European Association for the Study of Diabetes

European Association for the Study of Diabetes – 48th Annual Meeting October 1-5, 2012; Berlin, Germany Day #4 Highlights – Draft

Executive Highlights

After a full day of attending collectively dozens of sessions and an evening of filling our bellies with Brätwurst and Spätzle, we settled in for the evening to bring you our Day #4 EASD highlights. Day #4 at EASD was also German Unity Day, a full bank holiday here in Berlin – the banks and restaurants were closed today in Berlin, but it was still very packed and active at EASD!

Indeed, day #4 was certainly chock-full of new data. A highlight of the afternoon was the new phase 2b data for Merck’s once-weekly DPP-4 inhibitor MK-3102, which was shown to provide significantly greater reductions in A1c (~0.7 drop), 2-hour post-meal glucose, and fasting plasma glucose compared to placebo. Based on these encouraging results, Merck is advancing the drug into phase 3 at the 25 mg dose (this was at the high end of the 0.25 mg to 25 mg tested). Also of note, Dr. Robert Henry presented new phase 2 data for Intarcia’s ITCA 650, a miniature osmotic pump system that delivers exenatide subcutaneously over an extended period of time. ITCA 650 provided better A1c reduction than the equivalent total daily dose of exenatide twice daily injection (1.0% vs. 0.7% from low baselines of 7.9% and 8.1%, respectively), with less nausea; higher doses of ITCA 650 conferred even greater A1c and weight benefits. Given Dr. Henry’s statements on the problems with adherence with earlier generations of GLP-1, we do think the improvement could be quite striking (he said 30-70% of those on GLP-1 have adherence issues).

On the insulin front, we saw two encouraging (though quite technical) oral presentations on safety of next-generation insulin analogs. In an analysis of pooled phase 3a degludec data, antibody response to the new insulin appeared benign and similar to that for glargine. A later talk in the same session demonstrated that Lilly’s PEGylated insulin lispro has significantly lower in vitro affinity for the mitogenic IGF-1 receptor compared to other insulin analogs; hopefully later-stage safety will be positive as well. Insulin delivery was also featured in this symposium with impressive results presented on InsuLine’s InsuPad. There were also results on Generex’s buccal spray that were not as striking.

On the device side, the major highlight from today was a poster detailing a 25-meter comparative accuracy study. Fourteen of the 25 meters failed to meet the proposed ISO standards (95% within ±15 mg/dl for <100 mg/dl and ±15% for >100 mg/dl); Roche, Bayer, and Abbott topped the accuracy ratings from this study. We’ll be interested to see what happens when (and if) these new standards come out, potentially in 2013 per Dr. Lutz Heinemann’s comments on Day #1 – recall that the FDA meeting on meter accuracy happened in March, 2010! See https://closeconcerns.box.com/s/de57ce534d6c39ccbce3 for a report on this meeting. There was also a CGM and pregnancy study that was negative – we think the newest technologies have to be used to assess efficacy of CGM.

We also attended an afternoon symposium on novel drug therapies. Dr. Richard DiMarchi (Indiana University, Bloomington, IN) reviewed the potential of glucagon/GLP-1 and GIP/GLP-1 hybrids, and Dr. Andre Scheen (University of Liege, Liege, Belgium) discussed the potential of 11B-HSD1 inhibition as a treatment for diabetes. Given the recent discontinuation of several 11B-HSD1 inhibitors, Dr. Scheen stated that we have to wait for more selective and more potent 11B-HSD1 inhibitors to be developed before they will have clinical utility.

The day’s learning also included a symposium on diabetes and cancer in the packed Langerhans Hall. Dr. Lucien Abenheim (London School of Hygiene & Tropical Medicine, London, United Kingdom) presented results from the International Study of Insulin and Cancer (ISICA), a case-control study that found no increased risk of breast cancer with insulin glargine treatment (and no increased risk with increased dose or duration of use). Dr. Helen Colhoun (Public Health University of Dundee, Dundee, Scotland) provided an independent review of the study, commenting that it was reassuring that there was no hint of any cumulative exposure effect, but the power to detect an effect was limited; she considered the study as useful in adding to the body of evidence, but limited in the amount of new knowledge added.

Table of Contents 

Detailed Discussion and Commentary

Oral Presentation: Novel Therapies

EFFECT OF MK-3102, A NOVEL ONCE-WEEKLY DPP-4 INHIBITOR, OVER 12 WEEKS IN PATIENTS WITH TYPE 2 DIABETES MELLITUS

Ira Gantz, MD (Merck Sharp & Dohme Corp, Whitehouse Station, NJ)

Dr. Ira Gantz revealed Merck’s phase 2b data for the once-weekly DPP-4 inhibitor MK-3102. As we understand it, this is not actually “Januvia” once weekly though we assume it is something similar to Januvia. The study randomized 685 patients with type 2 diabetes to placebo or MK-3102 0.25 mg, 1 mg, 3 mg, 10 mg, or 25 mg. Over 12 weeks, all five doses of MK-3102 provided significant reductions in A1c (greatest placebo-adjusted change of -0.71%), as well as significant improvements in 2-hour post-meal glucose (greatest placebo-adjusted change of -45 mg/dl) and fasting plasma glucose (placebo-adjusted change of -21.6 mg/dl; full data in table below). No meaningful change in body weight was observed with any dose of MK-3102 relative to baseline. Regarding safety, similar rates of adverse events and hypoglycemia were observed across all six treatment groups, and those taking MK-3102 exhibited no significant changes in heart rate or blood pressure. Based on these encouraging results, Merck recently announced that it is advancing MK-3102 (at the 25 mg dose) into phase 3. While a once-weekly oral is a novel idea, we point out that most patients would still likely take other orals at some point; that said, for newly diagnosed patients, a once-weekly, with its adherence advantages, could be a great option. From a payer perspective, however, most will have to try metformin first. It’s said that about 22 percent of type 2 patients do not respond to metformin; for them, this may be a terrific option. Many patients already take fixed dose combinations of DPP-4 inhibitors and metformin, so adding MK-3102 would actually be adding one pill and one co-pay. That said, there would likely be adherence advantages for many that have problems remembering to take the fixed dose combination.

  • MK-3102 is an orally administered, highly-selective (IC50 = 1.6 nM) DPP-4 inhibitor with a half-life long enough to support once-weekly dosing (t1/2 of ~63 hours for the 25 mg dose). Eliminated mainly through renal excretion, the drug will likely require no dose reduction in patients with mild or moderate renal insufficiency, though like most once-daily DPP- 4 inhibitors, MK-3102 will likely be given at a lower dose in patients with severe renal impairment (as a reminder, linagliptin [Lilly/BI’s Tradjenta] is the only DPP-4 inhibitor that does not require dose adjustment in this patient subpopulation). Dr. Gantz also emphasized that because MK-3102 neither inhibits nor induces cytochrome P450 enzymes, drug-drug interactions are not anticipated.
  • The double blind, phase 2b study randomized 685 patients with type 2 diabetes to placebo or one of five doses of MK-3102 (0.25 mg, 1 mg, 3 mg, 10mg, or 25 mg) for 12 weeks on a background of metformin. Participants taking oral anti-diabetic drugs (OAD) prior to the trial underwent an eight-week wash-out period while those not on an OAD immediately began the single-blind placebo run-in period before randomization. Baseline characteristics were similar across all six treatment groups, with a mean baseline age of 54-56 years, BMI of 29-30 kg/m2, A1c of 7.9-8.1%, and duration of type 2 diabetes of three to five years. The study completion rate was similarly high between the six groups, ranging from 87% to 98%.
  • All doses of MK-3102 provided statistically significant (p <0.001) reductions in A1c compared to placebo. At all doses above 0.25 mg, A1c continued to decline throughout the 12- week treatment period. Three-point post-meal glucose tests revealed that all doses of MK-3102 provided statistically significant improvements in 2-hour post-meal glucose. A similar trend was observed for change in fasting plasma glucose (data provided below). No meaningful change in body weight was observed with any dose of MK-3102 relative to baseline. Dr. Gantz highlighted that the glycemic efficacy demonstrated by MK-3102 in this study was comparable to those reported for the once-daily DPP-4 inhibitors.

Table 1: Mean change in A1c, 2-hour PMG, and FPG from baseline

 

Outcome at Week 12

 

 

MK-3102 Doses

 

 

Placebo

 

0.25 mg

 

1 mg

 

3 mg

 

10 mg

 

25 mg

 

Change in A1c (%)

 

0.14

 

-0.14

 

-0.36

 

-0.35

 

-0.53

 

-0.57

 

Placebo-adjusted change

 

---

---

 

-0.28

 

-0.50

 

-0.49

 

-0.67

 

-0.71

 

Change in 2-hour PMG (mg/dl)

 

7.2

 

-10.8

 

-25.2

 

-27.0

 

-34.2

 

-37.8

 

Placebo-adjusted change

 

---

---

 

-18

 

-34.2

 

-34.2

 

-41.4

 

-45.0

 

Change in FPG (mg/dl)

 

3.6

 

1.8

 

-16.2

 

-10.8

 

-9.0

 

-18.0

 

Placebo-adjusted change

 

---

---

 

-1.8

 

-19.8

 

-14.4

 

-12.6

 

-21.6

  • All six treatment groups posted similar rates of adverse events (31-44%) and drug- related adverse events (5-8%), and no dose-dependent increase in the incidence of adverse events was observed. Only one serious drug-related adverse event was reported, in the MK-3102 25 mg treatment group. All MK-3102 treatment groups experienced a low incidence of hypoglycemia (0-2%) similar to that observed with placebo, and no episodes of severe hypoglycemia were reported during the study. Furthermore, those taking MK-3102 exhibited no significant changes in heart rate or blood pressure.

Questions and Answers:

Q: What is the effect of renal impairment on the level of the drug in plasma?

A: A clinical pharmacology was done in patients with mild, moderate, or severe chronic renal failure and in patients on dialysis. And the effect is in patients with severe chronic renal insufficiency and dialysis. There’s a modest increase in the AUC. So our plan is that in that specific population, we’ll reduce the dose of MK-3102 that we’re going forward with by 50%. That’s not because there are any adverse events associated with the greater AUC. It’s that we want to provide the same amount of coverage in those patients as in those without renal failure.

Q: What is your estimate regarding how many prescriptions are for monotherapy vs. for combination with metformin, because metformin is normally given twice daily. There are combination products, including those with DPP-4 inhibitors. How does that translate into the adherence advantage in those patients taking the combination?

A: I can’t quote you a specific prescription number, but as you know, not everyone is tolerant of metformin and in some patients, metformin is contraindicated. And as far as adherence, even if you’re taking metformin, those fixed dose combinations aren’t always available. And it might be an attractive option for a patient taking metformin to take MK-3102.

OPTIMIZING PHASE 3 DOSE SELECTION WITH ITCA 650: CORRELATION BETWEEN BASELINE HBA1C AND REDUCTION OF HBA1C AFTER 24 WEEKS OF TREATMENT

Robert Henry, MD (University of California, San Diego, California)

Dr. Robert Henry presented new phase 2 data for Intarcia’s extended-release-exenatide device, ITCA 650. Dr. Henry opened by reasoning that presently, poor adherence to GLP-1 therapy is hindering patients’ ability to optimize glucose control. ITCA 650 is a miniature osmotic pump system that delivers exenatide subcutaneously, eliminating the need for self-injection. A phase 2 dose-ranging study found that ITCA 650 provided better A1c reduction than the equivalent total daily dose of exenatide twice daily over 12 weeks; higher doses of ITCA 650 conferred even greater A1c and weight benefits. Additionally, ITCA 650 produced a lower rate and shorter duration of nausea than the equivalent dose of exenatide twice daily. Based on the balance between each dose’s A1c reduction, weight loss, and tolerability, data supported the use of 20 g/day as the initial dose and increasing to a final dose of 60 g/day as the regimen for phase 3 trials (expected to begin in 1Q13). We hope that, if brought to market, ITCA 650 could help improve adherence to GLP-1 treatment to improve patient diabetes outcomes in the long run. 

  • Dr. Henry opened by reasoning that presently, poor adherence to GLP-1 therapy is hindering patients’ ability to optimize glucose control. All currently approved GLP-1 agonists (Novo Nordisk’s Victoza, BMS/AZ/Amylin’s Bydureon, BMS/AZ/Amylin’s Byetta), and all late-stage candidates for that matter, require self-injection on a regular basis. Dr. Henry stated that adherence to GLP-1 therapy for patients with type 2 diabetes ranges from 30-70%, and that this has relegated this promising class to a third- or fourth-line position for treatment. He believes that reducing the burden of injections will lead to earlier and broader use along with better patient outcomes. ITCA 650 is a miniature osmotic pump system that delivers exenatide subcutaneously, eliminating the barrier of self-injection. The device is about the size of a matchstick and would be implanted subcutaneously. In in vitro tests, it demonstrated the ability to release fluid at a constant rate for 12 months.
  • A phase 2 dose-ranging study found that ITCA 650 provided better A1c reduction, and similar weight loss, at 12 weeks than the equivalent total daily dose of exenatide twice daily; higher doses of ITCA 650 conferred even greater A1c reductions. The trial consisted of two stages. In the first stage, 155 patients on a background of metformin were randomized to exenatide twice daily (n=53; total of 20 μg/day), ITCA 650 20 μg/day (n=51), or ITCA 650 40 μg/day (n=51) (patients had average baseline A1c’s of 8.0%, 7.9%, and 8.0%, respectively in the three treatment arms). After 12 weeks, exenatide twice daily produced a 0.7% A1c reduction, and both ITCA 650 20 μg/day and 40 μg/day produced a 1.0% A1c reduction. ITCA 650 20 μg/day and exenatide twice-daily both produced ~1.2 kg (~2.6 lbs) weight loss at week 12. During stage two of the study, patients remained on the same dose of ITCA 650, or had the dose increased by 40 μg/day, and patients on exenatide were switched to ITCA 40 μg/day or 60 μg/day (overall, n=20 for 20 μg/day, n=42 for 40 μg/day, n=46 for 60 μg/day, and n=23 for 80 μg/day). Those on 20 or 40 μg/day achieved 0.9% and 1.0% A1c reductions, respectively, and those on 60 or 80 μg/day achieved 1.3% and 1.4% reductions, respectively. A1c lowering was durable out to week 48. Weight loss on the 20 μg/day dose was 0.8 kg (1.8 lbs) at week 24, and for all higher doses was greater than 3 kg (6.6 lbs).
  • Additionally, ITCA 650 produced a lower rate and shorter duration of nausea than an equivalent dose of exenatide twice daily. The incidence of nausea was consistently lower for ITCA 650 20 μg/day compared to 20 μg/day of exenatide twice daily (2% vs. 20% by week 12); the mean duration of nausea on ITCA 650 20 μg/day was 17 days, versus 47.7 days for exenatide injections. Another testament to ITCA 650’s favorable tolerability profile was the 93% completion rate for stage one and 95% completion rate for stage two of the trial; 89% of patients in the exenatide arm completed stage one of the study, which is also very high. In general, though this is great to see, we aren’t typically successful forecasting adherence or patient interest from trials since there is certainly an unrepresentative cohort of patients that are “early adopters” – too, some patients participate in trials because they are paid.
  • The 20 μg/day to 60 μg/day dose sequence was chosen as the best regimen to use in phase 3 trials given the extremely low nausea rates for the 20 μg/day dose and good initial efficacy. Since the 80 μg/day did not outperform the 60 μg/day dose and, as expected, exhibited worse tolerability, it was removed from consideration. The 20 μg/day dose was selected as the introductory dose given, its good initial efficacy and favorable tolerability. The 60 μg/day dose exhibited generally similar average A1c reduction to the 40 μg/day dose, but conferred  better A1c reductions for those with higher baseline A1cs, and allowed a larger percentage of patients to achieve targets of ≤7.0% or ≤6.5%. Therefore, the 60 μg/day dose was selected as the standard dose. Phase 3 trials investigating the use of ITCA 650 for six-to-12 months will start in 1Q13.
  • The company states that the intended product label will call for treatment initiation at 20 μg/day for three months. Patients’ A1c response and tolerability will then be assessed in order to determine whether to proceed with a six or 12-month ITCA 650 60 μg/day. Based on the phase 2 results, Intarcia expects patients to achieve at least 1% A1c reduction after three months. A six-month device will be used in phase 3 studies due to time constraints, and a 12- month device will be used in the cardiovascular outcomes trial in order to gain approval for this duration. If the year-long device is approved, then, patients would under go one up-titration (from 20 to 60 μg/day) and then yearly replacements.
  • In the US, procedures for implanting, removing, and replacing non-biodegradable drug delivery devices is already reimbursed, and ITCA 650 would fall under this category. The company estimates that (depending on reimbursement rates) initial placement of the first ITCA 540 may cost roughly $150, with each subsequent removal and replacement costing $250 after reimbursement.

Questions and Answers:

Q: Were antibodies measured during these studies?

A: Levels were about 30%. They produced no effect on glycemic reduction.

Q: Were they neutralizing antibodies?

A: They were not neutralizing.

Q: What was the incidence of pancreatitis?

A: There was no incidence of pancreatitis at all.

