EASD 2013 featured rich discussion and commentary on long-term outcomes trials, especially on SAVOR-TIMI 53 and EXAMINE, the CVOTs for BMS/AZ’s Onglyza (saxagliptin) and Takeda’s Nesina (alogliptin), respectively. Overall, we do not believe that these two trials’ results will change prescribing practices (we do not think that most HCPs had very serious safety concerns, if any, about DPP-4 inhibitors to begin with), perhaps with slightly more reticence to prescribe DPP-4 inhibitors to patients at risk for heart failure and with slightly more reassurance on pancreatic safety risks. The discussion on SAVOR and EXAMINE centered about the increased risk of hospitalization for heart failure found in SAVOR and the trend toward the same result observed in EXAMINE. Although there was broad recognition that the signals were not linked to an increase in mortality, a number of KOLs, including Drs. Mansoor Husain (University Health Network, Toronto, Ontario, Canada) and Naveed Sattar (University of Glasgow, Glasgow, UK) emphatically called for more analysis of the hospitalization data. Given that a study on Novartis’ Galvus (vildagliptin) found that the drug had an effect on ventricular size, Dr. Sattar noted that a class-wide effect cannot be ruled out.
Other important safety findings (pancreatitis, hypoglycemia, kidney function) were also discussed, but were overshadowed by the heart failure discussion. The SAVOR group went to great lengths to conduct subanalyses on hypoglycemia in response to the finding that saxagliptin caused a slight increase in both mild and severe hypoglycemia – overall, clinicians did not express much concern regarding DPP-4 inhibitors and hypoglycemia risk; however, it was instructive to learn that saxagliptin did not have a significant impact on the risk of overall hypoglycemia unless patients were on sulfonylureas, or if they had a baseline A1c below 7% and were on combination therapy involving insulin. Looking forward, we think time-dependent analyses will be helpful to examine the temporal relationship between hypoglycemia and cardiovascular outcomes, which could shed light on hypoglycemia’s contribution to CV risk. Finally, most speakers found the pancreatitis findings in EXAMINE and SAVOR reassuring; however, as expected, most KOLS noted that the CVOTs had too few pancreatitis cases from which to draw meaningful conclusions.
In a corporate symposium sponsored by Novo Nordisk, Dr. Steve Nissen (Cleveland Clinic, Cleveland, OH) remarked that the FDA’s implementation of its 2008 CV guidance (which Dr. Nissen himself had a substantial role in drafting) has occasionally lacked thoughtfulness. He expressed particular puzzlement over the FDA’s decision to require a pre-approval CVOT for Novo Nordisk’s Tresiba (insulin degludec), especially given the FDA Advisory Committee’s positive vote on the candidate. A private corporate symposium sponsored by Sanofi delved deep into the subject of cardiovascular outcomes in diabetes, and featured heavyweights such as Dr. Philip Home (Newcastle University, Newcastle Upon Tyne, UK), Dr. Julio Rosenstock (Dallas Diabetes and Endocrine Center, Dallas, TX), and Dr. Hertzel Gerstein (McMaster University, Hamilton, Ontario, Canada). The conference’s scientific sessions featured a pair of symposia on UKPDS and DCCT/EDIC.
In our report below, talks highlighted in yellow are on our list of our ten favorite talks of the entire conference, which can be found compiled in our EASD 2013 Top Ten Talks Report (published concurrently with this report). Talks highlighted in blue are new additions to the report that were not included in our daily updates from Barcelona.
- Executive Highlights
- Cardiovascular and Other Major Outcomes Trials
- Oral Presentations: Clinical Interventions and Cardiovascular Outcomes
- Oral Presentations: Biomarkers and Risk Scores, Out with the Old, In with the New?
- Symposium: DPP-4 Inhibitors and CVD
- Symposium: UKPDS: 15 Years on from Barcelona
- Symposium: EASD/ADA Symposium: The DCCT/EDIC Study: 30 Years of Progress and Contributions
- Symposium: Rising Star
- Corporate Symposium: Cardiovascular Disease and Impaired Renal Function: Is there a Role for GLP-1? (Sponsored by Novo Nordisk)
- Private Corporate Symposium: Scientific Exchange and Expert Opinions on CV Outcomes in Diabetes (Sponsored by Sanofi)
- Opening Remarks
- The Current Regulatory Environment in Diabetes: What Needs Changing? What is About to Change?
- CV Outcomes Trials with New Glucose Lowering Agents: What are We Learning?
- Insulin and CV Outcomes: Ongoing Analyses of the ORIGIN Trial
- Balancing the Benefits and Risks of Glucose Lowering Therapies
- Highlights of the New 2013 ESC/EASD Guidelines for Diabetes and CV risk Prevention
- Panel Discussion
- Workshop: How Bad is Hypoglycemia?
- Workshop: Which Glucose-Lowering agent Do I Add Next?
- Corporate Symposium: Cardiovascular Risk Control: The Critical Aim of T2D Management (Sponsored by Lilly/BI)
- Corporate Symposium: SAVOR Trial: How May the Largest DPP-4 Inhibitor CV Safety Study Influence Day-To-Day Clinical Practice? (Sponsored by BMS/AZ)
- Corporate Symposium: Glucose Lowering Approaches: Short Term and Long Term Safety Considerations (Sponsored by Sanofi)
- Satellite Session: 6th CIBERDEM Annual Meeting
Cardiovascular and Other Major Outcomes Trials
Oral Presentations: Clinical Interventions and Cardiovascular Outcomes
Baseline Characteristics of Participants Enrolled in the Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Early Type 2 Diabetes (CAROLINA)
Julio Rosenstock, MD (Dallas Diabetes and Endocrine Center, Dallas, TX)
Dr. Julio Rosenstock spoke on the ongoing CAROLINA cardiovascular outcome trial for BI/Lilly’s Tradjenta (linagliptin), which he discussed recently during a Sanofi symposium on cardiovascular considerations in diabetes — read our coverage of his full talk on CVOTs on page 4 of our EASD 2013 Day #1 Report at http://www.closeconcerns.com/knowledgebase/r/19d6b5c0. Dr. Rosenstock spoke favorably about CVOTs during his introduction, stating that the current FDA regulatory approval process provides the opportunity to better assess long-term efficacy, durability, and safety of new agents. After discussing the design of the study (n=6,103, event-driven, with a glimepiride comparator group and estimated run time of six to seven years), he highlighted the exceptional differences between CAROLINA and other CVOTs for DPP-4 inhibitors, especially SAVOR-TIMI 53 (for BMS/AZ’s Onglyza [saxagliptin]) and EXAMINE (for Takeda’s Nesina [alogliptin]. The most important difference he outlined was that CAROLINA was the only trial of the three to use an active comparator, which (in his mind) makes for a more fair comparison. He also noted that the patients in CAROLINA have earlier-stage diabetes than the populations in SAVOR and EXAMINE (average baseline A1c of 7.2% in CAROLINA compared to 8.0% in SAVOR and EXAMINE). He noted that this demographic difference may give CAROLINA a better chance to demonstrate CV safety and perhaps even cardioprotection.
