September 22-27, 2013; Barcelona, Spain Day #1 Highlights - Draft

Executive Highlights

Bona nit from Barcelona, which is buzzing with La Mercè Festival’s (Barcelona’s annual carnival) fireworks, concerts, and fire runs. Still, the highlight for us was the ramping up of the 49^th Annual Meeting of the EASD, particularly a Sanofi event on CV outcomes in diabetes in which KOLs gathered to speak to an audience of highly respected physicians from all over the world. Sanofi’s VP of Global Medical Affairs, Dr. Riccardo Perfetti (Paris, France), opened the day-long event with remarks on the company’s recent decision to withdraw its US NDA for the GLP-1 agonist Lyxumia (lixisenatide) – this development underscored the relevance of the topic at hand since Sanofi’s decision to withdraw the NDA was largely based on a reluctance to unblind ELIXA CVOT interim data. This decision makes sense to us and we knew this was going to eventually come up when FDA effectively declined to discuss unblinding implications at previous advisory committee meetings. Dr. Julio Rosenstock (Dallas Diabetes and Endocrine Center, Dallas, TX) expressed support for Sanofi’s decision and opposition to the use of interim trial data in the approval process, during an extended discussion of recent CVOTs. How the FDA and other regulators will balance transparency/regulatory expediency with the problems associated with interim data disclosure (i.e., trial completion and rigorousness) is yet to be determined, to say the least.

More insightful commentary on regulatory agencies at the Sanofi event came from Dr. Philip Home (Newcastle University, Newcastle Upon Tyne, UK), who reviewed current regulatory challenges, and historical cases that have shaped today’s regulatory environment. He particularly criticized regulators’ tendency to react to safety scares by subsequently focusing great attention on specific safety issues rather than overall safety profiles. He also offered his opinion on recent regulatory discussions for Novo Nordisk’s Tresiba (insulin degludec) and J&J’s Invokana (canagliflozin). Additionally, Dr. Matthew Riddle (Oregon Health and Science University, Portland, OR) discussed data from landmark studies to demonstrate that the risk:benefit ratio for diabetes treatment is optimized by treating patients early – would that there were as much data to support this as we’d like!  

Additionally, we heard about the Diabetes Research on Patient Stratification (DIRECT) consortium, which is focused on identifying and validating biomarkers for glycemic deterioration and treatment response in efforts to individualize treatment for type 2 diabetes. We’re glad to see academia (20+ institutions) and Big Pharma (Novo Nordisk, Sanofi, Eli Lilly, and Servier) collaborate on this research.  

On the new technologies frontier, we were interested to hear comments on the need for standardized regulatory processes to be adopted across countries in order to accelerate the development of innovative technological solutions for patients. Given the importance of mHealth and social media, we hoped to hear more on the power of the diabetes online community during the broader symposia “How New Technologies & Social Media can Improve the Lives of People with Diabetes.”  However, it could be that our desire for more is indicative of the dearth of data and in these fields at large.

Last, Dr. Xavier Pi-Sunyer (Columbia University College of Physicians & Surgeons, New York City, NY) discussed Look AHEAD, which found that lifestyle intervention and standard care had similar CV event rates – and people receiving standard care took more medications annually. Thus, Dr. Pi-Sunyer’s concluded that overweight and obese people with type 2 diabetes can improve their CV outcomes by being more physically active and improving their diet; or by increasing the number of drugs they take.

Detailed Discussion and Commentary

Private Corporate Symposium: Scientific Exchange and Expert Opinions on CV Outcomes in Diabetes (Sponsored by Sanofi)

Opening Remarks

Riccardo Perfetti, MD, PhD (VP Global Medical Affairs, Sanofi Diabetes, Paris, France)

Dr. Riccardo Perfetti opened the symposium by remarking upon the relevance of the topic at hand, specifically commenting on Sanofi’s recent decision to withdraw its US submission for the GLP-1 agonist Lyxumia (lixisenatide). As Sanofi stated in its announcement earlier this month (see details at http://www.closeconcerns.com/knowledgebase/r/c7496472), Dr. Perfetti remarked that unblinding investigators to the interim results of Lyxumia’s CVOT, ELIXA, would have “gigantic negative consequences” on the continuation and interpretation of the study. He cited two past examples that informed the decision to remain blinded to the trial results: first, the FDA once previously refused to update a drug’s label to reflect new CVOT data showing CV benefit for a drug whose interim data been publicly disclosed because the interim data disclosure compromised the trial’s final results. One of these was for sulfinpyrazone (for gout). As we understand it, the FDA felt that the disclosure of the interim analysis had compromised the conduct of the study and did not accept to include the study results (or altered the product indication) once the study was completed. More recently, Dr. Perfetti said that J&J’s Invokana (canagliflozin) also went through a dramatic change of plans for its CVOT, CANVAS, after the disclosure of interim results at its FDA Advisory Committee meeting. The original plan for CANVAS had originally allowed for a trial expansion after the interim analysis, but the investigators felt that the rigorousness of such an expansion would have been compromised by the public disclosure of data, and so they canceled that part of the study. Dr. Perfetti noted that this resulted in a delay for full trial results.

The Current Regulatory Environment in Diabetes: What Needs Changing? What is About to Change?

Philip Home, DPhil, DM (Newcastle University, Newcastle Upon Tyne, UK)

Dr. Philip Home reviewed some of the regulatory challenges and historical examples that have shaped today’s regulatory environment. Dr. Home criticized regulatory agencies’ historical tendency to over-react to safety scares by subsequently focusing great attention to specific safety issues rather than focusing on overall safety profile (e.g., liver failure with troglitazone, CV risk with rosiglitazone, and pancreatitis risk with incretin-based therapies). One challenge that regulators face is the uncertainty that noisy data generate both for very infrequent events (e.g., the five-fold greater bladder and breast cancer imbalance found in dapagliflozin studies) or very frequent events (e.g., would one treat a numerical imbalance of 56 vs. 40 myocardial infarctions in a group of 2,500 people after one year a 40% increase or a chance difference?). He noted that regulatory agencies, subject to political pressure and external fright, react conservatively to such noise. As such, he finds large randomized-controlled trials (RCTs) very valuable (e.g., the ongoing diabetes cardiovascular outcomes trials) for shedding light on all possible adverse outcomes, no matter what the pre-specified primary outcome is. He would like to see large RCTs mandated for all newly licensed diabetes medications to assess a wide range of possible safety issues (not only focusing on CV safety). While he does not think it is not practical to try to apprehend all unexpected safety issues at the time of drug approval, he remarked that such issues will always crop up at some point and that such RCTs are the most rigorous way of finding them. Dr. Home emphasized that no medication is truly “safe” and that regulators must continue to consider the balance between risk and benefit.