GLUCAGON-BASED INCRETIN HYBRIDS: SEARCH FOR TRANSFORMATIONAL MEDICINES

Richard DiMarchi, PhD (Indiana University, Bloomington, IN)

Dr. Richard DiMarchi discussed the potential of glucagon/GLP-1 and GIP/GLP-1 co-agonists to improve glycemic control, body weight, and other metabolic parameters, reviewing some of the animal studies conducted to date. He noted that glucagon/GLP-1 co-agonism could work synergistically to decrease fat mass, while GIP/GLP-1 co-agonism has the potential to have additive effects on insulin secretion. In preclinical studies, both have been documented to improve body weight, fat mass, blood glucose, insulin secretion, and blood lipid and liver fat content. In addition, GIP/GLP-1 could provide a potential basis for less nausea, emesis, and gastric stasis. Dr. DiMarchi noted that Merck is exploring glucagon/GLP-1 hybrids in clinical testing, while Roche is exploring GIP/GLP-1 hybrids in clinical testing – the latter, of course, is the compound that Roche purchased from Marcadia in 2011 for $300 million plus significant potential for additional milestone payments.

  • Dr. DiMarchi provided the rationale for developing a glucagon/GLP-1 co-agonist, explaining that action at the two receptors could work synergistically to decrease fat mass. Specifically, chronic glucagon action decreases fat mass by increasing energy expenditure via the glucagon receptor, while GLP-1 decreases fat mass by decreasing food intake via the GLP-1 receptor. In addition, a glucagon/GLP-1 co-agonist should minimize the diabetogenic risk of a pure glucagon analog.
  • Glucagon/GLP-1 co-agonists have demonstrated promise for weight loss in preclinical studies. Initially, Dr. DiMarchi and his colleagues developed two chimeras – one with a low potency for the glucagon receptor and a high potency for the GLP-1 receptor (Chimera 1; 10.5% and 299.3% potency relative to the respective native molecules), and one with close-to- normal potency for both the glucagon and GLP-1 receptors (Chimera 2; 99.1% and 165%, respectively) (Day et al. Nature Chem Bio 2009). In DIO mice, treatment with a glucagon/GLP-1 co-agonist conferred significant reductions in body weight beyond GLP-1 alone, as well as improvements in blood glucose, lipids, cholesterol, and triglycerides. Food intake was comparable to GLP-1 treatment, while energy expenditure was increased with glucagon/GLP-1 treatment. In a subsequent study in a rodent model, it was shown that increasing the relative tone of glucagon versus GLP-1 (to an extent, without impairing glycemic control significantly) could provide further weight loss than balanced glucagon/GLP-1 co-agonism (Day, DiMarchi, and Pocai, J Peptide Science 2012). These findings were confirmed in nonhuman primates (Dr. DiMarchi noted that Merck will present the results at a future conference).
  • Dr. DiMarchi noted that he and his colleagues initially explored GIP/GLP-1 co- agonism because of their additive effects on insulin secretion (Nauck et al., JCE&M 1993). He and his colleagues developed a GIP/GLP-1 hybrid with a threefold increase in GLP-1 receptor activity, and a twofold increase in GIP receptor activity. Surprisingly, the GIP/GLP-1 hybrid (administered at 3, 10, or 30 nmol/kg/day) decreased body weight more than exendin-4 (administered at 10 or 30 nmol/kg/day) in a rodent model (Matthias Tschop & Research Group, University of Cincinnati). In nonhuman primates in which subjects were administered treatment eight hours prior to a graded dextrose infusion, a GIP/GLP-1 hybrid provided a greater increase in insulin secretion and decrease in glucose excursion than liraglutide.

Questions and Answers:

Q: Is there a specific advantage to having the potential for action on two receptors in one molecule, or would it be equally good to combine two peptides at appropriate concentrations?

A: There are actually three different approaches. The physical combination of two separate drugs has its own complications, as you’d have to register two individual molecules. Heterodimers – stitching one nonnative peptide and another by a covalent bond, can be troublesome because of the potential to cross- hybridize. It’s an inherent challenge, but there is no data to say they would be any inferior. We have chosen to make one molecule like a master key.

Q: You showed impressive weight loss with both the glucagon/GLP-1 combination and the GLP-1/GIP combination. Do you have any comment on what you see in lean animals? When animals reach a normal weight, does weight loss continue?

A: Our emphasis was to decrease body weight by increasing thermogenesis with the glucagon/GLP-1 molecule, whereas our emphasis with GIP/GLP-1 was primarily on glycemic control. We still don’t understand why they lose the body weight that they do, but they do. It’s very consistent in rodents and in nonhuman primates. One wants to use these in the obese setting, where we’re only reducing fatness, and I think that’s possible.

TARGETING THE GLUCOCORTICOID PATHWAY

Andre Scheen, MD, PhD (University of Liege, Liege, Belgium)

After reviewing cortisol’s role in hyperglycemia, Dr. Andre Scheen discussed the potential of 11B-HSD1 inhibition as a treatment for diabetes. He noted that while initial studies in rodent models appeared promising, clinical trials to date have shown lackluster efficacy. He noted that three 11B-HSD1 inhibitors previously in development – INCB13739, MK-0916, and MK-0736 – have all been discontinued from development after their phase 2 trials. Dr. Scheen pointed out that not a single abstract at EASD 2012 is devoted to 11B-HSD1 inhibition; he was nonetheless encouraged that there is still potential for these agents – research is ongoing to develop new, more potent 11B-HSD1 inhibitors (he stated that Lilly’s LY2523199 is in phase 2). Dr. Scheen believed that we have to wait for more selective and more potent 11B-HSD1 inhibitors to be developed before they will have clinical utility.

  • 11B-HSD1 is an enzyme found predominantly in the liver and adipose tissue that converts the less active cortisone into cortisol. Cortisol promotes gluconeogenesis in the liver, protein catabolism in the muscle, and lipolysis in adipose tissue, which ultimately can contribute to hyperglycemia. The 11B-HSD1 enzyme can be thought of as an intracellular amplifier of active glucocorticoid; as such, 11B-HSD1 inhibition could be a potential target to investigate as a treatment for diabetes.
  • In rodent models, 11B-HSD1 knockout/inhibition conferred improvements in metabolic parameters. 11B-HSD1 knockout mice were found to have reduced corticosterone (CORT) levels in fat cells, reductions of visceral fat (but expansion of peripheral fat), and protection against associated metabolic abnormalities, whereas 11B-HSD1 transgenic mice (able to overexpress activity) had increased CORT levels in the liver and visceral fat, increased liver fat and marked expansion of visceral fat, less favorable adipokine/cytokine profiles, and metabolic abnormalities (including high blood pressure) (Seckl et al., Recent Prog Horm Res 2004). Similarly, chemical inhibition of the 11B-HSD1 enzyme was found to decrease body weight, reduce plasma glucose excursions, and decrease insulin secretion (that is, reduce insulin resistance) in a rodent model (Wang et al., PLoS ONE).
  • Dr. Scheen commented that 11B-HSD1 inhibitors have had mediocre performance in clinical trials to date, reviewing a number of studies for MK-0916, MK-0736, and INCB13739. In a 12-week trial (n=154), patients with type 2 diabetes and metabolic syndrome   on MK-0916 treatment experienced some positive effects on body weight, waist circumference, systolic blood pressure, diastolic blood pressure, and lipid levels; however, there was a slight increase in LDL and no improvement in HDL; MK-0916 had no effect on fasting plasma glucose   or two-hour postprandial glucose, and marginal benefit on A1c at the 6 mg dose (Feig et al., DOM 2011). In a 12-week trial in obese patients with hypertension (n=211), MK-0916 only had a mildly beneficial effect on systolic and diastolic blood pressure; these were accompanied by modest weight loss, and overall, no favorable effects on the lipid profile (shah et al., JASH 2011). INCB13739 was demonstrated to improve glycemic control in patients with type 2 diabetes inadequately controlled on metformin in a 12-week study (n=302) (Rosenstock et al., Diabetes Care 2010). Patients receiving INCB13739 experienced a 0.56% A1c reduction, and a 24 mg/dl improvement in fasting plasma glucose relative to placebo; HOMA-IR decreased 24%, and  patients on study drug experienced an approximate 1 kg (2.2 lb) weight loss over the course of the trial. Dr. Scheen noted that it appears the clinical development of MK-0916, MK-0736, and INCB13739 have all been abandoned after their phase 2 trials; there are no trials listed on clinicaltrials.gov for any of the compounds. He pointed out that not a single abstract at EASD   2012 is devoted to 11B-HSD1 inhibition, but was nonetheless encouraged by the fact that there is still research ongoing to develop new, more potent 11B-HSD1 inhibitors (he stated that Lilly’s LY2523199 in phase 2).

Questions and Answers:

Q: Since these compounds affect intraabdominal fat, maybe it may just take longer than 12 weeks to show an effect?

A: I agree with you that we need longer studies to see what can happen.

Q: Do you think that targeting multiple tissues is one of the reasons for the lack of efficacy?

A: Type 2 diabetes involves many tissues in its pathophysiology, so I think it’s realistic to target several organs.

KRP-104, A DPP-4 INHIBITOR THAT UNIQUELY MATCHES EXTRACELLULAR TARGET LOCALIZATION WITH COMPOUND EXPOSURE, IS A SAFE AND EFFECTIVE CANDIDATE FOR TYPE 2 DIABETES (OP-111)

Jonathan Rosenblum, PhD (ActivX Biosciences, La Jolla, CA)

Dr. Jonathan Rosenblum presented results from rat and pharmacodynamic studies on KRP-104, a novel DPP-4 inhibitor, which Dr. Rosenblum stated ActivX is trying to make best-in-class by differentiating its functional selectivity. Dr. Rosenblum noted that upon ingestion, KRP-104 is quickly converted into GIS- 103, a DPP-4 inhibitor that cannot enter the intracellular space, in contrast to currently available DPP-4 inhibitors. Thus because GIS-103 is confined within a small space, it has a relatively high potency due to its high maximum concentration. Furthermore, since GIS-103 colocalizes with DPP-4 in the extracellular space, less drug concentration is required to block DPP-4 action. Dr. Rosenblum thus argued that KRP- 104 gives you “more bang for your buck” than its competitors. Substrate-based assays revealed that GIS-103 inhibits almost 0% of DPP-9 in an intact cell, while vildagliptin (Novartis’ Galvus) inhibits roughly 55% of DPP-9. GIS-103’s reduced affinity for DPP-9 may provide clinical benefits since DPP-9 has been implicated in skin lesion formation with certain compounds (he mentioned vildagliptin and sitagliptin – we were surprised at this assertion since none of the extremely early-stage associations have been found to be clinically or commercially significant). Similarly, after rats received a single dose of 10 mg/kg KRP-104, the ratio of GIS-103 in tissues to plasma was significantly smaller than that of either vildagliptin or sitagliptin (see table bellow for more details). Though the data appears to indicate that KRP-104 has lower off-target action than currently marketed DPP-4 inhibitors Dr. Rosenblum did not comment on whether this finding is clinically significant, even though KRP-104 has been studied in clinical trials. Phase 1 and phase 2 data indicate that KRP-104 provides comparable glycemic efficacy to other DPP-4 inhibitors; they have not at this stage shown better efficacy as far as we know. For more details, please see our GTCbio 2011 report at https://closeconcerns.box.com/s/77d4jps3scd2la48y1vr.

Tissue to Plasma Area Under Curve (AUC0-8) Ratios

 

Compound

 

Lung

 

Heart

 

Pancreas

Sitagliptin

~13

~8

~19

Vildagliptin

~2

~2

~4

GIS-103

~1

~0

~0

Oral Presentations: Insulin: Beyond Traditional Delivery

BUCCAL SPRAY INSULIN IN SUBJECTS WITH IMPAIRED GLUCOSE TOLERANCE: IMPROVEMENT IN HBA1C IS LOST AFTER 6 MONTHS OF WASH OUT THERAPY

Andreea Soara (University Campus Bio Medico, Rome, Italy)

Ms. Andreea Soara presented results on the use of Generex’s buccal spray insulin, Oral-lyn, in 11 patients with impaired glucose tolerance (IGT). Twenty-two participants were randomized to a treatment group (12 puffs of Oral-lyn at each meal, physical activity, and diet) or a control group (physical activity and diet). After six months of treatment, A1c declined by 0.4% in the Oral-lyn group (baseline: 6.2%) and remained stable at 6.1% in the control group. There was no increase in body weight, hypoglycemia, insulin antibodies, or other adverse events in the Oral-lyn group. Unfortunately, the A1c improvement was not sustained after a six-month post-trial washout period and the Oral-lyn group’s mean A1c returned to its pre-study baseline level of 6.2%. This was of course disappointing to see, though we think it would be interesting to follow the patients over a longer period and see if even the six-month period of better glycemic control would help reduce progression to diabetes. Ms. Soara concluded that Oral-lyn “appears to be a valuable tool for subjects with IGT” and the product’s features and simple administration favor compliance and improved quality of life in subjects affected by IGT. Of course, since relatively few people with IGT develop type 2 diabetes (according to Ms. Soara it is one third), treating people with prediabetes with Oral-lyn will have to be either highly cost-effective or based on other markers than just IGT alone. Further, we wonder if the company can concentrate the insulin to reduce the number puffs – 12 at one meal strikes us as on the higher side.

  • Generex’s Oral-lyn is a buccal spray insulin that is absorbed through the oral mucosa. Oral-lyn consists of human recombinant insulin (regular acting) that has been dissolved in a buffer at neutral pH. Ms. Soara noted that it is identical to an injection but with the addition of absorption enhancers and stabilizers. She further explained that the particles are large and cannot enter into the lungs. Oral-lyn reaches peak efficiency after one hour and has a bioavailability of 15%.

Questions and Answers:

Dr. Jay Skyler (University of Miami, Miami, FL): During the treatment period, was there a placebo in the control group?

A: No. Q: You had the subjects take 12 puffs at each meal. That sounds like a large number of puffs. Are you doing any research to diminish the number of puffs?

A: In a previous publication, we already studied varied dosages. In these types of subjects, we compared four puffs, six puffs, and 12 puffs. We noticed that only with 12 puffs was there a reduction in plasma glucose and no hypoglycemia. That is why we started with 12 puffs. We have to make sure we have an improvement without causing hypoglycemia.

REDUCED POSTPRANDIAL GLUCOSE EXCURSION IN TYPE 2 DIABETIC SUBJECTS USING THE INSUPAD DEVICE

Andreas Pfützner, MD, PhD (Institute for Clinical Research and Development [IKFE], Mainz, Germany)

Dr. Andreas Pfützner presented interim results from an ongoing trial of the InsuPad, a patch-like device worn on the skin that provides localized heating after injection. Sixteen participants with type 2 diabetes injected rapid acting insulin analogs either with or without the device (each patient completed the test under both conditions) before a standard liquid meal tolerance test. Glucose excursion data over 300 minutes demonstrated a significant 23% reduction in maximal glucose excursion (106 mg/dl vs. 137 mg/dl; p <0.05) and a significantly lower glucose excursion from 55 minutes to 140 minutes. Dr. Pfützner hypothesized that based on these initial findings, patients using the InsuPad should require less insulin (~20-30%) for postprandial glucose control in real world settings. A recently initiated trial in 160 type 1 patients is expected to complete by the end of this year and should shed more light on this hypothesis. We look forward to better understanding patient perceptions of the device, as we suspect many MDIs will perceive it as a hassle to wear and replace each day. Still, we see postprandial control as an area deserving more innovation and hope the company continues perfecting the approach.

  • For background, the InsuPad device applies localized heating after insulin injection. It is comprised of a disposable pad (containing the insulin injection window, which has space for six injections; intended for one day use) and a reusable control unit (contains the heating block, electronics, and a rechargeable battery). Using the product has four main steps: 1) the patient connects the electronics to the disposable pad and places the pad on the skin; 2) the patient injects meal insulin through the opening in the pad; 3) Insupad is activated automatically with each injection to deliver heat (39.5 degrees Celsius/103 degrees Fahrenheit) and stop after few minutes; and 4) the patient removes the disposable pad from the skin and the electronics are removed from the disposable pad and recharged. The product is being developed by InsuLine Medical and has already received CE marking.
  • Dr. Pfützner presented interim results from an ongoing study of the InsuPad device in 16 patients with type 2 diabetes using rapid acting insulin analogs. Participants had a mean age of 59 years old with a mean BMI of 29 kg/m2, and a mean A1c of 8.5%. The stated study objective was to test the effect of the InsuPad on post prandial glucose levels during a meal tolerance test and evaluate the safety of the device. Subjects injected 0.2 U/kg insulin before a standardized liquid meal and glucose and insulin measurements were taken from a venous line at various time points through the study. Each patient went through the protocol twice, once with the device (experimental group) and once without the device (control group).
  • Mean maximal glucose excursion was 23% lower in the InsuPad group (106 mg/dl vs. 137 mg/dl; p <0.05). Dr. Pfützner also showed the glucose excursion curve over 300 minutes post-meal consumption to highlight that from minute 55 to minute 140, the difference between groups was significant at most time points. Area under the glucose curve was only significantly lower in the InsuPad group from 0-120 minutes (p <0.05; 0-60, 0-180, 0-240, and 0-300 were also assessed); however, Dr. Pfützner believes that once the full analysis is done, the study will show “significant differences all over the place.”
  • The InsuPad device was well tolerated by all participants, said Dr. Pfützner. There were no reports of skin burns, redness, or irritation.
  • An open-label, randomized, parallel design study of the InsuPad patch in 160 patents with type 1 diabetes has already initiated. The study is meant to test the effect of the InsuPad in a real world setting. Dr. Pfützner hypothesized less insulin will be needed to maintain the same post prandial control when using the InsuPatch, which would be welcome for patients and payors. The first results are expected by the end of the year and data will hopefully be presented at ADA. Called the “Barmer Study,” it was designed with Barmer Health Care Insurance, one of the largest insurance companies in Germany. Pending positive results, InsuPad will hopefully be able to gain reimbursement for the device. We think this is an excellent example of a payor-industry collaboration that has the potential to benefit patients.