- As background for his presentation, Dr. Rosenstock briefly discussed the need for more cardiovascular outcomes data for specific diabetes therapies. He stated that the current FDA regulatory approval requirements provide an excellent opportunity to better assess the long-term efficacy, durability, and safety of new agents. While FDA-mandated cardiovascular outcomes trials (CVOTs) will help provide that information for more recently developed pharmacotherapies, Dr. Rosenstock mentioned that we lack convincing data on the safety profile of sulfonylureas (SFUs), a much older drug class.
- The CAROLINA CVOT, currently ongoing, is investigating the cardiovascular safety profile of linagliptin compared to that of glimepiride. The study will follow approximately 6,000 patients until 631 documented cardiovascular events occur; Dr. Rosenstock estimated that this will take approximately six to seven years total, but acknowledged that an extension is possible if the event rate is lower than expected. CAROLINA’s enrolled patients had a mean type 2 diabetes duration of six years at baseline; only 35% had established CV disease, and most were on at least one therapy for cardiovascular risk reduction. According to Dr. Rosenstock, the study is appropriately powered to demonstrate non-inferiority and (possibly) superiority.
- Dr. Rosenstock highlighted the exceptional characteristics of CAROLINA, especially the ways in which it differs from other DPP-4 inhibitor CVOTs. CAROLINA is the only CVOT for a major DPP-4 inhibitor that includes an active comparator group. Dr. Rosenstock dedicated a slide of his presentation to an in-depth comparison of CAROLINA with SAVOR-TIMI 53 (the CVOT for BMS/AZ’s Onglyza) and EXAMINE (the CVOT for Takeda’s Nesina). CAROLINA generally enrolled patients with less advanced diabetes (roughly six years since diagnosis, on average) compared to SAVOR and EXAMINE (whose patients averaged 12 and seven years since diagnosis, respectively). The average A1c of CAROLINA patients at baseline was 7.2%, compared to 8.0% in the other two trials. CAROLINA is also the only one of the three studies which did not enroll any patients on insulin therapy. Dr. Rosenstock commented that CAROLINA’s slightly healthier patient population make it more likely to demonstrate a cardioprotective effect than other DPP-4 inhibitor CVOTs.
Questions and Answers
Q: So one thing that strikes me is your prediction of a 2%-per-annum MACE rate in the comparator group, which is pretty high given the profile of your patients. If your study ends up being underpowered, or if your MACE rate estimate was too optimistic, what does that do to your chances of demonstrating non-inferiority?
A: You’re right that patients that don’t have cardiovascular risk factors will have a lower event rate, but that will be balanced out by patients who have established cardiovascular disease who will have a higher event rate of 2% to 3% per year. We’ve put a lot of thought into that estimate, and based on what we’ve seen in previous studies, I think that if anything our event rate expectation is conservative, but your concern is valid. Another important thing is that this is an event-driven trial – we will sit and wait until we get a certain number of events, which could possibly require an extension of the trial if the event rate is low.
Q: Why did you choose glimepiride as the comparator?
A: We want to have the most fair trial we can get, so we wouldn’t choose the worst sulfonylurea – we want the one that is the most widely used, the one that is most widely accepted, the one that gives you less hypoglycemia. We’re not going to force the study in one direction to benefit linagliptin.
Q: Since you have no placebo control, how would you discriminate whether you are doing better with the DPP-4 inhibitor or sulfonylurea?
A: We’re getting an opportunity to examine the natural history of diabetes. The ideal, you’re right, would have been to have three arms, including a placebo control. In CARMELINA, we’ll be comparing linagliptin versus placebo, due to regulatory requirements. However, I think CAROLINA is a more scientifically correct study.
Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome and Results (LEADER) Trial Design and Methods
Steven Marso, MD (Saint Luke’s Health System, Kansas City, MO)
Dr. Stephen Marso provided an overview of the design, methods, and baseline characteristics of the LEADER trial, the cardiovascular outcomes trial for liraglutide (Novo Nordisk’s Victoza). In the trial, patients have been randomized to liraglutide 0.6-1.8 mg or placebo in addition to standard of care, with anticipated treatment duration of 3.5-5 years. The primary endpoint will be time from randomization to the first occurrence of the composite cardiovascular outcome of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. Dr. Marso highlighted that a wide array of secondary endpoints will be measured, including an expanded composite cardiovascular outcome, death, acute coronary syndrome, cerebrovascular events, heart failure, coronary revascularization, nephropathy, retinopathy, pancreatitis, neoplasms, and thyroid disease. In terms of study design, all participants had a two-week-plus placebo run-in period to demonstrate that they could have at least 50% adherence to the regimen and the willingness to continue with the injection protocol for the duration of the trial. Study investigators estimate that the primary event rate would be 1.8% in both arms, and that up to 10% of patients would permanently stop treatment. Based on these assumptions, they calculated they would need a minimum of 8,754 subjects with a minimum follow-up of 42 months after randomization of the last subject to test non-inferiority of liraglutide versus placebo, and superiority (only if non-inferiority is met).
- LEADER includes patients in two cardiovascular risk cohorts: those with prior cardiovascular disease (CVD), and those without CVD. Those in the prior CVD cohort were ≥50 years of age at enrollment, and have at least one of the following: cardiovascular disease, cerebrovascular disease, peripheral vascular disease, chronic renal failure, or heart failure. Those in the no prior CVD cohort were ≥60 years of age at enrollment, and have at least one of the following: microalbuminuria or macroalbuminuria, hypertension and left ventricular hypertrophy by ECG or imaging, left ventricular systolic or diastolic dysfunction by imaging, or an ankle-brachial index <0.9.
- Of the 9,340 patients randomized, 7,592 (81%) have prior CVD, and 1,748 (19%) did not have prior CVD. At baseline, participants had an average age of 65 years, BMI of 32.5 kg/m2, A1c of 8.7%, and diabetes duration of 12.7 years. In terms of existing therapy: 5% were treatment naïve; 21%, 29%, and 4% were taking one, two, and three oral antidiabetics (OAD), respectively; and 42% were prior insulin users. Approximately 90% had hypertension, 77% had dyslipidemia, 57% had coronary artery disease, 17% had congestive heart failure, 18% had peripheral vascular disease, and 2% had eGFR <30 ml/min/1.73 m2 at baseline.
Questions and Answers
Q: Do you think the distribution of eGFR in your achieved sample of study entrants is typical of the background population with type 2 diabetes, given that 80% of them have cardiovascular disease? Or do you think you’ve managed to oversample people with worse renal function in this trial?
A: When the trial started, we thought we would need to oversample those with an eGFR of less than 30, but we didn’t have to oversample. We fell just short of the intended target of around 200. The short answer is that the profile of those with low eGFR is similar to the background CV risk of patients we enrolled; I don’t believe we overscreened or oversampled to get enough patients with eGFR less than 30. As background, the FDA recommended enrolling patients with eGFR less than 30, so the point was to oversample that population.
Q: Could you say something about the dosage estimate of insulin and rescue therapy you have? You have quite a high A1c to start with, so I could imagine there needing to be some handling of high glucose levels when injecting placebo for four years.
A: Being one of two cardiologists on the steering committee, my fear was that people would have a hard time injecting placebo for five years. The operational approach to the trial is a rather pragmatic one, as a global clinical trial. The way diabetes is managed around the globe is quite different. Our recommendations for rescue therapy and insulin treatment are highly regionalized, so we try to follow national guidelines and standards.
