 12 Units of Oral-lyn lowered overall glucose levels by 16.5% during a three-hour 75-gram oral glucose tolerance test (OGTT). Dr. Palermo concluded that Oral-lyn could be used to treat IGT, although we think this would be a difficult population to start on medications, particularly insulin. Even more difficult would be obtaining payor endorsement. Overall, we continue to believe non-injected insulin remains a challenging field due to lack of buy-in by key thought leaders (we can’t find any who will say anything stronger than they look forward to seeing large-study phase 3 data). We assume problems with absorption may pose difficulties, making dosing inconsistent and challenging, and there is certainly strong competition from injected insulins. Finally, we didn’t view the estimate of 10-15% for bioavailability as a positive – the implications for pricing and safety are negative in our view.
  • Bruce Buckingham, MD (Stanford Medical Center, Stanford, CA) gave a wonderful overview of closed loop technology (aka the artificial pancreas). He specifically gave credit to industry and the JDRF for driving and supporting research in the closed loop. He believes that all the pieces of the technology have come together, and showed results of human trials that yielded excellent blood glucose control. Areas for improvement include minimizing the delays in sensor and insulin action and dealing with meals and exercise. Medtronic has launched a pump in Europe that automatically suspends insulin delivery when the CGM reports hypoglycemia, which is the first step on the journey. But as we look forward, the fully closed loop may be approved first in the inpatient setting such as the ICU.
  • In the symposium on insulin pumps, Christopher E. Sadler, MA, PA-C, CDE (Diabetes and Endocrine Associates, La Jolla, CA) provided a comprehensive review of the state of pump technology for patients with type 2 diabetes. He categorized current pump features into ease-of-use and physiologic factors. Special features of various pumps were presented to provide examples of recent advances in this technology. Sadler also provided an overview of key components of software tools involved in retrospectively reviewing insulin data. He concluded by outlining the major challenges associated with advancing pump technology including reimbursement for providers, infusion site failures, and the overall hassle of managing multiple devices.
  • Bruce W. Bode, MD (Atlanta Diabetes Associates, Atlanta, GA) reviewed the limited research that has been conducted on insulin pumps in type 2 patients and outlined suggestions for the design of further studies. He paid particular attention to patient satisfaction and the clinical effectiveness of insulin pumps in this patient population. Overall, he concluded that pump therapy clearly improves glucose control and patient satisfaction.
  • During the MannKind symposium, Satish K. Garg, MD (University of Colorado Denver School of Medicine, Aurora, CO) compared the merits of prandial versus basal insulin therapy for type 1 and type 2 diabetes. Overall, he favored prandial insulin, particularly early in the progression of diabetes. He showed data demonstrating that diabetes therapies tend to be started late in the disease progression: the average A1c at initiation of therapy was 8.6% for diet and exercise, 8.9% for sulfonylureas, and 9.6% for combination oral agents (Brown JB et al., Diabetes Care, 2004).
  • Lawrence Blonde, MD (Department of Endocrinology, Diabetes, and Metabolism, Ochsner Medical Center, New Orleans, Louisiana) reviewed the history of insulin, with a special focus on advances in insulin delivery systems. He delved into the favorable customer satisfaction of Exubera, the first and only inhaled insulin to receive FDAapproval, which was subsequently removed from the market. Finally, he discussed MannKind’s recently accepted NDA submission to the FDA for Afresa, an inhaled insulin product, and concluded that despite the continual challenges posed to inhaled insulin, many physicians and patients continue to seek better delivery systems, and that inhaled insulin technology may result in improved patient outcomes and satisfaction.
  • Tim Heise, MD (Profil Institute for Metabolic Research, Neuss, Germany) talked about inhaled insulin’s potential role in the treatment of diabetes. He acknowledged Exubera’s flaws, but contended that its failure did not preclude the success of inhaled insulin overall. Among Exubera’s major drawbacks were the size and awkward shape of the inhaler, the nonlinear physiological effects of combining multiple doses, suggestions of an increase in rates of lung cancer, and poor marketing. He felt that Exubera had many positive qualities, however, and he presented studies involving Exubera to support the utility of inhaled insulin.
  • Eda Cengiz, MD (Yale University School of Medicine, New Haven, CT) presented an interesting study designed to investigate the effect on lispro (Eli Lilly’s Humalog) of mixing it with glargine (Sanofi-Aventis’ Lantus). Mixing caused a flattening of the time action profile of lispro resulting in a diminished peak concentration and a delay in time to peak concentration of three to four hours. This can result in early meal related hyperglycemia and later insulin related hypoglycemia, which is a troubling finding. This study was quite small (n=11) and was performed in teenage type 1s.
  • Guang-Wei Li, MD (Sino-Japan Friendship Hospital, Beijing, China) followed ten patients who underwent two-week insulin therapy at diagnosis; notably, 50% remained in remission from diabetes at one-year. The patients who remained in remission tended to have greater glucagon release in response to glucose infusion prior to insulin therapy (a key defect in diabetes), but also a greater improvement in glucagon function after insulin therapy compared to patients who remained diabetic. This suggests that pancreatic alpha- cells play an important role in the progression of type 2 diabetes and surprisingly, alpha-cell function may be a better predictor for long-term diabetes remission than beta cell function. This finding makes us curious about the impact of GLP-1 therapy at diagnosis of type 2 diabetes, since GLP-1 therapy has been shown to decrease abnormal alpha cell glucagon secretion as well as increase beta cell insulin secretion. We are very eager to see more research in larger populations. Not only do we see obvious benefit from remission, but we also assume that this population would have fewer difficulties going on to insulin when they were failing oral therapy (assuming all eventually do go on to be diagnosed with diabetes). We view this an important result, though a small trial – we expect and look forward to seeing more research done on this front.
  • At a corporate symposium sponsored by Novo Nordisk titled “Education Recognition Program – Trends in Diabetes Education,” Dr. Alan Garber MD, PhD, FACE (Baylor College of Medicine, Houston, TX) began a discussion on the use of insulin analogs in the treatment of type 2 diabetes by providing insight into the benefits that insulin analogs provide to such patients. He emphasized that the use of insulin in individuals with type 2 diabetes is a trade-off between increasing therapy and avoiding complications. Dr. Garber described how current insulin analogs allow for increased glycemic control. He concluded by describing how intensive insulin therapy is worthwhile due to its proven benefits on both microvascular outcomes and reducing risk factors. As we understand it from this symposium, studies on the insulin/Byetta combination have been done and “we are just waiting for final approval from the FDA.”
  • Rury Holman, FRCP (University of Oxford, Oxford, UK) seemed to mildly resist the weight-centric, incretin-focused buzz of this year’s meeting, where several leaders are recommending incretins over insulin in overweight type 2 diabetics. In a way, given the buzz on new therapies, a discussion of the best insulin to use seemed passé, but we suppose review never hurts. His conclusion was that basal insulin may be preferable to prandial or biphasic insulin, because of simpler regimen, less risk of hypoglycemia, and less weight gain – plus it’s a good base on which to add bolus when progressing to MDI. In the audience, of 51% endocrinologists, 15% PCPs, and 13% “others,” 67% said they start patients on basal once a day, while 20% said they start with premixed twice a day, a common choice in the UK.
  • Arturo R. Rolla, MD (Harvard University/Tufts University, Boston, MA) provided a compelling argument for the incorporation of intensive insulin therapy for early onset patients with type 2 diabetes into the ADA treatment algorithm. He enumerated the advantages insulin possesses compared to other treatment options – for example, that there is no upper dose limit. Furthermore, he detailed several studies indicating that remission rates are significantly higher in type 2 diabetes patients who use an intensive insulin regimen soon after their diagnosis. Dr. Rolla not only sees early intensive insulin therapy as a viable treatment option due to its positive effects on patient outcomes, but he believes that such therapy can restore impaired beta cell activity.
  • Alan Garber, MD, PhD, FACE (Baylor College of Medicine, Houston, TX) went over how to intensify insulin therapy, suggesting that patient self-titration often does better than physician titration, and that lower glycemic targets are better for reaching glucose goals (TITRATE study). Though, as Professor Holman said, we might start with basal insulin, it is important in intensification to move to other regimens rather than simply upping the basal. After one shot of insulin is failing, the two options are to go to multiple daily injections (MDI) or twice a day premixed – adding one bolus to cover a single meal will not work no matter what the meal.

Symposium: Pump Therapy 2009

UPDATE ON PUMP TECHNOLOGY 2009

Christopher E. Sadler, MA, PA-C, CDE (Diabetes and Endocrine Associates, La Jolla, CA)

Mr. Sadler provided a comprehensive review of the current state of pump technology for patients with type 2 diabetes. To kick off the lecture, he reviewed the currently available pumps and their respective suppliers. He categorized pump features into ease-of-use and physiologic factors. Special features of various pumps were presented to provide examples of recent advances in this technology. Mr. Sadler also provided an overview of key components of software tools involved in retrospectively reviewing insulin data. He concluded by outlining the major challenges associated with advancing pump technology including reimbursement for providers, infusion site failures, and the overall hassle of managing multiple devices.

  • Mr. Sadler categorized essential pump features into ease of use and physiologic factors. Ease of use features included reminders to check blood glucose, reminders to change infusion sets, and warning of low insulin levels in the reservoir. Physiologic factors include multiple basal rates (as low as 0.025 u/hr), combination bolus features, and bolus wizards that can calculate the amount of insulin required. Since pump technology cannot anticipate patient activity, human intervention is essential. Mr. Sadler believes the predominant problem of thebolus calculator is the failure of patients to (correctly) input blood glucose values and carbohydrate counts.
  • Mr. Sadler strongly suggested that patients and physicians should utilize pump features to retrospectively analyze blood glucose levels. He advised against frequent in- between meal corrections until a patient’s blood glucose trends are clear. Unfortunately, many physicians currently do not consistently review blood glucose levels because of lack of standardized software to do so.
  • Despite advances in pump technology, there are several challenges to widespread adoption of pump therapy. Reimbursement for providers continues to be a major challenge. Mr. Sadler also said that patients are constantly burdened with trouble shooting the pump, wearing multiple devices, and carrying back-up supplies in case the pump fails beyond repair. For some patients, the psychological burden can be overwhelming. Although combined continuous glucose monitoring (CGM) and pump therapy was not significantly more effective as measured by A1c levels, patients reported greater convenience and reported feeling more satisfied with therapy. We continue to believe that combined CGM/pump therapy is the future of type 1 diabetes management (to be followed, ultimately, by open-loop artificial pancreas), as reimbursement improves, technology advances, and the various industry players partner up.

PATCH PUMPS

Nancy J. Bohannon, MD, FACP, FACE (St Luke’s Hospital, San Francisco, CA)

The marvelous Dr. Nancy Bohannon (St Luke’s Hospital, San Francisco, CA) gave the best presentation we’ve seen to date on the exciting field of patch pumps. In her words: “Pumping is wonderful, but patch pumping offers a whole new dimension… hopefully to those with type 2 as well as type 1.” She cited more than ten companies developing patch pumps – some are mechanical, some electronic, some basal only, some bolus only, and some basal/bolus. All aim to be as small as possible; most can be operated through clothing or via a wireless controller. Some have a multi-part design that allows the minimum amount of material to be thrown away after each cycle. Dr. Bohannon suggested that for type 2 patients, an important need is to keep costs low for easier reimbursement. Companies to watch include Medtronic, Insulet, Calibra, Valeritas, Medingo, Medsolve, CellNOVO, NiliMEDIX, STMicroelectronics/Debiotech and Altea. Some other companies had specifically requested not to be mentioned in her review. In response to a questioner “from Switzerland”, Dr. Bohannon stated that at least two of these pumps in development would be launched within the next 12 months.

  • It would be best if we could start type 2 patients on insulin earlier in their treatment – patch pumps offer this hope. Most people with type 2 wait a long time before starting insulin – usually their A1c rises above 8% before that time. Then, after treatment with basal insulin, A1c rises again before mealtime insulin is prescribed. The earlier insulin is prescribed, the more we can avoid complications. Patch pumps may be a more convenient way to dose insulin.
  • The OmniPod (Insulet), launched in 2005, is the first patch pump, and incorporates a ‘pod’ placed on the body to deliver insulin, and a handheld remote controller (known as the ‘Personal Diabetes Manager’). A recent upgrade to the PDM provides a color display and downloading capability.
  • The Calibra ‘Finesse’ mechanical pump delivers bolus-only insulin or pramlintide (Symlin, Amylin). It adheres to the body, allows a three-day wear with up to 200 units of insulin (but doesn’t have to be completely filled), and has no electronics or battery. To deliver abolus, two buttons are pressed simultaneously for safety reasons. Pumps can be obtained with 0.5,1,2, or 5 units per squeeze. The patch is very slim – about the thickness of four stacked quarters. To obtain the small size, there is an external cannula driver that fits over the device, inserts the cannula and is then removed. It’s nearly invisible under clothing and is intended to be operated through the clothing.
  • The Valeritas V-Go disposable device delivers basal and bolus insulin, primarily for type 2 patients. The device comes in three fixed doses of 20, 30, or 40 units per 24 hours. It is purely mechanical and has no electronics. A bolus of two units can be given by clicking a button, with a maximum of 18 clicks (36 units) a day. The patch is replaced after 24 hours. The V-Go uses a 30-gauge floating needle that is inserted and withdrawn via buttons on the device (after use, the pump acts as its own sharps container). There are two buttons required for bolus delivery (again as a safety mechanism). The device fits well under clothing and can be operated through clothing. The pump has an external insulin-filling device, and both pump and filling device have been FDA- approved. However in response to patient feedback, the company is developing a new filling mechanism that is currently in front of the FDA.
  • The Medingo Solo is an electronic patch pump using a handheld controller, so could be suitable for both type 1 and type 2. The pump has an electronic portion and an insulin reservoir and fits into a disposable ‘cradle cannula’ that sits directly on the body. In this way, the electronics are re-used. The pump has a three-day life. Medingo is pronounced MEDingo not MedINGo.
  • The Medsolve Freehand is reported to be 80% smaller than the current OmniPod device. It is a disposable device containing up to 300 units. The company is not disclosing details publicly, but they have a large partner and are looking for another. Size is reported to be one cubic inch.
  • Altea Therapeutics’ device can deliver basal insulin, GLP-1, or pramlintide via a transdermal patch. The product is called the PassPort system. The company demonstrated proof-of-concept in 2007, and is working with Amylin/Lilly on GLP-1 and pramlintide.
  • Medtronic has well-developed plans to launch a disposable pump at some point in FY2011 (which ends in April 2010). We have little information to date, although there is a photo that implies that the product is similar in concept and appearance to Insulet’s OmniPod.
  • Other companies of note include:
    • CellNovo, which uses microfluidics to create a low power pump that can be used for three days on the body.
    • NiliMEDIX – indicate that they are soon to launch a single-use insulin pump. Concept pictures on their website also show a combined pump/CGM product.
    • STMicroelectronics and Debiotech are jointly marketing the “Nanopump”, a disposable pump small enough to be affixed to the body, yet with a 750 unit reservoir, because of the miniaturization of the pump itself.

INSULIN PUMPS FOR TYPE 2 PATIENTS

Bruce W. Bode, MD (Atlanta Diabetes Associates, Atlanta, GA)

Dr. Bode reviewed the limited research that has been conducted on insulin pumps and outlined suggestions for the design of further studies. He paid particular attention to patient satisfaction and clinical effectiveness of insulin pumps. Dr. Bode concluded that pump therapy clearly improved glucose control and patient satisfaction.

  • Dr. Bode began by examining the unique needs of patients with type 2 diabetes. In an analysis of patients with type 1 and type 2 diabetes using insulin, 89% of type 2 patients do not inject insulin outside of the home compared to 69% of type 1 patients. The metabolic advantages of continuous subcutaneous insulin infusions (CSII) include improved glycemic control, improved pharmacokinetic delivery of insulin, and enhancements in quality of life (QOL).
  • Dr. Bode concluded that pump therapy clearly improves glucose control. He described the need for well-controlled, randomized studies. He believes further research is needed to determine the appropriate type 2 candidates for pump therapy and the cost effectiveness of such a therapy.

CLOSING THE LOOP

Bruce A. Buckingham, MD (Stanford Medical Center, Stanford, CA)

The irrepressible Dr. Buckingham gave a wonderful overview of closed loop technology, (aka the artificial pancreas). He specifically gave credit to industry and the JDRF for driving and supporting research in the closed loop. He believes that all the pieces of the technology have come together, and showed results of human trials that yielded excellent blood glucose control. Areas for improvement include minimizing the delays in sensor and insulin action and dealing with meals and exercise. Medtronic has launched a pump in Europe that automatically suspends insulin delivery when the CGM reports hypoglycemia, which is the first step on the journey. But as we look forward, the fully closed loop may be approved first in the inpatient setting such as the ICU.

  • The artificial pancreas consists of an insulin pump, continuous glucose monitor (CGM), and algorithm (a control program). All these pieces are now in place. The main barriers to the development of the artificial pancreas are time delays (onset of action, sensor lag times), accuracy of sensor, biologic variability, and exercise.
  • Dr. Buckingham showed data highlighting a 17-minute delay in a commercial CGM sensor (which is about three to six minutes physiological delay and about 12 minutes of filtering delay in the sensor itself).
  • Rapid acting insulin takes about 45 minutes to reach full activity. There are methods for improving this speed, including VIAject insulin (Biodel), microneedles (for intradermal administration), local warming, hyaluronidase, and (the not-so-practical) intraperitoneal implanted pump. VIAject has a little earlier onset and about the same duration as a classic rapid acting insulin.
  • Dr. Gary Steil, in landmark paper (Diabetes 55:3344-3350 2006) showed very good overnight control using a PID algorithm. Dr. Roman Hovorka has also performed overnight work that increases time in the target zone from 34% to 67%, using an MPC algorithm. The PID algorithm uses a combination of the rate-of-change of glucose, the glucose level itself, and historical glucose over time to generate a control signal for insulin dosing. The MPC algorithm uses a model to predict the future, and finds the right insulin dose that makes its prediction align with target; it then updates its forecast based on a moving horizon concept. Medtronic has introduced the ePID algorithm – a modified PID to include ‘insulin on board’ (known as insulin feedback) which helps avoid postmeal hypoglycemia.
  • “The hardest thing in closed loop right now is meal disturbance.” Delivering insulin at the time of the meal is just not adequate for good control. Dr. Stu Weinzimer showed the use of a ‘hybrid’ model, which gives insulin 15 minutes ahead of time when the patient ‘announces’ the meal to the algorithm. In this work closed loop control delivered the equivalent of an A1c reduction from 7.1% to 6.4%, and 85% of the time in the target zone.
  • Meal detection algorithms are intended to detect a meal within a few minutes and dose insulin, to avoid hyperglycemia. The current state of the art algorithms will recognize 94% of challenge meals before glucose rises more than 40 mg/dl (2.2 mmol). Deciding how much insulin to give is difficult – especially with the need to avoid hypoglycemia.
  • Exercise is not well studied. But the use of an accelerometer or heart rate monitor within a device can give indication of when exercise is occurring. A new study at Yale will investigate fully closed loop control over a 2 day/3 night period including exercise.
  • In Europe, Medtronic has launched a low-glucose auto-suspend feature, in which the pump will suspend basal insulin delivery in response to a hypoglycemia alarm from the CGM. It would work even better if we could predict hypoglycemia coming rather than waiting for it. We could also imagine predicting and avoiding hyperglycemia. This ‘guardrail’ approach is called ‘treat-to-range’.
  • As we look forward, we expect that fully closed loop control will be first implemented in an inpatient setting, such as the ICU. For example a study in the pediatric ICU of a PID algorithm eliminated any hypoglycemia less than 55 mg/dl (3.1 mmol) after the startup time.

Oral Presentations: Developments in Insulin Delivery

SHOULD WE MIX LISPRO WITH GLARGINE? REMOVING THE GUESSWORK BY EUGLYCEMIC CLAMP STUDIES

Eda Cengiz, MD (Yale University School of Medicine, New Haven, CT)

Dr. Cengiz presented an interesting study designed to investigate the effect on lispro (Eli Lilly’s Humalog) of mixing it with glargine (Sanofi-Aventis’ Lantus). Mixing caused a flattening of the time action profile of lispro resulting in a diminished peak concentration and a delay in time to peak concentration of three to four hours. This can result in early meal related hyperglycemia and later insulin related hypoglycemia, which is a troubling finding. This study was quite small (n=11) and was performed in teenage type 1s.

  • There have been conflicting results regarding the potential risks of mixing insulin lispro (Eli Lilly’s Humalog) with glargine (Sanofi-Aventis’ Lantus). Using a euglycemic clamp study, Dr. Cengiz’s group investigated whether the early action profile of lispro is affected when mixed with glargine.
  • The study took 11 teenagers who had been on insulin pump therapy for at least three months and dosed the two insulins independently and in a mixed formulation. Dosing was based on a 0.2 unit/kg (lispro) and 0.4 unit/kg (glargine) regimen. The euglycemicclamp was held at 90 mg/dl (5.0 mmol). Investigators calculated glucose infusion rate (GIR), area under the curve (AUC), max GIR, and time to max GIR.
  • The study found that mixing lispro and glargine altered both the early and late time action profile of lispro. The peak concentration of lispro was lowered (max GIR reduced from7.1 to 3.9 mg/min) and time to peak action was delayed (from 116 to 209 minutes). Specifically, the AUC for lispro in the first 90 minutes was reduced by 75% from mixing. In terms of the late time action profile, the AUC between 210 to 300 minutes was actually increased by almost 50%. These effects on early and late lispro profiles could result in meal-related hyperglycemia and subsequent insulin-related hypoglycemia respectively.

Questions and Answers

Q: When you mixed the insulins, how long did you wait before injecting?

A: We injected immediately.

Q: Could you address the fact you are mixing different pH insulins. What happened to glargine?

A: We are still waiting to get the data.

BASAL INSULIN SUBSTITUTION WITH GLARGINE OR CSII IN ADULT TYPE 1 DIABETES PATIENTS—A RANDOMIZED CONTROLLED TRIAL

Joakim Bragd MD, (Karolinska Institutet, Stockholm, Sweden)

In the reported study, 15 seasoned pump users with type 1 diabetes were randomized to continue using CSII or to get a morning dose of glargine (Lantus by Sanofi-Aventis), administered via their pump, along with mealtime boluses as before. Concurrent CGM showed that CSII was associated with lower mean glucose, longer periods of glucose within target, and a lower A1c (6.5% versus 6.8%); baseline A1c was not specified although we know it was on the low side since inclusion criteria specified an A1c of 6- 8%. Dr. Bragd was surprised that there was no significant difference in glycemic variability, which is an indication in his clinic for starting CSII – he suggested the study wasn’t sufficiently powered to detect it.

  • CGM showed that patients on basal bolus therapy spent more time at higher glucose levels. CSII also was associated with lower mean glucose and a lower A1c.
  • It was surprising that there was no difference in glucose variability from basal- bolus therapy to CSII. Since glycemic variability is an indication in Dr. Bragd’s clinic to start CSII, he was surprised, but suggested the study was not sufficiently powered to detect a significant difference.