Questions and Answers:

Q: What’s the temperature achieved?

A: We applied 39.5 Celsius. There is a trial seeing whether going up to 40 has an impact and it seems further increase has further impact.

Q: Can subjects feel the temperature increase?

A: Some patients realize that something is going on, but not all of them do. It does not at all disturb patient’s wellbeing.

Q: Did you use a control device?

A: We have not, but we will in the future.

Q: What was the baseline glucose before the meal?

A: It was in the range 120-160 mg/dl.

Q: Was it the same in both groups?

A: Yes, there was no difference in mean baseline levels.

Q: You commented that there could be a reduction in the dose needed for insulin. What’s the mechanism behind that?

A: Faster onset of action leads to the shutting down of hepatic gluconeogenesis. We can expect to see a 20- 30% reduction in required prandial insulin dose.

Q: Do you have information on the pharmokinetics?

A: From this study we don’t because the study is still ongoing and we do those measurements at the end, but we know from previous studies that we see an acceleration – looking at t1/2 values – of approximately 20-25 minutes.

Q: If you didn’t use a dummy device, how could you ensure the depth of injection was the same?

A: The disposable pad is only a plastic window, so it is after the injection that the heat is applied. Basically, when you inject through the window without applying the heat it is like you are injecting without anything. And the same needles were used, so needle depth was not influencing the results.

Q: Why is there no pharmacokinetic data again?

A: We will measure that once we’ve completed all 20 subjects to make sure assay conditions for the insulin is standardized across all subjects.

INSULIN DEGLUDEC DOES NOT INCREASE ANTIBODY FORMATION COMPARED TO INSULIN GLARGINE: AN EVALUATION OF PHASE 3A CLINICAL TRIALS

Jitendu Vora, MD (Royal Liverpool University Hospitals, Liverpool, United Kingdom)

In this analysis of six phase 3 clinical trials of insulin degludec vs. insulin glargine, Dr. Jitendu Vora showed that few patients taking either analog experienced higher levels of insulin-related antibodies. The titers of antibodies were measured using radio-labeled insulin; the result was expressed as the fraction of the total insulin that bound to antibodies. Levels of degludec-specific or glargine-specific antibodies were low (roughly 1% or lower bound in the radio-labeled insulin assay). The researchers also assessed levels of antibodies that cross-linked with human insulin. The titers of these antibodies were fairly low in insulin-naïve patients with type 2 diabetes (around 2%), while titers were higher in people who had been previously treated with insulin whether they had type 2 diabetes (around 5%) or type 1 diabetes (around 10-20%). Dr. Vora further showed that mean antibody titer did not increase beyond the first several weeks of a study, and that few patients experienced an antibody increase of more than 10%. Some patients did experience significant increases in antibody levels, but Dr. Vora said that –encouragingly – antibody levels were not correlated with baseline A1c, change in A1c, insulin dose at the end of the trial, or injection-site reaction. This high-level analysis looked generally positive; we assume that we’ll get a chance to report on immunogenicity data in greater depth at degludec’s FDA advisory committee meeting on November 8.

Questions and Answers:

Dr. Philip Home (Newcastle Diabetes Centre, Newcastle University, United Kingdom): Some people, as you would expect, had relatively high antibody titers. You showed that it didn’t affect A1c, but was there evidence of other immunological phenomena?

A: There was no evidence of injection-site immunological reactions.

IN VITRO CHARACTERISATION OF NOVEL BASAL INSULIN LY2605541: REDUCED MITOGENICITY AND IGF-IR BINDING

Rebecca Owens (Lilly Research Laboratories, Indianapolis, IN)

In a comparative analysis of Lilly’s PEGylated insulin lispro (LY2605541, hereafter LY), Ms. Rebecca Owens showed that LY has lower in vitro binding to both isoforms of the insulin receptor (IR-A and IR- B), lower in vitro binding to the IGF-1 receptor (which can be involved in mitogenicity), and greater in vitro selectivity for IR-A vs. IGF-1 (roughly 100-fold greater than lispro). In assays of cell lines that overexpressed IGF-1, LY was also shown to have significantly lower IGF-1 binding compared to other insulin analogs. Ms. Owens further demonstrated that LY’s residence time on each IR isoform is similar to (and slightly shorter) than those of insulin lispro and insulin glargine, as opposed to the long residence time seen with the mitogenic insulin AspB10. As for what happens to LY once it has bound to the insulin receptor, Ms. Owens noted that the large PEG domain could theoretically interfere with the normal trafficking of activated receptors to the endosomes of the cell. An analysis suggested that low- dose LY has less trafficking than low-dose lispro, but the maximal trafficking response was similar for both analogs. This suggests that the PEG domain dose not prevent normal co-localization (though Ms. West acknowledged that the assay says nothing about how LY is processed once it’s inside the cell). As noted during Q&A, extrapolating in vivo activity from in vitro data is not always straightforward, so we hope that preclinical studies support LY’s safety and selectivity for the insulin receptor.

Questions and Answers:

Dr. Philip Home (Newcastle Diabetes Centre, Newcastle University, United Kingdom): Your in vitro affinities are down by 10-12 times. But in vivo clearance is through the insulin receptor, so it seems like circulating concentrations would be equivalently elevated by 10 times. At the same time, selectivity vs. IGF-1 is only fourfold lower than the other analogs. So won’t you get 2.5-fold more activation of IGF-1 in vivo? I’m not suggesting for a second that matters, but that is my interpretation of the data.

Oral Presentations: Can We Improve Outcomes in Diabetic Pregnancy?

THE EFFECT OF REAL-TIME CONTINUOUS GLUCOSE MONITORING IN DIABETIC PREGNANCY – A RANDOMIZED CONTROLLED TRIAL

Anna Secher, MD, PhD (University of Copenhagen, Copenhagen, Denmark)

Dr. Anna Secher presented a very disappointing study testing intermittent use of CGM in pregnant women with type 1 and type 2 diabetes. Patients in the CGM group (n=79) wore the Medtronic Guardian real-time CGM (Sof-Sensor) for six days at a time during weeks eight, 12, 21, 27, and 33 of pregnancy and were compared to a non-CGM control group (n=75). Patients had a well-controlled A1c at baseline (~6.7%), though a high rate of severe hypoglycemia (~18%) that one of the doctors in Q&A pointed out probably reflects significant glycemic variability. Overall, there were no significant differences between the two groups in any glucose parameters at any point in pregnancy. Further, rates of macrosomia, pre-term delivery, and neonatal severe hypoglycemia were not significantly different between the two groups. We were quite surprised to see such neutral results though we think the study suffered from a number of major limitations: 1) the trial was done before wide trial use of the Enlite or Dexcom Seven Plus or G4 was widely available; 2) intermittent use of CGM for only six day periods following five study visits (rather than continuous use); 3) low compliance with the prescribed intermittent wear (64%); and 4) high rates of baseline severe hypoglycemia that did not improve by the end of the study. Given these limitations, we are highly skeptical of these results and feel very strongly that CGM can be a very valuable tool for pregnant women with diabetes. We look forward to further studies of continuous, real-time CGM using next generation technologies. 

  • This study assessed the use intermittent real-time CGM as part of routine pregnancy care in 154 women with pre-gestational diabetes. Women with type 1 diabetes (80% of the study population) or type 2 diabetes were included and were randomized to an intermittent real- time CGM group or a non-CGM control group. In the CGM group, the Medtronic Guardian CGM (Sof-Sensor) was prescribed to be worn for six days at a time after study visits at weeks eight, 12, 21, 27, and 33. Both groups saw a diabetologist every second week and seven-point SMBG profiles were analyzed. Women willing to wear CGM between study visits were allowed to do so – the speaker did not mention how many women choose to do this, though we suspect a low number  did. Patients’ real-time CGM readings were used to adjust diet and insulin using locally developed guidelines,. No specifics were provided on the guidelines, though in Q&A, Dr. Secher suggested that severe hypoglycemia is a real problem at their clinic and this directs a lot of their focus. Patients were advised to conduct SMBG before and after meals (90 minutes) and at bedtime. Pre- prandial targets were 72-108 mg/dl and post-prandial targets were 72-144 mg/dl.
  • There were no significant differences at baseline between the CGM (n=79) and non- CGM (n=75) groups. Women were in fairly good control and had a baseline A1c of 6.6% in the CGM group and 6.8% in the control group. However, we note that the rate of severe hypoglycemia was quite high in both groups (18% and 17% respectively) at baseline. A questioner in Q&A pointed out that this suggests a high rate of glycemic variability. Duration of diabetes was 10 years in the CGM groups and 12 years in the control group. Only 22% of type 1 patients in the study were on insulin pumps.
  • There was no significant difference in A1c at any point in pregnancy between the two study arms. Patients in the two groups tested SMBG equally frequently throughout the study. In both groups, 16% of women had at least one event of severe hypoglycemia throughout the study. We were surprised and disappointed not to see a significant improvement in severe hypoglycemia in the CGM group, though given the intermittent use and low compliance, this was probably not surprising – technology has to be easier to use in order to expect positive results..
  • Rates of macrosomia, pre-term delivery, and severe neonatal hypoglycemia were not significantly improved with CGM use – surprisingly, these trended (non- significantly) in the opposite direction. In the CGM group, 45% of pregnancies had macrosomia, compared to 34% in the control group. Pre-term delivery occurred in 29% of CGM group pregnancies vs. in 22% of control pregnancies. Severe neonatal hypoglycemia occurred in 13% of CGM group pregnancies and 14% of control group pregnancies. All results were not statistically significant.
  • A subgroup analysis of type 1s and those who followed the protocol did not change the overall findings. In women with type 1 diabetes, macrosomia occurred in 50% of CGM pregnancies vs. 36% in the control group. Pre-term delivery happened in 32% of CGM pregnancies and 27% of control pregnancies. In a per-protocol analysis, the results were similar – macrosomia in 49% of patients for CGM vs. 34% in the control group and pre-term delivery/severe neonatal hypoglycemia in 24% of CGM patients vs. 22% of those in the control group. We would have been interested to see data for those patients that wore the CGM 24/7.

Questions and Answers:

Q: I’m wondering about the type of population selected. I was surprised by the low A1c – the controls and study group were very close to 6.5%. The frequency of severe hypoglycemia was 16-17%. This was probably a population with lots of glycemic variability. That probably explains the low A1c and the frequency of hypoglycemia. Based on the results of CGM, did you intervene?

A: We did intervene based on the results of CGM readings. We analyzed these results together with each woman and we used them to adjust insulin therapy. With the present form of CGM, you must use it together with plasma glucose measurement.

Q: What was the time duration you used CGM – three days or six days?

A: It was used for six days.

Q: And it was the iPro2?

A: No, the Sof-sensor.

Q: Was it approved for six-day use?

A: Yes.

Q: Can you explain the large difference in macrosomia in spite of similar control? The CGM group numbers were higher than in the control group.

A: We were disappointed with the results and very surprised. We were very surprised that the factual numbers were higher, though they were not statistically significant. We have had many considerations about why. One reason is that in our center, we have a lot of data on severe hypoglycemia and pregnancy. We really want to avoid severe hypoglycemia. Perhaps if we’re focusing too much on severe hypoglycemia, we might pay a price on maternal hyperglycemic complications.

Q: This was a courageous trial. But I guess it was designed to fail from the beginning. You used intermittent real time CGM. Dr. John Pickup showed that you need to wear the sensor at least 75% of the time. Why didn’t you use it continuously or as continuously as possible?

A: We did indeed use it as much as possible. Women were encouraged to use it extensively and free of charge. The trial design was with intermittent use. That was for several reasons. We have much experience with CGM and we knew that numerous alarms and other limitations in the system limit compliance. By asking the women to use it continuously, it would have been hard to find an unselected population and sufficient numbers of women.

Q: With real-time CGM, the results are better in patients on pump therapy. They can take boluses easier and reduce basal rates. What proportion of your patients were on pumps?

A: In the women with type 1 diabetes, 22% were on insulin pumps, and the majority of them had insulin pumps that could be connected to the CGM system. We hoped for even better results in that subgroup of women. We did not find any improvement in that group either.

Oral Presentations: The -Omics Frontier: Applications of New Technologies

GENOME-WIDE METHYLATION VARIATIONS PRECEDE DIAGNOSIS OF TYPE 1 DIABETES IN CHILDREN

Nancy West, PhD (University of Colorado, Aurora, CO)

Dr. Nancy West presented a preliminary study of DNA methylation analysis as a complement to genetic screening for type 1 diabetes. Using the DAISY database, her team retrospectively analyzed blood samples from 17 children who were diagnosed with type 1 diabetes shortly after the samples were taken and 17 age- and sex-matched children who did not get type 1 diabetes. The methylation changes clustered around 16 genes – four that have previously been associated with type 1 diabetes or other autoimmunity disorders, two involved in insulin and/or glucose regulation, and 10 that may represent novel risk markers of type 1 diabetes. Dr. West was encouraged to find molecular markers of type 1 diabetes that precede diagnosis, though further studies will be needed to validate the results. In particular, the researchers plan to analyze older DAISY blood samples from the same 17 children with type 1 diabetes, to see whether the methylation changes are present at (or before) birth, or whether the methylation is a response to changes in insulin and glucose that precede type 1 diabetes onset by just a few months (in which case they would be much less useful for population-wide screening).

Questions and Answers:

Q: The leukocyte population is known to be different between cases of type 1 diabetes and controls. Did you see whether the differences in whole-blood methylation might be due to this?

A: We have not studied this yet.

Q: We got a very messy picture with leukocytes, but we found a clearer analysis when we analyzed by type of monocyte.

A: Thank you for suggesting splitting monocytes into these groups.

Q: You said that preclinical changes in glucose control might confound the search for epigenetic predictors of type 1 diabetes risk. In earlier talks, the presenters on type 2 diabetes said something similar. Has anyone conducted a genetic comparison of type 1 and type 2 diabetes patients to try to isolate the methylation changes that are just due to glycemia?

A: That is an interesting strategy – thank you.

Q: DAISY has stored samples from further away in time, not so close to the diagnosis. Could you test samples from earlier on?

A: Yes – that is our plan. We have samples going back all the way to cord blood – before birth.

EARLY METABOLIC MARKERS OF THE DEVELOPMENT OF DYSGLYCAEMIA AND TYPE 2 DIABETES AND THEIR PHYSIOLOGICAL SIGNIFICANCE

Ele Ferrannini, MD (University of Pisa, Pisa, Italy)

In an engaging lecture, Dr. Ele Ferrannini discussed early research on two potential biomarkers of insulin resistance. He and his colleagues analyzed two large databases of metabolic data on people without diabetes at baseline, the RISC cohort (n=1,261) and the Botnia cohort (n=2,580 with strong family history of diabetes) to find molecules that were correlated with insulin resistance (as measured by oral glucose tolerance test), and they investigated two in particular: alpha-hydroxybutyrate (aHB), which is positively associated with insulin resistance, and linoleoyl-GPC (LGPC), which is positively associated with insulin sensitivity. In both cohorts, aHB and LGPC predicted risk of dysglycemia even after controlling for age, gender, BMI, familial history of type 2 diabetes, and each other (i.e., aHB predicted risk independently of LGPC, and vice versa). The two molecules also make sense as risk markers from a biochemical perspective, since each is a metabolic byproducts of other known players in the metabolic syndrome: branched-chain amino acids and/or free fatty acids. (The predictive value of aHB and LGPC relative to free fatty acids and branched-chain amino acids was not clear from this analysis. Indeed, Dr. Ferrannini emphasized that analysis of aHB and LGPC is still too early-stage for either to be used diagnostically: “I am not ready to replace ‘diabetes’ with ‘alpha-hydroxybutyratitis.’”)

  • Dr. Ferrannini opened by reviewing the qualities of a useful biomarker: for example, it is specifically and easily measurable in body fluids, it improves prediction algorithms, it tracks with the underlying pathophysiological mechanism, and it maps onto a disease pathway (possibly in ways that increase scientific understanding of that disease).
  • To see whether alpha-hydroxybutyrate and linoleoyl-GPC would track with improvement in insulin sensitivity, the researchers analyzed 26 morbidly obese patients before and one year after roux-en-Y gastric bypass. Mean BMI at baseline was 51 kg/m2, while one year after surgery mean BMI had fallen to 34 kg/m2. Insulin sensitivity doubled one year after surgery, and aHB concentration fell to half its baseline value – maintaining the inverse correlation seen in the RISC and Botnia cohorts. However, LGPC levels did not rise.  Dr. Ferrannini noted that both biomarkers have more complex roles in the body than he is aware; he said that both are doubtless involved in many processes beyond insulin resistance.