Q: Could you comment on your power calculations, and what your assumptions were with the withdrawal rate?
A: The initial assumption was that we would have less than 10% permanent dropouts. I think the trial is meeting or exceeding those expectations. We estimated an event rate of 1.8%. Given the high-risk nature of the population, prior epidemiological data, and prior studies, I suspect it will be higher than that.
Oral Presentations: Biomarkers and Risk Scores, Out with the Old, In with the New?
Investigating the Validity of the UKPDS Outcomes Equations in Current Clinical Practice
Phil McEwan, PhD (Swansea University, Swansea, United Kingdom)
Dr. Phil McEwan discussed the results of a study that recalibrated the UKPDS 68 risk equations to contemporary UK patient data and investigated the implications of using such recalibrated equations in health-economic evaluation. In the study, Dr. McEwan and colleagues used retrospective UK cohort data extracted from The Health Improvement Network (THIN) database, which includes ~6% of the UK population. Using this data, he and his team recalibrated risk equations from UKPDS 68 for myocardial infarction (MI), congestive heart failure (CHF), ischemic heart disease (IHD), stroke, end-stage renal disease (ESRD), blindness, and amputations. These equations were calibrated to two cohort profiles – a low-risk cohort (n=54,169; newly diagnosed type 2 diabetes, ages 25-65, BMI <45 kg/m2, no diagnosis of cancer), and an intermediate-risk cohort (n=68,990; at least 55 years of age with one cardiovascular risk factor in the year prior to their index date, diabetes duration of at least 10 years, age of 65 years or older, or A1c ≥7.5%). Comparing the original UKPDS 68 risk equations with the new THIN-calibrated equations, the UKPDS 68 risk equations appeared to significantly overestimate the risk of MI, and underestimated the risk of CHF, IHD, ESRD, and amputations. Applying both the UKPDS 68 and THIN-calibrated risk equations to a health-economic model, Dr. McEwan concluded that economic evaluations utilizing the UKPDS 68 risk equations are robust, and can be calibrated for specific groups.
Questions and Answers
Q: I was a statistician who worked on the UKPDS study. One thing that is very different is the care of the patients. I am not surprised that the rate of amputation is lower, because patients were seen every three to four months, and had their feet looked at by someone trained to look at feet problems. As such, they were much less likely to have had ulcers which progress. Some of these things might be explained by differences in clinical care.
A: That’s a great point. I think it’s helpful to try to provide insight into how much of a difference it’s likely to make.
Symposium: DPP-4 Inhibitors and CVD
Results from EXAMINE
William White, MD (University of Connecticut, Farmington, CT) and Simon Heller, MD (University of Sheffield, Sheffield, United Kingdom)
Dr. William White and Dr. Simon Heller presented results from EXAMINE, the cardiovascular outcomes trial for alogliptin (Takeda’s Nesina). The main findings from the study were initially presented at the European Society of Cardiology’s annual conference earlier this month – see our ESC 2013 Day #1 Report at http://www.closeconcerns.com/knowledgebase/r/2a8925c5 for our full coverage. In light of SAVOR’s finding that saxagliptin increased hospitalization for heart failure, EXAMINE investigators performed a post-hoc analysis of heart failure hospitalization in EXAMINE, which did not pre-specify hospitalization for heart failure as an endpoint (the pre-specified heart failure endpoint in was a composite of CV death plus hospitalization for heart failure, which EXAMINE investigators have noted is the standard in heart failure trials). EXAMINE’s pre-specified CV mortality and hospitalization for heart failure analysis found that the HR was 0.98 (95% CI: 0.82-1.21) with alogliptin treatment. The new post-hoc analysis showed that the HR for hospitalization for heart failure alone was 1.19 (95% CI: 0.90-1.58), while CV mortality alone was 0.84 (0.64-1.10). Although the hospitalization for heart failure result was not statistically significant, it trends in the same direction of SAVOR’s result.
Questions and Answers
Q: I have some problems with the numbers on heart failure. In Table 1 in the publication on September 2nd, you state that 28% of all patients in EXAMINE had preexisting congestive heart failure, amounting to some 750 patients with heart failure in each arm. Now you report a history of heart failure only in 400-some patients in each arm. Did you change the definition for this new analysis?
Dr. White: The number in the paper was at the time of randomization, so that could have included post-ACS heart failure. What we are reporting now is before the primary ACS event. That’s why the numbers are higher in the paper. We thought that from the standpoint of evaluating morbidity, it made more sense.
Q: Did you do a post hoc exploratory analysis to look at patients using sulfonylurea?
Dr. White: We did a subgroup analysis looking at those who were taking or not taking sulfonylurea, and there was no heterogeneity.
Q: Did you look at microalbuminuria between groups?
Dr. Heller: We did not measure microalbuminuria.
Comment: The only concern I have is with pancreatitis. I don’t think it’s appropriate to do statistics when you have 12 and five cases. The only thing we can say is that there is an imbalance, consistent with the concerns we have had. It is an imbalance that we need to take into consideration.
Dr. Heller: Alternative etiologies seemed to explain some of those cases. I agree that the numbers are small, but I think we could still conclude that these events were relatively unusual, which is reassuring, and that’s probably as far as we can go.
Q: Were investigators allowed to combine multiple medications, including insulin, on top of alogliptin? If so, why is it that such a low percentage of patients achieve an A1c of less than 7%?
Dr. Heller: The investigators were free to use whatever antidiabetic medications they so chose, and medications increased more in the placebo group, but you’re right, they didn’t match the A1c levels in both groups. I can’t speak for many investigators around the world, but clearly it is an issue, of inertia I presume.
Q: Do you think the percentage of patients who achieved an A1c of less than 7% may have affected the outcome?
Dr. Heller: Of course it’s worth remembering that the patients in the trial were at very high risk. Other intensive control trials suggest very aggressive and low A1c may have adverse consequences, so I’m sure that would be in the investigators’ minds when trying to improve A1c in this group. We don’t have data to conclude whether this affected the outcome.
Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes
Deepak Bhatt, MD (Harvard University, Cambridge, MA)
Dr. Deepak Bhatt took the stage to present the main results of the SAVOR-TIMI 53 trial, which investigated the cardiovascular effects of BMS/AZ’s DPP-4 inhibitor Onglyza (saxagliptin). This data was first presented at the European Society of Cardiology’s annual conference earlier this month along with the results of EXAMINE — see our ESC 2013 Day #1 Report at http://www.closeconcerns.com/knowledgebase/r/2a8925c5 for our full coverage of those presentations. The investigators designed a trial powerful enough to potentially demonstrate cardiovascular superiority, given that earlier studies had hinted at a slight cardioprotective effect. However, after two years of treatment, saxagliptin showed no significant effect on the composite primary composite outcome of cardiovascular death, myocardial infarction, and ischemic stroke. The DPP-4 inhibitor led to a somewhat modest A1c improvement of 0.5% (0.3% placebo-adjusted) from a baseline of 8%, although Dr. Bhatt noted that the modest difference was largely due to the escalation of treatment in the placebo cohort. He mentioned that there was a statistically significant increase in hospitalization for heart failure (a much-discussed signal during the weeks since ESC), but noted that the increase was relatively small in an absolute sense (0.7%), that it was not associated with an increase in mortality, and that most cases of hospitalizations were in patients with high levels of BNP (a protein associated with heart failure risk). No significant differences were seen between saxagliptin and placebo in subgroup analyses by age, baseline A1c, pre-existing CVD, or concomitant therapy, among other criteria. He ended by noting that further analyses of SAVOR data are ongoing, and will be presented at the American Heart Association’s annual conference on November 16-20 in Dallas.