CHANGES IN BASAL INSULIN INFUSION RATES WITH CSII: TIME UNTIL A CHANGE IN METABOLIC EFFECT IS INDUCED IN PATIENTS WITH TYPE 1 DIABETES

Lutz Heinemann, PhD (Profil Institute for Metabolic Research, Neuss, Germany)

This euglycemic clamp study, supported by Roche and Disetronic, was designed to evaluate the time required to make a change in the basal insulin infusion rate for patients on pump therapy. It included ten males with type 1 diabetes who received various continuous subcutaneous insulin infusion (CSII) rates (0.5, 1.0, and 2.0 U/hr) for four hours each. The authors showed that it takes up to four hours for a new steady state of insulin and glucose levels to occur after basal infusion rates are altered. One must therefore consider this delay in making basal infusion rate changes.

  • In the highest infusion rate of insulin, steady state was not reached before the time period was up. Insulin was infused at 0.5 units per hour, 1.0 units per hour, and 2.0 units per hour sequentially for four hours each. Insulinemia would increase after 30-60 minutes and continue to rise until plateau. Glucose infusion would increase similarly to maintain euglycemia. A plateau was not observed in the highest infusion rate, suggesting four hours was not enough time for equilibration.
  • Too frequent changes in basal insulin infusion rates are likely of limited clinical value, because of the time it takes for steady state to occur.
  • Asked whether faster acting insulins may induce a more rapid steady state, Dr. Heinemann said he would be cautious to assume that.

LONG-TERM CONTINUOUS SUBCUTANEOUS INSULIN INFUSION TREATMENT IMPROVED INSULINOGENIC INDEX AND PROINSULIN-TO-INSULIN RATIO IN LONGSTANDING TYPE 2 DIABETIC PATIENTS

Yun-Hee Noh (Chungju, Republic of Korea)

The authors of this study found that six months of pump therapy dramatically lowered A1c and improved beta cell function in patients with longstanding type 2 diabetes. Their study was designed to look at whether CSII could impact beta cell function in advanced type 2 patients. The study used insulinogenic index and proinsulin-to-insulin ratio as two ways of evaluating beta cell function. After six months of CSII therapy in 32 type 2 patients with mean duration of diabetes 11.3 years, mean A1c dropped from 9.1% to 6.7%. Notably, significant improvement in insulinogenic index and proinsulin-to- insulin ratio suggested some restoration of beta cell function. We find these results very impressive - they argues strongly for the utility of pump therapy in patients with a long history of type 2 diabetes, who may have as little beta cell function as type 1 patients. Notably, the best responders to CSII were those with higher baseline BMI, Dr. Noh said in Q&A – that was quite interesting from our view and merits further research.

  • There may be a partial restoration of early phase insulin response, after six months of CSII in longstanding type 2s. The 32 type 2 patients enrolled in this study had baseline A1c 9.1% and longstanding (11.3 yrs) diabetes. After six months of treatment, mean A1c fell to 6.7%. Insulinogenic index increased by 2.3 fold, and proinsulin-to-insulin ratio decreased by 44% when measured two hours postprandially. The authors are continuing the study to monitor how markers for beta cell function will continue to change. The best responders to CSII were those with higher baseline BMI, Dr. Noh said in Q&A – that was quite interesting from our view and bodes well for greater use of pumps in patients with type 2 diabetes.

AFRESA SUPPRESSES ENDOGENOUS GLUCOSE PRODUCTION EARLIER THAN A RAPID-ACTING ANALOG (LISPRO) AND INHALED EXUBERA

Robert Baughman, PhD (MannKind, Danbury, CT)

Dr. Baughman presented an open-label, single-dose, three-way crossover study in 18 insulin-dependent type 2 diabetes patients that compared the ability of 45 U Afresa (MannKind), 12 IU insulin lispro (Lilly’s Humalog), or 4 mg of Exubera (Pfizer) to suppress endogenous glucose production (EGP). All three doses produced equivalent overall suppression of endogenous glucose production (EGP) after a single administration ; notably the Afresa dose produced the earliest nadir of suppression (40 min vs. 75 min for lispro and 130 min for Exubera) and suppressed glucose more effectively in the first 60 minutes than the other two insulins. We appreciate the comparison of Afresa to other rapid-acting insulins in this study rather than to regular insulin. While the kinetics look promising, we note that safety is the main factor needed to garner FDA approval and reimbursement and convenience are essential to have any opportunity to enter the market. Still, we did see these results as differentiated. We are curious how fast the insulin action ends.

  • Dr. Baughman began with an introduction about Afresa inhaled insulin (previously Technosphere Insulin, or TI). A previous study has shown that 30 U of TI compared to 10 IU of lispro had a much earlier onset of action with a Tmax of 10 minutes vs. 60 minutes with lispro.
  • The current study was an open-label, single-dose, three-way crossover study in 18 insulin-dependent type 2 diabetes patients. Each subject received three euglycemic hyperinsulinemic clamp studies in which 45 U TI (roughly the same as 12 IU insulin), 12 IU insulin lispro, or 4 mg of Exubera were administered. Radiolabeled glucose was then infused to maintain glucose levels at 90 mg/dl, and the amount of glucose required to maintain euglycemia was measured as a proxy for endogenous glucose production (EGP). The authors found that TI had a higher peak concentration than Exubera and an earlier peak than both Exubera and lispro. Peak postprandial blood glucose also occurred later with TI than with the other two insulins.
  • Each of the doses produced equivalent suppression of endogenous glucose production (EGP) as measured by total amount of glucose infused. However, the TI dose produced the earliest nadir of EGP (40 minutes vs. 75 minutes for lispro and 130 minutes for Exubera). We note, however, that the actual graphs of EGP suppression do not look different though TI does produce a greater EGP suppression during the first 60 minutes after administration than the other two insulins.

Questions and Answers:

Q: What is the bioavailability of TI? What happens to the non-absorbed part?

A: For each 15 units of insulin in the cartridge, about four units are absorbed. The rest of the insulin is deposited in the oropharynx and swallowed. A small amount remains in the cartridge.

Q: Higher doses of lispro shift the insulin kinetics curve to the right. Does giving higher doses of TI also slow the kinetics?

A: The absorption rate does not change but you will see a movement of the curve to the right as the greater amount of insulin is cleared.

BUCCAL SPRAY INSULIN FOR THE MANAGEMENT OF POST-PRANDIAL HYPERGLYCAEMIA IN SUBJECTS WITH IMPAIRED GLUCOSE TOLERANCE

Andrea Palermo, MD (Rome, Italy)

Dr. Palermo presented a 15-patient open-label phase 2 study looking at the ability of Oral-lyn insulin to suppress postprandial glucose in people with impaired glucose tolerance (IGT). Oral-lyn is an oral insulin spray designed to be absorbed through the mucosa of the cheeks. He found that 12 Units of Oral- lyn lowered overall glucose levels by 16.5% during a three-hour 75-gram oral glucose tolerance test (OGTT). Dr. Palermo concluded that Oral-lyn could be used to treat IGT, although we think this would be a difficult population to start on medications, particularly insulin. Even more difficult would be obtaining payer endorsement. Overall, we continue to believe non- injected insulin remains a challenging field due to lack of buy-in by key thought leaders (we can’t find any who will say anything stronger than they look forward to seeing large-study phase 3 data). We assume problems with absorption may pose difficulties, making dosing inconsistent and challenging, and there is certainly strong competition from injected insulins. Finally, we didn’t view the estimate of 10-15% for bioavailability as a positive – the implications for pricing and safety are negative in our view.

  • This was an 15-patient open-label dose escalation phase 2 study looking at the ability of Oral-lyn insulin to suppress postprandial glucose in people with impaired glucose tolerance (IGT), a form of prediabetes. As a reminder, Generex’s Oral-lyn is a non-injected spray insulin that is absorbed through the mucosal surface of the inside of the cheek. Subjects were randomized to take four, six, or 12 Units (puffs) of Oral-lyn split into two doses before and 30 minutes into a three-hour 75-gram oral glucose tolerance test (OGTT).
  • While the four and six unit doses had no effect on glucose levels, patients receiving the 12 unit dose had a mean reduction of 16.5% in plasma insulin levels during the OGTT. The mean two-hour glucose value fell from 179 mg/dl to 124 mg/dl (p=0.01) and the mean three-hour glucose value fell from 127 mg/dl to 87 mg/dl (p=0.04). Notably, there were no adverse events such as hypoglycemia.
  • The authors conclude that treatment with Oral-lyn is an option for lowering postprandial hyperglycemia in patients with IGT. We believe that this would be a difficult patient population to start on medications, particularly insulin, even if it is in a non-injected form. Non-invasive insulin administration remains a difficult field because of strong competition with well-established injected insulins.

Questions and Answers:

Q: How much insulin did you use in this study?

A: One puff corresponds to one unit absorbed. The bioavailability is 10-15%.

Q: How do you imagine this insulin being used? How would it be practical?

A: Compared to an injected insulin there is no question that this is a very attractive way for patients to manage postprandial hyperglycemia. It would be interesting to see if we could restore A1c in the long term with by targeting the postprandial defect specifically.

Q: Would it be better to have a control group with subcutaneous insulin compared to buccal insulin?

A: Yes, of course. Giving insulin is protective of beta cells. This has been shown in previous studies.

THE ROLE OF ACUTE GLUCAGON RESPONSE IN LONG-TERM REMISSION OF NEWLY DIAGNOSED TYPE 2 DIABETES INDUCED BY SHORT-TERM INSULIN INTENSIVE TREATMENT

Guang-Wei Li, MD (Sino-Japan Friendship Hospital, Beijing, China)

Short-term intensive insulin control with pump therapy at diagnosis can induce long-term remission of type 2 diabetes. Dr. Li’s group followed ten patients who underwent two-week insulin therapy at diagnosis; notably, 50% remained in remission from diabetes at one-year. The patients who remained in remission tended to have greater glucagon release in response to glucose infusion prior to insulin therapy (a key defect in diabetes), but also a greater improvement in glucagon function after insulin therapy compared to patients who remained diabetic. This suggests that pancreatic alpha-cells play an important role in the progression of type 2 diabetes and surprisingly, alpha-cell function may be a better predictor for long-term diabetes remission than beta cell function. This finding makes us curious about the impact of GLP-1 therapy at diagnosis of type 2 diabetes, since GLP-1 therapy has been shown to decrease abnormal alpha cell glucagon secretion as well as increase beta cell insulin secretion. We are very eager to see more research in larger populations. Not only do we see obvious benefit from remission, but we also assume that this population would have fewer difficulties going on to insulin when they were failing oral therapy (assuming all eventually do go on to be diagnosed with diabetes). We view this an important result, though a small trial – we expect and look forward to seeing more research done on this front.

  • This study looked for factors associated with successful remission of type 2 diabetes after two weeks of intensive insulin treatment at diagnosis. Ten newly diagnosed type 2 diabetes patients received two weeks of intensive insulin treatment with CSII (continuous subcutaneous insulin infusion) therapy. The goal for CSII was FPG <6.1 mmol/l (110 mg/dl) and postprandial <8.0 mmol/l (144 mg/dl). Immediately after CSII the patients had mild restoration of first-phase insulin secretion and improved insulin sensitivity.
  • At one-year follow-up, 50% remained in diabetes remission. The patients who remained in remission had abnormal glucagon secretion in response to a 25-gram glucose infusion before CSII, but this resolved after CSII. In contrast, the patients who remained diabetic had less improvement in the acute glucagon response. Surprisingly, improvements in insulin sensitivity and first phase insulin secretion after CSII were not closely correlated with remission.
  • Dr. Li concluded that diabetes patients with a greater (dysfunctional) acute glucagon response (AGR) to glucose infusion and a better AGR reduction after CSII were more likely to achieve long-term remission, which suggests that pancreatic alpha- cells play a unique role in the induction of remission of type 2 diabetes. Thus, surprisingly, the acute glucagon response to glucose infusion may be a better predictor for long term remission that improvement of beta cell function.

Questions and Answers:

Q: Do you think the reason the patients who improved did better because their alpha cells were more diseased already?

A: Glucose toxicity induces alpha cell insulin resistance and correction of hyperglycemia improves the alpha cell response to insulin. In the prediabetes state there is already remarkable impairment of alpha cell function because IGT subjects with high levels of insulin also have high levels of glucagon.

Poster Presentations: Developments in Insulin Delivery

(479-P) COMPARATIVE EFFICACY AND SAFETY OF AFRESA AND A RAPID-ACTING ANALOG BOTH GIVEN WITH GLARGINE IN SUBJECTS WITH T1DM IN A 52-WEEK STUDY

Bergenstal R, Kapsner P, Rendell M, Boss A, Howard C, Chang P, Richardson P

MannKind’s inhaled insulin Afresa, currently under review by the FDA, has been touted by the company as a substantial improvement in terms of insulin kinetics and efficacy without weight gain. This study compared Afresa with insulin aspart, both on top on insulin glargine, for a period of one year. After the treatment period, subjects treated with Afresa showed statistically similar A1c changes (although the decrease with Afresa was substantially smaller, the difference was not significant), decreases in FPG and PPG, and a more favorable change in body weight compared to the insulin aspart group. There was a small decrease in hypoglycemia with Afresa treatment. We’re interested to see how Afresa fares— although this data looks somewhat promising, we anticipate that the product will face significant hurdles based on perceived safety and patient acceptance in the future.

  • This study was a multicenter, controlled, randomized clinical trial that aimed to define the glycemic control of Mannkind’s inhaled insulin Afresa in type 1 diabetes patients relative to insulin aspart (NovoLog). Patients were treated with insulin glargine (Sanofi-Aventis’s Lantus) and either Afresa (n = 301) or insulin aspart (n = 288). Efficacy endpoints were A1c, 1-hr post-prandial glucose (PPG), 2-hr PPG, fasting plasma glucose (FPG) following a meal challenge, and body weight. Patients enrolling in the trial had an A1c >7.0% and≤11.o% and were examined for 52 weeks.
  • The Afresa-treated group experienced comparable A1c reductions, greater reductions in FPG and PPG, and a more favorable change in body weight than the insulin group. After the 52-week treatment period, Afresa patients experienced a 0.13% A1c decrease, compared to a 0.37% decrease in the insulin group (p=0.08; from baselines of 8.4% and 8.5%). FPG decreased by 35.5 mg/dL in the Afresa group and 20.6 mg/dL in the insulin group (p=0.0012; baselines of 187 and 180 mg/dL), and the increase in 1-hr PPG versus pre-meal glucose was 20.9 mg/dL in the Afresa group and 40.5 mg/dL in the insulin group (p=0.002). Change in body weight was -0.5 kg (-1.1 lbs) in the Afresa group compared to +1.4 kg (3.1 lbs) in the insulin group (p<0.0001).
  • Afresa treatment resulted in a small but significant decrease in total hypoglycemia, and a non-significant trend toward a decrease in severe hypoglycemia. 86% of the subjects in the Afresa arm experienced a hypoglycemic event, compared to 92.7% of the insulin- treated subjects (p=0.01). The event rate for all hypoglycemic events was not significantly different between the two groups. 32.8% of the Afresa subjects experienced severe hypoglycemia during the trial compared to 37.5% of the insulin subjects, but this was not significant (p=0.24).

MannKind Sponsored Symposium: Emerging Directions in Insulin Delivery

UNDERSTANDING AND TARGETING PRANDIAL INSULIN IN GLYCEMIC CONTROL

Satish K. Garg, MD (University of Colorado Denver School of Medicine, Aurora, CO)

Dr. Garg compared the merits of prandial versus basal insulin therapy for type 1 and type 2 diabetes. Overall, he favored prandial insulin, particularly early in the progression of diabetes. He showed data demonstrating that diabetes therapies tend to be started late in the disease progression: the average A1c at initiation of therapy was 8.6% for diet and exercise, 8.9% for sulfonylureas, and 9.6% for combination oral agents (Brown JB et al., Diabetes Care, 2004).

  • Dr. Garg discussed the merits of prandial and basal insulin delivery. He cited a study by Monnier et al. (Diabetes Care, 2007) that found that prandial hyperglycemia occurs before elevations in fasting plasma glucose. He saw this as an opportunity for better treatment: it is clinically logical to treat only the elements of diabetes that have manifested, and so prandial insulin would be a logical treatment choice. On the subject of early intervention, he lamented the severity of diabetes that patients reach before being put onto anti-diabetic therapy.
  • He advocated tight glycemic control and cited the results of several studies to support his argument. He showed 30-year data from the DCCT, noting that retinopathy, nephropathy and cardiovascular disease are lower in intensively managed versus conventionally managed patients. He followed this with a table showing mortality results from UKPDS, STENO 2, ADVANCE, ACCORD, and VADT. A meta-analysis by Ray et al. (Lancet, 2009) reviewed several studies of glycemic control, and showed a combined 17% reduction in non-fatal myocardial infarctions (MI) and a 15% reduction of congenital heart defects (CHD). Despite ACCORD’s worrying results, there was no increase in all-cause mortality in the tightly controlled group.
  • There is inconsistent evidence in the literature regarding prandial and basal insulin therapy. Bastyr et al. (Diabetes Care, 2000) tested adding basal insulin (insulin NPH), prandial insulin (insulin lispro, Eli Lilly’s Humalog), or metformin to glyburide (a sulfonylurea). A1c was significantly lower in the insulin lispro group compared with metformin or NPH insulin. However, Bretzel et al. (Lancet, 2008) showed no difference between insulin glargine (Sanofi Aventis’ Lantus) and insulin lispro. The HEART2D trial also showed no significant difference in A1c drop between prandial and basal insulin.

IMPACT OF INNOVATION IN INSULIN DELIVERY SYSTEMS OF DIABETES MANAGEMENT

Lawrence Blonde, MD (Department of Endocrinology, Diabetes, and Metabolism, Ochsner Medical Center, New Orleans, LA)

Dr. Blonde reviewed the history of insulin, with a special focus on advances in insulin delivery systems. He delved into the favorable customer satisfaction of Exubera, the first and only inhaled insulin to receive FDA approval, which was subsequently removed from the market. Finally, he discussed MannKind’s recently accepted NDA submission to the FDA for Afresa, an inhaled insulin product, and concluded that despite the continual challenges posed to inhaled insulin, many physicians and patients continue to seek better delivery systems, and that inhaled insulin technology may result in improved patient outcomes and satisfaction.

  • Despite insulin’s undeniable effectiveness at treating hyperglycemia, it is used in a relatively low proportion of patients who could benefit from it; this prompted Dr. Blonde to review studies showing the reluctance of the patient population to adopt subcutaneous insulin infusion. A study by Rubin et al. showed an overwhelming preference for the insulin pen versus prior standard therapy.
  • There is uncertainty regarding the exact efficacy benefit of continuous subcutaneous insulin infusion (CSII) versus multiple daily injections (MDI). Surprisingly few studies have demonstrated the superiority of pumps over MDI in multiple populations. He mentioned a study directed by Hirsch et al., which found that diabetes patients treated with MDI therapy had worse glycemic control compared with patients on CSII therapy. He also cited a randomized study by Doyle et al. (n=32), which showed that patients treated with CSII had improved glycemic control. In a contradictory study, Raskin et al. reported no significant differences between glycemic control between CSII and MDI therapy; however in pump-treated patients, there were significant improvements in general patient satisfaction.
  • Exubera, the only inhaled insulin ever marketed, dramatically increased patient satisfaction. Despite the size of the device and dosing complexity of Exubera, Dr. Blonde analyzed an internal randomized study, which placed patients on either inhaled insulin or CSII for one year and found that patients randomized to Exubera reported a marked increase in patient satisfaction and when offered to continue with Exubera, 85% of patients chose to stay with Exubera whereas only 15% in the CSII group decided to continue therapy. Seventy-five percent of patients who were initially using CSII therapy chose to switch to Exubera and subsequently experienced a significant increase in patient satisfaction. We continue to believe that inhaled insulin is probably appropriate for a subset of patients, but that simplicity and cost are ultimately more important for most patients.

EMERGING DATA ON THE NEXT GENERATION OF INHALED INSULIN

Tim Heise, MD (Profil Institute for Metabolic Research, Neuss, Germany)

Dr. Heise talked about inhaled insulin’s potential role in the treatment of diabetes. He acknowledged Exubera’s flaws, but contended that its failure did not preclude the success of inhaled insulin overall. Among Exubera’s major drawbacks were the size and awkward shape of the inhaler, the nonlinear physiological effects of combining multiple doses, suggestions of an increase in rates of lung cancer, and poor marketing. He felt that Exubera had many positive qualities, however, and he presented studies involving Exubera to support the utility of inhaled insulin.

  • Anti-insulin antibody data from Afresa will be presented at the next EASD conference. Both Afresa and Exubera are associated with a decrease in the forced expiratory volume per one second (FEV1), although this seems to be less pronounced in Afresa than Exubera. In both inhaled insulins, this effect is non-progressive and reversible. Exubera was associated with an increased serum concentration of anti-insulin antibodies, although this was never shown to have any clinical relevance (Skyler et al., Diabetes Care, 2007).
  • Paradoxically, Exubera leads to a decrease in fasting plasma glucose but no change in postprandial plasma glucose. Although the cause of this has not yet been determined experimentally, Dr. Heise hypothesized that it could be due to residual insulin slowly releasing at night. To support his claim, he presented data from Rosenstock et al. (Diabetes Care, 2008) showing quick spikes in serum insulin levels during exercise. This suggests that residual insulin is stored in the lungs and is released during intense ventilation. Although Dr. Heise did not address this issue in his talk, an exercise-dependent release of insulin after inhalation of Afresa could complicate dosing.
  • Ceglia et al. (Ann Intern Med, 2006) compared the efficacy of subcutaneous and inhaled insulin (Exubera) over the course of 12 weeks, and found that subcutaneous insulin was more effective at lowering A1c than inhaled insulin. The study also showed that patients on inhaled insulin were more likely to undergo severe hypoglycemia than those on subcutaneous insulin, although the difference was small (odds ratio= 3.1, 95% CI 1.0-9.1). Rosenstock et al. (Diabetes Care, 2008), however, showed no difference in A1c reduction or rates of hypoglycemia between subcutaneous and inhaled insulin. There was also less weight loss in the inhaled insulin group (difference = 1.3 kg).
  • There are significant differences in the pharmacokinetics of Afresa and Exubera. Afresa is absorbed quicker and more thoroughly than Exubera. Also, combining multiple doses of Afresa seems to have a linear relationship with physiological effects; an inconsistent relationship between multiple doses of Exubera and a single combined dose was a major complaint with the drug.

Questions and Answers

Q: What is the difference between daily insulin dosages when insulin regimes of basal and other analogs were compared with MDI?

Dr. Garg: In a study in the Lancet last year, there was no difference between prandial and basal insulin. In other studies, there has been a difference in efficacy.

Q: Why do you think that there was such a modest improvement in A1c in patients that chose inhaled insulin?

Dr. Blonde: There was a great improvement. It was just a small difference compared to those on SC. So there was very significant reduction, and its not surprising that at the end of the study there was a greater improvement for inhaled insulin.

Q: Do you think that the reduced fasting blood glucose is due to a decrease in gluconeogenesis?

Dr. Heise: It might be, and there are several theories. There may be a bit of oral insulin, which is at least effective in very high doses. In most trials, A1c was different between subcutaneous insulin and inhaled insulin. The results are difficult to interpret.

Q: ADA recommendations are very thorough in coming up with advice and guidelines. Why do they not have a precise recommendation for postprandial blood glucose?

Dr. Garg: The ADA keeps the post meal targets higher than other organizations since there is not any real convincing data that lowering the post meal blood glucose down to 140 will result in superior outcomes.

Q: In all these trials that have been done with inhaled insulin, there has never been an up- titration study where physicians were given liberty to increase the dose of insulin.