  • Dr. Ferrannini also presented in vitro analyses of beta-cell function in which aHB was associated with higher glucose-responsive insulin secretion, while LGPC was associated with lower glucose-responsive insulin secretion. During Q&A, he said that aHB is also associated with better in vivo beta cell function but that LGPC levels did not seem to correlate with beta-cell function.

Questions and Answers:

Q: Branched-chain amino acids (BCAAs) have been shown to have protective effects on beta-cell viability. Might aHB be a marker of increased consumption of BCAAs and loss of this protective effect? Have you considered this possibility?

A: We have.

Q: You said these molecules might have a direct effect on insulin levels. Are they in any way related to beta cell function in vivo?

A: We find reciprocal associations in aHB and beta-cell function in vivo, but a relationship between LGPC and beta-cell function is not seen. Nor do we see LGPC changes after bariatric surgery. Biologically these molecules must be doing many different things of which I am aware of only a small portion.

Q: There are so many data showing that diabetes starts very early. Why do we not change the diagnosis of diabetes? Putting it at the onset of hyperglycemia means that half the beta cell is already destroyed. I propose that we all change the diagnosis of diabetes.

A: Yes, that is an interesting proposal. I think these are just preliminary data; I am not ready to replace diabetes with alpha-hydroxybutyratitis.

Q: You said that these could be independent predictors, but alpha-hydroxybutyrate is downstream of free fatty acids and branched-chain amino acids. So what is the added value?

A: I didn’t say that it was independent of those. I said that it was independent of the phenotypic predictors used in risk-stratification schemes such as FinnDiane. It’s also independent of glucose levels. If you control for amino acids in the analysis you reduce the predictive power. The predictive variable with the most power tends to butt out the others. The significance physiologically is a bit uncertain.

ENRICHMENT OF MRNA TRANSCRIPTS RRELATED TO RISK OF TYPE 2 DIABETES IN PATHWAYS INVOLVED IN INSULIN RESISTANCE: KORA S4/F4 COHORT

Maren Carstensen (German Diabetes Center, Duseldorf, Germany)

Ms. Maren Carstensen presented a prospective genetic analysis of 513 patients followed over a seven- year period, of which 50 developed type 2 diabetes. Patients were given glucose tolerance tests at baseline in 1999-2001 and at follow-up in 2006-2008. Those who developed type 2 diabetes were older (65 years vs. 63 years), had a higher BMI (31 kg/m2 vs. 28 kg/m2), a higher prevalence of hypertension (72% vs. 49%), and a higher A1c (5.8% vs. 5.6%). The researchers examined differentially expressed transcripts associated with the 50 cases of incident type 2 diabetes. After adjusting for age, sex, and BMI, the strongest associations were observed for eIF2 (eukaryotic translation initiation factor-2) signaling), eIF4/p70S6K (70-kDa ribosomal S6 kinase) signaling, and mTOR (mammalian target of rapamycin) signaling. There was also evidence for an enrichment of differentially expressed transcripts and pathways involved in endoplasmic reticulum stress, inflammation, immune responses, lipid metabolism, endocrine function, mitochondrial function and cell/tumor proliferation and apoptosis. Ms. Carstensen concluded by noting that this was the first prospective transcriptomics study on incident type 2 diabetes and the results could be used in the future for prediction of type 2 diabetes.

EXERCISE INDUCES ALTERED DNA METHYLATION IN ADIPOSE TISSUE THROUGHOUT THE HUMAN GENOME

Tina Rönn, PhD (Lund University, Lund, Sweden)

Dr. Tina Rönn’s presentation explored the effect of exercise on DNA methylation. Dr. Rönn reminded the audience that exercise has been shown to improve insulin sensitivity and weight control, but that the mechanism mediating these improvements is not fully understood. Striving to shed insight on exercise- mediated physiological improvements, Dr. Rönn conducted a study in 23 males analyzing DNA methylation and mRNA expression in adipose tissue biopsies before and after a six-month exercise intervention. The exercise intervention significantly improved participants’ VO2max, waist circumference, waist/hip ratio, diastolic blood pressure, pulse, and HDL levels, but importantly, had no affect on BMI. Dr. Rönn found a global increase in DNA methylation in subcutaneous adipose following exercise, and, looking at specific CpG sites (i.e., sites within the genome that are often methylated) that showed significant differences in methylation pattern, she found that 90% of CpG sites had increased DNA methylation and 10% had decreased methylation. Additionally, when comparing CpG sites that fell within gene regions and showed significant methylation differences pre- to post-intervention, Dr. Rönn found that 34% of sites also showed a difference in the mRNA expression of that gene.

  • The study showed increased DNA methylation within the ITPR2 gene, which is associated with waist/hip ratio (one of the clinical characteristics that changed significantly following the intervention). At baseline, the CpG site within the ITPR2 gene body averaged 56.8% methylation. Following the exercise intervention, the site had 63.3% methylation (p <0.0001). While this was one of the larger percentage increases in DNA methylation, it begs the question of whether a more successful exercise intervention (i.e., one resulting in improved BMI, LDL, or triglycerides) would have had more pronounced results on DNA methylation. Of course, methylation is only significant in this context if it is linked to changes in gene expression, which in turn need to be linked to physiological changes.
  • Dr. Rönn’s investigation into the effects of physical activity on gene expression nicely complements Dr. Tim Frayling’s (Peninsula College of Medicine & Dentistry, Exeter, United Kingdom) Minkowski lecture, in which he argued that today’s obesogenic environment amplifies the effect of risky genes. For our discussion on Dr. Frayling’s lecture, please see page 23 of our Day #3 highlights at http://www.closeconcerns.com/knowledgebase/r/f62fb4ae. Certainly, both talks underscore the importance of addressing the obesogenic environment we currently live in.

Poster Presentations

ACCURACY OF SELF MONITORING BLOOD GLUCOSE SYSTEMS IN DIFFERENT RANGES OF BLOOD GLUCOSE

F. Kulozik, I. Platten, and C. Hasslacher (Diabetesinstitut Heidelberg, Heidelberg, Germany)

This poster, which was supported by Roche, compared the accuracy of 25 commercially available blood glucose meters in a wide range of glucose values (60-300 mg/dl) in 37 insulin-dependent patients with diabetes. All 25 meters were accurate within the requirements of the current ISO 15197 standards, though 14 of the 25 meters failed to meet the proposed ISO standards (95% within 15 mg/dl for <100 mg/dl and 15% for >100 mg/dl). The five most accurate meters according to this study were: 1) the Roche Accu-Chek Compact and Bayer Contour Next USB (tie); 3) Roche Accu-Chek Mobile; 4) Abbott FreeStyle Lite; and 5) Sanofi iBGStar. Meters that failed to meet the proposed standards were mostly from smaller companies, though the LifeScan OneTouch Verio, Bayer Breeze and Contour Plasma, and Sanofi BGStar came up short of the new standards. Obviously, results vary based on strip lots, though we were encouraged to see fairly high sample numbers (250-300) in this study. It was positive to see a study with the newest meters included together, as some recent studies we’ve covered did not compare all in one study (e.g., Freckmann et al., Journal of Diabetes Science and Technology 2012; Bayer’s North American Comparator Trial on pages 30-31 of our AADE 2012 report at https://closeconcerns.box.com/s/aa421a745c27319a124b). The poster did not mention any study sponsor, surprisingly – we found out after our original viewing that Roche was the sponsor. Oddly, the Roche meter results were adjusted by 5% due to the strips’ hexokinase technology – we are in the midst of trying to get background on the rationale for this. In any case, we’ll be interested to see what happens with the new ISO standards – if they are indeed tightened, it should help push companies to further improve accuracy and could even bode well for CGM (e.g., calibration).

  • This study compared the accuracy of 25 commercially available glucose meters in five different blood glucose ranges in 37 insulin-dependent patients with diabetes (n=24 type 1, n=13 type 2). Patients had a mean age of 50 years, a mean A1c of 7.5%, a mean duration of diabetes of 17 years, and no concomitant use of substances that could affect blood glucose readings. Blood glucose levels ranged from 60-300 mg/dl in the study. For each SMBG system, 230-300 paired values were obtained. Results were compared to an internally and externally validated laboratory reference method (Hitado Super GL). Results from the reference standard were converted from whole blood glucose values to plasma equivalent blood glucose values using the formula: plasma equivalent blood glucose (mg/dl) = 1.11 x whole blood glucose (mg/dl). Results were compared to current ISO 15197 standards (95% within ±15 mg/dl and ±20% for <75 mg/dl and >75 mg/dl) and proposed standards (95% within ±15 mg/dl for <100mg/dl and ±15% for >100 mg/dl).
    • Since the Accu-Chek devices are calibrated by the hexokinase method, results from these meters were specifically adjusted by an increase of 5% (according to the poster, several studies have shown that blood glucose levels measured this way are 3.5-6.7% higher than glucose oxidase values). It struck us as somewhat odd that only the Roche meter results were adjusted. This also seemed somewhat unfair given that patients using the meters in a home-use environment would not see “adjusted” results on the meters.
  • The five most accurate meters were: 1) the Roche Accu-Chek Compact and Bayer Contour Next USB (tie); 3) Roche Accu-Chek Mobile; 4) Abbott FreeStyle Lite; and 5) Sanofi iBGStar. There was a wide range of overall accuracy between the glucose meters (80.4%-99.6%) and only three meters reached >98%. Accuracy was better at higher blood glucose values than at lower values. Data was collected and evaluated in the ranges of 50-99 mg/dl, 100- 149 mg/dl, 150-199 mg/dl, 200-249 mg/dl, and 250-300 mg/dl. For brevity in the table below,we have omitted the breakdowns and only included the overall data. Results below are presented as the percentage of values that meet the proposed ISO standards: within 15 mg/dl for <100 mg/dl and 15% for >100 mg/dl. The bold divider line denotes meters that failed to meet the 95% threshold.

Device

Overall Accuracy (n)

Accu-Chek  Compact

99.6%, n=282

Bayer Contour Next USB

99.6%, n=275

Accu-Chek Mobile

99.3%, n=294

Abbott FreeStyle Lite

97.7%, n=301

Sanofi iBGStar

97.6%, n=249

MyLife Pura

97.4%, n=271

Accu-Chek Aviva Nano

97.0%, n=303

LifeScan OneTouch Verio IQ

96.8%, n=278

LifeScan OneTouch Ultra Easy

96.8%, n=284

Bayer Contour USB

96.4%, n=248

LifeScan OneTouch Vita

96.2%, n=290

Beurer GL 40

94.9%, n=254

Bayer Contour Plasma

94.7%, n=284

FineTouch

92.6%, n=258

LifeScan OneTouch Verio

92.5%, n=265

A. Menarini Glucomen LX

92.0%, n=251

GlucoSmart  Swing

91.7%, n=253

A. Menarini Glucomen LX Plus

91.5%, n=246

Wellion Calla

91.3%, n=252

Sanofi BGStar

90.1%, n=302

SmartLab Mini

88.5%, n=253

Smart Lab Sprint

87.1%, n=280

Bayer Breeze

86.7%, n=249

Beurer GL50

85.5%, n=228

Omnitest 3

80.4%, n=245

  • All 25 meters tested met the current ISO 15197 requirements, though 14 of the 25 meters failed to meet the proposed ISO requirements. The investigators also looked at accuracy per the proposed ISO thresholds for the five different glucose range buckets evaluated in the study. Four meters met the proposed ISO standards for every single glucose range: Accu-Chek Compact, Accu-Chek Mobile, Bayer Contour Next USB, and the OneTouch Ultra Easy. Another six meters met the proposed ISO standards for four out of the five glucose ranges: Accu-Chek Aviva Nano, Sanofi iBGStar, Bayer Contour USB, FreeStyle Lite, MyLife Pura, OneTouch Verio IQ, and OneTouch Vita.
  • Roche gave financial support for this study.

Symposium: Diabetes and Cancer: Making Sense of the Data

DIABETES AND CANCER INCIDENCE: A FRAMEWORK TO ASSESS CONFOUNDING

Jeffrey Johnson, PhD (University of Alberta, Edmonton, Canada)

In his presentation, Dr. Jeffrey Johnson set a framework for the assessment of cancer incidence. He noted that the difficulty in studying the association between diabetes and cancer stems not only from the complex nature of both diseases, but also from a constellation of other factors including study biases and possible confounding variables. After briefly comparing randomized controlled trials and observational studies, he listed several factors that investigators should consider in order to more accurately characterize the relationship between diabetes and cancer: 1) whether the study investigates all cancers as a whole or specific cancer types – Dr. Johnson believes that the latter is more favorable since the magnitude of risk differs by cancer type; 2) the possibility of reverse causality; 3) the biologic mechanisms underlying the relationship; 4) common risk factors between diabetes and cancer; 5) potential confounding by indication – while most observational studies use a “even/never” classification (categorizing patients by whether they have ever taken a drug or not), Dr. Johnson prefers accounting for the time-varying cumulative exposure of a medication; and 6) possible study biases, such as detection bias and immortal time bias.

  • Dr. Johnson defined study bias as “any systematic error in a study that results in an incorrect estimate of the association between exposure and the risk of a disease.” Specifically, he noted that investigators should watch for possible detection bias (an artifact caused by the use of certain diagnostic techniques or the tendency on the part of the investigator to look more closely for an association in certain situations as opposed to others) and immortal time bias (when estimating drug exposure, the time between cohort entry and the person’s first drug prescription is described as “immortal” since the period is event-free [e.g., no death can occur for a patient to receive a prescription]. Incorrectly classifying this time period, or failing to include it in the data analysis, can inflate the perceived health benefits of a drug).
  • Dr. Johnson briefly discussed the ORIGIN trial results, which found no effect of insulin glargine therapy on cancer incidence (for our detailed coverage of the ORIGIN results, please see our ADA ORIGIN report at bit.ly/Nh5k9W). He applauded the authors for including cancer-specific data, noting that such information reassures that the risk of cancer did not differ between ORIGIN’s two treatment arms (standard care vs. insulin glargine). However,   he noted that due to the pattern of drug therapy used in both treatment arms, the determination  of cancer risk was neither clear nor simple. He reminded the audience that 11% of those on standard care received insulin (relative to 83% in the glargine group) and that participants in both groups used a range of oral anti-diabetic agents (such as metformin and sulfonylureas), each of which has been shown to have an association with cancer risk. Dr. Johnson stated that at best, the ORIGIN trial suggests that the specific combination of glucose-lowering therapies used in the glargine arm is not associated with a risk of cancer.

DIABETES AND CANCER MORTALITY: A FRAMEWORK TO ASSESS CONFOUNDING

Andrew Renehan, PhD (University of Manchester, Manchester, United Kingdom)

After distinguishing between the two main types of mortality studies, Dr. Renehan emphasized that selection allocation bias and immortal time bias are major issues in many studies. In ever/never exposure studies (i.e., treatment vs. no treatment), the assumption is that patients in the analysis remain on the drug for the period of the protocol. However, in reality it isn’t that straightforward – some patients only have a short duration of follow-up, some have been on the drug beforehand, etc. Immortal time bias poses a challenge in ever/never exposure studies, as the studies do not account for duration of treatment.

DIABETES, CANCER AND PATIENT REPORTED OUTCOMES

Lonneke van de Poll-Franse, PhD (Tilburg University, Tilburg, The Netherlands)

Dr. Lonneke van de Poll-Franse presented a study on patient reported outcomes among colorectal cancer (CRC) patients with diabetes. Data was obtained from the Eindhoven Cancer Registry, which collects information on patients’ sex, age, socioeconomic status, and co-morbidities at the time of cancer diagnosis, as well as data on the tumor stage and grade and the patients’ initial treatments. Her group’s study focused on patient reported outcomes (PRO) data from roughly 2,000 CRC survivors, among which 16% had diabetes at cancer diagnosis. To separate the effects of diabetes and CRC, the study included data from a normative population (760 people without cancer) matched for age, among which 12% had diabetes. Data revealed that CRC patients with diabetes had statistically significantly lower reported physical and cognitive functioning scores compared to people with only diabetes, only CRC, or neither disease (no significant difference was observed among the three latter groups for any PRO included in the presentation). Dr. van de Poll-Franse described the difference in physical and cognitive functioning as clinically significant. Similarly, people with both diabetes and CRC reported higher levels of fatigue, dyspnoea (difficulty breathing), erection problems, anxiety, and depression compared to healthy controls or those with only one disease. Dr. van de Poll-Franse ended her presentation by noting that greater investigation is required to determine the role of lifestyle and therapies for cancer and diabetes on PRO. Specifically, she mentioned that the recent inclusion of pharmacy data in the Eindhoven Cancer Registry revealed that roughly 6% of CRC patients use metformin, and that such information will hopefully help investigators determine the impact of different diabetes therapies on PRO in cancer patients.