A Diabetologist’s Interpretation of a Cardiovascular Study
Itamar Raz, MD (Hadassah Medical Center, Jerusalem, Israel)
Next, Dr. Itamar Raz discussed interesting secondary analyses of SAVOR-TIMI 53 data. In patients with A1c >7.0% at baseline, saxagliptin was significantly more effective at lowering A1c in patients also on metformin, insulin (alone or in combination), or sulfonylureas (the improvement was non-significant for saxagliptin monotherapy). Dr. Raz next provided an expanded analysis of patient renal function. Significantly more patients in the treatment arm progressed to a better category of renal function (defined by albumin/creatinine ratio) than in the control arm (11% vs. 9%), and significantly fewer patients from the treatment arm saw their renal function category worsen (13% vs. 16% with placebo), indicating that saxagliptin may prevent the deterioration of (or even improve) renal function. The first round of SAVOR data had shown that saxagliptin modestly but significantly increased the incidence of both minor and major hypoglycemia. The investigators conducted a thorough examination of hypoglycemia occurrence, and found that there was no risk increase for most patients, but a significant increase in patients on sulfonylureas (which are known to cause hypoglycemia) and/or those with a baseline A1c below 7%. Turning to pancreatitis, study adjudicators found 26 definite or possible acute pancreatitis events in the saxagliptin group compared to 25 in the placebo group (17 vs. nine cases of “definite pancreatitis”). However, the mean event duration was shorter in the saxagliptin group, and patients continued with saxagliptin treatment in 60% of cases. A scatterplot of the data shows that there was no temporal clustering of cases, as would be expected if the drug was directly causing pancreatitis.
- Dr. Raz began by presenting more detailed data on saxagliptin’s glycemic efficacy. Significantly fewer patients on the drug received new or increased doses of other diabetes drugs during the trial than in the placebo group, regardless of baseline A1c. Next, we saw data on the mean change in A1c segmented by concomitant therapy — patients on saxagliptin combination therapy with metformin, insulin, or sulfonylurea saw significantly greater drops in A1c than saxagliptin placebo patients on the same concomitant antidiabetic drugs. The difference in A1c change between the saxagliptin and placebo cohorts was not significant but trended towards an effect. Notably, this combination therapy analysis was limited to patients with baseline A1cs above 7% — we imagine that the investigators used this cutoff because patients with lower baseline A1c likely had smaller change, making it difficult to demonstrate statistical significance.
- Saxagliptin had a modest but statistically significant beneficial effect on renal function. Prior to the trial, the investigators pre-determined a series of categories based on albumin/creatinine ratio (<30, 30-300, and >300 mg/G). Patients underwent urinary albumin excretion tests yearly and at the end of the trial. Only 13% of patients in the saxagliptin arm shifted to a worse category, compared to 16% of the placebo group (p<0.001). Around 11% of saxagliptin patients saw an improvement in their renal function category, compared to 9% of placebo patients (p<0.001).
- The SAVOR study group conducted in in-depth analysis of hypoglycemia, perhaps in response to the finding of a significant increase in both mild and severe hypoglycemia in the saxagliptin arm. The study used a fairly broad definition of minor hypoglycemia: in addition to glucose measurements below 54 mg/dl, the definition included episodes with symptoms that were resolved after carbohydrate consumption with no blood glucose data. Severe hypoglycemia was defined as any event that required the assistance of another person (regardless of blood glucose). This analysis demonstrated that saxagliptin did not have a significant impact on overall hypoglycemia unless the patient was on sulfonylureas, or if they had a baseline A1c below 7% and were on combination therapy involving insulin. The only significant increase in major hypoglycemia was in saxagliptin patients who were treated with sulfonylureas and had a baseline A1c below 7%. This analysis should somewhat assuage fears about the early hypoglycemia data, as sulfonylureas’ impact on hypoglycemia is well known, and most patients with low baseline A1c had less of margin of error during treatment.
- Dr. Raz concluded by presenting a more in-depth analysis of the pancreatitis seen during SAVOR. As with some other incretin safety trials, the overall incidence of pancreatitis was low (making statistically significant differences unlikely) but there was a slight numerical imbalance. Adjudicators found 24 cases of any pancreatitis event and 17 cases of definite pancreatitis (compared to 21 and nine cases in the placebo group, respectively). However, Dr. Raz noted that the mean duration of pancreatitis cases was far less in the saxagliptin group compared to the placebo group (14 and 44 days, respectively), and that 60% of pancreatitis patients in the treatment arm continued uninterrupted on saxagliptin, suggesting that patients and providers did not see the drug as a causal factor. Dr. Raz also displayed a scatterplot of pancreatitis cases graphed against time (cases were fairly evenly distributed along the entire study time course) — he argued that if saxagliptin was causing pancreatitis, cases would be clustered towards the beginning of the trial. While this study was neither large nor long enough to definitely disprove the possibility of a pancreatitis effect, we found Dr. Raz’s arguments in this section convincing.
Questions and Answers
Q: Regarding the hypoglycemia you saw in the group on sulfonylurea with low A1c, could that have been a protocol problem?
A: As you saw, we recruited patients with A1cs below 6.5% — they comprised 8% of our patient total. We discussed the issue, and at the end of day we decided not to change the protocol. But this is something that will be discussed.
Q: Did most of the hypoglycemia cases happen early in the trial?
A: That is a good question – I don’t have the answer yet. Most probably happened during the earlier stages of the trial.
Q: I have a question about the increase in hospitalization for heart failure. The background treatment was different than in EXAMINE: fewer patients were on beta blockers and ACE inhibitors. Did you analyze the data by baseline cardiovascular medications? Also, did you see if there was an increase in BNP with sitagliptin compared to placebo?
A: We do have BNP data, more specifically pro-BNP levels, since BNP can be affected by DPP-4 inhibitors. We hope to have that data analyzed by AHA. It is important to keep in mind that the overall hazard ratio for the secondary endpoints was 1.02, so no sign of harm. The p-value for hospitalization was significant, but it is hard to interpret the significance of one item like that when the overall hazard ratio is neutral. An analysis looking for differences in sub-characteristics, including cardiovascular medications, is being done. We showed the preliminary BNP data here because we were looking for the group at highest risk, but in terms of clinical descriptors, the biggest risk factor for the development of heart failure was previous heart failure, and that was true in both arms. EXAMINE did not find a significant excess in heart failure – I commend the investigators for doing a lot of analyses. It takes a lot of effort. There are two explanations I can think of: one is that finding in our trial in spurious; the other is that the same effect exists in EXAMINE but the trial was not powerful enough to pick it up, and that if it was as powerful as SAVOR, the finding would have been significant there as well. But overall the data is reassuring to some extent, as the hospitalization for heart failure was isolated and did not lead to an increase in other cardiovascular outcomes.
Q: Did you analyze whether the occurrence of hypoglycemia was in any way related to the occurrence of the primary cardiovascular endpoint?