• Dr. Home made a few additional notable comments regarding regulators’ concerns over recent drugs such as Novo Nordisk’s Tresiba (insulin degludec) and J&J’s Invokana (canagliflozin). He remarked that the FDA’s concern over the excess CV risk (numerically, a 13-fold increase in events) seen in the first 30 days of CANVAS was “really pure nonsense” since the placebo group clearly had an artificially low level of events during that time and the curves eventually crossed. With regard to insulin degludec’s submission package, Dr. Home highlighted the FDA’s acknowledgement that no causation or plausible mechanism has been elucidated. Nonetheless, he also pointed out that when the FDA called for an extended dataset that provided data over a longer exposure period, the CV result was exacerbated rather than tending back toward the mean (which is what one would expect if an early fluke had produced the original result of concern).

• As another notable piece of advice, Dr. Home warned that when interpreting composite analyses and meta-analyses based on fewer than 50 events, “beware!” And with <100 events, “be cautious!” And for meta-analyses based on studies with diverse findings, “be skeptical!”

Questions and Answers

Q: According to all the results you showed in the table for degludec, what were the differences between original and updated data?

A: Essentially, the HRs were all worse in the updated data. The updated data were simply the data collected for patients following the original intended end of the studies. My only point was that those HRs were jumping around … if you see HRs in meta-analyses jumping around, you know they’re unreliable.

Dr. Julio Rosenstock (University of Texas Southwestern, Dallas, TX): There are some issues I will discuss in my talk, but the thing I think is important to emphasize is the difference between the EMA and the FDA. The EMA does not conduct their own independent evaluation, and they don’t have the same thoroughness as FDA.

A: EMA goes through the dossier closely but doesn’t run the analysis again. That is very true. I would also criticize the EMA; I think it is too closed and secretive. I would like to see a more open reporting. Having said that, having worked with the internal people, they are very good. They are sharp people who know their stuff.

CV Outcomes Trials with New Glucose Lowering Agents: What are We Learning?

Julio Rosenstock, MD (Dallas Diabetes and Endocrine Center, Dallas, TX)

Dr. Julio Rosenstock began his presentation by noting that the currently available data on diabetes therapies and cardiovascular risk, while suggestive of benefit, is far from conclusive. Additionally, he pointed out that most past studies examined treatment regimens rather than specific therapies, and cited ORIGIN as the only major trial so far that has had enough power to analyze a single drug and come out with a decisive, convincing result. The FDA’s more stringent CV safety requirements for diabetes drugs are somewhat unfair to industry, in Dr. Rosenstock’s mind, but at the end of the day, he is very much in favor of the CV safety requirement since it provides the opportunity to obtain valuable new data on drug safety. Much of the presentation was dedicated to an overview of ongoing and recently completed CVOTs. He came down harshly against the use of interim data from CANVAS (the CVOT for J&J’s Invokana [canagliflozin]), which he said compromised the integrity of the trial. By the same logic, he applauded Sanofi’s move to withdraw its NDA for Lyxumia (lixisenatide) in order to prevent biasing the result of its ELIXA CVOT. He expressed concern for the MACE signal seen in the initial Tresiba (insulin degludec) data, especially the fact that the initial signal was confirmed by an updated analysis of an extended dataset. Moving on to the recently disclosed results of SAVOR-TIMI 53 and EXAMINE (the completed CVOTs for BMS/AZ’s Onglyza [saxagliptin] and Takeda’s Nesina [alogliptin], respectively), he noted with concern that there was a numerical imbalance in pancreatitis cases in both studies, even though the difference was not statistically significant. Looking to the future, Dr. Rosenstock called for more trials to be conducted in patients without established CV disease, using active controls rather than placebo comparators.  

• Dr. Rosenstock began by noting that the majority of data that we have on diabetes therapies and CVD is on the effect of treatment intensity rather than on specific drugs. The limited data available on specific therapies, he stated, is insufficient to draw convincing conclusions. As an example, he cited a secondary analysis of metformin therapy from UKPDS — while metformin did seem to reduce patients’ risk of CVD, Dr. Rosenstock pointed out that the sub-study was insufficiently powered (342 patients on metformin). He cited ORIGIN as a rare example of a study sufficiently powered to convincingly analyze a specific drug.  

• The FDA’s requirement of cardiovascular safety data on all diabetes drug candidates is unfair for industry, in Dr. Rosenstock’s mind, but presents the opportunity to obtain valuable data. After a discussion of the FDA policy, Dr. Rosenstock discussed recent and ongoing cardiovascular outcomes trials for diabetes drugs.

  • Dr. Rosenstock expressed misgivings over using interim CVOT data in the approval process, as such data disclosure can compromise the integrity and validity of study data. He cited J&J’s Invokana (canagliflozin) as an example. He applauded the decision on the part of Sanofi to withdraw the NDA for Lyxumia (lixisenatide) in order to preserve the integrity of the ELIXA CVOT — read our coverage of that recent news at http://www.closeconcerns.com/knowledgebase/r/c7496472.

  • Dr. Rosenstock briefly expressed concern about the current cardiovascular data on Novo Nordisk’s Tresiba (insulin degludec), noting that the original data had a worrying signal for CV events that was confirmed (and amplified somewhat) by subsequent analysis. We hope that the results of Novo Nordisk’s planned CVOT will help clear up this uncertainty — it is scheduled to begin later this year (see our Novo Nordisk 2Q13 update at http://www.closeconcerns.com/knowledgebase/r/006471af for more details).

  • Dr. Rosenstock next moved onto SAVOR-TIMI 53, BMS/AZ’s CVOT for Onglyza (saxagliptin). He noted that while the study’s primary outcome was non-inferiority, it was powered to show superiority — we interpreted his view as slightly disappointed, though the safety results are certainly a positive in our view, especially given how hard it is to design a trial that will show safety and also superiority. The increase in hospitalization for heart failure and significantly higher incidence of hypoglycemia seen in the treatment arm must be analyzed, he stated emphatically – he did not mention that the heart failure risk was not accompanied by a concomitant increase in any CV outcomes including overall or CV mortality; we imagine that the increased hypoglycemia was limited to patients who were also on insulin or SFU therapy (no DPP-4s have ever been linked to significant hypoglycemia caused by the DPP-4 inhibitor, of which we’re aware). He also broke out the pancreatitis results, highlighting the numerical increase in acute pancreatitis seen in the saxagliptin group, even though the difference was not statistically significant due to the very small numbers. The same concern applied to the results of EXAMINE, Takeda’s CVOT for Nesina (alogliptin), in which the treatment arm had a numerically greater number of acute pancreatitis cases than the comparator arm. See our ESC 2013 Day #1 Report at http://www.closeconcerns.com/knowledgebase/r/2a8925c5 for our initial coverage of the EXAMINE and SAVOR-TIMI 53 data presentations.