Dr. Blonde: That’s a good point, and it would be help to have studies that have an intent-to-treat approach. It would be interesting to see a study where the investigators had an algorithm to increase the dose to reach an optimal target.

Q: In the concept of early intervention in diabetes, is treating the postprandial hyperglycemia the first thing to do?

Dr. Heise: Absolutely. The first abnormality that shows up is postprandial hyperglycemia. So from a clinical standpoint, it makes sense to attack the problem where it really is, which is the prandial hyperglycemia. If you can do this with inhaled insulin, then that’s great.

INTRODUCTION AND PROGRAM OVERVIEW: RESTAGING INSULIN THERAPY

Alan J. Garber, MD, PhD (Baylor College, Houston, TX)

Dr. Garber emphasized that the use of insulin in individuals with type 2 diabetes is always a trade-off between increasing therapy and avoiding complications. Dr. Garber described how current insulin analogs allow for increased glycemic control. He concluded by showing how intensive insulin therapy is worthwhile due to its proven benefits on both microvascular outcomes and reducing risk factors.

  • Dr. Alan Garber provided a background for the use of insulin therapies in people with type 2 diabetes. He first introduced the 2009 ADA treatment algorithm, emphasizing howthe algorithm is really a treat-to-fail approach with respect to insulin utilization—basal insulin is only added to the algorithm after a combination of metformin and lifestyle intervention fail; intensive insulin is only utilized after the previous combination fails.
  • Insulin therapy in patients with type 2 diabetes is a matter of trade-offs. While the need for insulin therapy for patients with type 1 diabetes is clear, it is not as defined in the type 2 population. Dr. Garber said that most often, use of insulin therapy in type 2 patients stems from the desire to avoid diabetes-associated complications Ultimately, negotiating the trade-off between increasing therapy intensity and minimizing complications determines whether insulin therapy is initiated.
  • Intensive insulin therapy is worthwhile for its benefits on patient outcomes. CharltonJ. et al. (Diabetes Care, 2008) illustrated that patient outcomes improved through the increased use of insulin therapy from 1996 to 2006. During this time period, all-cause mortality in patients with type 2 diabetes decreased from 47.9% to 25.2% in men and from 37.4% to 27.6% in women. Furthermore, Dr. Garber mentioned how DCCT, UKPDS, and ADVANCE illustrated how intensive insulin therapy improved microvascular outcomes and that Steno-2 revealed a significant reduction in multiple risk factors with intensive insulin therapy. Dr. Garber concluded by asserting that glycemic control is worthwhile for its known effect on reducing risk factors.

STARTING INSULIN STRATEGIES FOR PATIENTS WITH AN INADEQUATE RESPONSE TO ORAL THERAPY

Rury Holman, FRCP (University of Oxford, Oxford, UK)

Professor Holman seemed to mildly resist the weight-centric, incretin-focused buzz of this year’s meeting, where several leaders are recommending incretins over insulin in overweight type 2 diabetics. In a way, given the buzz on new therapies, a discussion of the best insulin to use may have seemed passé to some, but we know review never hurts, especially when so many millions of patients are out of good control. His conclusion was that basal insulin may be preferable to prandial or biphasic insulin, because of simpler regimen, less risk of hypoglycemia, and less weight gain – plus it’s a good base on which to add bolus when progressing to MDI. In the audience, of 51% endocrinologists, 15% PCPs, and 13% “others,” 67% said they start patients on basal once a day, while 20% said they start with premixed twice a day, a common choice in the UK, where Holman lives and teaches.

  • According to an audience poll many doctors still prescribe human insulin. Asked what percentage of the time you use insulin analogs versus human insulin, 16% of the audience said 25% of the time, 18% said 50%, 30% said 75%, and 39% said 100%.
  • Prandial and biphasic insulin create more impact on A1c than does basal insulin, but also cause more weight gain. Regardless, Professor Holman’s bottom line was that any kind of insulin works. Basal insulin also has the advantage of simplicity and less risk of hypoglycemia. In Q&A, he suggested that people diagnosed with an A1c over 8% should probably jump right to multiple daily injections (MDI).
  • Professor Holman was asked when he would use GLP-1 receptor agonists like exenatide (Byetta by Amylin/Lilly). He said the class has many attractive features like weight loss, some protection against hypoglycemia, and an impressive A1c drop – “but not as great as insulin.” He said we don’t want to rush from one agent with known long-term risk-benefit (insulin) to an agent without (GLP-1 analogs). He did concede that for patients where weight is amajor problem (Dr. Aronne would argue it is in all overweight patients), he would use incretins. He did not mention liraglutide specifically.

WHAT ABOUT INSULIN AS AN IMMEDIATE FIRST STEP FOR TYPE 2 DIABETES?

Arturo R. Rolla, MD (Harvard University/Tufts University, Boston, MA)

Dr. Rolla provided a compelling argument for the incorporation of intensive insulin therapy for early onset patients with type 2 diabetes into the ADA treatment algorithm. He enumerated the advantages insulin possesses compared to other treatment options – for example, that there is no upper dose limit. Furthermore, he detailed several studies indicating that remission rates are significantly higher in type 2 diabetes patients who use an intensive insulin regimen soon after their diagnosis. Dr. Rolla not only sees early intensive insulin therapy as a viable treatment option due to its positive effects on patient outcomes, but he believes that such therapy can restore impaired beta cell activity.

  • There is mounting evidence that intensive insulin treatment within one to two years of diagnosis can result in some remission. Li Y et al. (Diabetes Care, 2004) administered continuous subcutaneous insulin infusions (CSII) for two weeks to 138 newly diagnosed patients with type 2 diabetes with fasting glucose (FBG) > 200 mg/dl. Twelve months following, 47.1% of patients were still in remission and had regained beta cell function. These results were confirmed by similar studies testing different populations and (Ryan et al. Diabetes Care, 2004). Furthermore, subsequent studies found CSII to achieve the shortest average time to achieve remission (four days) and the greatest number of patients in remission after one-year (51%), compared to oral agents and multiple daily injections (n = 382).
  • Continued use of insulin in newly diagnosed patients significantly improves patient outcomes. Chan et al. (Diabetes Care, 2008) treated newly diagnosed patients with type 2 diabetes (FBG > 300 mg/dl or random BG > 400 mg/dl) with intensive insulin injections for 10- 14 days and followed up with either insulin injections or glipizide and metformin. The continued insulin injections resulted in a significantly greater number of patients achieving an A1c < 7% six and 12 months following initial insulin injections – a legacy, or metabolic memory, effect.
  • Although Dr. Rolla did not know of a mechanism for recovery of beta cell function, he firmly believed that the aforementioned studies provide compelling evidence for a restoration of beta cell activity – a “second wind.” Based on these studies, Dr. Rolla believes that the ADA treatment algorithm should incorporate an intensive insulin therapy for early onset type 2 diabetes patients. This has the additional benefit of patients knowing how to use insulin later in disease therapy when they need to use it everyday.

TREATMENT OPTIONS AFTER A SINGLE INJECTION OF INSULIN

Alan Garber, MD, PhD, FACE (Baylor College of Medicine, Houston, TX)

Dr. Garber went over how to intensify insulin therapy, suggesting that patient self-titration often does better than physician titration and that lower glycemic targets are better for reaching glucose goals (TITRATE study). Though, as Professor Holman said, we might start with basal insulin, it is important in intensification to move to other regimens rather than simply upping the basal. After one shot of insulin is failing, the two options are to go to multiple daily injections (MDI) or twice a day premixed – adding one bolus to cover a single meal will not work no matter what the meal. As we understand it from this symposium, studies on the insulin/Byetta combination have been done and “we are just waiting for final approval from the FDA.”

  • The TITRATE study showed that lower goals get more people to target. Tougher targets have better results than easier targets. When the FPG target range was 70-90 mg/dl, 64% of patients got to A1c below 7%, whereas when the FPG target range was 80-110 mg/dl, only 55% of patients got to A1c goal (Blonde et al., Diabetes Obes Metab 2009). Asked whether the lower target increased hypoglycemia, Dr. Garber said that it did to a “vanishingly small” extent, because “honestly,” you usually don’t get to the target anyway. As we understand it from this talk, studies on the insulin/Byetta combination have been done and “we are just waiting for final approval from the FDA.”
  • In North America, “we try and pour in endless amounts of basal insulin to try and submerge the glucose level under the brute weight of it.” Simply raising basal insulin dose is not adequate, emphasized Dr. Garber. It rather tends to fill in those valleys between meals with a hyperinsulinemic state, leading to greater hypoglycemia and weight gain. In Q&A, Dr. Garber said that once we get to 50 units or so of basal insulin, it is definitely time to think about adding mealtime. The two better options are to add multiple mealtime injections, or alternatively, to go to premixed twice or three times per day. Asked which was better, Dr. Garber said multiple daily injections were only very slightly better than twice daily premixed, only by 2/10ths of an A1c percentage point.
  • Covering a single meal with an insulin bolus is inadequate no matter the meal. The OPAL study showed that whether you add a bolus to cover breakfast or a bolus to cover the largest meal of the day (lunch or dinner) to a failing basal regimen, A1c drops only about 0.3 percentage points (Lankish et al., Diabetes Obes Metab 2008).

SELECTED PANEL Q&A

Q: Would you use incretins in combination with basal insulin, even though off-label?

Dr. Rolla: Yes, we’ve used it in patients in whom we are trying for weight loss. Studies on the combination have been done and we are just waiting for final approval from the FDA. You can add exenatide as prandial treatment along with basal insulin and, in our experience, this gives good results in glycemic and weight control.

Dr. Garber: I share those feelings. Exenatide, with a relatively short half-life, does have remarkably good postprandial impact, though the basal impact is not as good. It might be something you wish to use, though more common are patients who are exenatide failures who embark on a course of basal insulin.

Q: Does insulin use impact beta cell mass or function?

Dr. Rolla: We don’t have any way of measuring mass so for now we should use the term beta cell function. After bariatric surgery beta cell function improves immediately, but we can’t assume that there could be an improvement in beta cell mass that fast. A year after bariatric surgery or intensive insulin therapy, when you see that beta cell function is enhanced we might suspect that maybe there is also an increase in beta cell mass.

Q: Do you make therapy change decisions based on anything but A1c?

Dr. Rolla: Blood sugar and A1c. Don’t need anything else, like C-peptide. Dr. Garber: I make all my decisions based on A1c.

Obesity and Obesity Treatments

The issue of obesity seems to be gaining prominence with every meeting we attend—a welcome development in our view, as all indications suggest that treating obesity might help to ‘get at’ the root causes of diabetes and improve control. This year, the action centered around the three close-to-market companies developing obesity drugs: Arena, Orexigen, and Vivus. At the meeting, we saw new data from Vivus showing a placebo-adjusted 0.5% A1c drop with Qnexa use over one year—and we would emphasize that antidiabetic medication use decreased in the Qnexa group and increased in the placebo group. Orexigen likewise presented fairly impressive data on Contrave, but it appears that they did not meet the FDA’s categorical weight loss endpoint. Arena was comparatively silent at this meeting, presenting relatively little new data on locaserin. There were a number of interesting debates about bariatric surgery, as well—overall, it seems to be gaining acceptance both as a weight-loss tool and as a means for the resolution of diabetes. The big issues now are establishing the mechanism by which bariatric surgery affects diabetes and discovering a way to identify patients who will benefit the most from the procedure. Success in these areas will likely drive growth in bariatric surgery and allay fears in the medical community regarding the risks of the procedure, but it’s not clear when real progress will come.