A: We’re in the process of evaluating the relationship between hypoglycemia and the primary and secondary endpoints. It’s tricky to do those analyses though, because as previous analyses have shown, hypoglycemia is associated with a number of things, from cardiovascular death, to non-cardiovascular death, to cancer. What is necessary is to do time-dependent analyses, to examine the temporal relationships.
Q: Does the expertise of providers at the different sites have an effect in hypoglycemia – to be up-front, was there more hypoglycemia with cardiologists than with endocrinologists?
A: We don’t have the answer for that, as we didn’t do these analyses yet. One thing we can learn from SAVOR is that for patients who have A1c less than 7%, you shouldn’t add saxagliptin to a sulfonylurea. Most patients who had established cardiovascular disease came to us through cardiologists, and most of those people had an A1c between 7% and 8%. I believe we will find that most hypoglycemia was related to multiple risk factors.
Naveed Sattar, MD, PhD (University of Glasgow, Glasgow, UK)
Dr. Naveed Sattar ended the session with an energetic, no-holds-barred interpretation of SAVOR and EXAMINE results. He noted that the FDA’s new guidelines “force” study designs that may be less than ideal (i.e., they enroll higher risk patient populations to promote expediency), but that this is a reality of the times. He brought up the apparent paradox between the results of earlier DPP-4 inhibitor trials, which (when meta-analyzed) showed promise of a cardioprotective effect, and the results of SAVOR and EXAMINE, which were neutral. Dr. Sattar stated emphatically that we should not be surprised by this result, as A1c reductions as modest as those seen in SAVOR and EXAMINE (0.3 – 0.35%) couldn’t have an appreciable effect on cardiovascular risk in a mere two years. To be successful in such a time period, he argued that DPP-4 inhibitors would need to have pleiotropic effects on blood pressure or lipids. Overall, he argued, CV management is more effective when pursued through agents such as statins and blood pressure medications than through glucose lowering. In his view, statin use in SAVOR was suboptimal at 78%. He found the pancreatitis data from both trials reassuring, although he acknowledged that they are not enough to disprove a possible effect. The hypoglycemia results of SAVOR, in his mind, indicate that A1c targets should be relaxed in patients with cardiovascular disease. He found the reduction of progression to albuminuria seen with saxagliptin modest and generally unsurprising. He emphatically stated that the medical community must take the hospitalization signal in SAVOR seriously — given the similar but non-significant trend seen in EXAMINE, as well as data showing that the DPP-4 inhibitor Galvus (vildagliptin) had a slight effect on ventricular size, Dr. Sattar argued that we cannot rule out a class-wide effect.
Symposium: UKPDS: 15 Years on from Barcelona
Rury Holman, FMedSci (University of Oxford, Oxford, UK)
Fifteen years after primary results from the UKPDS were first presented at EASD in Barcelona, Dr. Rury Holman regaled the audience with a historical perspective of the study, reviewing its conception, execution, and (early, primary, and post-trial) results. He began by giving thanks to everyone involved in the trial, in particular paying respect to his mentor Dr. Robert Turner, who conceived of the UKPDS (jotting down the basic design on the back of an envelope in 1976) and saw the study through to the end. Providing an interesting anecdote, Dr. Holman noted that Dr. Turner didn’t get everything right in his initial brainstorm – on his back-of-the-envelope calculations, he estimated the study to cost to be ~£37,000 per year (which would have cost just over a quarter million pounds over seven years), while the actual costs reached ~£23 million by 1998. After reviewing results from the UKPDS, Dr. Holman summarized key lessons: 1) the study confirmed beyond a doubt that better glucose control reduced the risk of microvascular complications for those with type 2 diabetes; 2) there was a borderline significant finding that better glucose control may reduce the risk of macrovascular complications, confirmed by subsequent UKPDS post-trial monitoring (“the legacy effect”); 3) sulfonylurea is as effective as insulin in the prevention of late complications and cardiovascular events, with no evidence of excess cardiovascular mortality as suggested by the UGDP; 4) primary randomization to metformin showed significant reductions in cardiovascular and all-cause mortality; and 5) antihypertensive treatment is highly effective in delaying progression of diabetic retinopathy and nephropathy.
Global Impact of UKPDS Findings
David Matthews, MD (Oxford Centre for Diabetes, Oxford, UK)
Dr. David Matthews took the stage to discuss the lasting impact of the UKPDS study on diabetes care. He noted that there are now 82 numbered UKPDS publications, which have garnered over 37,000 academic citations. In his view, the UKPDS was the first study to provide definitive evidence that improved glycemic control reduces complications. He directly addressed the controversy over the almost-but-not-quite statistically significant (p=0.052) 16% risk reduction for cardiovascular complications seen in the original study results. He felt that the finding was very noteworthy even though it fell slightly short of the p=0.05 boundary, and made the claim that the effect size was more important than the statistical significance (or lack thereof). Dr. Matthews reminded the audience that the UKPDS played a large role in establishing metformin’s primacy in type 2 diabetes treatment, and is the basis of many type 2 diabetes care guideline documents. UKPDS also changed the way the diabetology community thought of diabetes, largely by introducing the concept of ‘beta cell failure’ to replace the idea of treatment failure. Dr. Matthews touched upon the much-discussed UKPDS finding that metformin reduced patients’ risk for cardiovascular outcomes — the result was statistically significant, but weakened somewhat by the fact that there were only 342 patients in the metformin arm. “Because of the UKPDS,” he concluded, “millions of people will have better outcomes and better lives – that is impact.”
Post Trial Monitoring Result of the UKPDS Sulfonylurea Plus Metformin Study
Rury Holman, FMedSci (University of Oxford, Oxford, UK)
After describing the potential safety concerns of sulfonylurea (SFU) in combination with metformin brought to light in the initial findings of the UKPDS SFU+metformin sub-study, Dr. Rury Holman presented unpublished follow-up results, which alleviated such worries. In the initial sub-study, after a median seven years on SFU, participants in that arm were randomized to continue on SFU monotherapy (n=269), or to add metformin (n=268). After an additional median follow-up of 6.6 years, those on SFU+metformin had an increased rate of diabetes-related deaths (RR=1.96; 95% CI: 1.02-3.75; p=0.039) and all-cause mortality (RR=1.60; p=0.041) compared to those on SFU alone (Lancet 1998). Dr. Holman explained that these initial findings could have been anomalous for a number of reasons, including the fact that the major effect appeared to be fewer deaths in the SFU alone group, not more deaths with SFU+metformin. Looking at 10-year post-monitoring results, neither safety signal remained – with SFU+metformin therapy, the relative risk of diabetes-related deaths was 1.18 (95% CI: 0.82-1.69), and the relative risk of all-cause mortality was 1.24 (95% CI: 0.95-1.60). Dr. Holman stated that these post-trial results suggested “the evil play of chance” in the original sub-study, as the number of events evened out over time. Though he found these results to be comforting, he nonetheless advocated for further studies to better characterize SFU+metformin and other combination therapies.
- Dr. Holman provided an overview of the Glucose Lowering in Non-Diabetic Hyperglycemia Trial (GLINT), which will further investigate the use of metformin as first-line therapy. The UK-based multicenter cardiovascular primary prevention trial will include men and women ≥40 years of age with A1c ≥5.5% and <6.5% and 10-year Framingham risk of ≥20%. Participants will be randomized to metformin XR (1,500 mg/day) or placebo. The study’s primary endpoint will be time to the composite cardiovascular outcome of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. In addition, cancer incidence will be examined as a secondary endpoint. In the five-year trial, a total of 11,834 patients will be enrolled (500 in the feasibility phase; the first patient and first visit will occur in September 2013).