• To conclude, Dr. Rosenstock questioned whether CVOTs are investigating the right kind of patients. He pointed out that most current CVOTs enroll patients with established cardiovascular disease, and many utilize placebo comparators. In the future, he proposed, trials should enroll patients without significant longstanding CVD, and consider using active comparators — he cited CAROLINA (the CVOT for BI/Lilly’s Tradjenta [linagliptin]) as an example of progress in the right direction in this regard, as it compares Tradjenta to the sulfonylurea glimepiride. We are extremely eager for this analysis and salute BI/Lilly for taking it on; on the other hand, we know that BI/Lilly also are doing a more typical CVOT to satisfy FDA. We also wonder whether this is the right population although given the vastly improved standard of care, we believe it would be challenging for trial execution to choose a different group.

Corporate Symposium: Scientific Exchange and Expert Opinions on CV Outcomes in Diabetes (Sponsored by Sanofi)

CV Outcomes Trials with new Glucose Lowering Agents: What are we Learning?

Julio Rosenstock, MD (Dallas Diabetes and Endocrine Center, Dallas, TX)

Dr. Julio Rosenstock began his presentation by noting that the currently available data on diabetes therapies and cardiovascular risk, while suggestive of benefit, is far from conclusive. Additionally, he pointed out that most past studies examined treatment regimens rather than specific therapies, and cited ORIGIN as the only major trial so far that has had enough power to analyze a single drug and come out with a decisive, convincing result on CV safety. The FDA’s more stringent CV safety requirements for diabetes drugs may sound somewhat unfair for industry to some, but at the end of the day, Dr Rosenstock is a strong supporter and very much in favor of the FDA CV safety requirement since it provides the opportunity to obtain valuable new data on drug safety. Much of the presentation was dedicated to an overview of ongoing and recently completed CVOTs. He came down harshly against the use of interim data from CANVAS (the CVOT for J&J’s Invokana [canagliflozin]), which he said compromised the integrity of the trial. By the same logic, he applauded Sanofi’s move to withdraw its NDA for Lyxumia (lixisenatide) in order to prevent biasing the result of its ELIXA CVOT. He expressed concern for the MACE signal seen in the initial Tresiba (insulin degludec) data, especially the fact that the initial signal was confirmed by an updated analysis of an extended dataset.

Moving on to the recently disclosed results of SAVOR-TIMI 53 and EXAMINE (the completed CVOTs for BMS/AZ’s Onglyza [saxagliptin] and Takeda’s Nesina [alogliptin], respectively), he noted with concern that there was a numerical imbalance in pancreatitis cases in both studies, even though the difference was not statistically significant. He pointed out that when the results of all the CVOT are pooled- analyzed with patient-level data we may able to make more conclusive statements regarding pancreatitis risk. In the meantime the jury is still out; the risk may be real but presumably very low, he pointed out.  Looking to the future, Dr. Rosenstock called for more trials to be conducted in patients without established CV disease, using active controls rather than placebo comparators.  

• Dr. Rosenstock began by noting that the majority of data that we have on diabetes therapies and CVD is on the effect of treatment intensity with multiple drugs rather than on specific drugs. The limited data available on specific therapies, he stated, is insufficient to draw convincing conclusions. As an example, he cited a secondary analysis of metformin therapy from UKPDS — while metformin did seem to reduce patients’ risk of CVD, Dr. Rosenstock pointed out that the sub-study was insufficiently powered (342 patients on metformin). He cited ORIGIN as a rare example of a study sufficiently powered to convincingly analyze a specific drug.  

• The FDA’s requirement of cardiovascular safety data on all diabetes drug candidates may sound unfair for industry to some, but Dr. Rosenstock is a strong supporter of these CV outcome trials because they provide the opportunity to obtain valuable data. After an explanation of the FDA policy, Dr. Rosenstock discussed recent and ongoing cardiovascular outcomes trials for diabetes drugs.

  • Dr. Rosenstock expressed misgivings over using interim CVOT data in the approval process, as such data disclosure can compromise the integrity and validity of study data. He cited J&J’s Invokana (canagliflozin) as an example. He applauded the decision on the part of Sanofi to withdraw the NDA for Lyxumia (lixisenatide) in order to preserve the integrity of the ELIXA CVOT — read our coverage of that recent news at http://www.closeconcerns.com/knowledgebase/r/c7496472.

  • Dr. Rosenstock briefly expressed concern about the current cardiovascular data on Novo Nordisk’s Tresiba (insulin degludec), noting that the original data had a worrying signal for CV events that was confirmed (and amplified somewhat) by subsequent analysis. We hope that the results of Novo Nordisk’s planned CVOT will help clear up this uncertainty — it is scheduled to begin later this year (see our Novo Nordisk 2Q13 update at http://www.closeconcerns.com/knowledgebase/r/006471af for more details).

  • Dr. Rosenstock next moved onto SAVOR-TIMI 53, BMS/AZ’s CVOT for Onglyza (saxagliptin). He noted that while the study’s primary outcome analysis was non-inferiority, it was powered to show superiority — we interpreted his view as confirming neutrality but he was somewhat disappointed but not surprised that it did not show CV protection, though the safety results are certainly a positive in our view. The increase in hospitalization for heart failure and significantly higher incidence of hypoglycemia seen in the treatment arm must be analyzed, he stated emphatically – he did not mention that the heart failure risk was not accompanied by a concomitant increase in any CV outcomes including overall or CV mortality; we imagine that the increased hypoglycemia was limited to patients who were also on insulin or SFU therapy. He also broke out the pancreatitis results, highlighting the numerical increase in acute pancreatitis seen in the saxagliptin group, even though the difference was not statistically significant due to the very small numbers. The same concern applied to the results of EXAMINE, Takeda’s CVOT for Nesina (alogliptin), in which the treatment arm had a numerically greater number of acute pancreatitis cases than the comparator arm. See our ESC 2013 Day #1 Report at http://www.closeconcerns.com/knowledgebase/r/2a8925c5 for our initial coverage of the EXAMINE and SAVOR-TIMI 53 data presentations.

• To conclude, Dr. Rosenstock questioned whether CVOTs are investigating the right kind of patients. He pointed out that most current CVOTs enroll patients with established cardiovascular disease, and many utilize placebo comparators. In the future, he proposed, trials should enroll patients without significant longstanding CVD, and consider using active comparators — he cited CAROLINA (the CVOT for BI/Lilly’s Tradjenta [linagliptin]) as an example of progress in the right direction in this regard, as it compares linagliptin to the sulfonylurea glimepiride.