Obesity and Obesity Treatments Highlights

  • W. Timothy Garvey, MD (University of Alabama, Birmingham, AL) reviewed the one-year results of a study investigating the effects of Vivus’s Qnexa (a combination of phentermine and topiramate) on glycemic levels in type 2 diabetes patients. The study showed that the combination was effective in decreasing A1c and cardiovascular risk, as well as promoting weight loss. After one year, there was a reduction in A1c of 1.6% in the treated group, compared to a 1.1% reduction in the placebo group (p=0.038). There was a concurrent increase in the use of diabetic medication in the placebo group and a decrease in medication use in the treated group (the A1c difference would likely have been greater but for more “rescues” in the placebo group). Qnexa is currently being evaluated for the treatment of obesity, and results like these make it more likely that Vivus will pursue a diabetes indication in the future. We were particularly impressed with the low side effects. Could Qnexa become a “Januvia for obesity”? Assuming safety data continues to mount, this is an exciting therapy for patients to consider. We look forward to seeing how it works in combination therapy with other diabetes agents.
  • Thomas Wadden, PhD (University of Pennsylvania, Philadelphia, PA) spoke about an 800-patient, 56-week phase 3 trial of Contrave (naltrexone and bupropion, Orexigen) for obesity. While the weight loss seen with monotherapy of either bupropion or naltrexone is negligible, the combination provides a powerful effect on hypothalamic neurons, leading to an anorectic effect. Results: 66% of Contrave patients achieved >5% weight loss compared to 42.5% of patients on placebo. We note that the FDA’s guidance on obesity drugs suggests two primary endpoints: a greater mean weight loss of 5% in the drug vs. control group or twice as many people in the drug group must achieve >5% weight loss compared to the control group; these results do not quite reach the latter.
  • Louis J. Aronne, MD (Weill-Cornell Medical College, NY) presented the results of a six-month study of VI-0521 (combination phentermine/controlled release topiramate, Qnexa, Vivus) in people with diabetes. Patients achieved significant reductions in weight, and although changes in A1c were small, this combination could ultimately be seen as a very compelling one. Dr. Aronne suggested that the differences between the groupswith regard to A1c would have increased if the study had been extended. We believe that Vivus is pursuing a valid strategy of combination therapy for the treatment of obesity and prevention of diabetes; although some question the side effects of topiramate used in VI-0521, we are comforted at the low dose used (about 10% of the highest dose used in the Topamax phase 3 obesity trial).
  • Samuel Klein, MD (Washington University School of Medicine, St. Louis, MO) presented a study that aimed to explore the use of a naltrexone+bupropion (NB) combination as a weight-lost therapy with minimal psychiatric side effects. This was a 56-week, multi-center, double-blind, placebo-controlled study targeting overweight patients (baseline BMI: 36.5) without recent occurrences of serious illness (n = 793), with both experimental and placebo groups receiving behavioral therapy. The NB combination resulted in a significant decrease in body weight (9.29% compared with 5.08% in placebo; p < 0.001) without significant increases in depression, psychiatric adverse events, anxiety, or depressed mood, Overall, NB shows promise as a weight-loss drug for its significant weight loss, its disassociation with adverse events, and it decreased incidence of depression (p = 0.03).
  • Steven R. Smith, MD Louisiana State University, Baton Rouge, LA) and Arena presented incremental data from the BLOOM study on lorcaserin, its weight loss drug candidate that targets the serotonin 5-HT2c receptor. The data presented were per- protocol analyses, which represent patients who completed one year of treatment according to the trial’s protocol. The per-protocol population analysis indicated that 66.4% of patients on lorcaserin lost 5% or more of their weight after 52 weeks compared to 32.1% of the placebo group, achieving the FDA categorical endpoint for new weight loss drugs. This is consistent with the intent-to-treat last-observation-carried-forward (ITT-LOCF) analysis (previously reported). The per-protocol analysis, however, falls shy of meeting the FDA’s average endpoint, since theplacebo-adjusted weight loss by this analysis is 4.8% (FDA mandates 5%). This is an improvement over the 3.6% placebo-adjusted weight loss found with the ITT-LOCF analysis
  • Louis Aronne, MD (Weill Cornell Medical College, New York, NY) discussed advances in pharmacotherapy, focusing on combination therapies in treating obesity. As he has discussed in numerous presentations over the last couple of years, he strongly believes that using smaller doses of medication in combination will not only achieve significant weight loss, but also sustain it. He provided several examples of combined drug therapies that demonstrated significantly better weight loss, both in magnitude and sustainability. Combination therapies mentioned by Dr. Aronne included Vivus’s Qnexa and Orexigen’s Contrave and Empatic. Dr. Aronne expressed great confidence that combination therapy is the future of obesity treatment.
  • Francesco A. Rubino, MD (Cornell Medical College, New York, NY) presented a thorough argument for the utility of bariatric surgery in the treatment of diabetes. It is well documented now that bariatric surgery (particularly Roux-en-Y and biliopancreatic bypass) has remarkable rates of diabetes remission (although many would counter that there is not yet significant follow up data). Nonetheless, eligibility for bariatric surgery is still predominately determined by body mass index (BMI). This reflects that the medical regulatory community has not yet completely accepted bariatric surgery as a metabolic treatment. On this note, he suggested that there the gut may be the root pathology of diabetes, and that bariatric surgery is actually treating the basic cause of the problem. He went so far as to suggest that weight loss on its own may not improve diabetes on its own at all: rather, it could be the interventions that lead to weight loss (diet, exercise, etc) that directly cause beneficial metabolic changes. Notably, Dr. Rubino disagrees with the current NIH guidelines on bariatric surgery. Namely, hefeels that the BMI cutoff of 35 kg/m2 (for people without serious obesity co-morbidities) excludes many patients who should be eligible to receive care while including patients that are unlikely to benefit.
  • Rena Wing, PhD (Brown Medical School, Providence, RI) presented the long- awaited results of the four-year follow-up of the Look AHEAD trial. As a reminder, the Look AHEAD trial was a randomized controlled trial examining the long-term effects of an intensive lifestyle intervention program on cardiovascular morbidity and mortality in overweight or obese persons with type 2 diabetes. The authors found that intensive lifestyle intervention (ILI) was effective in promoting weight loss and improving fitness through four years of follow up. ILI intervention improved glycemic control, systolic blood pressure (SBP), and HDL-C. Positive effects of ILI were seen across all four years for SBP. No significant differences were seen between groups at year four in diastolic blood pressure (DBP), hypertensive drugs, or ADA goal for DBP. There was speculation in the past that sustained weight loss may result in increased cardiovascular morbidity/mortality, but at four years, it seems as if ILI actually improved cardiovascular risk factors, as would be expected.
  • Walter J Pories, MD (East Carolina University, Greenville, NC) reviewed the metabolic effects of bariatric surgery. Although bariatric surgery was originally designed for weight loss, an unexpected benefit has been that metabolic conditions are resolved by a mechanism seemingly independent of calorie restriction and weight loss. He analyzed the factors that predict diabetes remission in bariatric surgery. In a fascinating presentation, he said that although insulin resistance is one of the cornerstones of diabetes, he suggested that it might not be the primary symptom; rather, hyperinsulinemia may induce a defensive mechanism by the body to prevent hypoglycemia. He concluded that given the potential of bariatric surgery, diabetes is no longer a “hopeless” disease. However, he was careful to note that bariatric surgery could not be given to everybody who needs the procedure. We would also note that many are looking for longer-term data.
  • Longtime bariatric surgery expert David E Cummings, MD (University of Washington, Seattle, WA) spoke on the metabolic effects of bariatric surgery. Bariatric surgery improves glycemic control and other metabolic parameters more than would be expected from the restriction of caloric intake alone. These metabolic improvements actually occur before any significant weight is lost, sometimes as quickly as one day after the completion of surgery. Because bariatric surgery has such dramatic impacts on diabetes, it has been proposed that some patients with diabetes who are not obese should be allowed to undergo bariatric surgery. Dr. Cummings reviewed data supporting the use of bariatric surgery in people with body mass index (BMI) >30 kg/m2, and presented data from an unpublished study looking at the effects of bariatric surgery in Asian Indians with BMIs of 22-25 kg/m2. In this particular study, there was 100% resolution of diabetes at nine months with maximum average weight loss of~20%. He reviewed various theories on what might cause these effects, focusing on hormonal mechanisms involving ghrelin, PYY and incretins. He briefly spoke about two relatively uncommon forms of bariatric surgery, ileal interposition and duodenal-jejunal bypass, both of which are weight-neutral.
  • Guilherme M. Campos, MD (University of California at San Francisco, San Francisco, CA) noted that while only 37% of patients with diabetes are achieving adequate glycemic control, 80% of patients who undergo roux-en-Y gastric bypass surgery (RYGB) have a complete resolution of type 2 diabetes. It is well known that this change in metabolism occurs via mechanisms independent of weight loss. This study enrolled 22non-diabetic morbidly obese subjects, assigning 12 to RYGB with calorie restriction and the rest to calorie restriction alone, to differentiate between the short-term effects of calorie restriction and surgery. After 15 days, metabolic parameters were compared. As expected, body weight and fat loss were not different after 15 days. There were no differences in peripheral glucose uptake, fasting insulin, or fasting glucose. There were increases in GLP-1 and insulin secretion in the RYGB group and increases in GIP in the calorie restriction group. After six months, there was significant improvement in peripheral glucose uptake that differed significantly according to the magnitude of weight loss.
  • John McElroy, PhD (Jenrin Discovery, Philadelphia, PA) presented preclinical data on Jenrin Discovery’s JD-5006, a peripherally active CB1 receptor antagonist that does not cross the blood brain barrier (BBB) in rodents. JD-5006 does not seem to cause the CNS toxicities that were observed when rimonabant was over-dosed in rodents. In diet- induced obese mice, 21 days of treatment with JD-5006 was approximately half as efficacious as rimonabant in reducing weight but produced comparable improvements in liver function, lipid levels, and insulin sensitivity. We found these data quite intriguing and look forward to seeing human data.
  • Rudolph L. Leibel, MD (Columbia University, New York, New York) discussed new research in the role of leptin and the physiology of weight loss. Leptin is a hormone released by adipose cells in proportion to the quantity of stored fat. It signals to the brain that there are sufficient energy reserves, and the brain in turn moderates hunger and metabolic rate. When people lose weight by dieting, their serum leptin levels decline, and as a result they become hungry and expend less energy at rest. This condition promotes weight gain, which may explain the “yo-yo” effect seen in dieting. Dr. Leibel presented evidence that the threshold concentration for leptin to be effective could be changed by diet, noting that it changes resulting from weight gain (which cause leptin resistance) are more enduring and harder to change than changes resulting from weight loss. He concluded by suggesting that future research should focus on rectifying the hypometabolic (deficiency in calories) and hyperorexigenic (elevated stimulation of appetite observed) states after weight loss rather than focusing on developing treatments to lose weight in the first place. This could change the common “bounce-back” seen in diets and allow sustained weight loss.
  • Bernard Zinman, MD (University of Toronto, Ontario, Canada) reviewed pharmacological and surgical treatments for type 2 diabetes with a focus on interventions targeting the unique pathophysiological basis of the disease. Although the causes of diabetes and obesity are not completely understood, he did not agree that bariatric surgery directly addresses the cause of diabetes or obesity. Rather, he believes that it introduces a new pathology to counteract whatever physiology is causing the disease in the first place. He reviewed various symptoms of diabetes, and the pharmacological treatments that can be used to address them. He characterized the stepwise fashion in which physicians typically prescribe antihyperglycemic agents as a “treat-to-fail” approach, in that therapies are used until the condition worsens and a more serious therapy is required. He advocated a wider adoption of the ADA’s “tier 2” treatment schedule, particularly incretin therapy. He was unsure of bariatric surgery’s place in the treatment of diabetes, since the mechanism of the benefits and the side effects have not been fully detailed. To standardize bariatric surgery as a treatment for diabetes and obesity, he said better-designed and longer-term studies would be needed.
  • F. Xavier Pi-Sunyer, MD (Columbia University, New York, NY) reviewed the questions that remain to be addressed regarding bariatric surgery. With theimpressive remission of diabetes seen after bariatric surgery, it is important to make sure that the mechanisms of action are understood and that the optimal patient population is determined. He felt that not enough is known about the comparative efficacy of different types of bariatric surgery, predictors of success, side effect profiles, and the physiological mechanisms involved. He noted that, for bariatric surgery to be more widely adopted, light must be shed on these unknowns. This will involve long-term, well-designed clinical trials. In particular, loss to follow- up must be improved and the long-term maintenance of metabolic benefits must be more thoroughly studied.
  • Randy J Seeley, PhD (University of Cincinnati, Cincinnati, OH), winner of this year’s Outstanding Scientific Achievement Award, delivered an exceptional presentation on the relationship between adipose tissue and the central nervous system (CNS). He prefaced his lecture by emphasizing the importance of collaboration in the scientific community and attributed his success to choosing problems that can make a difference and are medically relevant. His review of leptin, the PPAR gamma receptor, and pro-apoptotic proteins revealed many interesting and important relationships between adipose tissue and the CNS. These relationships affect our satiety and feeding behavior, and have important clinical implications in the treatment of obesity and type 2 diabetes.
  • Marzieh Salehi MD (University of Cincinnati, Cincinnati, OH) presented a small study showing gastric bypass enhances the incretin effect through increased GLP-1 secretion. Dr. Salehi explained that roux-en-Y gastric bypass surgery (GB) improves diabetes independent of weight loss. As has been widely discussed, the mechanism by which this occurs is not well understood. What is known however, is that the action of rerouting the gut increases GLP-1 secretion. An important finding in this study was that the enhanced GLP-1 action does not disproportionately increase insulin levels in gastric bypass patients with hypoglycemia. That said, there is a proportion of patients that suffer from hyperinsulinemic hypoglycemia following gastric bypass surgery.
  • Caroll M. Harmon, MD, PhD (University of Alabama, Birmingham, AL) discussed why bariatric surgery was being considered in pediatric populations – namely, the lack of effectiveness of behavior modification and drug therapy is very high, as are the dangerous comorbidities with which obesity appears. His center uses BMI >35 kg/m2 with severe comorbidities or BMI > 40 kg/m2 with minor comorbidities as part of the criteria for selecting surgical candidates. They also use a comprehensive set of psychological and other criteria. He discussed gastric banding and bypass in this population noting that the Lap Band (Allergan, by way of Inamed) was not FDA approved in people less than 18 years of age. During Q&A, he mentioned that studies are being conducted that may cause the FDA to lower this age cutoff to 14 years. Notably, he briefly mentioned sleeve gastrectomy as a procedure finding its way into the pediatric space.
  • Interestingly, Susan A. Phillips, MD (University of California at San Diego, La Jolla, CA) said she was originally asked to give a talk on the use of GLP-1 agonists in obese children (with or without diabetes) but did not feel there was any data at all to support that. She instead discussed their use in obese children with type 2 diabetes, a use she considers reasonable. In fact, she appeared quite positive on the use of GLP-1 agonists in children. She was at least confident the use will be approved (Amylin is sponsoring a phase 3 exenatide study in children, currently enrolling at 33 sites; target enrollment is 195 children ages 10-16, with primary outcome of glycemic control with exenatide as compared to placebo over 28 weeks), and dwelt little on the oft-cited “we need more studies to tell,“ which was refreshing although clearlyall the safety information needs to be moving forward. Notably, during the talk, Dr. Phillips essentially waved away concerns about both pancreatitis and thyroid c-cell tumors.
  • Kitt F. Peterson, MD (Yale University School of Medicine, New Haven, CT) explained four major relationships related to lipid mediated insulin resistance. 1) insulin sensitivity and age, 2) leptin treatment and lipodystrophy, 3) a low energy diet and obese patients with type 2 diabetes, and 4) rosiglitazone and obese patients with type 2 diabetes. Of the many conclusions she discussed in her talk, of particular interest was her contention that insulin resistance is in part a result of impaired mitochondrial function. She also discussed metabolic syndrome, which she hypothesized is a result of an inability to store carbohydrates in muscle.
  • Pirjo Nuutila, MD, PhD (Turku PET Centre, Finland) spoke about cardiac adiposity, metabolism and its relationship to obesity and type 2 diabetes. She emphasized that the accumulation of triglycerides within and around the heart is a sign of both fatty acid overload and increased fatty acid oxidation. Additionally, lipotoxicity (TG accumulation, ceramide formation) is associated with reduced myocardial energy efficiency. The decrease in the availability of fatty acids due to either dieting or obesity surgery rapidly improves functional abnormalities and also leads to improved endothelial function of the vessels. The prevention of fat oxidation and the increase of uncoupling improves glycemic control and the function of the failing heart. Both improved glycemic control and the loss of body weight predict cardiac functional recovery instead of changes in blood pressure or lipids.
  • Steven R. Smith, MD (Pennington Biomedical Research Center, Baton Rouge, LA) focused on ectopic fat in the liver and skeletal muscle and discussed whether accumulation of such fat was acquired or genetic. The majority of his talk was an extensive literature review, demonstrating evidence for both acquired and genetically facilitated accumulation of ectopic fat in the liver and skeletal muscle. He concluded that both acquisition and genetics play roles in ectopic fat accumulation. Although ectopic fat can be acquired by lifestyle habits, there is strong evidence for genetic/epigenetic epidemiology. He suggested that these epidemiological effects probably occur at cell programming.
  • Samuel Klein, MD (Washington University School of Medicine, St. Louis, MO) spoke about the effect of bariatric surgery and weight loss on body fat, specifically on ectopic and visceral fat. Ultimately, if a patient loses weight by bariatric surgery, they lose both ectopic and visceral fat. When a patient loses weight, certain fat depots lose weight more quickly than other depots as ectopic fat in different locations are differently sensitive to weight loss. A short period of caloric restriction can have a significant change on ectopic fat distribution and an 80% increase in hepatic insulin sensitivity.
  • Naomi Stotland, MD (University of California San Francisco, San Francisco, CA) discussed the recently released guidelines for gestational weight gain, emphasizing the importance of diet and exercise in achieving optimal gestational weight gain outcomes. Existing research on interventions to help women maintain their weight within guidelines is inadequate, which led her to conduct her own intervention using prenatal counseling. Subjects that participated in the intervention demonstrated no significant weight loss, but improvements in behavioral outcomes were shown. Although she finds prenatal counseling beneficial but currently inadequate, she is confident that excessive weight gain can be reduced among obese pregnant women using lifestyle interventions.
  • Ellen Nohr, PhD (University of Aarhus, Aarhus, Denmark) discussed her trade-off approach to pregnancy weight gain, and reported her findings investigating the relationship between weight gain and pregnancy risks. She emphasized the importance of taking into consideration the mother’s health in addition to the baby’s. Her findings suggested that the higher the mother’s body mass index (BMI) before pregnancy, the less they should gain during pregnancy. This relationship minimized risks such as large for gestational age (LGA), small for gestational age (SGA), cesarean delivery, and postpartum weight retention.
  • Teresa Hillier, MD, MS (Kaiser Permanente Center for Health Research, Portland, OR) discussed the risks of abnormal gestational weight gain during pregnancy. There are risks to both excessive weight gain (mother is more likely to be diet controlled, need insulin, and have a large for gestational age [LGA] baby) and too little weight gain (more likely to have a small for gestational age [SGA] baby), and noted the importance of optimizing control of both maternal glucose and maternal weight gain in patients with gestational diabetes. She noted that although glucose is an important independent risk factor, weight gain is also important. She echoed the sentiments of the other presenters in this symposium, and emphasized the importance of exercise and diet.
  • Michael Lu, MD (UCLA School of Medicine, Los Angeles, CA) discussed the rationale, methods, and conclusions of the new guidelines for gestational weight gain (GWG), recently published in May 2009. He reviewed several studies demonstrating the relationship between weight gain before and after pregnancy with maternal and child health outcomes. Of particular interest was his discussion on GWG and gestational diabetes (GDM). He reported on eleven studies that varied significantly in findings and conclusions. He explained these inconsistencies by noting the confounding factor: the measurement of total gestational weight gain instead of weight gain up until diagnosis of GDM. He ended by noting that the new guidelines are virtually the same as those from 1990. The most notable difference is the new pregnancy weight recommendations for obese women (5 to 9 kg [11 to 24.2 lbs]). He was careful to note that while gains less than five kilograms (11 lbs) may be beneficial; there was not enough data to support this advice.
  • During the orals session on Obesity, Nazneen Aziz, PhD (Interleukin Genetics, Waltham, MA) gave an interesting basic science oriented talk on the importance of genetics in predicting a patient’s responsiveness to obesity therapies. She cited the fact that most obesity studies report only mean group weight changes as a limitation to the efficacy of these therapies in a clinical setting because there is a great deal of variability in how individuals respond to intervention. She focused on a study looking at the genetic variability of four different single nucleotide polymorphisms (SNPs) within the perilipin gene, thought to be a gatekeeper of fat storage and mobilization. PLIN1/C and PLIN4/A carriers were more resistant to body weight fat loss under calorie restriction. There appear to be genetic interactions with the glycemic load of the diet as well. We agree with Dr. Aziz that this data is interesting because it implies that personalized weight loss programs (or drug therapies) could help individuals with particular genetic profiles to maintain healthy body weight. This study was small and we’d like to see more work like this.
  • Samuel L. Ellis, Pharm.D, BCPS, CDE (University of Colorado Denver Health Sciences Center, Denver, CO) pointed out that there are only limited data on obesity trends in patients with type 1 diabetes. Ellis discussed a retrospective 1,100-patient study performed by a Colorado community care clinic that found that the prevalence of obesity in type 1 diabetes patients aged 23 to 29 years increased from 10.4% to 15.7% in a five-year period. Interestingly, the overweight and obese patients had lower A1c levels than individuals in the normal BMI category, suggesting that weight gain is linked to better glucose control. Theoverweight and obese patients had higher blood pressure levels, higher LDL cholesterol, and lower HDL cholesterol compared to the healthy weight group. We agree with Ellis’s suggestion that the results of this study should serve as an impetus to devote future research to understanding the impact of obesity on complications and disease progression in T1D patients.
  • Barbara Corkey, PhD (OSI Pharmaceuticals, Melville, NY), described the discovery of PSN-AGX1, a commercially available Acyl CoA Synthetase (ACS) inhibitor, using a high-throughput human adipocyte assay; and described its therapeutic potential for decreasing triglyceride (TG) stores. 12,000 commercially available small molecules were screened for their function in decreasing TG levels. PSN-AGX1 proved to be the most efficacious compound, decreasing body fat by 21% and TG by 23% through the reduction of activity of the ACS1 and ACS5 proteins. Dr. Corkey concluded that ACS inhibitors show promise as therapeutic targets for patients with type 2 diabetes.
  • Sun H. Kim, MD (Stanford University, Palo Alto, CA) noted that post-prandial hypoglycemia is a known complication of gastric bypass surgery, but the characteristics that determine who will develop this are unknown. To better characterize those at risk, a study enrolled 18 patients who had had roux-en-Y gastric bypass surgery, nine who were asymptomatic and nine who had had documented glucose <50 mg/dl (<2.8 mmol) and neuroglycopenia as defined by altered mental status, loss of consciousness, or seizure. These patients were compared with 90 non-surgical controls. In oral glucose tolerance tests, symptomatic surgical patients were found to have an earlier glucose peak and a higher glucose at 30 minutes. The symptomatic and asymptomatic bariatric surgery groups, however, were similar, with peak insulin concentrations much higher than controls. Changes in glucose metabolism are common to all RYGB patients, and why some groups become symptomatic remains to be clarified.
  • Lisa A. Owens, MD (University of Ireland, Galway, Ireland) determined if obesity is the direct cause of adverse events, or if another factor such as diabetes was the root cause. This large study included pregnant women who did not have gestational diabetes mellitus (GDM) or impaired glucose tolerance according to the World Health Organization (WHO) criteria. Pregnancy outcomes were assessed by baseline body mass index (BMI) category, and the highest category had the most negative outcomes. Dr. Owens made the case that obese women are at risk for negative pregnancy outcomes, which should be better identified, assessed, and counseled in the future.
  • Linda A. Barbour, MD (University of Colorado, Denver, CO) collected data from 10 pregnant women to determine which parameters are predictors of high neonatal fat in infants. Changes in maternal triglyceride concentrations were identified as the key parameter. Four out of ten babies were born with >16% body fat as measured by Dual X-ray Absorptometry (DXA) scan, with two coming from lean mothers and two from obese mothers. it was the change from fasting triglyceride concentrations to early pregnancy (14-16 weeks) to late pregnancy (26-28 weeks) that predicted the high neonatal fat percentage. Postprandial triglycerides were not elevated in the subjects, and overall fasting triglyceride concentrations– while higher in obese women than lean women – were not predictive.
  • Heidi E. Kocalis (Vanderbilt University, Nashville, TN) explained that PPAR delta is a nuclear receptor that promotes cellular lipid oxidation, decreasing the lipid accumulation that is associated with insulin resistance. It is the most abundant isoform in the CNS, where energy homeostasis is regulated. Its deletion in rodent neurons leads to increased fat mass as well as insulin and leptin resistance. Given its multiple beneficial effects, sheconcluded that PPAR delta may be a promising CNS target in addition to the more peripheral PPAR gamma (TZDs) and alpha (fibrates).
  • Eleanor Scott, MD (University of Leeds, Leeds, UK) discussed the role of the circadian clock in the development of obesity. The study looked at the polymorphisms of the clock gene in humans and evaluated their relationship t0 metabolic syndrome. Possession of the T allele of the promoter of the clock gene and the TGT haplotype was associated with metabolic syndrome as defined by IDF criteria. On the other hand, possession of the C allele and the CGC haplotype seems to be protective against metabolic syndrome. The data also suggest that there are associations between the clock polymorphisms and dyslipidemia in humans. We look forward to more study from this field as anything we can learn about the genetics of the disease could ultimately play a role in the development of personally tailored therapeutic interventions.
  • Stephen R. Daniels, MD, PhD (University of Colorado School of Medicine, Aurora, CO) said once exercise and diet have been addressed (of course), pharmacotherapy is reasonable for hyperlipidemic pediatric patients. Many statins are approved for the pediatric population, for children as young as eight years old (pravastatin). The main point was that lipids should be addressed in the pediatric population, which may have to mean better screening methods.
  • Elke Guelden, MD (Institute for Clinical Diabetology, Duesseldorf, Germany) argued that in addition to increased risks for type 2 diabetes, adiposity may promote the development of type 1 diabetes as well. His talk focused on the inflammatory activities of mature adipocytes in Toll-like receptor 4 (TLR4) knockout mice.
  • Janet K. Snell-Bergeon, MPH (University of Colorado, Aurora, CO) presented an analysis looking at a representative subset of the SEARCH for Diabetes in Youth study. This study demonstrated three relationships in youths with type 1 diabetes: 1) a relationship between type 1 diabetes and elevated levels of inflammatory markers, 2) hypoglycemia and both increased inflammation and suppressed leptin, and 3) obesity and increased inflammatory markers and suppressed leptin. We found this lecture particularly interesting because of the focus on youths.

Outstanding Scientific Achievement Award Lecture

HOW OBESITY WENT TO OUR HEADS—NOVEL ASPECTS OF HOW ADIPOSE TISSUE COMMUNICATES WITH THE CNS

Randy J Seeley, PhD (University of Cincinnati, Cincinnati, OH)

Randy J Seeley, winner of this year’s Outstanding Scientific Achievement Award, delivered a compelling presentation on the relationship between adipose tissue and the central nervous system. He prefaced his lecture by emphasizing the importance of collaboration in the scientific community and attributed his success to picking problems that can make a difference and that are medically relevant. His review of leptin, the PPAR gamma receptor, and pro-apoptotic proteins revealed many interesting and important relationships between adipose tissue and the CNS. These relationships affect our satiety and feeding behavior, and have important clinical implications in the treatment of obesity and type 2 diabetes.

  • The adipose “bathtub”. He used a bathtub as a metaphor to explain energy regulation: constantly being filled with water (energy intake), and constantly draining water (energy expenditure). To maintain a constant weight, the rate of water coming in and water coming outneeds to be the same. In the body, that bathtub is the brain, regulating both food intake and energy expenditure. He noted that hormones are the signals that reflect these levels of energy, the most important of which is leptin. As a reminder, leptin is released by adipocytes and decreases food intake. Dr. Seeley believes that leptin resistance is the cause of obesity.
  • The PPARG receptor regulates food intake. Dr. Seeley conducted a study examining the mechanism of leptin resistance by investigating the PPAR gamma receptor. He explained that TZD drugs (PPARG agonists) resulted in weight gain, but PPARG antagonists demonstrated no differences compared with placebo in rats that were fed. However, in rats that were fasting, administration of PPARG antagonists resulted in decreased food intake. The same trend was seen when rats were given a high fat diet (no difference between groups in low fat diet, decreased appetite following PPARG antagonist in high fat diet). Altogether these results suggest PPARG regulates food intake and body weight.
  • PPARG antagonist pretreatment prior to leptin administration results in weight loss, implicating nutrients as important signals to the CNS. No difference was seen between rats given vehicle or leptin without pretreatment. Dr. Seeley went on to explain that this finding suggests that one component of what happens on a high fat diet that results in weight gain and leptin resistance has to do with PPARG. In addition to hormones, nutrients seem to have an important effect on the CNS. He also demonstrated that peripheral TZDs can act on the CNS, contributing to changes in feeding behavior.
  • Why do some people become obese, while others remain lean? This may be due to genetic underpinnings. Dr. Seeley demonstrated the significant genetic effects on obesity using two distinct strains of rats. C57 rats demonstrate markedly different weights on low fat versus high fat diets, while FVB rats demonstrate nearly no difference.
  • How quickly different individual can build blood vessels (i.e., angiogenesis) in adipose tissue is an important rate-limiting step that may explain differences in responses to high fat diets. One of the most interesting things about adipose tissue is that it must have the capacity to change size rapidly to accommodate changes in energy intake. This makes it very dependent on blood vessels. This suggests that if you can selectively modify adipose tissue’s blood vessels, one could change weight gain/adipose size—pro-apoptotic peptide does just this. He admitted that he was deeply skeptical of this approach because attacking adipose tissue like attacking a tumor frames it like the enemy, which he doesn’t believe in. He went on to say this way of thinking was like thinking of the bathtub as the enemy, instead of thinking of the water as the enemy. He suspected that use of pro-apoptotic protein would result in fatty liver and increased muscle lipid.
  • To test the potentially deleterious effects of pro-apoptotic protein (HF-PP), he initiated series of experiments in rats. Rats given HF-PP that had previously demonstrated TZD induced weight gain returned completely to baseline entirely due to body fat loss. HF-PP actually decreased food intake, which he attributed to 70% of the weight loss. It also appeared that animals actually have to be obese for HF-PP to effectively lower body weight. Mice on a low- fat diet demonstrated a very minimal effect when administered HF-PP.
  • These findings suggested that HF-PP is not merely toxic (if it was, it should cause decreased energy intake in all mice) and that it must target something different in obese individuals. These conclusions suggest that HF-PP would have lower risk of abuse in patients that are already lean. Taken together, these findings suggest that there are novel mechanisms that relay the status of adipose tissue vasculature to the CNS. Further confirming hissuppositions, HF-PP actually improved glucose tolerance in mice on a high fat diet. Furthermore, HF-PP reversed mitochondrial dysfunction induced by a high fat diet.
  • Dr. Seeley concluded by challenging our perceptions on obesity and cancer. He noted that the FVP mouse (that did not gain weight on a high fat diet) expressed only six of 27 genes related to angiogenesis whereas the C57 rats expressed 21. It is therefore not surprising that C57 rats demonstrated threefold more microvessels than FVP mice. He noted that like adipocytes, tumors also require vascularization to grow. Some studies have implicated obesity as a cause for cancer. Dr. Seeley suggested that these findings were not based on causation, but correlation; perhaps the ability to build vasculatures correlates with obesity and tumor growth.

Symposium: Treatment of Obesity

LEPTIN PHYSIOLOGY: AN UPDATE ON HUMAN STUDIES

Rudolph L. Leibel, MD (Columbia University, New York, New York)

Dr. Leibel talked about new research in the role of leptin and the physiology of weight loss. Leptin is a hormone released by adipose cells in proportion to the quantity of stored fat. It signals to the brain that there are sufficient energy reserves, and the brain in turn moderates hunger and metabolic rate. When people lose weight by dieting, their serum leptin levels decline, and as a result they become hungry and expend less energy at rest. This condition promotes weight gain, which may explain the “yo-yo” effect seen in dieting. Dr. Leibel presented evidence that the threshold concentration for leptin to be effective could be changed by diet, noting that it changes resulting from weight gain (which cause leptin resistance) are more enduring and harder to change than changes resulting from weight loss. He concluded by suggesting that future research should focus on rectifying hypometabolic (the deficiency in calories) and hyperorexigenic (elevated stimulation of appetite observed) states after weight loss rather than focusing on developing treatments to lose weight in the first place. This could change the common “bounce-back” seen in diets and allow sustained weight loss.

  • Leptin is one of the most important diet-related hormones. It is released by adipose cells in proportion to their size. Thus, the amount of circulating leptin in the blood is directly proportional to fat storage. In non-obese people, leptin suppresses food intake by acting on several areas in the hypothalamus. People who are obese generally release leptin properly, but possess leptin resistance in the brain. Dr. Arrone noted that, since a greater amount of leptin is needed to reach a state of satiety in some obese people, causing them to reduce weight will lead to a consistent feeling of hunger.
  • People and mice that have lost weight have a lower resting expenditure than at their original weight. However, this reduced energy expenditure is not equivalent to the resting energy expenditure of somebody who was naturally the person’s post-weight loss weight. At the same time, hunger is more pronounced, and so caloric intake increases. Thus, the body seems to “defend” its weight. Dr. Leibel felt that this was likely due to an increased threshold of leptin concentration necessary to achieve its satiating and energy expenditure-promoting effects.
  • Leptin rectifies physiological changes seen during states of reduced weight. In mice who have lost ~10% of their body weight, orexigenic hormones such as NPY and AGRP are increased in the brain, as well as lowered basal energy expenditure. This effect can be rectified by exogenous leptin administration.
  • Energy expenditure is inversely proportional to fat-free mass. A person losing weight does not follow this trend though: when they lose weight, their energy expenditure goes down to alower level than what would be expected in a person that would naturally be at that weight. For people who lose and maintain weight, this metabolic state does not seem to rectify itself. One study showed that even three years after losing 10% body weight, there was reduced resting energy expenditure.
  • Changes in leptin resistance are due to more than just changes in effector neurons. There are changes in both dendrite-dendrite and cell-body connections. Leptin increases the fiber density in the arcuate nucleus (Simerly et al., Science, 2004). He theorized that the physiological changes resulting from weight loss were due to chemical changes with neuropeptides, and that changes from weight gain are the result of structural and cellular changes. The therapeutic implication of this is that there is a great deal of resistance to weight loss.
  • He concluded by suggesting that future research should focus on rectifying the hypometabolic and hyperorexigenic state after weight loss rather than focusing on developing treatments to lose weight in the first place. This would change the common “bounce-back” seen in diets and allow sustained weight loss. He also feels that it is logical to focus on bringing the body back to a natural physiological state rather than inducing and maintaining an abnormal physiological state.

Questions and Answers:

Q: If the subject were put through a state of starvation and the body weight dropped and the threshold dropped, presumably the resistance to leptin would drop as well. So if you had given them leptin from the beginning, you would not have seen the rescue effect.