Symposium: EASD/ADA Symposium: The DCCT/EDIC Study: 30 Years of Progress and Contributions
Introduction and Overview
Bernard Zinman, MD (University of Toronto, Toronto, Canada)
Dr. Bernard Zinman provided a thorough overview of the design and results of the Diabetes Control and Complications Trial (DCCT) and the Epidemiology of Diabetes Interventions and Complications (EDIC), highlighting the beneficial effects of intensive therapy on microvascular and neurologic complications. DCCT was designed to evaluate how intensive glycemic control can prevent or reduce the progress of long-term complications, measured mainly through the incidence of retinopathy. Dr. Zinman reviewed the results of the study, highlighting the 2% drop in A1c in the intensive arm. Turning to EDIC, Dr. Zinman highlighted the “metabolic memory” phenomenon that allowed patients in the intensive group to experience the continued benefit of risk reduction past the end of DCCT. Dr. Zinman specifically noted the importance of this data collection for evaluating cardiovascular outcomes, since patients with type 1 diabetes provide a “pure glucose model” for examining the role glycemia plays in CVD (implying that patients with type 2 diabetes are NOT a good model to test this hypothesis). Dr. Zinman expressed his continued gratitude to the participants of the study and emphasized the incredible 95% retention of the surviving participants. For more information on DCCT and EDIC, please see page 226 of our ADA 2013 full report at http://www.closeconcerns.com/knowledgebase/r/94f937d8.
- Dr. Zinman also reminded the audience that the difference in A1c levels between the two groups could explain over 96% of risk reduction for all complications in the intensive control group. These complications included: sustained 3-step progression, severe non-proliferative diabetic retinopathy (SNPDR), laser treatment, CSME, albumin excretion rate (AER) >39 mg per 24 hours, and AER >300 mg per 24 hours.
- DCCT had a massive impact on diabetes public health for diabetes. Dr. Zinman noted that after DCCT, intensive therapy was advocated as the standard of care for people with type 1 diabetes. Additionally, government and public health agencies advertised DCCT as a way to lower barriers to intensive control, and in many areas, insurance coverage of intensive therapy supplies became mandatory.
William Tamborlane, MD (Yale University, New Haven, CT)
Dr. William Tamborlane gave the microvascular update from DCCT/EDIC, noting that the results have been “incredibly remarkable.” Indeed, the data was clear, consistent, and compelling for the three areas he covered: retinopathy, nephropathy, and neuropathy – it never got old to see slide after slide after slide demonstrating the benefits of intensive therapy on microvascular complications. Dr. Tamborlane’s summary said it all in a few bullet points: 1) intensive therapy reduces all microvascular disease substantially and consistently (it’s rare one can make such an absolute claim in medicine, though in this case, it’s justified!); 2) the benefits of intensive therapy are closely associated with reductions in A1c; 3) the early reduction in microvascular complications during the DCCT has translated to salutary effects on more advanced disease; and 4) metabolic memory applies to all microvascular complications. We note that his presentation condensed the three separate talks we saw in a similarly titled symposium at ADA 2013 – see pages 226-232 at http://www.closeconcerns.com/knowledgebase/r/94f937d8.
Trevor Orchard, MD (University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA)
Dr. Trevor Orchard reviewed the cardiovascular benefits of the DCCT/EDIC trial and highlighted that the benefits of intensive glycemic control have only increased as EDIC continues. He emphasized the risk reduction for cardiovascular events that patients from the intensive control group experienced, such as the reduction in atherosclerosis and clinically important outcomes of cardiovascular death, myocardial infarction, or stroke (57% reduction after 11 years!). Dr. Orchard also noted that they are not done with the full mediation model, and they plan do finish after there are 100 cardiovascular deaths, likely within the next few years. Additionally, there is currently a manuscript in progress on the analysis of mortality from DCCT/EDIC, now that there have been 50 deaths – however, all the data is embargoed until publication. For more information on DCCT and the cardiovascular disease update, please see page 227 of our ADA 2013 full report at http://www.closeconcerns.com/knowledgebase/r/94f937d8.
Gayle Lorenzi, RN, CDE (UCSD, San Diego, CA)
Ms. Gayle Lorenzi closed the session with a look at what’s next in DCCT/EDIC. She highlighted areas of continued exploration/redefinition along with future ancillary studies of gastric emptying, C-peptide, and hearing impairment.
- Areas of continued exploration and redefinition include: metabolic memory; triopathy; evidence-based guidelines for the frequency of retinopathy and nephropathy screening; glycemic variability; non-glycemic risk factors and outcomes; cognitive function; and health economics.
- Ms. Lorenzi shared details on three future ancillary DCCT/EDIC studies: gastric emptying, residual C-peptide secretion, and hearing in long-standing type 1 diabetes.
- Gastric emptying: This pilot study will occur at seven EDIC centers and include 80 participants. A C-spirulina gastric emptying breath test will be administered. The study is tasked with answering two main questions: “What is the prevalence of disturbances in gastric emptying?” and “How do they impact glycemic control?” The results will determine whether to expand the investigation and evaluate the full cohort
- Residual C-peptide: In a pilot study presented at ADA 2013, researchers found demonstrable C-peptide in 17% of 58 DCCT/EDIC patients. This upcoming study will examine the full DCCT/EDIC cohort and perform mixed-meal tolerance tests and measured C-peptide using three ultrasensitive assays. Outcomes include A1c over time/insulin dose, hypoglycemia, mediators/risk factors, and long-term complications. The trial will also permit a comparison of the three ultrasensitive assays.
- Hearing impairment: A study will examine the incidence and impact of hearing impairment in the DCCT/EDIC cohort. Researchers will examine its relationship to glycemic control.
Bernard Zinman, MD (University of Toronto, Toronto, Canada); William Tamborlane, MD (Yale University, New Haven, CT); Trevor Orchard, MD (University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA); and Gayle Lorenzi, RN, CDE (UCSD, San Diego, CA)
Q: Because there is a scarcity of data on limited joint mobility, I was wondering if you acquired any data on that from your studies?
Ms. Lorenzi: We completed a study looking at limited shoulder mobility as well as joint problems and function limitations within hands and fingers. We presented results at the ADA meeting in June, and the publication is pending [Editor’s note: For more information, please see page 230 of our ADA 2013 Full Report at http://www.closeconcerns.com/knowledgebase/r/94f937d8]. What I will tell you is that it was an evaluation that got such an enthusiastic response from participants because we were giving a voice to what many had been experiencing over the course of time.
Q: Are you planning to study incidence of cancer?
Dr. Zinman: Obviously as the study population ages, they develop diseases associated with their age group. With 1,441 patients, there are not enough incidences of cancer to show differences. Nonetheless, we are characterizing cancers and outcomes the best we can. We are definitely looking at it, but we are not sure if what we see will be clinically relevant.