Insulin and CV Outcomes: Ongoing Analyses of the ORIGIN Trial

Hertzel Gerstein, MD, MSc (McMaster University, Hamilton, Ontario, Canada)

Dr. Hertzel Gerstein began by characterizing insulin as a “miracle drug” due to its effect in type 1 diabetes, but noted that the insulin therapy for type 2 diabetes has been dogged by controversy over feared cardiovascular and cancer risks for decades. After providing an overview of ORIGIN’s design and central results, he shared and interpreted results from more recent analyses of ORIGIN data. To address concerns regarding insulin glargine’s potential atherogenicity, an ORIGIN substudy compared changes in carotid intima media thickness (CIMT) during the trial in patients from the insulin glargine and comparator arm — the data indicated that glargine treatment had no effect on plaque formation and may in fact have slowed progression of atherosclerosis. Dr. Gerstein spent a great deal of time discussing data recently presented at ESC on the association between hypoglycemia and CV risk in ORIGIN (see page 7 of our ESC 2013 Day #1 report at http://www.closeconcerns.com/knowledgebase/r/2a8925c5 for our coverage of that presentation). While severe and non-severe hypoglycemia was indeed higher for patients in the glargine arm, the effect of severe hypoglycemia on MACE and all-cause mortality was greater in the standard care group than in the insulin glargine group. Speakers that have commented on this result have remarked that this may be due to widespread sulfonylurea use in the standard care arm. He postulated that severe hypoglycemia may in fact be a marker rather than a direct cause of most cardiovascular events — we think this is a critical area of investigation and would love to gain more clarity on this front.

Balancing the Benefits and Risks of Glucose Lowering Therapies

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

Dr. Matthew Riddle discussed data from landmark studies to demonstrate that the risk:benefit ratio for diabetes treatment is optimized by treating patients early and that, contrary to conventional wisdom, there is no reason to withhold early use of insulin. In contrast, he noted that people for whom the risk:benefit ratio is poorer include people with high baseline A1c, clinical evidence of CV risk, poor response to treatment (<0.5% A1c reduction), and severe hypoglycemia or hypoglycemia unawareness. With regard to treatment modalities, he noted that metabolic surgery does not yet have a well-defined place in the treatment arsenal given that prospective studies are not designed well enough. He reviewed the benefits and risks of GLP-1 agonists, DPP-4 inhibitors, and SGLT-2 inhibitors, providing harsh criticism of the Butler et al. pancreatic morphology study. He noted that SAVOR and EXAMINE’s neutral outcomes just goes to show how much hazard is needed to interpret pooled analyses (since previous pooled analyses had suggested the CVOTs might come out positive), and that SGLT-2 inhibitors should be very low in the treatment paradigm since we do not yet know much about the risk:benefit ratio.

• Dr. Riddle presented a risk matrix plotting patient populations from landmark trials on a grid with diabetes duration on the x-axis, and CV risk on the y-axis. ACCORD enrolled a population with both long diabetes duration and established CVD, and it demonstrated potential “trouble” with intensive therapy (i.e., increased mortality). In comparison, UKPDS was in a newly diagnosed population with low CV risk, and it demonstrated long-term CV benefit with low risks. ORIGIN enrolled people with short diabetes duration but previous CVD. Dr. Riddle argued that ORIGIN showed low short-term risk of early glargine use (CV neutrality, increased risk of hypoglycemia but lower risk of mortality compared to standard care) with the benefits of decreasing progression from pre-diabetes to diabetes and potential improvements in microvascular outcomes down the road. Finally, he stated that there were no studies of people with long diabetes duration and no CV risk. Thus, he concluded that the available evidence supported earlier intervention for maximizing benefit and reducing risk.

Highlights of the New 2013 ESC/EASD Guidelines for Diabetes and CV risk Prevention

Peter Grant, MD (University of Leeds, Leeds, UK)

Dr. Peter Grant, co-chair of the newly released ESC/EASD 2013 guidelines on diabetes, presented the highlights and rationale behind the new guidelines. Compared to the previous 2007 guidelines, the 2013 version simplifies diabetes diagnosis, simplifies CV risk assessment, reverses the suggestion for aspirin use in people free from CVD, individualizes glycemic targets, individualizes blood pressure targets, and raises method of revascularization as an important issue. With regard to diabetes diagnosis, the 2013 guidelines now recommend use of A1c and FPG with an OGTT if still in doubt. This brings the ESC/EASD in line with the ADA and WHO on diagnostic guidelines. With regard to CV risk assessment, the new guidelines recommend simply assigning all people with diabetes a “high risk” CV status, with the presence of any additional risk factors raising the status to “very high risk.” Dr. Grant said that this was one recommendation he slightly disagreed with since he believes there is still a “low risk” group of people with diabetes that have comprehensive risk factor control. Finally, Dr. Grant reminded the audience that guidelines are not rules, so clinical judgment should ultimately inform when to violate the guidelines. Please see page 8 of our ESC Day #1 Highlights at http://www.closeconcerns.com/knowledgebase/r/2a8925c5 for more comments from the co-chairs Dr. Grant and Dr. Lars Ryden.

Panel Discussion

Peter Grant, MD (University of Leeds, Leeds, UK); Matthew Riddle, MD (Oregon Health and Science University, Portland, OR); Jeffrey Probstfield, MD (University of Washington Health Sciences Center, Seattle, WA); Julio Rosenstock, MD (University of Texas Southwestern, Dallas, TX)

Questions and Answers

Q: Does insulin have a better cardioprotective effect than GLP-1 analogs?

Dr. Rosenstock: Neither of the two has shown to be cardioprotective.

Q: Does the panel think that CVOTs are needed for glucose lowering drugs?

Dr. Gerstein: I think that’s a really interesting question. I think we have glucose lowering drugs for a lot of reasons – for one, they improve patients’ quality of life. Also these drugs definitely improve microvascular complications like nerve disease and eye disease in the short term. Third, people have diabetes for the rest of their lives, and people are living longer. It very well may be that many of the drugs in development will have remarkable cardioprotective effects. We didn’t know that lipid lowering had remarkable cardioprotective effect until statins. But yes, I believe in the future, and I do think that some of these drugs will have a cardioprotective effect.

Dr. Riddle: It’s a good question because I think there are two separate related issues. One is that yes, we do need RCTs – big ones, long ones, early in the natural history of drug. Whether to demonstrate superiority or the best way to use the drug, yes we do need them. We always learn things we didn’t know we would learn. The other issue is the safety issue. That is not always so reliable addressed with RCTs. We need prospective, well-structured data collection registries to collect that data as well.