A: Yes, this is true. This suggests that the system is very susceptible to declines in body weight, but is not as susceptible to weight gain. I’m thinking that the mechanism behind this is will turn out to be structural. I think that there will be changes that change the clockwork of the neural system.

Q: So if you maintain or increase energy expenditure, you don’t think there will be a compensatory change in food intake?

A: In these experiments, we clamped food to make our measurements. Because leptin has the dual effect of food intake and energy expenditure changes, I think that you would not see compensation in food intake.

UPDATE ON THE LOOK AHEAD TRIAL

Rena Wing, PhD (Brown Medical School, Providence, RI)

Dr. Wing presented the long awaited results of the four-year follow-up of the Look AHEAD trial. As a reminder, the Look AHEAD trial was a randomized controlled trial examining the long-term effects of an intensive lifestyle intervention program on cardiovascular morbidity and mortality in overweight or obese persons with type 2 diabetes (n=5,145). The authors found that intensive lifestyle intervention (ILI) was effective in promoting weight loss and improving fitness through four years of follow up. ILI intervention improved glycemic control, systolic blood pressure (SBP), and HDL-C. Positive effects of ILI were seen across all four years for SBP. No significant differences were seen between groups at year four in diastolic blood pressure (DBP), hypertensive drugs, or ADA goal for DBP. There was speculation in the past that sustained weight loss may result in increased cardiovascular morbidity/mortality, but at four years, it seems as if ILI actually improved cardiovascular risk factors.

  • Dr. Wing presented the year four results of Look AHEAD trial. As a reminder, the Look AHEAD trial was a randomized clinical trial examining the long-term effects of an intensivelifestyle intervention program on cardiovascular morbidity and mortality in overweight or obese persons with type 2 diabetes (n=5,145). Participants in Look AHEAD were randomly assigned to intensive lifestyle intervention (ILI) or diabetes support and education (DSE; the control group). The primary hypothesis was that the incidence rate of the first post-randomization occurrence of a composite outcome, including cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for angina over 13.5 years of follow-up would be reduced in the lifestyle intervention compared to the diabetes support and education group. She noted that other outcomes included all-cause morality, cardiovascular disease risk factors, costs and cost effectiveness, diabetes control and complications, general health, hospitalizations, quality of life and psychological outcomes.
  • Observational studies have suggested that weight loss or weight cycling may be associated with increased morbidity/mortality. Although weight loss is strongly recommended for overweight patients with type 2 diabetes, and short-term studies demonstrate benefits of weight loss for lipids, blood pressure, insulin sensitivity, and glycemic control, there is a lack of data on long-term benefits. Given the observational studies implicating weight loss in increased morbidity, Wing found this lack of data particularly concerning.
  • Factors presented at year four comparing ILI and DSE were: weight, fitness, and CVD risk factors. She jokingly noted that the long-term results related to cardiovascular morbidity and mortality would have to wait until the conclusion of the trial.
  • Before discussing the findings, Wing proudly announced the impressive retention rate of approximately 95%. Specifically, in the ILI arm, 94% of randomized and 96.5% of current subjects were retained, and in the DSE arm, 93% and 95% were retained, respectively. She also emphasized how well the control and ILI subjects were matched. Patients in the ILI arm had an average BMI of 35.9 kg/m2, a mean weight of 100.9 kg (222 lbs), and 114 cm waist circumference.
  • Intensive lifestyle intervention (ILI) was effective in promoting weight loss and improving fitness through four years of follow up. As a reminder, all participants were given the goal of losing ten percent of their bodyweight, and the study weight loss goal was seven percent. Patients in the DSE arm lost on average 1% of their body weight at one year, and maintained the loss for four years. Patients in the ILI arm initially lost 8.6%, but the weight loss diminished as time went on (6.4% in year two, 5.1% in year three, and 4.7% in year four. Wing was excited to present a data analyses suggesting that a plateau was approaching in weight regain in the ILI arm. A similar trend was seen in the two arms were evaluated for differences in fitness; the ILI group saw a 20.9% increase in fitness at year one, 15.1% in year two, 5% in year four, while the DSE group demonstrated an increase in fitness in the first few years, but by year four had returned to baseline. We were disappointed to see weight loss return to under 5% of total body weight.
  • Patients in the ILI arm required less antidiabetic medication and insulin. Over time, more and more patients were placed on diabetes medications. However, many more subjects added medications the control group. This was true in patients that started the study with no medications, and those that were on medications to begin with. In both cases, this difference was statistically significant. The finding that patients in ILI took fewer medications and insulin could be important from a cost-effectiveness perspective (they need to buy fewer drugs and doses of insulin). A formal cost-benefits analysis directly comparing each intervention was not performed in the study.
  • ILI intervention improved glycemic control, SBP, and HDL-C. At every time period, more subjects from the ILI arm met the ADA goal for A1c of less than seven percent. This was particularly pronounced at year one, but it held true all the way to year four. Furthermore, subjects in the ILI group demonstrated significantly better measures of systolic blood pressure at every time point. Additionally, IDI demonstrated improved for triglyceride levels across years, but the effect was no longer significant at year four.
  • There were no significant differences between groups at year four for diastolic blood pressure (DBP), hypertensive drugs, or the ADA goal for DBP. There was a significant overall effect on diastolic blood pressure, but it dissipated at year three and four. Furthermore, individuals in the DSE group initially required more antihypertensive drugs, but by year four, there were comparable numbers of subjects on these medications in both arms. The prevalence of achieving the ADA goal for DBP was highly significant at year one, but diminished over time.
  • DSE demonstrated a significant overall improvement in measures of LDL cholesterol. This improvement was particularly significant at years three and four, and was significant across all four years. However, Wing contended that this change was related to the use of statins (a drug that reduces cholesterol). Among individuals not using statins at baseline, 23% DSE started at year one compared to 15% in ILI. A similar pattern was seen at years two, three, and four. When corrected for clinic, baseline level, and medication use, LDL changes across the four-year interval between groups were no longer significant.
  • Altogether, these findings do not support past speculation that sustained weight loss may result in increased cardiovascular morbidity/mortality, because at four years, it seems as if ILI actually improved cardiovascular risk factors. From our view, this is the major “win” of the trial” since the weight reduction loss at year four, while still significant, is far lower than at year one and we’re not sure of its clinical significance. In Q&A, a point about drugs and weight gain was raised and we’re eager to see analysis on this.

Questions and Answers

Q: The ILI group demonstrated some drift back to baseline. Have you done a comparison of those that maintained weight loss and those that returned back to baseline?

A: We certainly have plans to do analysis such as that. However, in this study the primary analysis is intent to treat—comparing the two arms.

Q: Given the fact that the DSE group has used anti-diabetes medications that primarily causes weight gain, do you think the differences in weight loss across groups could be due partially to these drugs?

A: We have not gone on to do these analyses of specific medications yet in this study.

COMBINATION PHARMACOTHERAPY - WHAT CAN BE ACHIEVED

Louis Aronne, MD (Weill Cornell Medical College, New York, NY)

Dr. Aronne discussed advances in pharmacotherapy, focusing on combination therapies in treating obesity. As he has discussed in numerous presentations over the last couple of years, he strongly believes that using smaller doses of medication in combination will not only achieve significant weight loss, but also sustain it. He provided several examples of combined drug therapies that demonstrated significantly better weight loss, both in magnitude and sustainability. Combination therapies mentioned by Dr. Aronne included Vivus’s Qnexa, Orexigen’s Contrave and Empatic, and Amylin’s pram/leptin. Dr. Aronne expressed great confidence that combination therapy is the future of obesity treatment.

  • Dr. Aronne began his talk by commenting broadly on the plateau effect. He noted that gluttony is a disorder of the neuroendocrinological axis. Once weight is lost, leptin levels drop, which leads to increased food consumption characterized by a lack of satiety. The plateau phenomenon, he explained, is caused by a double pronged attack of an increased food intake caused by lack of leptin and reduction in energy expenditure that is exaggerated—more so than the decrease in food intake.
  • He believes that using smaller doses of medication in combination will break through this barrier. He explained that when people are treated with centrally acting medications, nothing is being done to stop ghrelin and other similar hormones from stopping patients from losing weight.
  • He went on to provide evidence of the plateau effect. This effect was seen in lap banding operations, vertical-banded gastroplasty, and gastric bypass (Sjostrom L et al., NEJM 2007). He noted that even though the BMI is elevated in these patients, leptin levels remain in the normal BMI range (he was careful to explain that this was a clinical observation), which explained the weight regain.
  • How do we overcome this? His answer was to treat it in a physiologic manner. He noted that patients prefer the lap band because they feel it has fewer side effects. He wondered if we could combine lap banding with something else that would achieve the same weight loss as gastric bypass. He believes that it is not just pharmacotherapy, but a combination of all kinds of treatments that will be successful when it comes to treating obesity.
  • He provided several examples of combined drug therapies that demonstrated significantly better weight loss than monotherapies, both in magnitude and sustainability. A paper by Boozer et al. (Metabolism 2001) demonstrated that leptin plus sibutramine therapy resulted in twice as much weight loss as sibutramine monotherapy. Furthermore, leptin monotherapy was comparable to placebo. He noted that this was the first evidence of such combined drug synergy. Since then, similar results have been shown in phentermine plus topiramate (Vivus’ Qnexa), bupropion and naltrexone (Orexigen’s Contrave), bupropion and zonisamide (Orexigen’s Empatic), and pramlintide and leptin combined therapies (in development by Amylin).
  • Some side effects were discussed, but Dr. Aronne did not seem concerned. Adverse events in Qnexa trials included headache, paraesthesia , upper respiratory infection, constipation, and a very small incidence of depression. He noted that some people were depressed before joining the trial, and some were already taking antidepressants. Pramlintide and phentermine combined therapy demonstrated a significant increase in blood pressure, but he suggested that a lower dose of sibutramine could give the same degree of weight loss. He suggested that the dose used might have hit a maximal level of effect. He also noted that given the extremely high drop- out rates in obesity trials (some reaching 40%), the completer population might be a better pharmacoeconomic expression of real life. While some dismiss trials with high drop-outs, from our view, the obese population is so big that if there is a large percentage that stayed in the trial, there is probably a large group that could adhere to drugs.
  • He suggested that successful combined therapies work by tricking the brain into ignoring weight loss. As a result, weight continues to be lost. He was very enthusiastic about this approach. Some advantages of combination therapy he noted were greater weight loss, fewer side effects given the amount of weight loss (if you try to go beyond the plateau by increasing the dose of a drug, side effects increase). He believes in using the lowest dose that is effective, and combining it with other drugs in a rational manner.
  • He also discussed combinations of naturally occurring hormones from the gut, pancreas, and adipocyte. Of particular interest was his presentation of preclinical data of a combined leptin, amylin, and pramlintide treatment, which produced weight loss comparable to gastric bypass. Furthermore, this combined treatment reduced adiposity significantly more than any of the drugs alone.
  • Dr. Aronne believes combined therapy is the future of obesity treatment. He believes we need to better understand target systems and counter-regulatory systems, develop central and peripheral nervous system targets, and develop rational combined surgical and medical therapy.
  • At the end of his presentation, he declared, “I look forward to treating a lot more obesity with a lot fewer of the complications.”

Questions and Answers

Q: Do you see some combination between some surgical and pharmacological treatment? Can we use a less invasive surgical operation with a pharmacological intervention?

A: Minimal invasive procedures (i.e., stimulators, band) in conjunction with medication, yes. If we give a GLP-1 agonist following gastric bypass, can we obtain better outcomes? We have to look at surgery as another tool. Some patients that have surgeries regain the weight. We do not blame the patient. We need to find a way to reach normal physiology.

Q: If you first treat with a single agent in your combination therapy paradigm, and if you add a second drug at that time, one could envision that you would get bigger bang for the buck.

A: This field is really in its infancy, so those on-off therapies haven’t been looked at. Dr. George Bray has looked at intermittent therapy, and it appears that it can be effective. Unlike blood pressure or lipids, you may be able to use drugs in an intermittent paradigm. It may be possible to unwind these (leptin) systems.

BARIATRIC SURGERY AND THE TREATMENT OF OBESITY

Francesco A. Rubino, MD (Cornell Medical College, New York, NY)

Dr. Rubino presented a thorough argument for the utility of bariatric surgery in the treatment of diabetes. It is well documented now that bariatric surgery (particularly Roux-en-Y and biliopancreatic bypass) has remarkable rates of diabetes remission (although many would counter that there is not yet significant follow up data). Nonetheless, eligibility for bariatric surgery is still predominately determined by body mass index (BMI). This reflects that the medical regulatory community has not yet completely accepted bariatric surgery as a metabolic treatment. On this note, he suggested that there the gut may be the root pathology of diabetes, and that bariatric surgery is actually treating the basic cause of the problem. He went so far as to suggest that weight loss on its own may not improve diabetes on its own at all: rather, it could be the interventions that lead to weight loss (diet, exercise, etc) that directly cause beneficial metabolic changes. Notably, Dr. Rubino disagrees with the current NIH guidelines on bariatric surgery. Namely, he feels that the BMI cutoff of 35 kg/m2 (for people without serious obesity co-morbidities) excludes many patients who should be eligible to receive care while including patients that are unlikely to benefit.

  • Bariatric surgery leads to metabolic effects that would not be anticipated from weight loss alone. In particular, diabetes and hyperlipidemia both have a very high rate of resolution (or at least remission) after bariatric surgery, which occurs much more quickly and dramatically than improvement from weight loss alone. Rats that have undergone given Roux-en- Y gastric bypass surgery maintain their resting energy expenditure, which drops after weight loss due to diet.
  • Controversially, he suggested that weight loss may not actually improve diabetes on its own. Rather, it may be the intervention that led to the weight loss, such as diet, exercise, or surgery that directly causes both weight loss and metabolic improvements. This is supported by the fact that, in surgery, resolution of metabolic pathologies actually precedes weight loss. He posited that, if weight loss leads to resolution of diabetes, that equivalent weight loss using different interventions should yield similar metabolic benefits. He presented data showing the contrary; even when adjusting for different degrees of weight loss, metabolic parameters improved more after surgery than after dieting.
  • He hypothesized that the very root of diabetes physiology could be the bowel. He supported this theory with several points: there is significant involvement of the GI tract in glucose homeostasis, the gut has extensive signaling pathways that are tightly linked with metabolism and hunger, and epidemiological data that shows that the increasing rate of diabetes cannot be explained wholly by weight.
  • He disagrees with the current NIH guidelines on bariatric surgery. Namely, he feels that the BMI cutoff of 35 kg/m2 (for people without serious obesity co-morbidities) excludes many patients who should be eligible to receive care while including patients that are unlikely to benefit. He noted that bariatric surgery is a limited resource, and that only 1% of all patients with a BMI >30 (the NIH cutoff for people with serious obesity co-morbidities) have access to it.
  • He weighed the risks and benefits of bariatric surgery. Although there is a risk of mortality associated with bariatric surgery, the risk is very low compared to most other surgeries (Dimick et al., JAMA, 2004). He downplayed this risk, noting that the risks of bariatric surgeries are comparable to other surgeries that are considered standard and very low risk.
  • The most important issue in this field is re-thinking obesity and diabetes to focus on diabetes and obesity as a disease, as a whole. He felt that a great deal of diabetes and obesity science focused in on very small aspects of the diseases, but that a larger view should be taken. Bariatric surgery seems to improve all aspects of diabetes and obesity.

Questions and Answers:

Q: Can we recommend bariatric surgery in a patient with diabetic nephropathy?

A: We’re only looking at bariatric surgery for diabetes recently, but there seems to be evidence that there are improvements in diabetic nephropathy with gastric bypass surgery at least.

Symposium: Bariatric Surgery in the Treatment of Diabetes

THE EFFECTS OF BARIATRIC SURGERY PROCEDURES ON THE METABOLIC CONTROL OF TYPE 2 DIABETES

Walter J Pories, MD (East Carolina University, Greenville, NC)

Dr. Pories reviewed the metabolic effects of bariatric surgery. Although bariatric surgery was originally designed for weight loss, an unexpected benefit has been that metabolic conditions are resolved by a mechanism seemingly independent of calorie restriction and weight loss. He analyzed the factors that predict diabetes remission in bariatric surgery. Although insulin resistance is one of the cornerstones of diabetes, he suggested that it might not be the primary symptom; rather, it may be that hyperinsulinemia induces a defensive mechanism by the body to prevent hypoglycemia. He concluded that give the potential of bariatric surgery, diabetes is no longer a “hopeless” disease. However, he was careful to note that bariatric surgery could not be given to everybody who needs it.

  • Bariatric surgery has progressed significantly in the past 50 years. Early on, there was a great deal of hype on bariatric surgery, but the procedures were primitive. Many patients had to have their surgeries redone, and others died. He expressed that he felt the hype was misleading, but that this has improved.
  • Dr. Pories was the first surgeon to study the metabolic benefits of gastric bypass surgery. He published a 1995 paper, now famous, titled, “Who would have thought it? An operation proves to be the most effective therapy for adult-onset diabetes mellitus,” (Pories et al., Ann Surg 1995) which reported the remission of diabetes in several patients following gastric bypass surgery.
  • He analyzed the factors that predict diabetes remission in bariatric surgery. He found that diabetes remission was dependent on age and duration of diabetes. Older patients with longer duration of diabetes do not have as much success as younger patients with shorter durations. He theorized that this could be due to the survival of pancreatic beta cells: if there are no remaining beta cells, then there can be no remission of diabetes.
  • He suggested that insulin resistance might not be the primary symptom of the disease, but rather a defensive mechanism against hyperinsulinemia. He felt that the gut was a potential culprit that should be considered. Based on this theory, he proposed that skipping the pathological area of the gut would resolve diabetes. Indeed, surgical techniques that skip more of the small intestine lead to greater levels of remission.
  • He showed unpublished data looking at the concentration of insulin after a meal challenge before and after surgery. After surgery, insulin levels are almost completely corrected. He feels that the most elegant proof of this interaction between surgery and resolution of diabetes was performed by Dr. Rubino (who chaired this session). In this study, Dr. Rubino took a lean rat model of diabetes and showed that exclusion of the duodenum from the gastrointestinal tract led resolved the diabetes. In another study, he compared the results of a closed gastric sleeve (which prevents food from coming into contact with the proximal small intestine), a fenestrated gastric sleeve (a gastric sleeve with holes in it that allows for food to pass through), and a placebo surgery. Only the closed gastric sleeve led to remission of diabetes.
  • Dr. Ramos, from Brazil, has performed duodenal-jejunal laparoscopic bypass in lean patients with diabetes, and has shown that there are significant improvements in BMI, A1c, postprandial insulin, fasting blood sugars, and post prandial blood sugars.
  • He concluded that diabetes is no longer a “hopeless” disease. Gastric bypass is as safe as standard procedures such as cholecystecotomy when performed at a center of excellence. He pleaded to diabetologists and endocrinologists to assess and provide long-term follow-up for these patients. He admitted that he believes that surgery is not possible for the 23 million Americans that need it, and that other therapies will need to be developed.

Questions and Answers:

Q: How do you see the balance between mortality and morbidity when compared to treatments that are not as efficacious, but are safer.

A: I don’t think that anybody in the audience believes that the medical treatments don’t have any mortality or morbidity. Recent studies have shown this. No studies are completely safe, and we need to accept this.

Q: I was wondering about long-term problems with osteoporosis or malabsorption?

A: Yes, there is a tremendous problem in patients who do not take vitamins. We have seen many vitamin- deficiency syndromes, and this is why surgeons need the help of diabetologists so badly.

EFFECTS OF BARIATRIC SURGICAL PROCEDURES ON GASTROINTESTINAL HORMONE SECRETION

David E Cummings, MD (University of Washington, Seattle, WA)

Dr. Cummings spoke on the metabolic effects of bariatric surgery. Bariatric surgery improves glycemic control and other metabolic parameters more than would be expected from the restriction of caloric intake alone. These metabolic improvements actually occur before any significant weight is lost, sometimes as quickly as one day after completion of surgery. Because bariatric surgery has such dramatic impacts on diabetes, it has been proposed that patients with diabetes who are not obese should be allowed to undergo bariatric surgery. Dr. Cummings reviewed data supporting the use of bariatric surgery in people with BMI >30 kg/m2, and presented data from an unpublished study looking at the effects of bariatric surgery in Asian Indians with BMIs of 22-25 kg/m2. In this particular study, there was 100% resolution of diabetes at nine months with maximum average weight loss of ~20%. He reviewed various theories on what might cause these effects, focusing on hormonal mechanisms involving ghrelin, PYY and incretins. He briefly spoke about two relatively uncommon forms of bariatric surgery, ileal interposition and duodenal-jejunal bypass, both of which are weight-neutral. Despite this, there is resolution of diabetes, further supporting a hormonal role in bariatric surgery separate from caloric restriction.

  • Dr. Cummings spoke about the potential mechanisms by which gastric bypass is so effective. The first suggestion was that the resolution was due to diabetes was weight loss, but there has since been a switch in thinking. The rapidity of the improvement suggests that there is another mechanism. Weight loss happens too slowly to explain the resolution of metabolic symptoms of diabetes, which occurs just after a few days. There is more proof in the lower rate of diabetes remission after gastric banding, where there is weight loss but no bypass of the gut.
  • An unpublished study by Lee et al. randomized patients with BMI >30 kg/m2 to sleeve gastrectomy or gastric bypass. At six months, the weight loss was equivalent, but there were very different glycemic results. Nearly forty seven percent of the sleeve gastrectomy group completed the study with an A1c <7%, while 93.3% in the gastric banding group reachedA1c <7%. In general, there is poor correlation between the amount of weight loss and the probability of diabetes remission.
  • An unpublished study by Shaw and Cummings is evaluating the effects of bariatric surgery in Asian Indians with BMIs of 22-35 kg/m2. They are all considered overweight or obese for Indian specific criteria all have severe type 2 diabetes. The mean duration of diabetes is nine years, 80% of them were on insulin, the average A1c was 10.1%. At nine moths, BMI fell from28.9 kg/m2 to 23.0 kg/m2, hypertension was improved in most, dyslipidemia was improved an nearly all subjects. Fasting plasma glucose dropped from 233 to 89 mg/dl after nine months, A1c fell to 6.1%. From this data, the authors predicted 10-year cardiovascular risk using UKPDS risk engine. There were dramatic decreases in risk. In this study, there was a 100% remission of diabetes after three months, most of which had resolved at one month. All remission persisted to seven and nine month milestones. The maximum weight loss was 20%. Although this is a great deal of weight loss, it is very unlikely that this would have led to this degree of diabetes remission. These results are better than what is seen in most studies, which generally show around 84% diabetes remission with 30-35% weight loss.
  • In rare cases, nestidioblastoma is seen after bariatric surgery, in which there is hyperinsulinemia that leads to hypoglycemia. One theory to explain this is that patients have grown more beta cells to compensate for insulin resistance, and that correcting diabetes leaves them with an over-functional pancreas. However, this type of hypoglycemia usually happens at two to four years after surgery, which does not correlate with the very quick resolution of diabetes or weight loss. Some proposed factors that could account for this are changes in gut hormones (particularly GLP-1, Ghrelin and PYY). Notably, we hear questions on this frequently from endocrinologists.
  • Ghrelin is a stomach and proximal intestinal hormone that stimulates food intake and may be involved in the effects of bariatric surgery. Ghrelin secretion increases in response to dietary weight loss. It is logical that this hormone could be altered with gastric bypass, since gastric bypass removes a ghrelin-secreting area from the gastrointestinal tract. Cummings et al. showed that ghrelin levels in the blood are very low in people after gastric bypass. He theorized that the degree of ghrelin response is dependent not on leptin but on insulin: thus, rectifying abnormal insulin could rectify ghrelin.
  • Another theory to explain the metabolic benefits of gastric bypass is the undigested food reaching distal regions of the GI tract stimulates the release of beneficial hormones. There is evidence from several studies that GLP-1 and PYY are increased after gastric bypass surgery. All common types of bypass surgery show this effect. This increase in the release of hormones is stimulated with food, and thus the incretin effect (the increased insulin response with orally ingested glucose compared to intravenously injected glucose).
  • Illeal interposition, another kind of bariatric surgery, removes a portion of the distal ileum and replaces it in the proximal small intestine. This form of surgery seems to have significant effects in resolving diabetes without leading to weight loss. Since this form of surgery is not restrictive, this lends credibility to the hypothesis that there is a metabolic effect of bariatric surgery that is unrelated to changes in caloric intake. Rubino et al. has shown in animal models that this form of surgery also leads to resolution of diabetes similar to 
  • Duodenal-jejunal bypass, another non-restrictive bariatric surgery, also leads to metabolic benefits without weight loss. There is no gastric restriction, no caloriemalabsorption and no weight loss. Nonetheless, oral glucose tolerance tests (OGTTs) were improved in a rat model after this surgery, despite the lack of weight loss.