Q: I have a question concerning the rate of severe end-stage complications. Renal impairment was low in both the intensive group and the conventional group compared to the historical data that Dr. Zinman showed. I wondered what you thought about that in terms of metabolic memory – in the DCCT, participants’ A1c levels were 9% on average. You also didn’t mention blood pressure in your model for CVD. I was wondering if you tried to unpack these things at all.
A: The one slide I left out was the one that shows predictors of metabolic memory. Your baseline A1c levels at entry also indicated risks of developing complications. I think old data shows that some of these patients were under horrible control. The conventional control may have been better than the treatment 10 years previously, and having an A1c of 8% for years before the study may provide benefits. We were seeing hardly any retinopathy in the adolescent population (those older than 10 who had diabetes more than three years); their A1c levels were under 8% for decades.
Dr. Orchard: We were only controlling for baseline. We excluded with hypertension. I agree that hypertension is a major risk factor, and we discuss hypertension in a separate paper.
Comment: Is CVD related to incidence of hypertension?
Dr. Orchard: We are going to look at that, but we are going hold off until we have 100 cases.
Q: Do you have any data on continuing or not-continuing problems with hypoglycemia in the intensive group? Do they continue to have an excess of hypoglycemia in EDIC?
Dr. Zinman: No one in the study is going back to conventional treatment; the A1c targets achieved are just not nearly as low as they were for the intensive group in the DCCT. Disappointingly, I think there are still significant rates of hypoglycemia. They are less, but not significantly less.
Dr. Orchard: It is more apparent than real because we collect data annually and extrapolate for the year; there is a bias of ascertainment. The DCCT period up to EDIC is problematic, however, now the difference between two groups is all gone.
A: In the Type 1 Diabetes Exchange, A1c levels are a huge risk factor for severe hypoglycemia. For CGM trials and new analogs, we are certainly seeing that we are able to lower A1c without increasing the risk for hypoglycemia.
Symposium: Rising Star
The CAMERA Study: Investigating The Effects of Metformin in Non-Diabetic Patients With Coronary Heart Disease
David Preiss, MD (University of Glasgow, Glasgow, Scotland)
The CAMERA (Carotid Atherosclerosis: Metformin for Insulin Resistance) study was a randomized control trial investigating metformin use in patients without diabetes but with established coronary heart disease (n=173). The primary endpoint was change in progression in carotid intima-media thickness (IMT), while secondary endpoints included carotid plaque score progression and change in several metabolic parameters. Baseline characteristics were comparable across metformin and placebo groups, with an average age of 63.5 years and BMI of 30 kg/m2. Participants were drawn from an already high-risk population of individuals on stains for an average of 6.5 years. After 18 months, researchers found no effect on all measures of CV risk, including cIMT (p=0.29), carotid plaque (p=0.89), and cholesterol levels (both non-HDL and HDL). Significant changes were only observed in markers of diabetes risk, as weight, BMI, triglyceride, HOMA-IR and GGT levels were appreciably lowered. Such results verify the efficacy of metformin in reducing risk of progression to type 2 diabetes, though the drug’s potential to mitigate CV risk was not substantiated by this study.
- There are indications that metformin imparts CV benefit. This was suggested specifically by the overweight subset of UKPDS, in which those on metformin did markedly better in terms of CV outcomes than those on lifestyle modifications alone, and researchers speculated that this finding was independent of glycemic improvement.
Questions and Answers
Q: Is 18 months long enough to see an effect?
A: There should be longer and multi-center trials, but the majority of IMT studies have been 1-2 years long. That’s pretty typical for this type of study, so certainly we could speculate that if it was longer with more patients we could have showed some sort of benefit.
Q: What was the change in systolic blood pressure?
A: Essentially no change in metformin versus placebo.
Q: Given the weight loss you saw, and all these patients were obese, how would you characterize using metformin as a weight loss option?
A: We’ve had a bit of discussion of this. We have a safe, CV useful drug. Maybe we should consider using it in bigger numbers than we do now.
Corporate Symposium: Cardiovascular Disease and Impaired Renal Function: Is there a Role for GLP-1? (Sponsored by Novo Nordisk)
The History of Cardiovascular Disease Trials in Diabetes and Overview of Ongoing Trials
Steven Nissen, MD (Cleveland Clinic, Cleveland, OH)
In front of an audience of several thousand people, Dr. Steven Nissen, the mastermind behind the FDA’s 2008 CV requirement for type 2 diabetes drugs, reviewed the history of cardiovascular trials in diabetes and emphasized the importance of characterizing drugs beyond their effects on glucose. He cited examples of when a gluco-centric view of diabetes failed to bring to light either positive or negative CV outcomes of a drug (e.g., negative effects of muraglitazar and rosiglitazone and positive CV effects of pioglitazone). This prompted him to recommend a procedure to the FDA that he thought represented a balanced way of bringing new drugs to market in a timely fashion while allowing us to be more informed about these drugs’ effects on clinically relevant outcomes. Notably, he remarked that the FDA’s implementation of the CV guidance has not always been “as thoughtful as we would like.” He was “completely puzzled” by the FDA’s recent decision to require a pre-approval CVOT for Novo Nordisk’s long-acting insulin analog Tresiba (insulin degludec), especially because the 2008 FDA Advisory Panel that convened to discuss the diabetes CV requirements explicitly exempted insulins from the requirement, and because and the Advisory Panel that convened to discuss Tresiba voted 8-4 to approve it. “If you torture the data enough,” he remarked, “eventually it will confess,” implying that the FDA had gone looking for trouble in the degludec submission package and eventually convinced themselves of a CV risk. Overall, we think Dr. Nissen was quite cardio-centric; during the presentation he downplayed the importance of glycemic control for the prevention of microvascular complications such as blindness, neuropathy, and kidney failure. On the other hand, he very rationally argued that it is in patients’ and prescribers’ best interests to gain as much knowledge about a drug’s effects as possible in a way that minimally delays bringing new therapies to market – if only the idea were so simple to implement in practice.
A Role for GLP-1 in Cardioprotection?: Effects on Cardiovascular Remodelling and Acute Myocardial Infarction
Thomas Engstrøm, MD (Rigshospitalet, Copenhagen, Denmark)
Dr. Thomas Engstrøm presented compelling evidence of the possible cardioprotective effects of GLP-1 receptor agonists. His talk centered on the agent’s application in pharmacological conditioning, an experimental technique used to reduce reperfusion injury following an ischemic insult. Data indicate that the duration of occlusion determines the relative contributions of reperfusion and ischemic injury to the final myocardial damage. While preconditioning is an established means of modifying infarct size, recently postconditioning has also gained medical acclaim as a powerful means of attenuating myocardial damage. In fact, mechanical postconditioning, which uses balloon inflations and deflations, was shown to increase the salvage index by 32%. Turning to the possibility of pharmacological postconditioning, Dr. Engstrøm explored the use of GLP-1 analogs, which he believes acts as a cardioprotective ligand by stimulating the salvage pathway. When low concentrations of exenatide were administered to rats during the postconditioning process, infarct size was reduced by 42-50%. Repeating this experiment with a GLP-1 antagonist or inactive GLP-1 abolished the protective effect. Over the last five years, this finding has been reproduced in many species – in the human setting, the salvage index increased by 15% overall. Because no reflow [impeded blood flow to ischemic tissue after relieving the occlusion] is associated with poor clinical outcomes, GLP-1 analogs may be a promising candidate to protect against ischemia-reperfusion injury and limit infarct size.