Q: Any thoughts on the increase in hospitalization for heart failure with saxagliptin?

Dr. Rosenstock: No. It’s an interesting thing — I think that it will be critical to see the data from EXAMINE. Twelve percent of patients in SAVOR had previous CHF, in EXAMINE it was much higher. And we’re talking real CHF. I think that they need to go back and look at those patients.

Dr. Riddle: I have nothing to add – it’s unknown.

Dr. Probstfield: I think there’s a good chance it’s by chance alone. Even if you use a conventional correction for it, it doesn’t reach statistical significance.

Q: Peter, you should have considered this extensively when you were looking at all of the issues related to setting the guidelines. Are the CV trials adequate to assess the non-safety issues?

Dr. Grant: We’ve got ourselves in a bit of a mess – it’s incredible difficult to judge what they actually mean. Even hearing experts talking about it, they give contradictory views on what these trials are telling us. Really, I feel that as diabetologists we’ve become victims of our own success in this area. The cardiologists are driving the agenda, but they don’t think diabetes is a complex disease, and we’re getting ourselves to a place where the tail is wagging the dog a bit. We need to come to a consensus on how to manage this.

Q: Are the CV studies adequate to generalize results to most other patients with type 2 diabetes?

Dr. Grant: I don’t think they are, because so much of what we’re seeing is contradictory and difficult to interpret. All you can really say is that if you lower blood glucose, you will get short-term benefits in terms of microvascular disease, and potentially long-term benefits.

Dr. Gerstein: I think it’s ridiculous to make CV conclusions based on two-year trials. If you looked at the effects of gastric bypass on death for 1.5 years, you would see no effect, even in people with triple vessel disease. You need time for intervention to bear fruit. For blood pressure lowering, it’s fast. For statin use, it’s pretty fast, but at two years you get a better effect than at one or three years. For glucose, you need four-to-five years to see metabolic effects. So I think short trials will never tell you the answer for CV effects.

Dr. Rosenstock: I second what Hertzel said, and I would add that I think we’re looking at the wrong patients. I think it’s hard to believe that we’re going to reverse cardiovascular disease when it’s already well established. Type 2 diabetes patients are in it for the long run – these studies should not be stopped when they do the primary analysis; they should continue to see if there is an effect. That’s why I’m interested in the CAROLINA trial.

Dr. Riddle: I support the idea that this is a long-term problem. We should think of heart disease as a 20-year complication of poor metabolic control. Most heart control is the result of some metabolic disturbance that was not treated long before. What I want to emphasize is I think we’re barking up the wrong tree. We’re taking the wrong approach to find the most severely affected patients in an attempt to turn back the clock. You don’t improve ESRD by trying to improve glucose control or improve stroke by blood pressure control.

Q: I think chronic disease like diabetes should be looked at in terms of quality of life along with cardiovascular metrics. Do you agree that quality of life outcomes are important?

Dr. Gerstein: Yes.

Dr. Riddle: Well, sure. I think it’s very important. I would add to that that patient-reported outcomes and other behavioral measures should be linked to behavioral observations like retention in a trial and keeping appointments with study investigators or a doctor. There are ways to assess the behavioral side of a management problem better than we have, and we need to do that to improve the design of trials.

Workshop: How Bad is Hypoglycemia?

Pratik Choudhary, MD (King’s College Hospital, London, UK); Stephen Davis, MBBS (University of Maryland School of Medicine, Baltimore, MD)

Drs. Pratik Choudhary and Stephen Davis discussed the consequences of hypoglycemia, focusing on cardiovascular safety and quality of life. Notably, Dr. Choudhary noted that of UK hospital admissions for hypoglycemia, 10% are for people with type 1 diabetes, and 90% are for people with type 2 diabetes (which is perhaps a greater proportion than most might expect). Of the people with type 2 diabetes, 50% were SFU-treated and 50% were insulin-treated. Dr. Davis remarked that a blood glucose of 50 mg/dl for two hours activates the same (or worse) proinflammatory, athrothrombotic, and endothelial dysfunction factors as two hours of hyperglycemia. In the discussion following the presentation, the group came to the consensus that all hypoglycemia, even non-severe hypoglycemia, is serious and influences therapy despite the fact that non-severe hypoglycemia has not been associated with increased CV risk or death (e.g., in ORIGIN) and was not associated with increased automobile accidents in the UK in a study conducted by Dr. Choudhary. The presenters also suggested that non-severe hypoglycemia was a predictor of severe hypoglycemia, which is a marker for CV risk and death. The group agreed that for someone with a previous myocardial infarction, one should be cautious about intensifying glucose control for fear of hypoglycemia. With regard to whether hypoglycemia was a risk marker for CVD or a causal factor, the group was split. Some thought it was only a marker, while others, including the sole cardiologist in the room, thought that there were causal mechanisms. Finally, the group agreed that nocturnal hypoglycemia is worse than daytime hypoglycemia due to the inability to treat quickly that can result in much higher costs as well as the worry that it causes patients and families.

Corporate Symposium: How New Technologies & Social Media Can Improve the Lives of People with Diabetes (Sponsored by IDF Europe)

Patient and Community Engagement, Outreach Programs for mHealth and ePatient

Paul Buchanan (CEO TeamBG, Great Britain, UK)

Mr. Paul Buchanan, founder of TeamBG (a diabetes and exercise non-profit) and Great Britain Diabetes Online Community (#gbdoc on twitter), relayed to the audience how a type 1 diabetes diagnosis at age 45 shaped the development of his twitter community and founding of TeamBG. Most notable was his discussion of the mHealth Grand Tour, a unique clinical study to examine the role of technology in diabetes management. Participants rode from Brussels to Barcelona from September 5 to September 18 wearing the Dexcom G5 CGM. Each rider had his or her glucose levels (as well as heart rate and bike computer statistics) transmitted wirelessly to smartphones – very cool! The data from the ride is currently being analyzed at the University of Newcastle (we can’t imagine the number of data points), and Mr. Buchanan remarked that he hoped the results would demonstrate a “clear need for technology in the management of chronic conditions.” It’s great to see such a cool use of the G5 out in the real world – as a reminder, Dexcom has said the Gen 5 CGM system (mobile platform, new transmitter, new algorithm, improved applicator), will be rolled out in several stages over the next two years.” We know many patients that are clamoring for a mobile CGM platform – what will be most interesting is to see how things go with the FDA. Certainly, Dexcom Share will be an early indicator, which was submitted to the FDA in July.