  • Dr. van de Poll-Franse’s study included data from the Eindhoven Cancer Registry, which collects data from an area in the south of the Netherlands that hosts 2.4 million inhabitants and is served by ten hospitals and two radiotherapy institutes. Started in 1955, the registry tracks roughly 20,000 new cancer diagnoses per year, collecting data on patients’ sex, age, and socioeconomic status, as well as data on the tumor stage and grade and the patients’ initial treatments (e.g., type of surgery, radiotherapy, systemic therapy). Since the mid-1990s, the registry has collected information on patients’ comorbidities at the time of cancer diagnosis, and has gathered patient reported outcomes since 2004 from different cohorts of cancer survivals. Dr. van de Poll-Franse ended her introduction by noting that roughly 20% of CRC patients have diabetes at the time of cancer diagnosis, and that CRC patients with diabetes are treated less aggressively.
  • Dr. van de Poll-Franse concluded her presentation by noting that several questions remain, including those regarding the role of lifestyle and therapies for cancer and diabetes on patient reported outcomes (PRO). Specifically, she cited a recent article in JAMA reporting that metformin provides neurological benefits by encouraging new neuron growth and enhancing memory in mice (Hampton, JAMA, 2012). To Dr. van de Poll-Franse, such findings suggest a possible therapeutic value for metformin in patients with various neurological disorders. She then mentioned that the recent inclusion of pharmacy data in the Eindhoven Cancer Registry has revealed that roughly 6% of CRC patients use metformin, and that such data will hopefully help investigators determine the impact of different diabetes therapies on PRO in cancer patients.

THE INTERNATIONAL STUDY OF INSULIN AND CANCER

Lucien Abenhaim, PharmD, PhD (London School of Hygiene & Tropical Medicine, London, United Kingdom)

Dr. Lucien Abenhaim presented results from the International Study of Insulin and Cancer (ISICA), a systematic case-control study assessing the relative risk of breast cancer associated with the use of individual insulins (glargine, lispro, aspart, and human), and the associated risk of insulin glargine with other insulin analogs and human insulin. The study found no difference in risk of breast cancer in patients using glargine or other individual insulins, and that the duration and dose of insulin glargine were not associated with increased breast cancer risk. Dr. Abenhaim noted that the study was powered to conclude that insulin glargine (for a mean duration of 3.2 years) had an odds ratio of less than 1.4; the power for subgroup analysis was limited.

  • This case-control study assessed the relative risk of breast cancer associated with the use of individual insulins, and compared the associated risk of insulin glargine with other insulin analogs and human insulin. Ninety-two large breast cancer centers were identified in the UK, France, and Canada; of the 39,958 patients diagnosed from January 2008 to June 2009, 6.2% were identified as patients with diabetes. Of this subset, 41.3% were eligible to include in the study (age, cancer stage, insulin use, and glargine use were very similar to patients who were not included in the study). Controls (with diabetes) were obtained from 582 general practitioner practices. Cases (n=775) and controls (n=3,050) were on average 52-53 years old; over 96% were on oral antidiabetic medications, and approximately 25% were on insulin (the average time to insulin initiation was 11.3 years). The proportion of patients in the case and control groups with A1c below 6.5%, from 6.6-8.0%, and above 8.0% were similar, as was the rate of complications.
  • Insulin use (of less than eight years in duration) was not associated with an increased risk of breast cancer. In addition, insulin glargine was not associated with an increased risk of breast cancer versus lispro (OR=0.85; 95% CI: 0.48-1.50), aspart (OR=1.10; 95% CI: 0.64-1.89), or human insulin (OR=1.29; 95% CI: 0.78-2.13).

 

Insulin <8 years

 

Adjusted Matched OR

95% Confidence

Interval

Glargine

1.04

0.76-1.44

Lispro

1.23

0.79-1.92

Aspart

0.95

0.64-1.40

Human

0.81

0.55-1.20

Past use of any

insulin (≥8 years)

 

0.93

 

0.61-1.42

  • The duration of dose of glargine use were not associated with breast cancer risk. Those who used glargine for less than four years had an adjusted matched OR of 1.15 (95% CI: 0.70-1.89), while those who used glargine for four to seven years had an adjusted matched OR of 0.94 (95% CI: 0.51-1.74). Those who used less than 27 units of glargine per day had an adjusted matched OR of 1.10 (95% CI: 0.61-1.97), while those who used at least 27 units of glargine per day had an adjusted matched OR of 1.02 (95% CI: 0.59-1.75).

Questions and Answers:

Q: Was there any difference in outcomes in breast cancer patients treated with glargine and metformin versus treated with glargine but not metformin?

A: We did an interaction analysis, and there was no interaction with metformin. Metformin by itself was slightly protective; however, the non-effect of insulin glargine was the same in those with and without metformin use.

INDEPENDENT COMMENTARY ON ISICA

Helen Colhoun, MD, PhD (Public Health University of Dundee, Dundee, Scotland)

Dr. Helen Colhoun provided independent commentary on the International Study of Insulin and Cancer (ISICA), highlighting a number of strengths and weaknesses of the study. Strengths included: 1) the inclusion of 2,469 breast cancer cases of patients with diabetes; 2) good characterization of the tumor type; 3) the inclusion of reasonably extensive covariate data; 4) the attempt to model the cumulative effectives of exposure; and 5) contextualization of any effect of insulin glargine versus other insulins. Subsequently, she pointed out that the reliance on patient recall of prescriptions was likely to be highly inaccurate, especially in relation to the quantification of duration and dosage. In addition, she stated that random misclassification would bias the odds ratio toward the null. Dr. Colhoun also wondered why study investigators went through such a laborious method to identify patients with breast cancer and diabetes, then obtain information on their medication use through recall, when there are currently so many good drug databases and disease registries. She stated that case-control studies have all the same problems as cohort studies: 1) those who are destined to receive the drug may be at higher or lower prior risk of cancer; 2) negative allocation bias will hide a drug’s effect; 3) positive allocation bias will cause a drug to appear as though causally related to cancer when it is not; and 4) propensity scores and covariate adjustments cannot ever completely address this issue. Dr. Colhoun commented that it was reassuring that there was no hint of any cumulative exposure effect, but the power to detect an effect was limited; she considered the study as useful in adding to the body of evidence, but limited in the amount of new knowledge added.

EPIDEMIOLOGICAL STUDIES OF DIABETES AND CANCER: THE NEED TO GO BEYOND CONVENTIONAL APPROACHES

Helen Colhoun, MD, PhD (Public Health University of Dundee, Dundee, Scotland)

Dr. Helen Colhoun proposed that epidemiological studies test for cumulative effects within users, since this method would not be subject to between-person allocation bias. She briefly reviewed a number of observational studies (Ruiter 2011, Lind 2011, Manucci 2010, Suissa 2011, Fagot 2012, Andersson 2012, and Boyle 2012) of insulin glargine and cancer that considered the effects of cumulative exposure, concluding that the studies suggest there is no cumulative effect of insulin glargine on total cancer. In closing, Dr. Colhoun stated: 1) there have been too few studies on the cumulative effects of insulin glargine on cancer risk to date, and that more data are needed; 2) the results are mixed, but mostly reassuring in terms of the effects of insulin glargine on colorectal cancer (nonetheless, it requires further examination); and 3) any future studies should report the effect of including time-updated terms for both ever use and cumulative use.

Questions and Answers:

Q: I’m curious to hear your thoughts on some of the early signals and concerns for the new SGLT-2 class and its potential cancer risk. Insulin glargine has been out there for a long time, and that makes it possible to do a study with this type of rigor behind it. I just wanted to hear your thoughts on how we should think about a new class showing a potential link to cancer, and the importance of doing studies like this to give us confidence.

A: I think it’s really important. I think that it’s really difficult to ever get complete safety reassurance from RCTs, because most randomized trials of diabetes drugs are not going to have sufficiently long follow-up to be able to provide reassurance about every site-specific cancer. We will always need observational studies in addition. I do think that the three initial studies of insulin glargine in Diabetologia were flawed they couldn’t look at cumulative exposure, and the effects were likely due to allocation bias. But, I think something useful they’ve done is to stimulate discussions about the appropriate methods in this field. What’s becoming a lot clearer now is the right way and the wrong way to analyze these data. We need to have multiple repeated studies in different populations to really show an effect as likely causal and real. As a community, we need to stop going off the deep end when someone reports an odds ratio above one – we need to take a step back and evaluate the methodology.

Symposium: Is Type 1 Diabetes an Enterovirus Disease? (Dedicated to the Memory of Professor Keith Taylor)

EVIDENCE OF VIRAL INFECTION IN THE PANCREAS OF PATIENTS WITH TYPE 1 DIABETES

Noel Morgan, PhD (University of Exeter Medical School, United Kingdom)

Dr. Noel Morgan began the symposium by trying to answer the question “Can new insights be gained into the molecular events that cause type 1 diabetes in humans by analysis of autopsy pancreas sample?” To answer this question Dr. Morgan and his research team studied autopsy samples from two cohorts (total n=89). They found viral protein 1 (VP1, the major structural viral protein) in 44 of the 72 samples they studied from children who had type 1 diabetes, whereas in 50 samples from children without diabetes, VP1 was found in only three samples . (However, on average only ~5% of islet cells in people with type 1 diabetes were positive for VP1.) Believing that viral induction and activation of the immune response would generate a specific, detectable, “foot print” within islet cells, Dr. Morgan looked at the expression of protein kinase R (PKR, an enzyme that protects the body against viral infections) and double-stranded RNA (dsRNA is produced by enteroviruses but not human cells). He found that 87% of the cells that were positive for VP1 contained PKR and that dsRNA is present in beta cells of people with type 1 diabetes. Dr. Morgan concluded that both these signals are consistent with the “foot print” of previous enteroviral infection in people with type 1 diabetes. During Q&A he explained that the cause of type 1 diabetes is probably not the virus itself, but rather an inappropriate immune response to the virus.

  • Autopsy pancreas samples from two cohorts were used for this study. One was from British children who died shortly after being diagnosed with type 1 diabetes (n=72, mean age 12.6 years, mean post-diagnosis survival ~8 months). The other, from the National Network for Pancreatic Organ Donors with Diabetes (nPOD), contained samples from Americans (mean age25.7 years) who survived longer after diagnosis (mean ~11.6 years). Dr. Morgan said that one advantage of the latter cohort is that sample processing has been more strictly controlled.
  • Dr. Morgan identified several different markers that are consistent with beta cells sustaining an enteroviral infection. First, he found protein kinase R (PKR) in 87% of the cells that were positive for viral protein 1 (VP1), corroborating that these cells had been infected by a virus. PKR fights viral infections by arresting translation so that viruses cannot replicate. But this also slows the cell’s own translation, which could contribute to beta cell death. Additionally, Dr. Morgan found that myeloid cell leukemia sequence 1 (Mcl-1), an anti-apoptotic (programmed cell death) protein is selectively depleted in islet cells expressing VP1 and PKR. He hypothesized that the increased levels of PKR in beta cells might degrade MCl-1, increasing sensitivity to pro- apoptotic stimuli and resulting in beta cell loss. Also found in the beta cells of people with type 1 diabetes were double stranded RNA (dsRNA) and melanoma differentiation-associated protein 5 (Mda5), a cellular sensor for dsRNA. Since viruses create dsRNA but human cells do not, these findings also indicate that the beta cells had been infected by a virus.

Questions and Answers:

Q: There is always an argument that what you are showing is a very late-stage event. Have you looked at the pancreas of people who are at risk for type 1 diabetes, but do not have it yet?

A: We have not been able to do that yet, but I believe the nPOD [National Network for Pancreatic Organ Donors with Diabetes] collection will make that possible.

Q: Is it fair to say that the majority of people who have these viral infections will not develop type 1 diabetes?

A: That is correct. We are not saying that virus per se is the causal agent, but how people respond to the infection. This is also what genetic studies suggest.

HOW VIRAL INFECTIONS CAN ACCELERATE OR STOP DIABETES

Matthias von Herrath, MD (La Jolla Institute for Allergy and Immunology, La Jolla, CA)

Building on Dr. Morgan’s talk in the same session, Dr. Matthias von Herrath offered further perspective on the relationship between viral infections and type 1 diabetes. One objection to the relevance of viruses is that only ~5% of beta cells in people with type 1 diabetes are positive for viral proteins. But Dr. von Herrath proposed that type 1 diabetes might develop over the course of several relapses and remissions, with each relapse causing an increase in autoantibodies and more beta cell destruction. Complicating the picture further, Dr. von Herrath described how some viral strains might cause diabetes while others might prevent it. He showed that in mouse models, more severe infections tend to accelerate the development of diabetes while less severe infections can abrogate diabetes. Based on these findings Dr. von Herrath said that a vaccine could be used to prevent serious infections that cause diabetes, potentially reducing their severity enough to even make them protective against diabetes. He also suggested that risk of autoimmunity could be reduced by exposing children to pathogens that are no longer common in our hygienic environment, such as parasitic worms – a bold approach to preventive care that we think would get a mixed reception from parents.

  • As Dr. von Herrath explained, viruses that infect beta cells can cause a strong inflammatory response, including the upregulation of major histocompatibility complex 1 (MHC 1). In mouse models with virally induced type 1 diabetes, the upregulation of MHC 1 is a prerequisite for beta cells to be recognized and destroyed by CD8+ (killer) T cells. In normal mice, MHC 1 levels go back to normal shortly after the mouse is infected, but in diabetes model mice MHC 1 levels stay elevated. Similarly, humans with type 1 diabetes can have elevated MHC 1 levels for up to eight years after diagnosis. However, this elevation is not always due to an inflammatory infiltrate (like a virus), which makes Dr. von Herrath wary of attributing causality.
  • Citing the hygiene hypothesis, Dr. von Herrath explained that the more infections an immune system encounters, the more tuned it becomes to fighting off an infection and then returning to its normal state. Upon being infected by a virus, a person’s immune system’s regulators (T regs) are decreased, and the immune system is ramped up to fight off the infection. Soon after, however, T reg levels are reestablished, reducing the immune response. This is necessary, because a long duration of high immune activity could result in autoimmunity. The immune system gets better at turning itself on and off the more times it goes through the process, Dr. von Herrath stated. This implies that modern hygiene, while generally a good thing, interferes with the immune system’s ability to train itself. He proposed that some things that have “fall[en] to the wayside” might need to be therapeutically brought back. In particular he suggested the use of parasitic worms that do not reproduce or grow into full parasites; these worms could potentially tune peoples’ immune systems (and prevent autoimmunity) without making them sick. Though we see the therapeutic value, we question if parents would be comfortable with giving worms to their children.

Questions and Answers:

Q: I am a little confused. If viruses protect from diabetes, as you have shown, why should we have a vaccine against them?

A: You would have to develop a vaccine to those viral strains that replicate to higher levels or are associated with diabetes in humans, but not against strains that are not associated with diabetes. Also, the vaccine could reduce the severity of the infection so that it will be less deleterious. A good vaccine could cause a severe infection to either be less deleterious or even protective.

Q: Brilliant as usual. You mentioned the hyperglycemia expression of MHC 1 in beta cell. What about MHC 2?

A: We have not done this in detail at this point. In mice it has been difficult to attribute any MHC 2 to beta cells. In the humans we have not looked at class 2. Right now we are looking at subsets of class 1.

Comment: We had the chance to look for MHC 2m and we found it expressed in some endothelial cells.

PROSPECTS FOR A PREVENTIVE VACCINE

Heikki Hyöty, MD, PhD (University of Tampere, Tampere, Finland)

In his presentation, Dr. Heikki Hyöty sought to answer the question, “Is there enough evidence to start the development of an enterovirus vaccine against type 1 diabetes?” His answer: yes. As evidence that enteroviruses cause type 1 diabetes, he cited that the odds ratio for people with type 1 diabetes testing positive for an enterovirus is about ten. Further, Dr. Hyöty noted that the seasonality changes in type 1 diagnosis rates parallel that of enteroviruses. He admitted, however, that neither of these facts signifies causality. In Dr. Hyöty’s view, developing an effective vaccine against a type-1-diabetes-causing virus will require more research on what enterovirus serotypes (sub-species) cause diabetes – essentially, it is impossible to develop a single vaccine against the more than 100 enterovirus serotypes out there. By comparison, the polio vaccine is effective because it targets the three enterovirus serotypes that cause polio. Looking at 41 enterovirus serotypes in the Finnish Type 1 Diabetes Prediction and Prevention Project (DIPP; n=183 case children plus two matched control children for each case child), Dr. Hyöty found that children with the coxsackie B virus 1 (CBV1) had an odds ratio of 1.6 for developing type 1 diabetes (p <0.02). A similar study (VirDiab; n=454) performed in a broader population from the European Union corroborated that CBV1 is correlated with an increased risk for type 1 diabetes. According to Dr. Hyöty, CBV1 is the most common enterovirus serotype in the United States and results in severe systemic infections in newborns. He estimated, however, that <5% of children who have such an infection develop type 1 diabetes. Dr. Hyöty believes that a vaccine could prevent more than 50% of diabetes cases, though he did not explain how he reached this number.

Questions and Answers:

Q: Is there an interaction between risk genotypes and being positive for CVB1?

A: We are actually working on this question. There are statistical problems as we divide groups into smaller and smaller groups. There is some evidence that there is an association but we need a much larger cohort

Q: Is the fetal pancreas more sensitive to CVB?