Questions and Answers:

Q: You commented on the severe hypoglycemia two to four years after GB.

A: One possibility is an unknown beta cell hypertrophic factor, but also it could be a result of GLP-1.

TREATMETNT OF TYPE 2 DIABTES – BARIATRIC SURVERY VS. PARMACOTHERAPY

Bernard Zinman, MD (University of Toronto, Ontario, Canada)

Dr. Zinman reviewed pharmacological and surgical treatments for type 2 diabetes with a focus on interventions targeting the unique pathophysiological bases of the disease. Although the causes of diabetes and obesity are not completely understood, he did not agree that bariatric surgery directly addresses the cause of diabetes or obesity. Rather, he believes that it introduces a new pathology to counteract whatever physiology is causing the disease in the first place. He reviewed various symptoms of diabetes, and the pharmacological treatments that can be used to address them. He characterized the stepwise fashion in which physicians typically prescribe antihyperglycemic as a “treat-to-fail” approach, in that therapies are used until the condition worsens and a more serious therapy is required. He advocated the wider adoption of the ADA’s “tier 2” treatment schedule, particularly incretin therapy. He was unsure of bariatric surgery’s place in the treatment of diabetes, since the mechanism of the benefits and the side effects have not been detailed fully. To standardize bariatric surgery as a treatment for diabetes and obesity, he said better-designed and longer-term studies would be needed.

  • Dr. Zinman’s goal in this talk was to review the underlying pathophysiology of type 2 diabetes and the treatments that are used to address the symptoms of the disease. Although the true cause of diabetes is unknown, he does not believe that bariatric surgery is actually “fixing” the problem. Rather, he characterized bariatric surgery as the introduction of a new pathology to balance or counteract another pathology.
  • Diabetes is a complex disease with many elements, and there are pharmacological therapies that address these symptoms individually. He highlighted improperly regulated gluconeogenesis (treated with metformin), insufficient insulin secretion (treated with sulfonylureas and meglitinides), and insulin resistance (treated with thiazolidinediones). Although bariatric surgery affects all three of these symptoms, it does not address the original cause of the symptoms. The mechanism by which it imparts such a broad change, however, is not
  • He joked that there are two kinds of insulin resistance: the resistance in the peripheral tissue and the resistance of physicians to prescribe it. He called this resistance “clinical inertia.” He characterized the current stepwise approach to treating diabetes as “treat-t0-fail”. He also noted that treatment is started later than it should be. Patients are started on metformin or sulfonylureas well over a year after an initial confirmed A1c of >8%. He advocated early treatment and stabilization to even out therapy rather than just waiting for incremental treatments to fail. He supported the wider adoption of the “tier 2” ADA treatment guidelines, particularly incretin therapy, since preventing weight gain is a priority for him in early treatment of diabetes.
  • He felt that not enough is known about bariatric surgery. In particular, he noted that most studies of bariatric surgery had major methodological flaws, and that much longer durations would be needed. Loss of patient contact is also a serious issue: many studies lose ~50% ofpatients to follow-up. There is a consensus that more well-designed clinical trials are necessary for bariatric surgery versus pharmacotherapy. These studies need to be long-term to compare efficacy and safety to define bariatric surgery’s role in the treatment of diabetes.

Questions and Answers:

Q: I’d just like to comment that giving metformin at the point of diagnosis is always the best therapy. It takes away emphasis from the lifestyle aspect of intervention.

A: Interestingly, this has not been a contentious issue for the ADA, but it has been for others. We felt that we did not want to detract from the lifestyle intervention, but that lifestyle intervention is not sustained and we wanted to compensate for that with metformin.

Q: Just a comment about surgery that need to be recognized. There have been several surgeries showing that there are benefits in people qualified for surgery.

A: Those who are very obese with all these other comorbidities really do benefit from bariatric surgeries. The question is: will this occur in individuals who are not obese. Will they have the same metabolic effects? I don’t know!

Q: What do you envision as the endpoints of bariatric surgery trials?

A: I think that’s an excellent question, and the first one should be glucose control, A1c. Another one should be cardiovascular outcome, at least as a secondary outcome. There are other outcomes too that would be important. Francesco [Rubino] is actually planning such an experiment right now.

Q: Do you think that there is a chance for screening patients by putting them on early intensive therapy and then giving them bariatric surgery if they don’t?

A: The people who benefit most from bariatric surgery are low duration diabetics. So that could very well be the best method of selection, what you just said.

UNANSWERED ISSUES IN BARIATRIC SURGERY

Xavier Pi-Sunyer (Columbia University, New York, NY)

With the impressive remission of diabetes seen after bariatric surgery, it is important to make sure that the mechanisms of action are understood and that the optimal patient population is determined. Dr. Pi- Sunyer reviewed what is not yet known in bariatric surgery. He felt that not enough was known about the comparative efficacy of different types of bariatric surgery, predictors of success, side effect profiles, and the physiological mechanisms involved. He noted that, for bariatric surgery to be more widely adopted, light must be shed on these unknowns. This will involve long-term, well-designed clinical trials. In particular, loss to follow-up must be improved and the long-term maintenance of metabolic benefits must be studied more fully.

  • He felt that those at the highest risk of co-morbidities for obesity or diabetes should be prioritized. This includes people who are heavier, older and have more co-morbid conditions. He acknowledged that people with a long duration of diabetes tend to have worse outcomes after bariatric surgery (likely because their beta cells have been completely ablated), but maintained that bariatric surgery was a good option for those who have more difficulty taking care of their health, including people with low income.
  • Surgical professional societies want to expand insurance coverage of bariatric surgery to people with BMI >30 kg/m2. This is a controversial subject, and many physiciansbelieve that bariatric surgery is inappropriate for people with BMIs below 30 kg/m2. Surgeons contend that the surgery treats more than just obesity, and that a measure of obesity is an inappropriate cutoff.
  • He is not sure which of the bariatric surgeries is the best. Although there has been some data comparing the weight loss and diabetes remission of Roux-en-Y gastric bypass, sleeve gastrectomy, and biliopancreatic diversion, there is insufficient evidence to weigh all the costs and benefits associated with such complex procedures. Gastric banding has been gaining favor in the US, but this is because it is easier to perform than Roux-en-Y gastric bypass rather than its efficacy in treating diabetes and obesity.
  • Centers of excellence provide guidance from specialty groups in which centers were optimal for bariatric surgery. Certified centers meet minimum requirements for surgeon experience, resources, and operations per year.
  • There are still unresolved issues regarding the rates of all-cause mortality in bariatric surgery. He believes that reducing the mortality seen in bariatric surgery is the most important goal in bariatric surgery. The SOS study, Flum-Washington State study, and Adams et al. have all shown reductions mortality in surgery versus matched controls. Mortality is also decreasing from people getting medical therapy, since medicine is improving the co-morbidities associated with diabetes and obesity. He did not feel confident that in mortality numbers for bariatric surgery patients in many studies, since so many are lost to follow-up: it is not infrequent to see ~50% patient dropout rate by the end of the study.
  • There are still side effects that need to be addressed with metabolic surgery. Gallstone formation and cholecystitis is seen in 30% of patients who have received operations at six months. Administering the drug “ursodiol” can prevent this. It is expensive and poorly tolerated. Re-operation sometimes becomes necessary.
  • There is a range of other side effects that must be considered with bariatric surgery. Although there have been several studies showing that there is an overall improvement in psychological metrics after bariatric surgery (including quality of life statistics), malabsorption (especially of vitamin D), vomiting (in 10-20% of patients one year after the procedure), and hyperinsulinemic hypoglycemia.
  • The mechanism by which diabetes is resolved is still not understood. Also, it is not known how durable the remission of diabetes is. There are very few studies that have looked at the long-term remission of diabetes. He thinks that we need to study this more closely. The dramatic weight loss and glycemic improvements do not persist indefinitely for everybody, and the reasons need to be understood to optimize the effects of bariatric surgery.

Questions and Answers:

Q: Do you think that a share of patients should consider early surgery?

A: Yes, and I think that we need to generate some five and six year studies on this subject.

Symposium: Controversies in Pediatric Obesity and Diabetes

HYPERLIPIDEMIA—USE OF STATINS

Stephen R. Daniels, MD, PhD (University of Colorado School of Medicine, Aurora, CO)

Dr. Daniels said once exercise and diet have been addressed (of course), pharmacotherapy is reasonable for hyperlipidemic pediatric patients. Many statins are approved for the pediatric population, for children as young as eight years old (pravastatin). The main point was that lipids should be addressed in the pediatric population, which may have to mean better screening methods.

  • There should be a paradigm of CVD prevention in the pediatric population. Autopsy studies have shown that fatty change (the initial stage of atherosclerosis) and even some fibrous plaques (a later stage) may begin to occur as early as the first decade of life. Furthermore, children and adolescents with high cholesterol are more likely than the general population to have high cholesterol.
  • Current screening protocols unfortunately would still miss 30-60% of children with high cholesterol. The protocol recommended by the National Heart Lung and Blood Institute entails screening children whose parents or grandparents had CVD at age 55 or earlier, whose parents have high cholesterol (over 240 mg/dl), or who have other risk factors, such as obesity, hypertension, and diabetes. Unfortunately, family history can be difficult to obtain, and parents may be too young to have had an event or have not had lipids measured.
  • Though several statins are approved for pediatric use, there is not sufficient data to use ezetimibe in children. While several statins are approved for the pediatric population, ezetimibe, which reduces intestinal absorption of cholesterol, does not have sufficient data to justify use in children.

PEDIATRIC BARIATRIC SURGERY

Caroll M. Harmon, MD, PhD (University of Alabama, Birmingham, AL)

Dr. Harmon discussed why bariatric surgery was being considered in pediatric populations – namely, the lack of effectiveness of behavior modification and drug therapy is very high, as are the dangerous comorbidities with which obesity appears. His center uses BMI >35 kg/m2 with severe comorbidities or BMI > 40 kg/m2 with minor comorbidities as part of the criteria for selecting surgical candidates. They also use a comprehensive set of psychological and other criteria. He discussed gastric banding and bypass in this population and expressed disappointment that the Lap Band (Allergan, by way of Inamed) was not FDA approved in people less than 18 years of age. During Q&A, he mentioned that studies are being conducted that may cause the FDA to lower this age cutoff to 14 years.

  • A procedure as radical as surgery is being considered in pediatric populations because of the high prevalence and multiple medical complications of pediatric obesity. Dr. Harmon cited troubling statistics regarding childhood obesity. Currently, there are up to 2 million obese children in the US. In terms of comorbidities, 86% of children diagnosed with diabetes are overweight or obese. Freedman et al. (Pediatrics, 1999) found that 58% of a cohort of 813 overweight schoolchildren had at least one cardiovascular disease risk factor. Furthermore, their overweight status could be used to identify 50% who had two or more risk factors.
  • Behavior modification and drug therapy do not seem to have provided robust results but we do not have any long-term data for surgery either.
  • Pediatric bariatric surgery requires investment in creating a program viable for pediatrics. The Children’s Center for Weight Management developed in Birmingham, AL incorporates both prevention and treatment (which includes bariatric surgery). The center also involves a research center, and a multidisciplinary healthcare team.
  • Dr. Harmon discussed criteria considered for selecting surgical candidates. Candidates for surgery must have serious comorbidities if BMI >35 kg/m2, or minor comorbidities and BMI>40 kg/m2. They must be physiologically mature (Tanner stage IV), committed to assessment before and after surgery, committed to avoiding pregnancy for at least one year after surgery, and adhere to nutritional guidelines in addition to other requirements.
  • The gastric band is not yet FDA approved in people younger than 18. He characterized the gradual weight loss vs. gastric bypass as potentially a good thing in this population. Nadler et al. (Pediatric Surg, 2008) have performed a gastric banding study in teenagers and showed good resolution of comorbidities after a year. Complications thus far recorded include mild hair loss, n=14), iron deficiency (13), and a number of others including the need for frequent adjustments of the band.
  • Dr. Harmon discussed his hospital’s experience with pediatric gastric bypass procedures. Data published by Lawson et al. (J Ped, Surg, 2006) showed mean BMI dropped 37% from a baseline of 56.5 kg/m2 following Roux-en-Y gastric bypass compared to 3% in nonsurgical patients (it was pretty impressive as the nonsurgical group did not have weight gain). Complications were reported in 40% of patients in the surgery group. These ranged from dumping syndrome, staple leaks, hernia, to severe Beri-beri with sequelae over two months. One child died while waiting for insurance to approve his surgery. More recent data from the Inge et al. (Pediatrics, 2009) showed 60% excess weight loss after one year, diabetes remission, decrease in hypertension, cholesterol, and triglycerides, as well as improvement in beta cell function and insulin resistance. Long-term impact is yet to be determined.
  • He briefly mentioned sleeve gastrectomy as a procedure finding its way into the pediatric space.
  • There are still a lot of unanswered questions regarding long-term risk/benefit ratios. The Teen Longitudinal Assessment of Bariatric Surgery study is being used to obtain these much-needed long-term data. They are looking to enroll 200 adolescents who have had a Roux-en-Y gastric bypass procedure. The study will compare teenage bariatric surgery data to adult data as pertains to effects on weight, comorbidities, and importantly complications.

Questions and Answers

Q: How do you decide which procedure to offer?

A: The Lap Band is only approved for kids 18 and over, which limits you. The FDA recently looked at a trial looking at the lap band in teens and the cutoff age may drop to 14 years.

Q: Are liver biopsies done on all kids?

A: It’s specific to the center. All the kids have steatosis and many have inflammation.

Q: Do you do psychological evaluation of the families as well?

A: Certainly. That’s why it takes such a long time.

ARE GLP-1 AGONISTS APPROPRIATE FOR THE OBESE CHILD WITH TYPE 2 DIABETES MELLITUS?

Susan A. Phillips, MD (University of California at San Diego, La Jolla, CA)

Interestingly, Dr. Phillips said she was originally asked to give a talk on the use of GLP-1 agonists in obese children (with or without diabetes) but did not feel there was any data at all to support that. She instead discussed their use in obese children with type 2 diabetes, a use she considers reasonable. In fact, she appeared quite positive on the use of GLP-1 agonists in children. She was at least confident the use will be approved (Amylin is sponsoring a phase 3 exenatide study in children, currently enrolling at 33 sites; target enrollment is 195 children ages 10-16, with primary outcome of glycemic control with exenatide as compared to placebo over 28 weeks), and dwelt little on the oft-cited “we need more studies to tell,“ which was refreshing although clearly all the safety information needs to be moving forward. Notably, during the talk, Dr. Phillips essentially waved away concerns about both pancreatitis and thyroid c-cell tumors.

  • Amylin is sponsoring a phase 3 exenatide study in children, currently enrolling at 33 sites. Target enrollment is 195 children ages 10-16, with primary outcome of glycemic control with exenatide as compared to placebo over 28 weeks. Dr. Phillips said in Q&A that assuming FDA approval, she would use GLP-1 agonists in her pediatric type 2 patients when she would normally have started to think about adding insulin.
  • Recent data on exenatide in children shows similar pharmacokinetics and effects as in adults. A randomized study of 13 adolescents given single doses of exenatide, of 2.5 mcg and 5 mcg, showed similar dose-dependent duration of plasma level, similar area under the curve, similar maximum plasma level, similar reduction in plasma glucose, and similar glucagon suppression (Malloy et al., Clinical Therapeutics, 2009).
  • Dr. Phillips essentially waved away concerns about both pancreatitis and thyroid c- cell tumors. One recent study showed that there was no difference in the incidence of pancreatitis in those taking exenatide as compared to metformin/glyburide combination therapy (Noel et al., Diabetes Care, 2009). Another showed no differences in calcitonin (marker for thyroid c-cell tumor) levels in liraglutide vs. placebo, though since an increase was seen in rodents, she conceded that “the jury is still out” (Dore et al., Curr Med Res Opin, 2009).

Symposium: Ectopic Fat and Obesity

MUSCLE, LIVER AND ABDOMEN

Kitt F. Peterson, MD (Yale University School of Medicine, New Haven, CT)

In her presentation, Dr. Kitt Peterson explained four major relationships related to lipid mediated insulin resistance. 1) insulin sensitivity and age, 2) leptin treatment and lipodystrophy, 3) a low energy diet and obese patients with type 2 diabetes, and 4) rosiglitazone and obese patients with type 2 diabetes. Of the many conclusions she discussed in her talk, of particular interest was her contention that insulin resistance is in part a result of impaired mitochondrial function. She also discussed metabolic syndrome, which she hypothesized is a result of an inability to store carbohydrates in muscle.

  • In the first study that Dr. Peterson presented, subjects took the oral glucose tolerance test (OGTT) to investigate the relationship between insulin sensitivity and age. Subjects were matched for age, body weight, BMI, body fat, fat mass, lean body mass, fasting glucose, and fasting insulin. She noted a previous study by Harris et al. (1993) that demonstrated a significantly higher incidence of glucose tolerance and obesity in older patients.
  • OGTT testing in elderly people demonstrated insulin resistance in the muscle. Use of hypoglycemic clamps demonstrated that the insulin resistance was ascribed to muscle insulinresistance, attributed to lipid buildup. Furthermore, a correlation between lipids in the muscle or liver and insulin resistance was demonstrated. Lipids are thought to impair the ability of the cell to take up plasma glucose such that more insulin is required to induce plasma glucose uptake.
  • Peterson provided two possible explanations for age-induced insulin resistance. 1) In older people, cells develop defects such that they take up more fat or 2) that a mitochondria defect prevents oxidation of substrates resulting in fat buildup in the muscle or liver.
  • Microdialysis of fat cells suggested that insulin resistance was not caused by defects in the fat cells. No differences in glycerol release from adipocytes between young and elderly people were shown. Furthermore, no differences were found in basal rates or insulin suppression (via clamp) in young and old people.
  • Measurements of ATP synthase flux using 31P NMR and of the TCA cycle using 13C NMR indicated impaired mitochondrial function in elderly subjects. Results from these tests demonstrated a 40% reduction in TCA flux and ATP synthesis in older people. Dr. Peterson added that it is unclear if impaired mitochondrial function is the major contributor to insulin resistance.
  • Dr. Peterson went on to discuss leptin treatment in 3 patients with lipodystrophy. These subjects demonstrated typical symptoms of lipodystrophy: paucity of fat, insulin resistance, hypertriglyceridemia, fatty infiltration of liver and other tissues, deficiency of adipocyte hormones (e.g., leptin). Subjects were matched to controls, and treated with leptin.
  • Lipodystrophic patients achieved normal fasting glucose after three to eight months of leptin treatment. Lipodystrophic patients had severe muscle insulin resistance and hepatic insulin resistance prior to treatment. Leptin significantly increased muscle glucose uptake and suppression of glucose production. Lipids in the muscle and liver also decreased significantly following leptin treatment. Leptin also decreased energy intake (decreased appetite) significantly from 4000 to 1000 calories, which she believes was the major contributor to normalization of fasting glucose.
  • A low energy diet significantly reduced liver fat and glucose production, and modulated insulin sensitivity towards normal levels in obese patients with type 2 diabetes. A pool of patients with type 2 diabetes was put on a weight loss diet of ~ 13000 calories a day. After 10 to 13 weeks, they had normal. It is worth noting that no changes were seen in IL-6, TNF-a, Resistin, RBP-4, which are often associated with insulin resistance. Given this particular finding, she suggested that these markers may emerge later in the development of insulin resistance.
  • Rosiglitazone improved insulin sensitivity, reduced hepatic fat, and increased extramyocellular fat in obese patients with type 2 diabetes. She suggested that TZD might act by increasing the fat cell volume, the expansion of which sucks up the fat from insulin responsive organs, leading to improved insulin sensitivity. She added that insulin resistance is often attributed to fat build up in insulin responsive organs.
  • She concluded with a discussion on metabolic syndrome, which she hypothesized is a result from inability to store carbohydrates in muscle. These carbohydrates then go to the liver, which leads to ectopic fat build up in the liver. When older people are fed a high carbon diet, they demonstrate significantly decreased muscle glycogen. This explains why older people have lower insulin tolerance. She noted that this study will be presented at ADA in much more detail at poster 1311 on Saturday at 10:30.

Questions and Answers

Q: Have you looked at nutrition in older versus younger subjects or the effect of dietary intake?

A: For these studies, we feed patients for three to four days before testing ~55% carbohydrate, during study ~65% carbohydrate. As shown in first study with OGTT, when you give glucose to older people, they show insulin resistance.

Q: Any more thoughts about why lipodystrophic patient needed 4000 calories per day prior to leptin treatment?

A: Leptin has some suppression of appetite. Prior to leptin treatment, the calories were going to the muscle and liver.

HEART AND BLOOD VESSELS

Pirjo Nuutila, MD, PhD (Turku PET Centre, Finland)

Dr. Nuutila spoke about cardiac adiposity, metabolism and its relationship to obesity and type 2 diabetes. She emphasized that the accumulation of triglycerides within and around the heart is a sign of both fatty acid overload and increased fatty acid oxidation. Additionally, lipotoxicity (TG accumulation, ceramide formation) is associated with reduced myocardial energy efficiency. The decrease in the availability of fatty acids due to either dieting or obesity surgery rapidly improves functional abnormalities and also leads to improved endothelial function of the vessels. The prevention of fat oxidation and the increase of uncoupling improves glycemic control and the function of the failing heart. Both improved glycemic control and the loss of body weight predict cardiac functional recovery instead of changes in blood pressure or lipids.

Questions and Answers

Q: Is there more brown fat in females than males?

A: Yes, there is more brown fat in females than males and brown fat happens more frequently in females than males. There are smaller masses of brown fat in females.

ECTOPIC FAT—WHAT’S ACQUIRED? WHAT’S GENETIC?

Steven R. Smith, MD (Pennington Biomedical Research Center, Baton Rouge, LA)

Dr. Steven Smith focused on ectopic fat in the liver and skeletal muscle and discussed whether accumulation of such fat was acquired or genetic. The majority of his talk was an extensive literature review, demonstrating evidence for both acquired and genetically facilitated accumulation of ectopic fat in the liver and skeletal muscle. He concluded that both acquisition and genetics play roles in ectopic fat accumulation. Although ectopic fat can be acquired by lifestyle habits, there is strong evidence for genetic/epigenetic epidemiology. He suggested that these epidemiological effects probably occur at cell programming.