• Mr. Buchanan said that when he was diagnosed, there was no place for patients to ask questions that affected their daily life (e.g., What happens with my license? How will this affect my mortgage?) After participating in a US weekly twitter conversation (#DSMA), Mr. Buchanan decided to start his own for other patients with diabetes in Great Britain. The conversations have been a great success, with thousands of participants in 22 countries at the end of the first year. For more information, see #GBDOC’s impressive website at http://www.gbdoc.co.uk/gbdoc/About_gbdoc.html

• Mr. Buchanan called the inability for patients to send healthcare data from France to their HCP in the UK “madness,” and highlighted the need for regulators to examine what will keep patients the safest. For Mr. Buchanan, this means keeping the communication lines open between HCPs and patients. We certainly agree, though we think a key challenge is in presenting data in a way that providers can digest and in a reimbursement system where they can get paid.

• “Health is like religion…it has to be made personal to be sustainable.” Mr. Buchanan emphasized that patients have to want to incorporate tools into their life in order to be successful He questioned why we expect apps will be any different from past technologies (such as scales and mirrors) that have failed to change our behavior throughout the years. He noted that technologies have to be a tool to engage patients rather than a to be used as a regulatory stick. Mr. Buchanan also cautioned app developers to remember that patients are not the same as “normal consumers” and developers must consider what will engage patients the most.

• TeamBG encourages people with diabetes to achieve their exercise goals, and also educates people with diabetes about the benefits of sports and exercise. For more information, see TeamBG’s website at http://www.teambloodglucose.com/TeamBG/Mission.html

Use of Social Media & New Technologies from the Perspective of PWD

Claire Pesterfield, RN (Cambridge University Hospitals NHS Trust, Cambridge, UK)

Ms. Claire Pesterfield, a self-described “diabetic diabetes nurse,” delivered a lively talk balanced by her ability to speak from the dual-perspective of a healthcare provider and a patient living with type 1 diabetes since the age of 13 years. Her well-structured presentation alternated between the HCP and patient voice, allowing her to highlight the disparities and alignments that exist between their respective desires. One of her biggest points was that people with diabetes lead multifarious lives with many more demands than just management of their chronic condition; however, the price for not letting diabetes-care be all-consuming is often felt in the clinic. Ms. Pesterfield then advocated on behalf of patient-centered goals that aim to achieve optimal control within acceptable limits. Currently, Ms. Pesterfield sees doctors’ focus as being purely on reaching rigid target A1c targets. Additionally, Ms. Pesterfield expressed the need for more technologies and strategies that are seamless, safe, and effective. Given the title of her talk, we were disappointed that Ms. Pesterfield did not capitalize on her unique position as a provider and a patient to discuss how both can leverage the diabetes online community. She briefly mentioned the ability of Facebook to dispel social isolation; however, she did not delve into the power of other online platforms to disseminate information and engage stakeholders.

How Mobile Solutions Can Help People with Diabetes

Benjamin Sarda (Orange Healthcare, France)

Mr. Benjamin Sarda explained that when he began his career, the main focus of his customers (typically government and pharmacies) was to reduce the cost of healthcare. This could be done in three ways: getting rid of hospital beds, getting rid of bad habits, and getting rid of emergency medical events. Mr. Sarda remarked (rather astutely, we thought) that efforts to eliminate one problem typically lead to another. Within the past five years, however, technology has provided some solutions to take on these three problems. He outlined several ways that innovations have helped decrease readmission rates and increase patient compliance in cases like sleep apnea and cardiac events. Mr. Sarda used the last part of his presentation to describe the mHealth Grand Tour (which we saw a brief video synopsis of!) – he hopes this study, which used the Dexcom Gen 5 CGM system, will provide data showing that technology is useful for better healthcare in patients with diabetes. We, too, are excited to hear the results of this trial since good technology can really make a profound difference in glycemic control (provided it is used in an optimal way). We wish Mr. Sarda had spent more time discussing diabetes-specific technology, though much of his presentation focused on other healthcare examples.

• CGM, heart rate, and bike data from the mHealth Grand Tour is currently being analyzed at the University of Newcastle. The information that will be analyzed includes how riding affects blood sugar levels during the day and night; how different athletes manage their diabetes (insulin and glucose); how high-performance athletes with type 1 diabetes manage their diabetes compared with non-competitive athletes with type 1 diabetes; and how people with diabetes can teach people without diabetes how to prevent low blood sugar levels during a ride.

Panel Discussion

Moderator: Sophie Peresson, MA (IDF Europe Regional Director, Brussels, Belgium)

Panelists: Paul Buchanan (Founder and CEO, TeamBG, Great Britain, UK); Claire Pesterfield, RN (Cambridge University Hospitals NHS Trust, Cambridge, UK); Benjamin Sarda (Head of Marketing, Orange Healthcare, France)

Q: I have a challenge for you two, Mr. Buchanan and Ms. Pesterfield. There is a huge problem of discrimination of people with diabetes. How can you protect personal data, for example when you are applying for a job? How do you make sure that your employer is not seeing that you have diabetes on social media outlets such as Facebook?

Mr. Buchanan: It is an interesting question. I suppose you have to get to a point of having interviewers asking interviewees to view their social media profiles. However, what interviewers are seeing on social media is not limited to chronic conditions. There are also people on social media who post themselves doing very stupid things. I think in order for social media outlets such as Facebook to be used more as a forum for chronic diseases, social media needs to become a more mature platform. From the perspective of protecting personal data, the easy answer is to look at current mobile technology and banking, which use encrypting. It is true that even these can be hacked – any data can. So, one reply is to regulate employment law and educate people on what is appropriate to put on social media; another reply is to look at social platforms that allow you to develop an avatar or a personality that you can use to be anonymous. There are few people in GBDOC [Great Britain Diabetes Online Community] that are personally identifiable, and those posts are rational and published responses. You need to remember that with any community you get extremes in ideas.

Mr. Sarda: If someone posts on the internet that he or she has type 1 diabetes, there is nothing you can do about it. Most countries have regulations on nonmedical data, and it is not legal to use the same data centers to host YouTube and personal medical data. Most players are asked to invest in dedicated data centers with high-level security centers for medical data. In Europe, the standards for health data are higher than the standards for protecting bank data. But if you put everything on Facebook… [shrug].

Q: I was interested in the CGM data and its transmission from country to country. I just assumed that if I had a mobile phone app, I could send data without being restricted by regulations. IDF and various member associations are very much involved in advocacy, and we have regular sessions in Parliament to discuss these big issues. What can these organizations do to help change regulations to make things easier?