A: The young are very sensitive to CVB because their immune system is still developing.

Q: Is there any correlation between type 1 diabetes and mumps?

A: There have been some publications on this topic. Overall I don’t think mumps can play a major role. One argument against mumps causing type 1 diabetes is that the incidence of diabetes has not decreased since the mumps vaccine was started.

Symposium: Hypoglycemia and Mortality in Diabetes

HAVE WE LEARNT FROM CLINICAL TRIALS?

Sophia Zoungas, PhD, MBBS (Monash University, Victoria, Australia)

Dr. Sophia Zoungas presented on severe hypoglycemia in the ACCORD, ADVANCE, and VADT studies. We appreciated that Dr. Zoungas concluded her presentation with a review of research insights from ACCORD, ADVANCE, and VADT analysis, but even more so, that she concluded with the clinical implications: 1) choose approaches to glucose lowering that minimize risk of severe hypoglycemia; 2) ensure patients are educated about avoidance and management of hypoglycemia; 3) experience of severe hypoglycemia should lead to an examination of comorbid diseases that may produce adverse outcomes; and 4) persistent attempts to intensify therapy in non-responsive high risk patients should be avoided. Dr. Zoungas’ presentation added to the discussion of the role of severe hypoglycemia in excess mortality in a thoughtful manner – she suggested that severe hypoglycemia could be both a direct cause of severe hypoglycemia and a marker for other comorbid diseases that cause the excess mortality. Certainly, the discussion of cause vs. association is far from over, but as Dr. Zoungas’ clinical tie-in at the end of her presentation reminded us, the most important thing is that severe hypoglycemia is being seriously considered and appropriately addressed in the clinical setting.

  • Patients in the VADT had a longer duration of diabetes and had a greater percentage of patients entering the trial already on insulin therapy. It follows then, that by the end of the study, in the intensive treatment by the end of the trial a greater percentage of patients were on insulin therapy compared to in ACCORD or ADVANCE. Dr. Zoungas thought the differences in diabetes duration and insulin therapy could help explain the differing rates observed in severe hypoglycemia between the trials.
 

Insulin Therapy at End

Severe Hypoglycemia

 

Study

Duration of Diabetes (years)

Insulin Therapy at Start

 

Intensive

 

Standard

 

Intensive

 

Standard

ACCORD

10

35%

77%

55%

10.5%

3.5%

ADVANCE

8

1.5%

40%

24%

2.7%

1.5%

VADT

12

52%

89%

74%

19.2%

9.9%

  • Dr. Zoungas believes that the different titration patterns account for the differing patterns in severe hypoglycemia between the ACCORD and ADVANCE trials. Dr. Zoungas explained that in the intensive ACCORD arm, therapy was rapidly titrated. As such, the highest rates of severe hypoglycemia occurred early in the trial. In ADVANCE however, titration was much slower (i.e., started on oral agents, then basal, then more complex insulin regiments) and the higher rates of hypoglycemia were thus observed later on.
  • Dr. Zoungas argued that the majority of cases of severe hypoglycemia could be potentially be prevented with education. She began by reviewing the most frequent immediate antecedents to severe hypoglycemia recorded in ACCORD: 1) variation in food intake (i.e., missed or delayed meal) preceded 48% of events; 2) exercise (either unexpected or more vigorous than expected) preceded 15% of events; and 3) incorrect insulin use preceded 9% of events. Variation in food intake and exercise made for antecedents that could be mediated through education. Moreover, if patients were better educated on the frequent symptoms associated with hypoglycemia then they could know what to look out for and prevent the severe episodes.
  • Dr. Zoungas believes that severe hypoglycemia cannot be ruled out as a direct cause of increased mortality. ADVANCE showed no close temporal relationship between severe hypoglycemic events and adverse endpoints and no dose response (where patients with mild hypoglycemia would have had an increased risk of adverse outcomes) and ACCORD investigators did not attribute excess mortality to hypoglycemia; however, Dr. Zoungas argued that in these trials there is no way to account fully for the downstream cascade of pathophysiological consequences resulting from severe hypoglycemia.
  • Severe hypoglycemia could also be a marker of risk. Dr. Zoungas suggested that severe hypoglycemic events may reflect the effects of co-morbid diseases that increase a patient’s vulnerability to both severe hypoglycemia and adverse clinical outcomes. Importantly, Dr. Zoungas emphasized that viewing severe hypoglycemia as a cause of excess mortality and as a marker of risk for a comorbid disease causing excess mortality were not mutually exclusive
    • Consequently, severe hypoglycemia should lead to an examination of patients for comorbid diseases. Providers shouldn’t just alter therapy in response to severe hypoglycemia, she said, but should first think more broadly about why the patient is presenting with severe hypoglycemia at that time.
  • Persistent attempts to intensify therapy in non-responsive high risk patients should be avoided. While she seemed to have disagreed with the ACCORD investigators on the role of severe hypoglycemia in mortality, on this clinical implication they certainly agreed.
  • The relationship between severe hypoglycemia and adverse events may be different for younger patients with type 1 diabetes than the comparatively older patients with type 2 diabetes analyzed in these studies. She suggested that younger patients with type 1 may be able to compensate better for the negative effects of severe hypoglycemia.

Questions and Answers:

Q: Can you cut the data to look at the effect of sulfonylureas?

A: These were not monotherapy studies; the majority of patients are on complex algorithms so the proportion of patients on a single agent is small. We’ve looked at SFUs as an independent variable, but in fact when you put it in a model with other variables it seems to be accounted for by renal function and other factors. The SFUs did not seem to be associated with increased mortality

Q: In someone who is hypoglycemia naïve, is that first episode more dangerous?

A: In ADVANCE there were so few reported repeated episodes that there’s no sensitivity to examine effects. So there are small numbers and we can’t make conclusions with any confidence about whether repeated or isolated event have any association on mortality. By talking with other trials, maybe we can do that in the future.

Comment: You didn’t consider the ORIGIN trial. Why not start early and keep A1c down from the beginning? In this case even treatment with SFUs does not increase hypoglycemia because patients will still have counter regulatory mechanisms.

A: I’ll take that as a comment, thank you.

DEAD IN BED SYNDROME

Simon Heller, MD, FRCP (University of Sheffield, Sheffield, UK)

Dr. Simon Heller reviewed severe hypoglycemia and “dead in bed syndrome,” focusing mostly on cardiac-related experimental evidence. Dr. Heller emphasized that dead in bed is a clinically relevant problem – citing data from Thordarson and Sovik, Diabet Med 1995, dead in bed syndrome appears to occur in 6% of all deaths in people with diabetes younger than 40 years old. Indeed, Dr. Heller noted that his clinic has lost two young patients to nocturnal hypoglycemia. He spent most of his presentation discussing some of the experimental data linking hypoglycemia to death, including 1) a prolonged QT interval; 2) rises in circulating adrenaline concentrations and falls in circulating potassium levels caused by insulin induced hypoglycemia; 3) increased activity in sympathoadrenal fibers innervating the heart; 4) subclinical or overt autonomic neuropathy within the heart; and 5) mutations or polymorphisms affecting the relevant proteins concerned with the cardiac action potential. Interestingly, more males seem to die from dead in bed syndrome than females – Dr. Heller hypothesized that this was due to increased vagal tone in males. In closing, he reemphasized that dead in bed is relevant clinically, appears to be associated with nocturnal hypoglycemia, and warrants further investigation.

Questions and Answers:

Q: What is the effect of hypoglycemia on late changes in the autonomic nervous system? The sympathetic defect remains 16 hours after induction of hypoglycemia.

A: You’re talking about Freeman and colleagues in Boston. In non-diabetic individuals they induced hypoglycemia and depressed the sympathetic responses 24 hours later. You could imagine the vagal response might be unbalanced – that’s another potential mechanism that needs to be looked at.

Q: You talked about the importance of autonomic neuropathy. What do we know about interference with beta blockers?

A: Good question. It’s important to remember that these individuals have short duration diabetes. Fewer have evidence of neuropathy. We have done a study using beta blockers in people with diabetes, and in an experimental situation, we could obliterate the QT interval. On other hand, if bradycardia is causing a problem, it’s not a great idea. Before we advocate using them, we need more investigation.

Q: Regarding type 1 diabetes, is the use of human insulin as a basal insulin (vs. analogs) responsible?

A: In terms of causing this problem, it’s irrelevant as far as I can tell. We’ve had a 16-year old and a 22- year old die on human insulin. But we emailed two patients treated with analog insulin that also ended up dying.

Symposium: Oral Therapies: New Targets

NEW ROUTES TO ENHANCING THE ACTION OF INSULIN

Stefano Del Prato, MD (University of Pisa, Pisa, Italy)

Dr. Stefano Del Prato began this review lecture by noting that, despite the recent “renaissance” of type 2 diabetes drug development, the only available therapies that improve insulin sensitivity are metformin and the TZDs. He proceeded to discuss investigational agents that might also enhance the body’s response to insulin. One investigational strategy is to try to mimic metformin and act through AMP kinase. AMPK activators that have been studied for type 2 diabetes include members of the thienopyredone family and derivatives of D-xylose; Dr. Del Prato said that the mechanism was powerful but is difficult to make tissue-specific. An alternative strategy is to improve upon the TZDs, as is being attempted with PPAR-alpha/-gamma dual agonists (e.g., aleglitazar), PPAR-alpha/-delta/- gamma triple agonists (e.g., indeglitazar), and selective PPAR modulators (SPPARMs, e.g., INT131). Dr. Del Prato suggested that the most promising approach of all is to develop agents acting along the intracellular insulin-signaling pathway. On this note, he expressed particular enthusiasm for FGF21- based agents and also mentioned insulin mimetics, PTP1b inhibitors, antioxidants, anti-inflammatory agents, and blockers of fatty acid oxidation. He said that one thing seems sure: that the complex pathophysiology of type 2 diabetes will lead to an increasingly complex set of therapies. (Roughly 150 type 2 diabetes drugs are in development, he mentioned). Dr. Del Prato’s prediction is thus that diabetologists in the future will need, more and more, to become specialists – a prediction that seems sadly incompatible with the enormous incidence of the disease and today’s poor reimbursement for diabetes care.

  • Inspired by the mechanism of metformin, several drugs in development activate AMP kinase in order to improve insulin sensitivity and reduce inflammation. Dr. Del Prato looked in particular at two families of AMPK activators. The thienopyredones include A- 769662, which was shown to have positive effects on blood glucose and triglycerides in preclinical research (Cool et al., Cell Metab 2006). He also mentioned derivatives of D-xylose, such as E-36, which improved insulin sensitivity and decreased blood glucose. Dr. Del Prato explained that the many potential benefits of AMPK activation include increased glucose uptake and lipid oxidation in the skeletal muscle, increased exercise capacity, improved vascular function, and improved lipid profile. However, he cautioned AMPK activation is difficult to make tissue-specific, and potential side effects of global exposure cardiomyopathy and increased appetite. In this vein Dr. Del Prato briefly mentioned SIRT1 activation as an alternative way to achieve benefits on multiple organ systems, though the candidate that he seemed most excited about was resveratrol in the form of Pinot Noir.
  • The most advanced insulin-sensitizing drug currently in development is Roche’s aleglitazar, a PPAR-alpha/-gamma dual agonist that is being studied in a 7,000- patient cardiovascular outcomes study called ALECARDIO. The 150 ug dose of aleglitazar causes similar glycemic benefits to 45 mg pioglitazone, with better lipid effects (Henry et al., Lancet 2009). Side effects like weight gain and edema were reduced relative to pioglitazone, but still present – and Dr. Del Prato said that he thinks the side effects will be important to keep in mind. He seemed somewhat more optimistic about PPAR-alpha/-delta/-gamma agonists, such as indeglitazar, which has been shown to lower body weight while improving glycemia (Artis et al., PNAS 2009). An alternative to achieve efficacy with minimal side effects is offered by selective PPAR modulators (SPPARMs); as an example, Dr. Del Prato described phase 2a data for INT131 showing improvements in general metabolic profile (Dunn et al., J Diabetes Complications 2011).
  • In the third stage of his talk, Dr. Del Prato consulted a diagram of intracellular insulin signaling and reviewed the variety of therapeutic targets along this pathway. He explained that PTP-1b inhibitors could theoretically remove a major barrier to insulin signaling, and many agents have been studied. However, as detailed in a recent review (Verspohl, Pharmacol Rev 2012), such inhibitors need to be highly charged molecules – making oral dosage a “tremendous challenge.” Fatty acids are another big challenge to insulin signaling, and blocking fatty acid oxidation with teglicar improves blood glucose – but unfortunately also increases liver triglyceride content (Conti et al., Diabetes 2011). The mechanism for which Dr. Del Prato seemed most enthusiastic was FGF21 signaling, which involves the liver and potentially brown fat. In a db/db mouse model, FGF21-based therapy has been shown to confer significant metabolic benefit (Wu et al., Sci Transl Med 2011).

Symposium: Diabetes and Acute Coronary Syndrome

ROLE OF DIABETOLOGIST

Peter Gæde, MD, DMSc (Copenhagen University Hospital, Copenhagen, Denmark)

Dr. Peter Gæde explored the topic of whether patients with diabetes and acute coronary syndrome (ACS) should be treated intensively with insulin. He argued that hyperglycemia (acute hyperglycemia more so than chronic hyperglycemia) contributes to morbidity and mortality associated with ACS, but that data from randomized control trials of diabetes patients experiencing ACS provide evidence that using intensive insulin treatment to control blood sugar does not decidedly improve outcomes. In multiple studies (e.g., DIGAMI and DIGAMI-2) patients assigned to intensive insulin therapy did not actually achieve better glycemic control than patients in the standard care arm, so results are difficult to interpret. However, Dr. Gæde argued that what has been established is that when studies find that patients with more intensive glycemic control experience higher mortality, it is primarily because intensive insulin treatment results in more hypoglycemia, and hypoglycemia has been recognized as a predictor of mortality (e.g., in NICE-SUGAR, the largest study to compare intensive vs. standard glucose control in the ICU, moderate and severe hypoglycemia were associated with increased mortality). He stated that the highest priority for diabetes control for patients with ACS should be avoiding hypoglycemia.

Questions and Answers:

Q: Glucose variability is a popular topic now – any comments? Is variability or absolute glucose level most important?

A: As I alluded to earlier, variability is very important. If you look at some observational trials, you see patients that have very high glucose excursions on two hour-post prandial tests, and these patients have a very high risk for complications.

Q: Given the risk of hypoglycemia and given that you have been speaking only of insulin treatment, do you see a role for alternative diabetes treatments under these conditions?

A: Yes. I always say we need a statin for glucose, because if we could just lower glucose without the side effects or hypos, things would be very different. I think GLP-1s may head in that direction but I think we don’t have the data to say that yet.

MANAGEMENT AFTER DISCHARGE

Guy Rutten, MD, PhD (University Medical Center, Utrecht, Netherlands)

Dr. Guy Rutten gave a compassionate talk emphasizing the need to treat not only disease, but patients as a whole. He noted that many patients with both diabetes and acute coronary syndrome (ACS) find it hard to manage both diseases at once, neglecting one disease if they prioritize the other. He called for a tailored approach in which patients and primary care physicians are proactive in consolidating treatments prescribed by cardiologists and diabetologists. During Q&A, he noted that glycemic control after discharge for ACS might realistically have to take a back seat to blood pressure and lipid control.

Questions and Answers:

Q: Regarding the problem of adherence to treatment – especially with regard to handling both diseases – what can be done? Is it just a matter of awareness or support? Or is there a potential technical solution? Should we use a system to track use of treatment?

A: People who are not adherent are, on average, less well educated and less well informed. I would emphasize the ADA recommendations. If each hospital has a structured system so that the patient talks with a diabetologist or cardiologist upon discharge for even five to 10 minutes to emphasize the need for continuing use of medications and suggest that the patient go to their primary care physician with a discharge form, it would ensure there is not a gap in the continuation of care. Perhaps a technical solution might work, but I think a discharge consultation is very valuable.

Q: What kind of A1c target would you propose for a patient with ACS in the first three months of discharge? Should we be stringent or less so?

A: Of course A1c is important but I think also in the months after discharge, blood pressure and lipids are even more important. But of course, if they let diabetes slip then, it would not be good. It’s not realistic to strive for strict glycemic control in the first month. We should be glad if they just continue all medications and can cope with the two diseases and keep A1c stable. If you look at the stratification analysis of UKPDS, I think between 7% and 8% would be a realistic goal.