  • Dr. Steven Smith focused primarily on ectopic fat in the liver and skeletal muscle. He began by defining ectopic fat as “the abnormal storage of lipid in tissues other than adipose tissue”.
  • Liver fat moves very quickly in the upward or downward direction. Subject fed either low or high fat diet for two weeks. Liver fat generally decreased significantly (20+-9%) on low fat diet, increased by around 35% in the high fat
  • Individuals with family history of type 2 diabetes have higher concentrations of ectopic fat in the liver. People of Hispanic and African-American have higher heritability of ectopic fat.
  • There exists a negative correlation between lipid in skeletal muscle and insulin sensitivity. He presented three models that explain increased lipids in skeletal muscle: 1) inability to expand the subcutaneous adipose tissue leads to dysfunctional adipose tissue which leads to ‘spillover’ into ‘downstream’ tissues and disordered adipokine secretion, 2) dysfunctional muscle fatty acid metabolism leads to ‘back-up’ of lipid into ‘upstream’ tissues, 3) both dysfunctional adipose tissue and dysfunctional oxidative pathways are necessary (two ‘hit’ hypothesis).
  • Studies suggested that there were genetic or epigenetic trends that resulted in ectopic fat. One of the consequences is impaired mitochondrial function, which results in dysfunctional oxidative pathways. Patients with type 2 diabetes oxidize lipids much less rapidly than control patients.
  • Dr. Smith concluded that ectopic fat is genetic, but can also be acquired. Although ectopic fat can be acquired by lifestyle habits, there is strong evidence for genetic/epigenetic epidemiology. He suggested that these epidemiological effects probably occur at cell programming.

THE INFLUENCE OF SURGERY ON ECTOPIC FAT

Samuel Klein, MD (Washington University School of Medicine, St. Louis, MO)

Dr. Klein spoke about the effect of bariatric surgery and weight loss on body fat, specifically on ectopic and visceral fat. Ultimately, if a patient loses weight by bariatric surgery, they lose both ectopic and visceral fat. When a patient loses weight, certain fat depots lose weight more quickly than other depots as ectopic fat in different locations are differently sensitive to weight loss. A short period of caloric restriction can have a significant change on ectopic fat distribution and an 80% increase in hepatic insulin sensitivity was seen as well. Heart muscle and skeletal muscle lose triglycerides more slowly than other organs. Bariatric surgery is currently the most effective therapy of type 2 diabetes and obesity. After bariatric surgery, there is a significant increase in hepatic, skeletal, and adipose insulin sensitivity as well as a reduction in intrahepatic fat and endoplasmic reticulum (ER) stress. If instead of bariatric surgery liposuction is performed to remove subcutaneous fat, there is no significant benefit in insulin’s ability to stimulate glucose uptake or insulin sensitivity. The same result is seen with an omentectomy that removes visceral fat. In order to have the beneficial effects of weight loss, the metabolic changes need to occur which do not happen if the fat is simply removed.

Questions and Answers

Q: When you remove 0.8 kg, I would expect to see a worsening of the situation as the patient will continue to eat the same amount.

A: The patients used in the study are weight stable and thus do not gain weight. The patients who come back for follow-up are weight stable.

Symposium: Advances in the Understanding of Obesity and Weight Gain During Pregnancy

REDUCING PREGNANCY WEIGHT GAIN IN OBESE WOMEN

Naomi Stotland, MD (University of California at San Francisco, San Francisco, CA)

Dr. Stotland discussed the recently released guidelines for gestational weight gain, emphasizing the importance of diet and exercise in achieving optimal gestational weight gain outcomes. Existing research on interventions to help women maintain their weight within guidelines is inadequate, which led her to conduct her own intervention using prenatal counseling. Subjects that participated in the intervention demonstrated no significant weight loss, but improvements in behavioral outcomes were shown. Although she finds prenatal counseling beneficial but currently inadequate, she is confident that we can reduce excessive weight gain among obese pregnant women using lifestyle interventions.

  • The Institute of Medicine released new guidelines for gestational weight gain in May 2009. The original guidelines came out in a 1990 effort to reduce low birth weight. Since then, the obesity epidemic has brought light to the excessive weight gain some women experience during pregnancy. The most notable addition to the guideline is an upper limit to how many pounds obese women(greater than 30 BMI) should gain (the new guideline suggests 11 to 20 pounds). A recent clinical finding demonstrated that half of obese women gained at least 25 pounds during pregnancy.
  • Existing research on interventions to help women maintain their weight within guidelines is inadequate. She recommended that women should learn the importance of optimizing preconception BMI (perhaps considering bariatric surgery as an option) and that prenatal care should include counseling on diet and physical activity. Furthermore, she noted the importance of studying new ways to help women gain weight within guidelines, and to study the cost-effectiveness of such interventions.
  • Dr. Stotland believes pregnancy is a ‘teachable moment’, but providers need new tools. During pregnancy, women are in a heightened emotional state and are more concerned about their health and weight because they care about the health of their baby. This idea is supported by epidemiological studies that demonstrate that women receiving appropriate weight gain advice during pregnancy are better able to maintain their weight within the guidelines. Alarmingly, a third of women report receiving no counseling at all. She went on to discuss several studies demonstrating improved outcomes following interventions focusing on exercise and diet. She also mentioned her group’s current pilot intervention program, Keep Fit, which demonstrated better behavioral outcomes but no difference in weight gain.
  • Most obese women are gaining weight above and beyond the current guidelines. Dr. Stotland emphasized the need for more data establishing the safety of minimal weight gain or weight loss during pregnancy for obese women. Although she finds prenatal counseling beneficial but currently inadequate, she is confident that we can reduce excessive weight gain among obese pregnant women with lifestyle interventions.

Questions and Answers:

Q: Have you been looking at ketones at all in these programs when women have been trying to get their weight under control? Is the extent of the weight gain enough to induce ketonuria?

A: No, we haven’t examined this. These studies are pretty new and ongoing. Previous studies haven’t reduced weight gain to that degree, but I think it will be seen in these new studies.

Q: Could you comment on recent findings that weight gain lower than the new guidelines is advisable?

A: I think what people are most concerned about is that there is some older epidemiological evidence that small gestational age babies result from restricting diet and weight gain. It puts pressure on us to find out what’s safest for the baby. There could be an adverse effect with weight loss just as there could be one associated with weight gain.

RISKS ASSOCIATED WITH PREGNANCY WEIGHT GAIN

Ellen Nohr, PhD (University of Aarhus, Aarhus, Denmark)

Dr. Nohr discussed her trade-off approach to pregnancy weight gain, and reported her findings investigating the relationship between weight gain and pregnancy risks. She emphasized the importance of taking into consideration the mother’s health in addition to the baby’s. Her findings suggested that the higher the mother’s BMI before pregnancy, the less they should gain during pregnancy. This relationship minimized risks such as LGA, SGA, cesarean delivery, and postpartum weight retention.

  • Dr. Nohr discussed her trade-off approach to pregnancy weight gain. She explained that guidelines in the past were insufficient, because they focused only on the health of the baby. She believes that in order to determine the most efficacious guidelines, one must evaluate the trade-offs in risks between mother and infant for different weight gains. Her study focused on investigating on whether the trade-offs depend on BMI.
  • Her study analyzed data from the Danish national birth cohort. The cohort consisted of 100,000 primarily Caucasian women and their offspring. Eight percent of women in the cohort were obese. Data was collected by interview at sixteen weeks, thirty weeks, half a year, and one and a half years. Weight gain in pregnant women was categorized into low, medium, high, and very high. She noted that background risks of most pregnancy outcomes increased with elevated BMI (risks of small for gestational age [SGA], large for gestational age [LGA], emergency cesarean delivery, and postpartum weight retention). A logistic regression was used to analyze the relationship between weight gain and these pregnancy risks.
  • She concluded that the safest weight gains were different in women of different weights. Underweight women should avoid low gain and rather feel free to gain weight to the upper limit. Heavier women may benefit from avoiding high and very high weight gain. Especially obese women may benefit from low gain. These suggestions minimize the risk for SGA, LGA, cesarean delivery, and postpartum weight retention.
  • Further study investigating differences in parity yielded insignificant results. Similar trends were seen in primiparous women and multiparous women. She was careful to note the limitations in both studies. As always with observational data, causation remains poorly understood and counterfactual arguments should be considered.

Questions and Answers:

Q: How reliable is the self-reported BMI?

A: We did a validation study where we compared the report from mother and the report from the physician. It was actually quite good.

Q: Did you exclude the pregnant diabetic population from this data?

A: Women with diabetes are excluded.

Q: What happens when a woman doesn’t gain any weight?

A: If they see an obese woman with no gain, if she has normal pregnancy and is healthy, they tell her it is a normal thing but make sure she has a healthy diet.

Q: Timing of weight gain during pregnancy--any comments on when you gain the weight?

A: The way we collected this data, we cannot study the timing of weight gain.

PREGNANCY WEIGHT GAIN IN GESTATIONAL DIABETES MELLITUS - IMPLICATIONS FOR THE FETUS

Teresa Hillier, MD, MS (Kaiser Permanente Center for Health Research, Portland, OR)

Gestational diabetes (GDM) is defined as any degree of glucose intolerance with onset or first recognition during pregnancy. A previous study demonstrated correlation between birth outcomes and plasma glucose levels at two hours. Dr. Hillier discussed the risks of excessive gestational weight gain (the mother is more likely to be diet controlled, more likely to need insulin, and more likely to have a large for gestational age [LGA] baby) and too little weight gain (more likely to have a small for gestational age [SGA] baby), and noted the importance of optimizing control of both maternal glucose and maternal weight gain in patients with gestational diabetes. She noted that although glucose is an important independent risk factor, weight gain is also important. She echoed the sentiments of the other presenters in this symposium, and emphasized the importance of exercise and diet.

Questions and Answers:

Q: Some studies show that the use of metformin decreases the risk of macrosomia and weight gain in the mother. Did you use any therapies in these studies?

A: During the study time period, only insulin was used.

Q: Could you comment on your strategy for insulin therapy in GDM? Targets? Strategies?

A: I can’t give you the exact targets but it was strict control.

RE-EXAMINATION OF PREGNANCY WEIGHT GUIDELINES

Michael Lu, MD (UCLA School of Medicine, Los Angeles, CA)

Dr. Lu discussed the rationale, methods, and conclusions of the new guidelines for gestational weight gain (GWG), recently published in May 2009. He reviewed several studies demonstrating the relationship between weight gain before and after pregnancy with maternal and child health outcomes. Many of these studies had been discussed in the symposia before his speech. He also noted the shift from only focusing on the child’s health, to focusing on both patients in a discussion of tradeoffs very similar to Dr. Nohr’s. Of particular interest was his discussion on GWG and gestational diabetes (GDM). He reported on eleven studies that varied significantly in findings and conclusions. He explained these inconsistencies by noting the confounding factor: the measurement of total gestational weight gain instead of weight gain up until diagnosis of GDM. This measurement leads to inaccurate conclusions because usually upon diagnosis, treatments are offered to patients. He ended by noting that the new guidelines are virtually the same as those from 1990. The most notable difference is the new pregnancy weight recommendations for obese women (5 to 9 kg [11 to 24.2 lbs]). He was careful to note that while gains less than five kilograms (11 lbs) may be beneficial; there was not enough data to support this advice.

Oral Presentations: Obesity and Obesity Treatments

ONE-YEAR TREATMENT WITH VI-0521 IN TYPE 2 DIABETES DEMONSTRATES CONTINUED GLYCEMIC IMPROVEMENT AND WEIGHT LOSS

F. Timothy Garvey, MD (University of Alabama, Birmingham, AL)

Dr. Garvey reviewed the one-year results of a study investigating the effects of Vivus’s Qnexa (a combination of phentermine and topiramate) on glycemic levels in type 2 diabetes patients. The study showed that the combination was effective in decreasing A1c and CV risk factors, as well as promoting weight loss. After one year, there was an A1c decrease of 1.6% in the treated group, compared to a 1.1% decrease with placebo (p=0.038). We were very impressed with trial design in this study. For example, interestingly, people with stable depression were included in the study, a rarity in obesity drug trials. Dr. Garvey emphasized the real-world characteristics of the population: subjects represented a wide range of duration and severity of diabetes, more than 75% had three or more metabolic/CV risk factors, and the study included a large minority population. Both placebo and treatment groups were managed to standard-of-care guidelines with diabetic medication. There was a concurrent increase in the use of diabetic medication in the placebo group and a decrease in medication use in the treated group (the A1c difference would likely have been greater but for more “rescues” in the placebo group). Qnexa is currently being evaluated for the treatment of obesity, and results like these make it more likely that Vivus will pursue a diabetes indication in the future. We were particularly impressed with the low side effects. Could Qnexa become a “Januvia for obesity”? Assuming safety data continues to mount, this is an exciting therapy for patients to consider. We look forward to seeing how it works in combination therapy with other diabetes agents.

  • VI-0521 is a single-dose combination of 15 mg phentermine and 92 mg topiramate (also known as Qnexa) for the treatment of type 2 diabetes. The primary endpoint was glycemic control after 56 weeks. 130 patients with an average BMI of 35 kg/m2, a baseline A1c of 8.5% to 8.7%, and who were drug naïve or on oral therapy were randomized to 52 weeks of treatment with Qnexa or placebo on top of standard-of-care treatment. We were very impressed with trial design in this study. For example, interestingly, people with stable depression were included in the study, a rarity in obesity drug trials. Dr. Garvey emphasized the real-world characteristics of the population: subjects represented a wide range of duration and severity of diabetes, more than 75% had three or more metabolic/CV risk factors, and the study included a large minority population. Both placebo and treatment groups were managed to standard-of-care guidelines with diabetic medication.
  • After one year, there was an A1c decrease of 1.6% in the treated group, compared to a 1.1% decrease with placebo (p=0.038). There was a concurrent increase in the use of diabetic medication in the placebo group and a decrease in medication use in the treated group. The percent of patients achieving an A1c less than 7% was 53% with Qnexa treatment and 40% with placebo. The effect was more pronounced in patients with higher baseline A1cs. Weight loss was 9.4% of body weight in the treatment group and 2.7% in theplacebo group. The number of patients achieving greater than 5% weight loss was 65% in the treatment group and 24% in the placebo group, and the percent achieving greater than 10% loss was 37% and 9% respectively. Fasting glucose decreased by 43.5 mg/dl (2.4 mmol/dl) in the treatment group, compared to 25.5 mg/dl (1.4 mmol/l) in placebo. There were significant improvements in waist circumference, systolic BP, and fasting glucose, decreasing the number of subjects with three or more CV risk factors over the course of the study in the treatment group compared to the controlled group. The most common adverse events were paresthesia (10% in the treatment group and 0% in the controlled group) and nausea (6% in the treatment and 0% in the controls). There were three serious adverse events, none of which were drug-related, and no severe hypoglycemia. Four times as many control subjects required rescue. The study completion rate was an impressive >90%.
  • The results of this study suggest that Qnexa might become a powerful option in the treatment of type 2 diabetes. While the compound is currently completing phase 3 trials for the treatment of obesity, results like these suggest to us that Vivus will likely pursue a diabetes indication in the future.

Questions and Answers:

Q: How did you choose various doses of this compound?

A: This completes the phase 2 development of this indication, and this seemed to be the dose with the best efficacy for the side effects.

Q: Can you tell us more about the serious AEs and baseline medication use?

A: Lumbar disc, costochondritis, and I forget the third—clearly not related to the drug. Most of these patients were on metformin, sulfonylurea, or combinations, and they were well matched.

Q: Were there any self-reporting questionnaires? Did you see whether glycemic effects were more than expected from weight loss?

A: Yes, the combination measure of QOL was improved compared to placebo. There were also psychological profiles administered, and there was no negative effect of the drug. We didn’t study whether the effects were due to weight loss, and I can’t say whether it was in proportion or out of proportion to the weight loss.

WEIGHT LOSS WITH VI-0521 (PHENTERMINE/CONTROLLED RELEASE TOPIRAMATE) STOPS PROGRESSION TOWARD TYPE 2 DIABETES IN OBESE NON-DIABETIC SUBJECTS

Louis J. Aronne, MD (Weill-Cornell Medical College, NY)

Dr. Aronne presented the results of a six-month phase 3 study of VI-0521 (combination phentermine/controlled release topiramate, Qnexa, Vivus) in people with diabetes. Patients achieved significant reductions in weight (9.2% and 8.5% of each arm), and although changes in A1c were small, this combination could ultimately be seen as a very compelling one. Over 60% of patients treated with VI-0521 achieved 5% weight loss, compared to 15% for the placebo. Dr. Aronne suggested that the differences between the groups with regard to A1c would have increased if the study had been extended. We believe that Vivus is pursuing a valid strategy of combination therapy for the treatment of obesity and prevention of diabetes; although some question the side effects of topiramate used in VI-0521, we are comforted at the low dose used (about 10% of the highest dose used in the Topamax phase 3 obesity trial).

  • Weight loss has the potential to prevent the progression of insulin resistance and type 2 diabetes. Dr. Aronne discussed the results of a six-month study of VI-0521 (phentermine/controlled release topiramate), examining its effects on weight, A1c, and other parameters.
  • In the study, patients achieved 9.2% and 8.5% weight loss for the high and low dose of VI-0521, compared to approximately 1.7% weight loss for placebo. Notably, over 60% of patients treated with VI-0521 achieved 5% weight loss, compared to 15% for the placebo. There was a slight increase in A1c in the placebo group, compared to a very slight reduction in the VI-0521 groups. However, Dr. Aronne suggested that the differences between the groups with regard to A1c would have increased if the study had been extended. Longer studies will be required to fully characterize the potential benefits of the weight loss with VI-0521 on diabetes and other comorbidities of obesity.
  • Safety data and tolerability was very good overall in the study. There were no serious adverse events in the trial. Despite enrolling a large number of patients with a history of depression, there was no depression signal in the study.

NALTREXONE+BUPROPION COMBINATION CAUSES SIGNIFICANT WEIGHT LOSS: A 56-WEEK PHASE 3 STUDY

Thomas Wadden, PhD (University of Pennsylvania, Philadelphia, PA)

Dr. Wadden spoke about an 800-patient, 56-week phase 3 trial of Contrave (naltrexone and bupropion, Orexigen) for obesity. While the weight loss seen with monotherapy of either bupropion or naltrexone is negligible, the combination provides a powerful effect on hypothalamic neurons, leading to an anorectic effect. Results: 66% of Contrave patients achieved >5% weight loss compared to 42.5% of patients on placebo. We note that the FDA’s guidance on obesity drugs suggests two primary endpoints: a greater mean weight loss of 5% in the drug vs. control group or twice as many people in the drug group must achieve >5% weight loss compared to the control group; these results do not quite reach the latter.

  • In combination, naltrexone and bupropion may work in concert to produce a powerful anorectic effect. Bupropion activates POMC neurons in the hypothalamus while naltrexone blocks the auto-inhibition of POMC neurons. Through a negative feedback loop, naltrexone can serve to amplify the effects of bupropion.
  • This large randomized phase three trial was carried out over 56 weeks. Over 800 patients participated at nine trial sites. Ninety percent of the participants were female and average age was forty-six years old. Participants had to have a BMI 30-45, or a BMI above 27 with controlled hypertension and/or dyslipidemia. Patients were titrated on the naltrexone/bupropion combination therapy over a period of four weeks until a dose of 32 mg naltrexone and 360 mg bupropion was reached.
  • Study completion rate was 58% overall. Twenty-six percent of drop-out was due to adverse events, usually nausea. The data discussed below are the modified intent-to-treat analysis. Other complaints included constipation, dizziness, dry mouth, and tremor. According to Dr. Wadden, the side effects usually resolved by the end of the four-week titration period. There was no change in depression and suicidality in the experimental group. There were two cases of cholecystitis in patients with weight loss >15%.
  • Patients treated with the combination drug therapy showed more weight loss than the placebo group. Sixty-six percent of patients on the drug therapy achieved a body weightloss of >5%, compared to 42.5 percent of patients on the placebo. There were also improvements in other areas: waist circumference decreased and HDL levels increased. Patients reported improvements in quality of life, physical functioning, self-esteem, and control of eating.
  • Dr. Wadden suggests that the combination therapy of naltrexone with bupropion will be an effective tool in fighting obesity and promoting weight loss. We agree that the results are intriguing, but there is also a high “placebo” effect, which may also be tapping into the benefits of the behavior modification. We hope that it is clear to patients that intense behavior modification may be necessary to see impressive changes in body weight.

John McElroy, PhD (Jenrin Discovery, Philadelphia, PA)

Dr. McElroy presented preclinical data on Jenrin Discovery’s JD-5006, a peripherally active CB1 receptor antagonist that does not cross the blood brain barrier (BBB) in rodents. JD-5006 does not seem to cause the central nervous system (CNS) toxicities that were observed when rimonabant was over- dosed in rodents. In diet-induced obese mice, 21 days of treatment with JD-5006 had about half as much efficacy as rimonabant in reducing weight but produced comparable improvements in liver function, lipid levels, and insulin sensitivity. We found these data quite intriguing and look forward to seeing human data.

  • The original CB1 receptor antagonists were designed to target CB-1 receptors in the brain, with weight loss secondary to appetite suppression. They also improved lipid levels, glycemic control, fat metabolism, and fatty liver disease. Unfortunately, they were associated with psychiatric side effects, which is why all the research programs were discontinued at the end of 2008.
  • Evidence suggests that inhibition of CB1 receptors in peripheral tissues also has beneficial effects. The glycemic and lipid effects of CB1 receptor antagonists in humans cannot be fully explained by the effects on weight loss. The weight loss in rodents persists even after appetite has returned to normal. Direct injection of rimonabant into the rodent brain does not produce the same effect as oral rimonabant.
  • Jenrin’s lead compound JD-5006 is an orally active CB1 receptor antagonist that does not cross the blood brain barrier (BBB). In rodents, JD-5006 achieves therapeutic levels in the periphery without any CNS effects. A 21-day study dosing JD-5006 in diet-induced obese (DIO) mice produced therapeutic levels in the plasma and sub-therapeutic levels in the brain. Dr. McElroy pointed out that overdosing of rimonabant in animals causes CNS effects like alopecia (hair loss due to excessive scratching), combative behavior, and hypersensitivity. These CNS effects were not seen at any tested dose of JD-5006.
  • JD-5006 has less weight loss efficacy than brain-penetrant CB1 receptor antagonists but possibly comparable metabolic effects. In the 21-day study, it produced 50% less weight loss than the brain-penetrant CB1 receptor antagonists. However, it had as much efficacy in reducing liver weight, triglyceride levels, and ALT concentrations (a measure of fatty liver disease). It produced comparable efficacy to rimonabant in decreasing plasma glucose levels during an oral glucose tolerance test. A seven-day study in DIO mice found 20% weight loss with rimonabant vs. only 5% weight loss with JD-5006, but comparable effects on glucose levels.

Questions and Answers:

Q: With rimonabant you get a very acute decrease in food intake that then tapers off. Did you measure food intake with your compound?

A: Food suppression is about half of that of rimonabant, paralleling the weight loss.

Q: Are both liver and fat targeted?

A: Drug concentrations were measured in liver, muscle, fat, blood, and brain, and we believe that the main effect is in the liver.