Mr. Buchanan: I am happy to speak from a patient’s perspective. The reason for this challenge is that there is no harmonization across member states. There is no standardized language or protocol, and in some counties it is illegal to transmit patient information outside the boundaries of that particular country. For instance, there was one case in which CGM data had been moving across several countries. Data was being sent to smart phones, where patients weren’t allowed to see it because it was blinded, and then to a cloud based platform, where there had to be a delay of 30 minutes before the information was made visible to ensure that there was no chance of people making therapeutic decisions based off the data. Why does it take four to six years to bring a device to market? Because of the regulatory framework! By the time regulators make up their minds that something is safe, we have already moved on. There is a lack of innovation today not because of the costs of innovation itself, but the costs of the time scale to get the approvals. We still need regulatory approval, but it can be harmonized; the regulatory framework needs to move in time with technological solutions that currently exist as well as those developing for future use.

Mr. Sarda: Each and every country in Europe has their own regulation about medical data; is not the same from country to country. From an industry perspective, we need a common agreement. There is an international third party that is writing down guidelines for standardization; this will help make things cheaper and safer. As for the time issue, we need to be FDA cleared – we want to provide patients technologies and solutions that are strong and validated.

Comment: It seems to be that you have highlighted the extraordinary situation of being unable to transmit data across countries. This is a challenge for organizations such as IDF and other chronic disease associations – we need to show this to parliament and make them see the actual problems that you face.

Ms. Peresson: We know what the problems are from a diabetes perspective, and Benjamin brought in the other perspective. I think that starting to have this conversation with all stakeholders will speed up developments, but we are only beginning the discussion now. If you want to contact us, please do not hesitate. I will now ask the panelists if there is anything they would like to add to close the session.

Mr. Buchanan: I want to challenge the audience and EASD. I am going to read you some quick, terrifying statistics for those of you who are new to diabetes. There are thousands of children with diabetes in Great Britain. The median A1c is above 8% – this has not improved in a decade. In ten years, the world has revolutionized in terms of social media, the Internet, and global communication. Why is there such a disparity between this and diabetes? Diabetes has one of highest failure rates for chronic condition there is. Why is this? Out of every one million people with diabetes, 841,000 patients fail on all measures of success that the UK has decided upon. It cannot be that technology is what is stopping us from succeeding. This is your business and this is your industry. We need you to do this. Please be good at what you do.

Ms. Pesterfield: I’ve had diabetes for 20-odd years, and I’ve been a diabetes nurse for half of it. It’s frustrating because we’ve seen so many things come in, but we still have some of the same frustrations and regulations. I’m often caught on the fence between what I want as a patient and what I can offer as a healthcare professional. One problem is that people only look to the next year and next election to find things to fund, and we need to start looking 20-30 years ahead in order to make those funding decisions.

Satellite Session: DIRECT – Personalized Medicines in Type 2 Diabetes

Objectives and Opportunities

Hartmut Rütten, MD, PhD (Sanofi, Frankfurt, Germany)

Dr. Hartmut Rütten outlined the objectives and opportunities of the DIRECT (Diabetes Research on Patient Stratification) consortium, which includes over 20 academic institutions and four pharmaceutical companies (Novo Nordisk, Sanofi, Eli Lilly, and Servier). Overall, the consortium aims to identify and validate biomarkers for glycemic deterioration and treatment response, in efforts to further individualize treatment for type 2 diabetes. As such, the DIRECT consortium intends to: 1) provide a high-quality European database that includes detailed phenotypic information; 2) provide a systems biology platform integrating clinical data, biological data, genomics, metabolomics, and other relevant data; 3) develop novel data mining tools and algorithms to generate stratification and response biomarker candidates; 4) develop industrialized biomarker assays; 5) validate biomarker candidates; and 6) assess response (or lack of response) to established therapies in well-defined subpopulations. In closing, Dr. Rütten highlighted a number of opportunities the DIRECT academic/industry consortium provides, including access to well-characterized cohorts, access to a broad range of technologies, and access to a large European database for systems biology. For more information on DIRECT, please visit: www.direct-diabetes.org.

What Are We Doing, and When Will We Deliver?

Ewan Pearson, PhD (University of Dundee, Dundee, United Kingdom)

Dr. Ewan Pearson discussed the DIRECT consortium’s progress to date, emphasizing its focus on developing biomarkers to predict glycemic deterioration (Work Package 2 [WP2]) and treatment response (WP3). To better phenotype glycemic deterioration (WP2), DIRECT consortium members are looking at a number of measures (e.g., MMT, MRI for liver and pancreatic fat, GWAS, targeted and non-targeted metabolomics, metagenomics, etc.) both for those with prediabetes (n=2,700) and those with recently diagnosed diabetes (n=1,000) over an 18-month follow-up period. In WP3, DIRECT consortium members aim to perform extensive phenotyping of extreme drug responders and non-responders to gain insight into potential biomarkers for treatment response. For example, DIRECT investigators intend to assess a wide array of measures for those treated with GLP-1 agonists, including (but not limited to): beta cell function at initiation, hyperglucagonemia at baseline (and suppression by drugs), GLP-1 secretion at baseline, beta cell GLP-1 sensitivity, the impacts of drugs on gastric emptying, targeted and non-targeted metabolomics, and genomics. In addition to GLP-1 agonists, the consortium will also be looking at metformin and sulfonylurea extreme responders and non-responders, and will be investigating predictors and mechanisms for diabetes remission following bariatric surgery.

Questions and Answers

Q: It’s great that you’re looking at the usual suspects – metformin and sulfonylureas. Is there any provision for any of the new promising pipeline drugs to plug into this model and predict their success in clinical trials?

A: Academic study sites are limited to dealing with available drugs. But, a number of these [new candidates] are being developed by [our] pharma partners. One would hope at the very least that signals we get might impact [how they look at] response to their drugs. What we would like to get is their data, and bring it into the database, but it may be a bit more of a challenge.