Symposium: Novel Mediators of Metabolic Stress

ADIPOSE TISSUE SENESCENCE AT THE CROSSROAD BETWEEN INFLAMMATION, ADIPOSE TISSUE DYSFUNCTION AND INSULIN RESISTANCE

James Kirkland, MD, PhD (Mayo Clinic, Rochester, MN)

Dr. James Kirkland argued that aging is the single biggest risk factor for many of the diseases that affect society and thus, interfering with aging mechanisms could help delay multiple diseases (like type 2 diabetes and obesity). He reviewed evidence suggestive of close links between fat tissue and aging – decreasing visceral fat surgically increases maximum lifespan and obesity. Furthermore, lipodystrophies are associated with an increase in many age-related diseases. Dr. Kirkland believes there is a link between fat and the life- and health-span and as such, his research has concentrated on cellular senescence in fat tissue. Dr. Kirkland reviewed a series of in vitro and murine studies to demonstrate that senescent fat cell progenitor cells (i.e., the preadipocyte precursor cell) accumulate both with aging and with obesity and that preadipocytes (i.e., adipocyte precursor cells) interfere with normal adipogenesis, and have a pro-inflammatory secretory state that attracts macrophages. Dr. Kirkland then showed that by ameliorating the senescence-associated secretory phenotype, he could increase fat mass and decrease frailty in elderly mice. The next step, said Dr. Kirkland, is to extend these studies to explore adipose senescence in obesity and diabetes.

THE INFLAMMASOME IN ADIPOSE TISSUE INFLAMMATION AND INSULIN RESISTANCE

Rinke Stienstra, PhD (Radboud University, Nijmegen, The Netherlands)

Dr. Rinke Stienstra presented on the role of the inflammasome in insulin resistance and therapeutic potential of targeting the inflammasome. For background, the inflammasome, he said, is the “guardian of the intracellular environment.” Importantly, he argued that the inflammasome controls caspase-1 activation, which in turn enhances cytokine production and leads to insulin resistance. Dr. Stienstra suggested that during obesity, inflammasome-mediated caspase-1 is activated in adipose tissue. Thus, he posited that 1) inhibiting caspase-1 could reduce inflammation and improve insulin sensitivity and 2) blocking downstream effectors of caspase-1 activation could similarly improve insulin sensitivity. He highlighted several agents that potentially acted through these mechanisms including: 1) glyburide (the most widely used sulfonylurea for the treatment of type 2 diabetes in the US), which been shown to block inflammasome activation; 2) diarylsulfonylureas, which inhibit cytokine release and are currently being investigated in obese animals; and 3) anakindra, an IL-1 receptor agonist (i.e., blocks downstream effectors of caspase-1).

Questions and Answers: 

Comment: Glyburide is an inhibitor of the inflammasome, but my understanding is that the doses necessary far exceed levels we can obtain in the clinic so perhaps we should not believe too much in this drug.

Merck – Press Conference: Living Diabetes: Journey for Control

LIVING DIABETES: JOURNEY FOR CONTROL

Merck has sponsored a new global survey of physicians and people with type 2 diabetes, called Living Diabetes: Journey for Control. The key finding is that there is a mis-match between what the HCPs claim was discussed and what patients actually remember. For example, for whatever reason, about a third of patients can’t recall talking about their A1c/blood glucose levels with their physician. Clearly, very important information has not been relayed or is not being acted upon. This applies in all topics – such as blood glucose management, hypoglycemia, cardiovascular health, and emotional support. Merck has followed up the survey by creating a very useful patient worksheet. This serves as a guide to make sure that all the key discussions are explicitly conducted between the doctor and patient.

  • According to recent estimates, there will be 552 million people with diabetes globally by 2030. Diabetes currently accounts for 11% of total healthcare expenditures in adults. In a recent NHANES survey in the USA, only about 50% reached A1c targets (<7%), only 42% reached cholesterol targets (LDL <100mg/dl) and only 43% achieve blood pressure targets (<130/80mmHg). Very few simultaneously achieve all three targets.
  • The ‘Living Diabetes: Journey for Control’ online survey was conducted in eight countries with physicians (n=807) and people with type 2 diabetes (n=899). The countries surveyed were Australia, China, India, Mexico. UK, Germany , UAE, and Saudi Arabia. The survey was conducted in July and August 2012 by Bryter.
  • Some important findings of the survey include:
    • There is a big mismatch between patient recall and physicians’ claims. Patients remember much less of what the HCPs suggested was discussed. This is exaggerated with lifestyle factors. E.g. nearly 100% of physicians discuss blood glucose levels, but only two thirds of patients recall it.
    • Only 67% of patients were provided with education and information to manage hypoglycemia.
    • 25% patients skip meals as result of work and 44% patients had recent hypoglycemia at work, but 76% do not discuss their occupation/work hours with their physician.
    • 53% reported recent symptoms of hypoglycemia. But 38% believe it’s because of stress (which is not a factor). 37% say their HCPs don’t discuss hypoglycemia, and 31% can’t recall being informed about ways of reducing the risk of hypoglycemia.
    • About half of patients don’t have access to an educator or nutritionist.
    • 45% of patients didn’t discuss cholesterol at routine checkups.
    • HCPs are reluctant to discuss emotional and cultural factors with patients, including treatment of diabetes while fasting for religious reasons.
    • Only 38% of patients were asked about emotional health when diagnosed, 66% were not made aware of available emotional support.
  • Patients may need to grieve their lost health. They go through the usual stages - denial, anger, depression, acceptance, which can take up to a number of years. This is because it’s challenging to integrate diabetes identity into self-concept. For this reason, HCPs need to provide options for emotional support. The survey suggests that this is a particularly weak area.
  • Merck has created an individual lifestyle checklist, that a patient can use with his/her physician – to make sure the gaps are filled. The checklist covers all the important topics that need discussing over time. It’s to be distributed in the surveyed countries through various channels including patient advocacy organizations, and should be a very useful resource.

Diabetes Expert Panel Discussion (Sponsored by Sanofi)

HOW COULD THE NEW ADA/EASD POSITION STATEMENT ON TYPE 2 DIABETES ADVANCE DIABETES CARE?

David Owens, MD (Cardiff University, Wales, UK) Luc Van Gaal, MD, PhD (Antwerp University Hospital, Antwerp, Belgium), Andreas Pfeiffer, MD, PhD (Charité University of Berlin, Berlin, Germany), and Eleuterio Ferrannini, MD, PhD (University of Pisa, Pisa, Italy)

Moderated by Dr. Eleuterio Ferrannini (University of Pisa, Pisa, Italy), Sanofi’s panel discussion touched on several key topics including considerations for implementing individualized therapy, the need to intensify treatment sooner in the progression of diabetes, and the potential value of combining basal insulin with GLP-1 agonists. A significant portion of the discussion focused on what the panelists believed to be the greatest barrier to personalized medicine: the fact that doctors only have roughly seven minutes to spend with each patient. The panelists agreed that a critical step to providing effective diabetes care will be reorganizing the healthcare system to better support diabetes therapy, and to use diabetes educators as a way to teach patients about their medications.

PANEL DISCUSSION

Dr. Ferrannini: David, it's a sort of a time honored notion that diabetes is a genetic disease, but you emphasized the impact of the environment and of changes in the environment. Would you like to say a few words on genetic factors?

Dr. Owens: There is always a genetic susceptibility. There are more genetic markers that are being recognized, especially in terms of obesity, which make people more susceptible to obesity if they find themselves in an environment with excess nutrients. We're beginning to understand these factors and recognize them.

Dr. Ferrannini: It wasn't too long ago that diabetes was viewed as a relatively benign condition. People thought it was just the blood glucose level being too high. But, as you all can see, diabetes carries the baggage of severe complications, and it's a complex disease to treat. I will ask, "What are the current goals of diabetes treatment?" It is understood that it is complex. What are the goals that we currently believe are the right ones?

Dr. Van Gaal: Before going into the goals, I think you have correctly introduced the way that I teach my students. When I explain type 2 diabetes, I say that it is more than glucose alone. If you construct goals and targets, you have to take into account not only the glucose targets, but also the lipid, blood pressure, and weight aspects of the disease. Those are also important drivers. You have to take into account the comobidities that patients may already have at the beginning of their disease. You have to make a judgment about their cardiovascular status, their kidney function – these are all aspects that are part of the overall assessment. Of course, we start with the glucose control and then there are the new guidelines that say that an A1c below 7% is still the average target, though somebody likes the idea of suggesting a target to 6.5%. This has to be individualized. I think that the goals and the targets have to be balanced in between the effects of what we'd like to see and what the final outcome is. This is a message for not only students, but also for patients: having a nice figure on their lab sheet is just cosmetic, and we don't need cosmetic. What we need is to avoid the complications, which are driven by the glucose, the blood pressure, the lipids, the weight, and many other factors. That, for me, is the target and overall goal.

Dr. Ferrannini: In the context of achieving a goal or target for A1c or any other target, how important is monitoring of the patient in the case of blood glucose monitoring and more in general, in the case of monitoring blood pressure or lipids? I think this is something that is very prevalent at the meeting here.

Dr. Pfeiffer: I think one thing which is very impressive is that when a patient monitors his blood sugar, he sees what happens when he does certain things. He can learn what food does to him, and that has quite an impact. A number of studies have shown that even in pre diabetes, people learn that moving or walking after eating lowers their blood sugar. For diabetes, what's important – apart from having control over hypoglycemia – is that patients can individualize their own responses. It is almost impossible to change people's feeding habits. People generally eat what they eat, and they love what they eat. But it's better if they know more about it and adjust their food intake – maybe cut down by one piece or eat something else. You can achieve a lot on the educational side by knowing the glucose.

Dr. Ferrannini: I think the message is that diabetes can't be managed unless the patient participates in the whole process of managing the disease. And this past June, a position statement was issued jointly by the ADA and the EASD. The main focus of which is patient centered approach to the disease. Do you care to comment?

Dr. Pfeiffer: This has been a change from previous guidances, which gave algorithms. We have clearly learned that glycemia is not the only goal – there are other things that are important. There are many ways to reach the goal and there isn't that much information telling us which treatment is better. It's important to say that the guideline gives doctors the possibility to negotiate with the patient about his goals. It gives doctors the possibility to adjust the therapy and to justify it to the regulatory authorities. The doctor can say, "The patient doesn't want insulin because he doesn't want to gain weight. I can't give this compound, and this affects the reimbursement." So this guideline affects doctors and patients.

Dr. Ferrannini: Because of the variability in the clinical phenotypes of patients, there is almost no such thing as "diabetes" or "type 2 diabetes", but there are type 2 diabetic patients. The idea is to explore the prevalence, the needs, the opportunities, and the resources of the individual patient to agree with the patient on what is best for him. Either regarding the best treatment or the best sequence of treatments. Perhaps it is useful to remind ourselves that the major reason for treatment failure is the loss of compliance, which is not necessarily the patient's fault, but is probably the fault of the interaction between the doctor and the patient. The idea is that it is not longer acceptable for the doctor to just write a prescription for the patient and say, "This is the pill you should be on. I'll see you in six months. Bye bye." Could we follow up on this with the next video? [Video on the ADA/EASD position statement]

Dr. Ferrannini: This position statement is a long document that maybe you don't wish to read from the first to the last word. But it might be helpful to ask how to implement this. Suppose you're a doctor, how would you put this in reality? How do you implement this personalized approach?

Dr. Pfeiffer: As it nicely shows, it's something where the patient should be interested in the disease. The doctor should explain to the patient the risk and benefit of the therapy – what the patient gets if he does what. What does the patient get if he doesn't eat his sweets and adopts a healthier lifestyle? What does exercise do? The doctor has to explain the benefits, and what the patient may get from the therapy, and the patient should understand what his benefits are and be convinced to do what will help him. He can express his preference for certain approaches because there's no strict way to go about treatment: it's flexible. We'll have to see how much the healthcare system can really deal with that. It's helpful to develop suitable therapies and increase compliance. I very much like this approach.

Dr. Ferrannini: So if I were a patient, Andreas would ask my age because one of the reason for diabetes is that the population is aging. Regarding diabetes in the elderly, you have to think about whether the elderly is frail or doesn't have resources or lives alone and can't take care of hypoglycemia. Age is a very important factor. But that's not the only consideration. Then we have to think if the patient is also hypertensive, or if the patient's lipid profile is OK. What is his body weight? Does he need to lose weight or just prevent from gaining more weight? Regarding the guidelines, is it that we don't have any rules, or are there recognizable pathways or tracks that we can follow?

Dr. Van Gaal: The consequence of the new guideline is that a fixed strategy for patients doesn't exist. This is the new aspect of the personalized approach – it is the biggest novelty of these new guidelines, and I think that the medical community should become aware of that. That's the important role of journalists: to transfer that message to medical doctors. I’m convinced that many physicians, in their contract with their patients, were already applying such a personal approach. But there are some general guidelines. We start a patient with type 2 diabetes on metformin, which is the overall gold standard to start with, except if there are contraindicated for it. As you have learned, type 2 diabetes is a progressive disease so very often, you will have to increase the dose and you will have to add other oral agents. In my personal opinion, it should be done faster in the history of type 2 diabetes. We as physicians are waiting too long. This is part of what we call "medical inertia." Patients are also pushing us a little bit. The next gold standard is – when the time comes – using insulins. You can also give GLP-1 and modern therapies, and you can go into combination therapies. But negotiating with the patient and trying to explain why this or that approach is best, this is most likely the most important strategy in helping the patient accept the medication. Let's not forget that at the same time, lifestyle intervention is a red line through the whole process. For example, make people attentive to their smoking habits. I recently learned that among people with type 2 diabetes, roughly 20% are still smoking and as you know, nicotine abuse is bad for diabetes, for insulin resistance, for cardiovascular disease, and especially for the outcome that we try to avoid: eye disease. Smoking is extremely bad for these endpoint situations. So within the guideline, we have a nice sequence of therapies, but don't forget the lifestyle as a red line throughout.

Dr. Pfeiffer: Wouldn't you expect that A1c might go up and you might perhaps get off target?

Dr. Van Gaal: We should not weaken the target, but as you know (and this is also part of the new guidelines), for some patients, you should be very strict. These are the younger patients or the patients with a shorter duration of the disease and who don’t have a huge risk for hypoglycemia or existing cardiovascular disease. We've learned from a large number of outcomes trials that if you've had a cardiovascular problem or if you are prone to show hypoglycemia under existing therapy, then hypoglycemia is a potential risk for morbidities, and potentially for mortality. Then you have to be less strict. Then you should use a target of 7% or even 7.5%, and maybe a higher target in elderly patients, on the condition that you focus on the other aspects of the disease such as the lipids, the blood pressure, and so on. So it's not one figure that is the target for all of diabetes. That is part of the individualized approach as well.

Dr. Ferrannini: The question that Andreas posed is very pertinent. There is a risk that by talking about personalized medicine – which is the mantra these days – you invite or encourage doctors to loosen up on the disease targets, or on following up with their patients. But Andreas also alluded to some of the obstacles that stand in the way of personalized medicine. For example, the fact that physicians only have seven to ten minutes to deal with any one single patient. Andreas, from your perspective, what do you see as the major hindrance of personalizing your approach?

Dr. Pfeiffer: I think it's the everyday reality of practicing medicine. This is money driven. A doctor in Germany gets very little money from a patient. Doctors have to see 50 patients a day. How much time does he have to discuss with a patient? Also, many patients want doctors to tell them what to do, and to have the doctor push them to adopt more healthy behaviors. This kind of "obligation to pressure" for the doctor might feel more lost in this new approach. So you have two sides - the autonomous patient and the patient who wants to be told what to do.

Dr. Owens: I think there are some concerns. We've had guidelines before, and you well know that there are guidelines out there that people will continue to use and completely ignore the new guideline. The thing to consider is that if we are going to do personalized medicine, we have to do it properly. The general doctor has seven minutes to see the patient, educate the patient, decide on the therapy, educate the patient about glucose monitoring, and so on. Therefore, we have to reorganize our system. There is a commitment by our government to give better education for all patients with diabetes. They have to put their hands in their pockets and contribute. In our clinic, we have 30 patients to see in an afternoon. It's like walking into a tunnel: you go in one side and you hope to get out the other side alive. We need another approach. We need our diabetes educators and we need to use these guideline to convince our organizations that we should readdress how we do diabetes care. Because this is serious. This is not an innocent bystander disease. By the time we diagnose type 2 diabetes, 20% of patients already have eye complications. If you examine their cardiovascular system, 60-80% will also have these complications in place. The patient is told that this group of therapy has these advantages and these disadvantages. It's up to the clinician to balance what's the best approach for that individual at that time. It takes time, and the individual physician can't do that. We have no time to have these bystander patients in our hospital or organization. We must discharge them to primary care. We should use this guideline to make our argument to redress the way we approach this very, very serious condition. Unless we do so, it'll cost the payors a lot in the long term.

Dr. Ferrannini: This is why we're here. So you can become advocates for the need to change the approach to the disease. Also I've noticed that recently, when you first see a patient with diabetes, this patient has been on the internet already and has read a lot of things about diabetes and will ask all sorts of questions. As you know, the information on the web is precious, but uncontrollable. Patients will read about the side effects of drugs and will come to you with questions. It's part of the educational process to make sure that you are better informed than the patients, and that you explain to the patients why you're using this drug and not another. This is new to the field of medicine, but it applies to diabetes just as well.

[Video on the history, development, and use of insulin]

Dr. Ferrannini: So insulin. When you first mention it to a patient as a possibility, generally speaking, his or her reaction is negative. Not only because they don't like injections and finger pricking, but because they know that this hormone, although it saves thousands of lives, is risky because of hypoglycemia and it will make patients gain weight. And also, on the medical side of things, I think it's fair to say that insulin has been traditionally viewed as the very last resort to diabetes treatment: when everything else fails, then you go on insulin. That attitude associates the idea of insulin treatment with the idea of a severe, advanced, complicated stage of the disease. This is another concept that is slowly changing.