Q: To me, food intake is a major indicator of CNS effect. This means there is a CNS effect.

A: Not necessarily. There can be peripheral drug targets that can subsequently reduce food intake. Drugs that slow gastric motility reduce food intake, for example. There are CB1 receptors in the GI tract. The drug doesn’t reach the IC50 in the brain so there cannot be an effect on the brain.

Q: You could try to knock out the CB1 receptor in different organ systems to test this. They would have to be tissue-specific knockouts.

A: We will be doing that with a partner.

Q: Do you have any active metabolites?

A: We have not studied this yet. We’ll be doing in vivo receptor occupancy studies in the brain later this month.

INSULIN SECRETION MEDIATED BY GLP-1 ACTION IS ENHANCED FOLLOWING ROUX- EN-Y GASTRIC BYPASS SURGERY

Marzieh Salehi, MD (University of Cincinnati, Cincinnati, OH)

Dr. Salehi presented a small study showing gastric bypass enhances the incretin effect through increased GLP-1 secretion. Dr. Salehi explained that roux-en-Y gastric bypass surgery (GB) improves diabetes independent of weight loss. As has been widely discussed, the mechanism by which this occurs is not well understood. What is known, however, is that the action of rerouting the gut increases GLP-1 secretion. An important finding in this study was that the enhanced GLP-1 action does not disproportionately increase insulin levels in gastric bypass patients with hypoglycemia. That said, there is a proportion of patients that suffer from hyperinsulinemic hypoglycemia following gastric bypass surgery.

  • Dr. Salehi presented a study with the hypothesis that accentuated GLP-1 action in gastric bypass contributes to enhanced insulin secretion in general and to a greater extent in patients with hypoglycemia. The study examined 10 asymptomatic patients after gastric bypass, 11 patients with gastric bypass and documented hypoglycemia, and eight non- surgical controls with normal glucose tolerance. Some patients were given the GLP-1 receptor antagonist, exendin 9-39 and insulin secretion was measured in all patients who were given a liquid mixed meal.
  • Following surgery, asymptomatic and symptomatic hypoglycemia patients, the incretin effect was 86±1% and 85±2%, respectively. The incretin effect in the control group was 76%. Endogenous GLP-1 accounted for 49% and 54% (respectively) of incretin- stimulated insulin release compared to the control (26%).
  • Overall, they concluded that gastric bypass enhances the incretin effect through increased GLP-1 secretion. An important finding was that the enhanced GLP-1 action doesnot disproportionately increase insulin levels in gastric bypass patients with hypoglycemia. Endogenous GLP-1 has no influence on the emptying of a liquid meal from the stomach in either control subjects or those with gastric bypass. Drugs that mimic this effect may have significant therapeutic benefit.

PERILIPIN GENE VARIANTS IDENTIFY INDIVIDUALS WHO ARE RESPONSIVE TO THE CARBOHYDRATE COMPOSITION OF LOW CALORIE DIETS FOR BODY-WEIGHT AND FAT LOSS

Nazneen Aziz, PhD (Interleukin Genetics, Waltham, MA)

Dr. Aziz gave a very interesting basic science oriented talk on the importance of genetics in predicting a patient’s responsiveness to obesity therapies. She cited the fact that most obesity studies report only mean group weight changes as a limitation to the efficacy of these therapies in a clinical setting because there is a great deal of variability in how individuals respond to intervention. She focused on a study looking at the genetic variability of four different single nucleotide polymorphisms (SNPs) within the perilipin gene, thought to be a gatekeeper of fat storage and mobilization. PLIN1/C and PLIN4/A carriers were more resistant to body weight fat loss under calorie restriction. There appear to be genetic interactions with the glycemic load of the diet as well. We agree with Dr. Aziz that this data is interesting because it implies that personalized weight loss programs (or drug therapies) could help individuals with particular genetic profiles to maintain healthy body weight. This study was small and we’d like to see more work like this.

SHORT-TERM EFFECTS OF GASTRIC BYPASS SURGERY VS CALORIC RESTRICTION ON GLUCOSE DISPOSAL AND GASTROINTESTINAL (GI) HORMONE SECRETION IN MORBIDLY OBESE PATIENTS

Guilherme M. Campos, MD (University of California at San Francisco, San Francisco, CA)

While only 37% of patients with diabetes are achieving adequate glycemic control, 80% of patients who undergo roux-en-Y gastric bypass surgery (RYGB) have a complete resolution of type 2 diabetes. It is well known that this change in metabolism occurs via mechanisms independent of weight loss. This study enrolled 22 non-diabetic morbidly obese subjects, assigning 12 to RYGB with calorie restriction and the rest to calorie restriction alone, to differentiate between the short-term effects of calorie restriction and surgery. After 15 days, metabolic parameters were compared. As expected, body weight and fat loss were not different after 15 days. There were no differences in peripheral glucose uptake, fasting insulin, or fasting glucose. There were increases in GLP-1 and insulin secretion in the RYGB group and increases in GIP in the calorie restriction group. After six months, there was significant improvement in peripheral glucose uptake that differed significantly according to the magnitude of weight loss.

PROGRESSION OF OBESITY IN ADULT PATIENTS WITH TYPE 1 DIABETES AND ITS IMPACT ON CLINICAL OUTCOMES

Samuel L. Ellis, Pharm.D., BCPS, CDE (University of Colorado Denver Health Sciences Center, Denver, CO)

There are only limited data on obesity trends in patients with type 1 diabetes. Ellis discussed a retrospective 1,100-patient study performed by a Colorado community care clinic that found that the prevalence of obesity in type 1 diabetes patients aged 23 to 29 years increased from 10.4% to 15.7% in a five-year period. Interestingly, the overweight and obese patients had lower A1c levels than individuals in the normal BMI category, suggesting (perversely) that weight gain is linked to better glucose control. The overweight and obese patients had higher blood pressure levels, higher LDL cholesterol, and lower HDL cholesterol compared to the healthy weight group. We agree with Ellis’s suggestion that the results of this study should serve as an impetus to devote future research to understanding the impact of obesity on complications and disease progression in T1D patients.

  • This retrospective longitudinal study represents data from over 1,000 patients taken over five years. Patients were classified into three weight categories: healthy weight (<25 BMI), overweight (25<BMI<30), and obese (>30 BMI). The average age of patients ranged from 23 to 29 years old through the five years of the study with baseline A1c’s average 8.5% and equal male/female participation. Average BMI at baseline was 24.3.
  • The prevalence of overweight and obese patience increased over the five-year period of the study. The prevalence of obesity increased to 15.7% during the duration of the study from a baseline of 10.4%. The overweight population reached 34.9%, up from 26.7% at baseline. This represents an absolute increase of 5.3% in obesity prevalence in the T1D patient population studied, which is higher than the NHANES average of 3.9% and higher than the state’s BRFSS 3.4% average.
  • There were clear differences in blood pressure, cholesterol levels and A1c levels across the different BMI categories. Both the overweight and obese patients groups had higher average blood pressure readings than the healthy weight group. The obese and overweight patients also had elevated LDL cholesterol levels and lower HDL cholesterol levels. The overweight and obese patients had lower A1c levels than the healthy weight patients. This is an interesting finding because, as Ellis suggested, it may indicate that weight gain is a consequence of tighter control. There were no differences between groups in insulin dosage on a unit/kg per day comparison.

INHIBITION OF ACYL COA SYNTHETASE DECREASES FAT STORAGE IN HUMAN ADIPOCYTES AND BODY WEIGHT AND FAT MASS IN DIO MICE

Barbara Corkey, PhD (OSI Pharmaceuticals, Melville, NY)

Dr. Corkey described the discovery of PSN-AGX1, a commercially available Acyl CoA Synthetase (ACS) inhibitor, using a high-throughput human adipocyte assay, and described its therapeutic potential for decreasing triglyceride (TG) stores. Twelve thousand commercially available small molecules were screened for their function in decreasing TG levels. PSN-AGX1 proved to be the most efficacious compound, decreasing body fat by 21% and TG by 23% through the reduction of activity of the ACS1 and ACS5 proteins. Dr. Corkey concluded that ACS inhibitors show promise as therapeutic targets for patients with type 2 diabetes.

  • PSN-AGX1 is a target for decreasing triglyceride (TG) levels. Dr. Corkey employed a function-based screen approach to screen a library of 12,000 commercially available small molecules for their function in decreasing TG levels. Compounds were tested for function, toxicity, cellular activity, and potency. PSN-AGX1 was determined to be the best candidate based on these criteria. PSN-AGX1 was shown to lower body fat by 21%, TG levels by 23%, and the HOMA index by 32%.
  • PSN-AGX1 functions by decreasing long chain acyl CoA synthetase. Labeled fatty acid incorporation studies indicated that PSN-AGX1 likely functioned by mediating fatty acid synthesis. Enzyme activity measurements, western blots, and RNA expression data confirmed this function, illustrating that PSN-AGX1 functions by decreasing levels of ACS1 and ACS5, two proteins involved in long chain acyl CoA synthetase. In summary the data indicate that the selective targeting of ACS proteins may have novel therapeutic implications for patients with type 2 diabetes.

PLASMA GLUCOSE AND INSULIN REGULATION IS ABNORMAL FOLLOWING GASTRIC BYPASS SURGERY WITH OR WITHOUT NEUROGLYCOPENIA

Sun H. Kim (Stanford University, Palo Alto, CA)

Post-prandial hypoglycemia is a known complication of gastric bypass surgery, but the characteristics that determine who will develop this are unknown. To better characterize those at risk, the authors enrolled 18 patients who had had roux-en-Y gastric bypass surgery, nine who were asymptomatic and nine who had had documented glucose <50 mg/dl (<2.8 mmol) and neuroglycopenia as defined by altered mental status, loss of consciousness, or seizure. These patients were compared with 90 non- surgical controls. In oral glucose tolerance tests, symptomatic surgical patients were found to have an earlier glucose peak and a higher glucose at 30 minutes. The symptomatic and asymptomatic bariatric surgery groups, however, were similar, with peak insulin concentrations much higher than controls. Changes in glucose metabolism are common to all RYGB patients, and why some groups become symptomatic remains to be clarified.

  • Hypoglycemia after roux-en-Y gastric bypass surgery is common, with one-third of patients having a glucose <50 mg/dl (<2.8 mmol) after a 75-gram glucose challenge. Of the symptomatic surgical patients, 33% had a nadir <50 mg/dl; 33% of asymptomatic patients also had a nadir <50 mg/dl. This was significantly different than the controls, of whom only 10% had a nadir <50 mg/dl.
  • The degree of hyperinsulinemia correlates with the degree of hypoglycemia in RYGB patients. The insulin secretory response appears to be out of proportion to insulin resistance in both symptomatic and asymptomatic RGYB patients. Both groups had an insulin peak double that of controls.
  • In surgical patients who have symptomatic hypoglycemia, response to a 75-gram oral glucose tolerance test suggested an earlier glucose peak and higher glucose levels at 30 minutes. This minor difference was the only difference identified between the two groups of RYGB patients. Other issues to be further elucidated include whether there may be differences in counterregulation and how responses to a mixed meal test may differ between groups.

ATLANTIC DIP: THE IMPACT OF OBESITY ON PREGNANCY OUTCOME IN GLUCOSE TOLERANT WOMEN

Lisa A. Owens, MD (University of Ireland, Galway, Ireland)

Dr. Owens set out to determine if obesity is the direct cause of adverse events, or if something else such as diabetes was to blame. This large study included pregnant women who did not have GDM or impaired glucose tolerance according to the WHO criteria. Pregnancy outcomes were assessed by baseline BMI category, and the highest category had the most negative outcomes. Dr. Owens made the case that obese women are at risk for negative pregnancy outcomes, which should be better identified, assessed, and counseled in the future.

  • Obesity has been implicated in negative pregnancy outcomes. This study aimed to further determine the direct effects of obesity on pregnancy outcomes by excluding patients with gestational diabetes or impaired glucose tolerance according to the WHO criteria.
  • The subjects included 1,441 women from Ireland, 95% Caucasian with a mean age of 31 years old. Thirty percent had previous miscarriages. The mean body mass index (BMI) was26.5 kg/m2, but results were stratified by BMI category for analysis. Fifty-five percent of women had BMI>25 kg/m2.
  • Negative pregnancy outcomes were correlated with an increase of BMI. Statistical results for all parameters except congenital malformations showed a significant difference between the normal weight (BMI <25 kg/m2) and obese patients (>30 kg/m2).

BMI

category (kg/m2)

Percent

of women in study in this BMI

range

Emergency

cesarean sections

Pregnancy

induced hypertension

All

hypertension

Macrosomia

Congenital

malformations

<25

45%

10%

4%

5%

17%

1.3%

25-29

35%

14%

9%

10%

22%

1.4%

30-39

19%

18%

9%

11%

27%

2.5%

>40

1%

19%

       
  • Dr. Owens concluded by claiming that obese women are at risk for negative pregnancy outcomes, which should be better identified, assessed, and counseled in the future.

CHANGE IN FASTING TRIGLYCERIDES FROM EARLY TO LATE GESTATION IS HIGHLY PREDICTIVE OF NEONATAL ADIPOSITY

Linda A. Barbour, MD (University of Colorado, Denver, CO)

Dr. Barbour collected data from 10 pregnant women to determine which parameters are predictors of infants with high neonatal fat. Changes in maternal triglyceride concentrations were the key. Four out of ten babies were born with >16% body fat as measured by DXA scan, with two coming from lean mothers and two from obese mothers. It was the change from fasting triglyceride concentrations to early pregnancy (14-16 weeks) to late pregnancy (26-28 weeks) that predicted the high neonatal fat percentage. Postprandial triglycerides were not elevated in the subjects, and overall fasting triglyceride concentrations– while higher in obese women than lean women – were not predictive.

  • This prospective study includes analysis of pregnancies of women, either lean or obese, who did not have gestational diabetes at the start of the study. Maternal measurements were taken early in pregnancy and late in pregnancy. The baby’s fat percentage was measured after birth. Measurements of fasting and postprandial triglycerides, glucose, and insulin were measured to assess which factors affect neonatal adiposity.
  • The ten women in the study were split into lean or obese groups for analysis, but neonatal adiposity was not correlated with maternal weight. The lean group had a body mass index (BMI) of 23 kg/m2 and 33 kg/m2 for the obese group.
  • Four babies were born with excess body fat, greater than 16% as measured by DXA scan. Two were born to obese mothers, and two to lean mothers.
  • Change in fasting triglycerides from early pregnancy (14-16 week) to late pregnancy (26-28 weeks) was the strongest common factor in the mothers of the 4 babies with higher adiposity. The change for these mothers was in the range of a 90% increase. The lean group had triglyceride values in the range of 100 mg/dl (5.6 mmol/l) early in pregnancy, and the obese group in the range of 150 mg/dl (8.3 mmol/l). Both groups increased late in pregnancy by about 50 mg/dl (2.8 mmol/l). Postprandial triglyceride concentrations did not differ with stage of pregnancy.
  • While there were other differences between the lean and obese groups, these differences were not predictive. More insulin was present later in pregnancy to suppress fatty acids. Glucose profiles were measured for 72 hours with fixed meals, and were not correlated with neonatal obesity. Some people developed gestational diabetes during the study, but none had it at study entry.
  • Ultrasound measurements of thigh fat and liver length were predictive of neonatal adiposity.
  • Study constraints such as the small sample size may be addressed as the study continues. Dr. Barbour spoke about increasing the sample size by analyzing more subjects and following the infants to the age of one year.

DISRUPTION OF THE CIRCADIAN CLOCK IS ASSOCIATED WITH OBESITY AND THE METABOLIC SYNDROME: RESULTS FROM MURINE AND HUMAN STUDIES

Eleanor Scott, MD (University of Leeds, Leeds, UK)

Dr. Scott discussed the role of the circadian clock in the development of obesity. The study looked at the polymorphisms of the clock gene in humans and evaluated their relationship t0 metabolic syndrome. Possession of the T allele of the promoter of the clock gene and the TGT haplotype was associated with metabolic syndrome as defined by IDF criteria. On the other hand, possession of the C allele and the CGC haplotype seems to be protective against metabolic syndrome. The data also suggest that there are associations between the clock polymorphisms and dyslipidemia in humans. We look forward to more study from this field as anything we can learn about the genetics of the disease could ultimately play a role in the development of personally tailored therapeutic interventions.

NEURON SPECIFIC DELETION OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR DELTA LEADS TO INCREASED SUSCEPTIBILITY TO DIET-INDUCED OBESITY

Heidi E. Kocalis (Vanderbilt University, Nashville, TN)

PPAR delta is a nuclear receptor that promotes cellular lipid oxidation, decreasing the lipid accumulation that is associated with insulin resistance. It is the most abundant isoform in the CNS, where energy homeostasis is regulated. Its deletion in rodent neurons leads to increased fat mass as well as insulin and leptin resistance. Given its multiple beneficial effects, she concluded that PPAR delta may be a promising CNS target in addition to the more peripheral PPAR gamma (TZDs) and alpha (fibrates).

  • PPAR delta activation promotes lipid oxidation. Lipid accumulation is associated with inflammatory signaling, which leads to CNS insulin and leptin resistance. By regulating fatty acid metabolism, PPAR delta is positioned to regulate neuronal insulin and leptin sensitivity.
  • Neuronal PPAR delta deletion leads to dramatic changes in body composition. Animals with PPAR delta deleted have increased fat mass even on a low-fat diet, and this phenotype is accentuated on a high-fat diet. These knockout animals gained fat mass at two times the rate of the controls. In fact, neuronal PPAR deletion increases the susceptibility to diet- induced obesity.
  • Neuronal PPAR deletion leads to leptin resistance. As a key hormone signal in energy homeostasis, leptin resistance leads to obesity. Thus, it appears that neuronal PPAR delta is critical in lipid oxidation, insulin sensitivity, and leptin sensitivity.

TOLL-LIKE RECEPTOR 4 CONTROLS THE MATURATION AND THE DEVELOPMENT OF INFLAMMATORY ACTIVITIES OF ADIPOCYTES IN THE NOD MOUSE

Elke Guelden, MD (Institute for Clinical Diabetology, Duesseldorf, Germany)

With so many interesting talks on other tracks, the number of attendees in the morning session of the Immunology/Transplantation track was sparse. In one of the first talks of the morning, Dr. Guelden argued that in addition to increased risks for type 2 diabetes, adiposity may promote the development of type 1 diabetes as well. His talk focused on the inflammatory activities of mature adipocytes in Toll-like receptor 4 (TLR4) knockout mice.

  • Toll-like receptor 4 (TLR4) has a significant role in adipocyte (fat cell) maturation.
  • Toll-like receptor 4 is an important regulator of inflammatory activity and is also expressed in adipocytes. In mouse models, Dr. Guelden found that non-obese diabetic mice with TLR4 defects exhibited an accelerated diabetes development (p<0.01) with increased body weight (p<0.0001). Visceral adipose tissues of mutant mice also had smaller adipocyte size (668 ±4.3 um2) compared to wild type mice (963 ±4.13 um2).
  • Chronic activation of TLR4 is also involved in the progression of diabetes in non- obese diabetic mice. Chronic activation of TLR4 resulted in an immune response, releasing IL- 6, (a cytokine linked with inflammation), and increased MCP-1. Dr. Guelden concluded that the maturation and development of inflammatory activity in adipocytes plays an important role in the development of type 1 diabetes.

INFLAMMATORY MARKERS ARE INCREASED IN YOUTH WITH TYPE 1 DIABETES: THE SEARCH CASE-CONTROL (SEARCH CC) STUDY

Janet K. Snell-Bergeon, MPH (University of Colorado, Aurora, CO)

In this lecture, Janet K. Snell-Bergeon presented an analysis looking at a representative subset of the SEARCH for Diabetes in Youth study. This study demonstrated three relationships in youths with type 1 diabetes: 1) a relationship between type 1 diabetes and elevated levels of inflammatory markers, 2) hypoglycemia and both increased inflammation and suppressed leptin, and 3) obesity and increased inflammatory markers and suppressed leptin. We found this lecture particularly interesting because of the focus on youths.

  • Janet K. Snell-Bergeon presented a case control study of the SEARCH trial designed to determine whether youth with T1D had higher levels of inflammatory markers, and if high levels of inflammatory markers correlated with worse glycemic control. SEARCH CC participants with type 1 diabetes (mean age = 15 years, range = 8-23 years) and without diabetes (mean age = 15, range = 10-23) were measured for inflammatory markers interleukin-6 (IL-6), C-reactive protein (hsCRP), fibrinogen, and leptin. Multiple linear regressions were used to investigate differences in inflammatory markers and levels of HbA1c independent of age, sex, race, tanner stage, and BMI.
  • Youth with T1D demonstrated generally higher levels of inflammatory markers. At all levels of glycemia, levels of IL-6 and fibrinogen were significantly elevated in patients with T1D. A similar trend was demonstrated for hsCRP, but was only significant when hbA1c was greater than or equal to 9.3%. Given these data, Janet K. Snell-Bergeon suggested that type 1 diabetes is characterized by excess inflammation that is independent of adiposity, pubertal status, and duration.
  • They also found a correlation between hyperglycemia and inflammation, as well as suppressed leptin. Worsening glycemic control led to significantly higher levels of fibrinogen, a significant trend of increased hsCRP across levels of hypoglycemia, and significantly lower levels of leptin. These data suggest that poor glycemic control is associated with elevated levels in markers of inflammation and suppression of leptin.
  • Analysis of obesity data demonstrated a similar trend. Levels of IL-6 and fibrinogen were significantly elevated across all levels of obesity while hsCRP was only significantly heightened in normal weight patients with diabetes compared with normal weight controls. A significant trend of increased hsCRP, fibrinogen and decreased leptin were also demonstrated across all levels of obesity.
  • Partial correlation between inflammation and lipids was found. There was an association between IL-6 and HDL-c in patients with type 1 diabetes. Furthermore, a significant correlation between CRP and Fibrinogen, and total LDL-c and apoB was found. In controls, fibrinogen levels were related with LDL-c and apoB.
  • We think further studies investigating hyperglycemia induced leptin suppression and obesity in patients without diabetes should be done, because such studies could provide support for tight glycemic control as a preventative measure for obesity.

Questions and Answers

Q: Did you look at a potential relationship between duration and inflammation?

A: We did examine duration. No correlation was found.

Poster Presentations: Obesity and Obesity Treatments

(1730-P) NALTREXONE+BUPROPION COMBINATION CAUSES SIGNIFICANT WEIGHT LOSS WITHOUT WORSENING PSYCHIATRIC SYMPTOMS

Klein S, Wadden T, Erickson J, Dunayevich E, Billes S, Kim D, Pi-Sunyer FX

The goal of this study was to explore the use of a naltrexone+bupropion (NB) combination as a weight- lost therapy with minimal psychiatric side effects. This was a 56-week, multi-center, double-blind, placebo-controlled study targeting overweight patients (baseline BMI: 36.5) without recent occurrences of serious illness (n = 793), with both experimental and placebo groups receiving behavioral therapy. The NB combination resulted in a significant decrease in body weight (9.29% compared with 5.08% in placebo; p < 0.001) without significant increases in depression, psychiatric adverse events, anxiety, or depressed mood, Overall, NB shows promise as a weight-loss drug for its significant weight loss, its disassociation with adverse events, and it decreased incidence of depression (p = 0.03).

  • This study examined the psychological and weight loss profile of the combination of naltrexone and bupropion (NB; Orexigen’s Contrave). The study randomized 793 patients to 32 mg naltrexone and 360