Satellite Session: 6^th CIBERDEM Annual Meeting

Summary of the Results of the Look AHEAD Trial

F. Xavier Pi-Sunyer, MD, PhD (Columbia University College of Physicians and Surgeons, New York City, NY)

Dr. Xavier Pi-Sunyer provided insightful commentary on the Look AHEAD study’s primary results, which were originally presented at ADA. As a reminder, the primary results are based on almost 12 years of data on the impact of an intensive lifestyle intervention program on cardiovascular morbidity and mortality in obese or overweight individuals with type 2 diabetes. Dr. Pi-Sunyer reminded attendees that the lifestyle intervention did not significantly improve cardiovascular outcomes relative to standard of care, resulting in the intervention being terminated early. Dr. Pi-Sunyer’s take away from the Look AHEAD trial was that overweight and obese people with type 2 diabetes can improve their cardiovascular outcomes in one of two ways: 1) by being more physically active and improving their diet or 2) by increasing the number of drugs they take. As a reminder, on average people in the intervention arm used significantly fewer medications per year compared to those receiving standard care, and specifically reduced the number of diabetes, lipid-lowering, and anti-hypertensive medications. Dr. Pi-Sunyer noted, however, that people receiving the lifestyle intervention arm experienced significant improvement in some measures, including sleep apnea, cardiovascular risk factors (except LDL cholesterol), urinary incontinence, and overall quality of life. For more details on the Look AHEAD trial, as well as its primary results, please see pg. 20 of our ADA 2013 Report – Healthcare Delivery, Cost-Effectiveness, Lifestyle, Prevention, and Epidemiology at http://www.closeconcerns.com/knowledgebase/r/0691a23e.

Questions and Answers

Q: There appears to be a link between type 2 diabetes and Alzheimer’s disease. Did you take into account this situation in your group? Did the person with diabetes and Alzheimer’s disease have a different result than those without?

A: At first we did not do cognitive assessments. The reason is because we did not have enough money. We also enrolled some people who only spoke Spanish and had a lot of American Indians enrolled, who are not particularly literate. So we did not do it at the beginning. However, we are doing it now. We just put in a request to follow people for another five years. Based on what we have seen for other factors, we think that it is likely that cognitive assessments of the two groups would have been similar. Still, we will see if we get a differential over the next five years. It is a very good question.

Q: You have stated that patients in Look AHEAD on the lifestyle intervention had a significantly reduced use of drugs. So at the end, is this intervention cost effective?

A: This study was finished just the end of last year. We are doing all of the cost analysis. I do not have that for you now. The way we did this intervention was quite expensive. We did track all the medications so we can get the medication costs for the two groups. It has not been published yet, because it is still being done. My suspicion is that it will come out to be similar cost effectiveness.

Q: How do you know that those in the intervention arm worked out more?

A: We don't know. Many of them are health conscious people – they volunteered for a 13-year trial. Some of them got quite upset when they were randomized to the control group. Many of them went and did other things; some went to weight watchers, some used meal replacements. We do know that those in the control were not as fit and that they did not lose as much weight. Could they have done something else? Sure.

Q: The results are a little bit depressing. I have seen that in the intervention group all the risk factors improved but LDL cholesterol. Can you extend a little bit on the lack of efficacy of reducing LDL in not reducing outcomes?

A: We have known that LDL cholesterol is extremely important for CV risk. We also know that weight loss is not particularly good at lowering LDL. This trial confirmed that. If I did a similar trial again, I would also put in strong anti-LDL medications in order to try and get their LDL below 70 mg/dl. Most of the intervention group had an LDL above 70 mg/dl. We did not impact LDL overall and that might have made a huge difference.

Q: Do you have any data on people’s smoking habits?

A: We did not allow smokers in. The reason we didn't was because we felt it would not be ok to go 13.5 years to not tell a smoker to not smoke and we were concerned that a big anti-smoking campaign would compound the results. However, at least in our country, very few obese diabetic patients smoke. Maybe they are addicted to food and not smoke. Certainly type 2 diabetes patients already are told not to smoke very strongly by their doctors.

Q: What I saw was that in the first year the results are splendid, then in the follow up the weight is increasing. What happened? Have you looked at adherence?

A: We have self-reported data on physical activity. They did their physical activity at or near home; they did not do it at the center. We do not know how accurate their results are and clearly the physical activity went down over time. Whether that is a function of age, fatigue, boredom, I do not know. We assume that the compliance with the diet also changed over time. The only measures of that are the weight and the waist circumference. But the risk factors all went down and stayed down pretty well.

PREDAPS Study: Data Presentation

Francesc Xavier Cos, MD (Institut Catala de la Salut, Barcelona, Spain)

Dr. Francesc Xavier Cos presented baseline data from PREDAPS, a prospective, observational study being conducted of people with and without prediabetes in Spain (n=2,022). The aim of PREDAPS is to determine the risk of a person with prediabetes developing type 2 diabetes or vascular complications, and the risk factors associated with those progressions. Participants visited a participating primary care center and were between the ages of 29 and 75 years; people with and without prediabetes were enrolled (1:1). At baseline 21.5% of the 1,184 participants with prediabetes, 51.9% had prediabetes as defined by A1c and impaired fasting glucose, 26.7% only had prediabetes as defined by A1c, and 21.5% only had impaired fasting glucose. Risk factors positively associated with prediabetes included 1) age; 2) past family medical history of type 2 diabetes (particularly a maternal history); 3) past medical history of high blood pressure, dyslipidemia, or coronary heart disease; 4) gestational diabetes; 5) having offspring; 6) use of antihypertensive or lipid-lowering agents; 7) obesity; and 8) high triglycerides, fasting plasma glucose, or A1c. Risk factors negatively related with prediabetes included tobacco consumption and consumption of daily sweets. We wonder if the association of consuming sweets with not having prediabetes could be the result of people aware of their prediabetic status making lifestyle changes, including improving their diet. Unfortunately, Dr. Cos did not state what percentage of participants with prediabetes was aware of their disease status entering the trial. Dr. Cos is planning to follow the study population for ten years, though this is dependent on funding. We hope he is able to accomplish this as we think a fuller understanding of prediabetes’ pathology could help researchers develop agents to prevent the progression to type 2 diabetes. Additionally, it will be interesting to see how prevalent vascular complications are among people with prediabetes in this study.

Questions and Answers

Q: We are attending a lot of people of different ethnicities. How did you account for minority status?

A: We have not explored that yet. There is a very low rate of minorities across Spain. If we recruited minorities, we would likely find a disproportionate number of minorities in places like Barcelona. However, that would bias our overall recruiting.

Q: Don't you think that your cohort should start implementing the lifestyle protocol used in Look AHEAD?

A: Look AHEAD was also presented at ADA. To be honest, when we compare our data to other countries – it is clear that our standards are very high. Still, lifestyle is a challenge. We are also involved in the DE-PLAN project. The DE-PLAN project has obtained strong results in Catalonia. It took high-risk patients, was found to work and was cost efficient. So I think this is how we can implement lifestyle intervention in primary care. I think that doing four hours just one time and then providing reminders – like in the diabetes educator-PLAN- is reliable and doable. However, doing it with a coach is not affordable for any system.

-- by Adam Brown, Poonam Daryani, Hannah Deming, Jessica Dong, Hannah Martin, Manu Venkat, Vincent Wu, and Kelly Close

Some small  changes have been made to this report since September 23.