Dr. Owens: I think what you've illustrated is that there is a look of horror on patients' faces when you mention insulin. They relate this to people they've seen. They do view insulin as a last resort. So therefore, it's the end of the road as far as they're concerned. But it is again emphasized in this guideline that in personalized medicine, one should engage with the patient and explain what this life-giving hormone is capable of giving. And if it's to be used successfully, there are certain rules of engagement that need to be conveyed. The problem is that we've conveyed over the past years that insulin is the last resort. If you asked us what our patients’ A1c levels are before starting insulin, I'm sure it's greater than 8%. We know that the target is 7%, so therefore we are guilty of clinical inertia. This is a description of the fact that we have allowed things to continue without intervening. It's no wonder that people have complications. We've seen surveys were people are sitting with high A1c levels for years before starting insulin. When we start insulin therapy, the average A1c is 8% or 8.5%, and 80% of these people already have complications. That is a lesson. When we assess and adjust therapies, this guideline tells us what groups of oral agents we can use. At the same time, we need to be guided by the outcomes of these different agents and the target is clearly 7%. It may be higher in the elderly, or maybe lower in the younger individuals. We must be guided by this, and must use these therapies. We should use them individually and in combination to aim for the target. But we should accept the fact that we should also move quickly through the various therapies. Not too rapidly, but in the past we've done it much too slowly. The introduction of insulin has been too late. What these guideline indicate is that even after we have started metformin, we have the option of all the oral agents, all the parental agents, and insulin to follow on to metformin. We've seen several studies recently that the best outcome, very often, is through the early introduction of insulin. Because we know it's effective in virtually all patients. It has other actions apart from lowering blood glucose. We hope that those effects can contribute to a patent’s well being. But we also have to avoid hypoglycemia. There are certain insulins in type 2 diabetes that reduce the risk of hypoglycemia. But of course, monitoring the insulin, choosing the right insulin – these are all things the clinician should be aware of, and should discuss with the patient and implement with nurses and other caregivers. I've implemented insulin at an earlier stage. We've seen studies from China in which some people with type 2 diabetes will have an A1c above 9%. And if you implement intensive insulin therapy for two weeks, their blood glucose normalizes even if you stop the insulin therapy. And 50% of those individuals remain in remission for up to one year thereafter. So there are several examples. So we are finding out a way, but the key thing is that our target determines how we progress through our therapy, both before and within the insulin therapies that we now have.

Q [from the audience]: Should physicians consider A1c as a biomarker, as a target, or both?

Dr. Pfeiffer: A1c is an indication of average blood glucose over the past three months. In response to your question, I would say both. One reason why it's a target is that we haves used it in studies and it is what we know about. The other reason is that it's a biomarker of control. Some patients have low compliance. There is a nasty study where the doctors thought the patients took their medications two thirds of the time and patients said it was only one third of the time. It's really amazing. A1c helps you know what is happening. A1c helps you realize where the patient is. It’s still the biomarker for risk and the best one we have.

Dr. Van Gaal: In the personal contact with your patient, A1c is a control parameter that is extremely powerful for communication. In my practice, patients comes in and ask what their A1c values are from their last blood tests and when I give them the figure, they start to comment on the figure and on how good or bad it is. I don't have to do it for them anymore. They do it and I agree with what they say. It is an indication that they have learned. This is education. This is extremely important and powerful for their understanding of the disease.

Dr. Owens: Of course, we've discussed with the patient and agreed upon a target. If they are above their target, A1c is an easy way to know that you've got a problem. But blood glucose monitoring tells you where the problem is. So if you want to call A1c a target or a surrogate, it's a surrogate. In terms of solving the problem, you have to do that in terms of monitoring blood glucose.

Dr. Ferrannini: We should not forget that yes, A1c is a marker, and it has become the benchmark for assessing the value of new dugs or new combinations of drugs. But it's also a mechanism: it does tell you that your glucose has been higher than it should be. The body doesn't like that because too much glucose is toxic. A1c is directly related to vascular damage. It's both a marker and an endpoint to the extent that we still believe that high glucose is itself toxic to the tissue, especially the vascular tissue. There it contributes to the microvascular, and later, the macrovascular complications. So I would say that it's both. It’s important to explain that to the patient, that it's not just some biomarker.

Q [from the audience]: Do we absolutely have to accept that contact between the physician and patient is limited to seven minutes?

Dr. Pfeiffer: I think David pointed out that there is a request to the system to change that. Teaching is basically accepted, but in practice, it's quite different because you get a certain reimbursement for the patient and the doctor has to pay his income. We should use more diabetes personnel and nurses, which we do in Germany, but that's different in different countries. We know that you have to reiterate the teaching regularly. Even people with a long duration of diabetes benefit from being reminded of what to do. You should institute a system where the doctor has more time. We say that intellectual medicine is not paid for – what's paid for is machine medicine. This has to be changed. The problem for the system is how do they change it?

Dr. Ferrannini: At the level of policy makers, this is a carryover from the old concept that diabetes is a simple disease, and that it doesn't need more than seven to ten minutes with the PCP to be managed. This is the sort of revolution that we have to implement. You have to help us.

Dr. Owens: I think that we cannot have too many doctors too quickly. This is very clear for us. Some states have diabetes nurse educators who more or less execute an extensive support program. I think one of the best developments we have in the UK in terms of diabetes care is the employment of such people. I would encourage physicians to use diabetes educators. They are much better at educating than we are, and we must recognize that. I think that it's the only option for many countries to carry out diabetes care. It's using the nurse educators, and I will strongly emphasize that we should use these people and educate more of them. But of course, I think we need to ensure that they are qualified. In some countries, the educator can prescribe medication. I think that's an important point.

Dr. Van Gaal: I wanted to add that the fact that some doctors are spending little time with the patient is one of the reasons for the failure to treat obesity, which is a huge driver of diabetes and diabetes complications. You see that good results can be obtained in clinical trials where the patient comes to the doctor and receives a lot of time. This is an additional factor that drives the failure of lifestyle intervention in general.

Dr. Ferrannini: Technology is also helping. Let's look at the final video and discuss the ways that technology is helping and could help in the future.

[Video on the ADA/EASD position statement and new developments]

Dr. Ferrannini: So technology: when insulin was first extracted from the pancreas, it was regular insulin, rapid insulin. That saved thousands of lives. But the problem is that it has to be geared to the meal that follows it, in terms of the timing, size, and composition of the meal. One technological advancement that has made a difference in diabetes therapy is the development of basal insulin. And also, of course, the availability of glucose meters, which are portable contraptions that can measure blood glucose accurately. We would like to spend the next few minutes on basal insulin and the concept of combination therapy. This could be, pragmatically speaking, a very useful tool for patients. So what is basal insulin?

Dr. Van Gaal: It's an insulin that has a relatively flat profile. It's mostly given once daily and has as a major target the reduction of fasting glucose levels. Why is that? Because basal insulin is limiting the production of glucose from the liver. People always think that glucose only comes from what we eat, but our own body is producing glucose in the liver. That is often seen overnight, and we see that much more in people who are overweight and obese. Basal insulin focuses on fasting glucose, but there still needs to be something else during the day.

Dr. Ferrannini: If you provide insulin that appears in the bloodstream in spikes, you increase the risk of hypoglycemia. The advantage of a basal insulin is that it doesn’t spike, so you have a lower risk of hypoglycemia, which is very significant, particularly for at-risk patients (those who are older, frail, and/or living alone). And you can reduce this risk with a basal insulin. This will take care of the fasting plasma glucose. And it will block endogenous glucose production. If you do not achieve your target, what are the other options?

Dr. Pfeiffer: Well, one of the problems with exercise or with food is that the amount of insulin you need and the timing of the dosing is complicated. You have a glycemic index, so when you eat different types of carbs, the blood sugar can rise rapidly or slowly. So there are many variables that can interfere with predictable care. And this is something to target. If you administer a short-acting insulin, you’re always a little off target, so it’s better to adjust the dose. When you give the basal insulin, you have the lowering of blood glucose, and you also give the beta cells time to relax. You take away the strain on the beta cells, who no longer have to work overnight. So then the combination therapy makes life a lot easier for the patient. He has one shot of insulin – which is quite acceptable to the patient – and then you add a second agent that regulates the prandial glucose. This approach works quite well. The doctors were faster here than the regulatory authorities. That’s why I think it’s a promising approach that gives a lot of flexibility to the patient. The patient doesn’t have to worry all day about his blood glucose. He can regulate the basal levels and leave the rest to what his body can do.

Dr. Ferrannini: Technology has also helped us develop new agents such as GLP-1 agonists. The original physiology of incretin hormones was discovered in this country. The doctors had been thinking of the gut as just a six-meter long tube. But in fact, it turns out that the gut is an endocrine organ. So technology has made it possible to identify the hormone, produce the hormone, and now they are drugs. The two things you want to avoid – hypoglycemia and weight gain – can be managed by combining insulin treatment with a GLP-1 agonist, for reasons that maybe you can discuss. What is a GLP-1 agonist?

Dr. Owens: Coming back to the interaction with the patient, don’t forget that when we speak about A1c, that parameter is driven 50% by fasting glucose and 50% by postprandial glucose. For 75% of the day, people are not in the fasting state. If you have an approach like GLP-1 that can tackle these spikes, this is a new, interesting, and challenging approach. GLP-1 is released from specific cells in the gut only after you eat. If you eat, you release these hormones and they do several things. They affect beta cells to produce extra insulin when it is needed and secondly, they have effects on the brain to lower appetite, and that’s an extra benefit. Also, GLP-1 has an effect on the stomach - delaying gastric emptying – that has an effect on postprandial peaks. The native GLP-1 is unfortunately only active for a few minutes and for that reason, research has developed drugs that block the destruction of these hormones. That’s why the DPP-4 blockers also exist. The GLP-1 agonists have a nice effect on the postprandial excursion. If you then add a GLP-1 as an extra approach on top of basal insulin (the gold standard for reducing fasting glucose levels), you will temper these spikes. It’s good not only for overall diabetes control: these peaks are also potentially dangerous for the vessel wall because they induce stress. So brining down all the postprandial excursions like you can do with a GLP-1 agonist has powerful benefits in the future.

Dr. Ferrannini: Do you agree that positioning both early insulin use and GLP-1 agonists, despite the fact that we need more experience with the combination, is one way to approach the new patient-centered paradigm and the individualization of therapy? Do you think there is enough evidence to do so?

Dr. Pfeiffer: I just heard an excellent presentation on a meta-analysis of 40,000 cases that were treated with incretin-based therapy that showed a reduction in cardiovascular outcomes of 40%. If that is confirmed by prospective studies, your guideline might be outdated quite soon. So it’s a vey promising approach, I think. We definitely need the endpoints. There is a lot of evidence that GLP-1 acts on other organs, and may have beneficial cardiovascular effects, but we are a bit careful after what happened with the TZDs. We had compounds that we hoped would be fantastic, but they didn’t turn out that way. That’s why endpoint studies are necessary. But on the way there, we can say that for many patients, GLP-1 agonists are a good treatment that helps patients achieve their goals, and that doesn’t harm them.

Dr. Van Gaal: Diabetes is more than just glucose. If you have a therapy that has other effects – for example, it may be cardioprotective or neuroprotective – then you can offer that additional benefit to patients. Then your goal of doing more than just glucose control is potentially realized.

Dr. Ferrannini: But you have to correctly set the expectations for the patient. You have to say that while GLP-1 agonists can prevent weight gain, patients shouldn’t expect the weight loss to become significant in just a few weeks. Having a dialogue with your patient is critical. Patients probably don’t know what to expect, such as how much weight they will lose over a period of time.

Dr. Owens: I think that you’ve come to a very important concept. The key thing is that when you introduce a therapy, you need to optimize it. Only 50-60% of patients reach target. We should chose a reasonable dose without putting patients at risk for hypoglycemia and weight gain. The key message is to optimize therapy. We know that 50-60% of patients respond, but of course, if you introduce basal inulin at an early stage, you might get 75% responding. Of course, there are people who do not reach target with basal insulin alone. The key thing is that for the first time now, we have almost an ideal combination [Editor’s note: we presume he is referring to basal insulin + GLP-1]. Insulin improves glycemic control, but for every 1% reduction in A1c, we can expect a weight gain of around 2.5 kg. But with the combination, we can neutralize that. We can also minimize, or not rely on increasing, the insulin dose. So the insulin dose can be limited, which puts the patient at less risk. In terms of weight and other aspects such as cardiovascular side effects, I personally think that the cardiovascular benefit of GLP-1 is something we should heavily concentrate on. Of course, they could also have a neuroprotective effect. For this cohort of individuals who will likely succumb to cardiovascular disease in the course of their diabetes, this is a great population to neutralize that risk.

Q [from the audience]: What is the relationship between the general practitioner and the specialist in helping the patient? What should be the ideal relationship?

Dr. Owens: I think this is an extremely important point. No question. I think that all of us are involved in educating our students and in educating doctors in primary care. I personally run a postgraduate course for doctors in primary care on diabetes. I think we recognize that there’s no way we can use these wonderful new drugs unless the people who have access to them can use them adequately. It’s a huge level of responsibility for us to train our primary care colleagues and other colleagues in primary care who are responsible for the patient. Otherwise, it’s a waste of money if we don’t use the drugs properly. This is a big responsibility. We recognize it. We’re making small inroads into this, but it’s a major requirement.

Dr. Ferrannini: Can I follow up on that? Are you saying that the patient with diabetes should be seen by a specialist team initially, and then be handed over to a general practitioner?

Dr. Owens: Type 2 patients appear at different stages of the disease. I think we need to know where our competencies are in respect to what we can do in primary care, and what we can do in secondary and tertiary care. These complement one another. If primary care physicians are educated, they can look after the patient up to a certain threshold. For example, I refer my patients with renal and eye disease to specialists when they reach a certain threshold. I have competences to a certain extent. We need to ensure that people are able to optimize their competencies within their limits.

Dr. Pfeiffer: There’s one aspect of the health organization that differs between countries. If you really want the doctor to explain all the aspects of diabetes, you need a diabetes educator or a diabetes specialist. In Germany, we have 5,000 diabetes specialists who just see patients with diabetes. They send the patient back to the general practitioner, but it would be deal for them to see the patient at least once a year. The average practitioner has between 100-300 diabetes patients.

Dr. Owens: I’d certainly like to see all my diabetes patients, but I think that in view of the magnitude of the problem, we should encourage that patients be helped in the primary care situation. Here, we have a diabetes specialist within primary care – what we call “general practitioners with a special interest” – and they have a direct relationship with the secondary care provider. And they are sometimes almost at the same level. They are surrogate specialists within primary care.

Q [from the audience]: As I understand it, there are many stages of this disease, because it is not steady. First is the acceptance of the disease by the patient. Then comes compliance, then management. What is the most important? Also, do you think that because of the financial crisis, patients may not be able to afford their therapies?

Dr. Owens: That’s a fundamental question when we discuss diabetes. It’s a challenge for the individual and for society. As we have said very often, most people will get type 2 diabetes because they have a certain behavior or lifestyle. And it takes a long time for them to enjoy their lifestyle and to become obese while doing so. There is then an enormous requirement of acceptance and understanding on behalf of the patient when they get diabetes. Behavioral changes are critical for changing patients’ lifestyle and to increase compliance. We know that a lot of people don’t reach their target because they are not compliant. It is hugely important, and maybe we physician haven’t been trained that well in supporting patients with type 2 diabetes and helping them change their behavior. I think that’s fundamentally important and that again comes down to how much time you have with the patient and how you monitor them. We recognize the need, but I don’t think we necessarily have the solution yet. We all try in different ways. Different programs are looking into how to do lifestyle management. Which is why we should try it with our nurses because they are better at it and have more time. The guidelines emphasize that there is an individual element. So behavioral science is rather critical, and our pediatric colleagues use it very well. They very often have psychologists with them in their clinics. I’m not necessarily suggesting that we do that, but we have to accept that behavioral therapy is critical.

Dr. Ferrannini: Regarding the economy, yes it’s going to hurt. It’s also one of the reasons why in the ADA/EASD position statement, cost is a dimension by which to evaluate the difference treatment options. So we have to consider that new medications are more costly than generics. In times of economy crunch, rather than letting the patient go untreated, one suggestion is to revert to cheaper drugs. This happens also in places where the patient or the care provider cannot afford more expensive drugs. That’s why some drugs that specialists in certain parts of the world would not prescribed (such as sulfonylureas) have not been scratched off the list because these drugs can still have a place under certain circumstances.

Dr. Owens: In the guidelines, each drug category contains a long a list of advantages and disadvantages, as well as the cost. So I think the guidelines have recognized the importance of cost. Within the guideline, you can make the choice.

-- by Nina Ran, Hannah Deming, Adam Brown, Jessica Dong, Kira Maker, Joseph Shivers, John Close, and Kelly Close

 

Editor’s note: After this report was published, we learned (on October 5) that Roche had given financial support for “Accuracy of Self Monitoring Blood Glucose Systems in Different Ranges of Blood Glucose” – we hadn’t realized this when we first published this report on October 4. This has now been noted in the report."