- Postconditioning entails administering short episodes of ischemia during reperfusion, after a prolonged insult. The talk focused on the novel use of GLP-1 analogs in this technique, which Dr. Engstrøm differentiated from ischemic preconditioning. This latter procedure differs from postconditioning in that the myocardium is subjected to short periods of ischemia to build resistance to a subsequent insult.
- During ischemia, mitochondria explode from an influx of water through the mPTP pores, irreversibly killing the cell. GLP-analogs, which are resistant to DPP-4 degradation, stimulate the salvage pathway by keeping the mPTP pores in a closed state. Dr. Engstrøm proposed this as a mechanism of GLP-analog activity in postconditioning, though he mentioned that other plausible explanations also exist.
Moderator: Eduard Montanya, MD (University of Barcelona, Barcelona, Spain)
Panelists: Zachary Bloomgarden, MD (The Mount Sinai Hospital, New York, NY); Thomas Engstrøm, MD (University of Copenhagen, Copenhagen, Denmark); Steven Nissen, MD (Cleveland Clinic, Cleveland, Ohio); Jorge Plutzky, MD (Brigham and Women’s Hospital, Boston, MA)
Dr. Montanya: Steve, your presentation on SFUs was challenging. If a company were to request FDA approval now for a SFU, would they be approved?
Dr. Nissen: They would have to perform a two stage trial, first to rule out an upper confidence interval of 1.8, and then 1.3. Unless the SFU had a truly unique feature, I don't think any pharmaceutical company would spend the money to bring it to market because we have so many generic drugs. They would have to do an outcome trial, and I don’t know what result of that would be.
Dr. Montanya: How can you submit interim analysis of a cardiovascular trial without the risk of the FDA devaluating the remaining part of trial?
Dr. Nissen: Excellent question. What do you do when you have completed a trial to rule out the 1.8 but not the 1.3? We submitted a request that would require the FDA to hold confidential results of interim analysis until the full trial is completed. This went through a whole series of legal reviews. We went up and down the highest levels of the FDA, and the FDA has now developed this as a policy, so that if a new drug is brought to market and rules out 1.8 – and this I think would apply to insulin degludec – then that data can be submitted but it cannot be publically released because that would undermine the ultimate trial to rule out 1.3. The FDA has agreed to keep confidential interim results.
Dr. Montanya: What is the effect of weight reduction as provided by some of the GLP-1 agonists? When you think about the results of the Look AHEAD study, there was weight reduction but no impact on CV outcomes. What are your thoughts on the outcome on CV disease with weight reduction?
Dr. Plutzky: This is a very interesting issue. We need to think in a more integrated way about the relationship between adiposity and how it changes to caloric excess. Adiposity plays an important functional, physiological role. As we try to expand our fat depots, that’s where we see pathologic deposition of fat in pathologic locations, (visceral fat, liver, skeleton muscle). As patients begin to experience significant weight loss, you see a reversal of excess fat in those abnormal locations. You lose it first in visceral fat, the liver, and skeleton muscles, as opposed to subcutaneous fat. As a result, it’s reflecting shifts in how fatty acids are being handled. It also seems to reverse inflammatory pathways. Those will continue to hold up as we have more evidence for weight loss. Certainly the most gratifying thing in the clinic is how metabolic parameters improve with even modest weight loss. We remain hopeful that weight loss will help reverse some of the pathologic pathways.
Dr. Montanya: What about adverse events in elderly populations using liraglutide? You think they would benefit from adjustments such as a slow titration compared to the younger population or some differences in administration?
Dr. Bloomgarden: Slow titration is clearly appropriate for all individuals treated with liraglutide developing GI intolerance. That’s really the way we all use the drug clinically. We explain to them that they can stay at lower doses and adjust it, in consultation with us. We don’t see a substantially higher likelihood of adverse effects in this group, but we need to emphasize with them, like anyone else, the need to be in communication.
Dr. Montanya: The populations chosen for these cardiovascular outcome trials are those that are already at high risk. How can the trials be translated to the general population?
Dr. Nissen: It’s a huge problem. Companies want to study very high-risk patients so that they can get to 122 events quickly and get the drug on the market. But it is different population, and may be a population more resistant to seeing benefits. I would like to see some companies do longer trials in lower risk populations where there may be greater potential for benefit. The economics drive us to use high-risk populations because getting 620 events from low-risk groups could take a sample size of 20,000 or more, and that is costly and takes a long time. But looking at the legacy of UKPDS, I wonder if seven to eight year studies might be a way we would be able to better understand the potential to reduce CV outcomes.
Dr. Bloomgarden: A further caveat of the difficulty of undertaking this type of study: there was a study that looked at the prevalence of cardiovascular disease in healthy people with diabetes, and they came up with a shocking finding that the likelihood of CV disease, let alone events, was on the order of 0.6% of the populations, so that their hope to see evaluate noninvasive measures of CV disease failed utterly. What if we took a population of 3,000 people with an event rate of 0.6%? At one year, assuming those receiving and not receiving drug had the same number of events, it would be 18 in each group, if you look at the shape of the bell curve, it would exceed 1.8 by a little bit. So a drug that had absolutely no effect in a moderately large number of individuals would then be dinged as having a signal. These studies can only be undertaken by the government in collaboration with industry. I went though the numbers once – you would need 50,000 persons studied for a decade. As much as some people like to think that the pharmaceutical industry is guilty of trying to save all the money they can, we can’t ask the industry to undertake a study of that magnitude. Yet we have a world in which millions of people are developing diabetes and those studies are of critical importance.
Dr. Plutzky: There are a number of subtle clinical variables to consider. When do you begin your statin? Or did you initiate later? To what extent are these subtle variables, or other variables like degree of liver fat, inflammation, visceral fat, etc. coming into play and potentially changing results? We’re not yet able to separate patients that we assume are part of a homogenous population but may not be in terms of these slight variations.
Dr. Engstrøm: Some people think that we now have treatments that are so good with event rates that are so low that we can’t improve them anymore – we can do better. If you look at studies with big cohorts of patients, there are some subsets of populations that have high rates. We need to define those cohorts and be more aggressive in our development of drugs to treat those cohorts.
Dr. Montanya: Can we consider that there is a class effect between the different GLP-1 agonists? What are you thoughts on incretin therapies?
Dr. Plutzky: There are core aspects to their action, but we have to look at evidence to see if there are differences among the various insulin modulators. It’ll be challenging to assume that they’re the same. Some aspects will be similar among them, but we really need to look at signals in data to understand them.
Dr. Nissen: Every time we think we understand something, we get a surprise. When the TZDs were introduced, it seemed like they have similar glucose lowering effects. Why shouldn’t pioglitazone and rosiglitazone be similar? Looking beneath the surface we certainly saw lipid differences, but that’s a little bit of a different, more complex model. What I’ve learnt is that you can trust, but you must also verify. We may believe there is commonality, but we have to verify first. That’s why each of the GLP-1 analogs is doing a clinical trial. If they all show the same benefits, then six to seven years from now somebody can say I told you so, but until then I'm going to keep my eyes and ears open.
Dr. Montanya: Why are the potential dangers of insulin not taken into account? What is the basis for that?
Dr. Nissen: Endogenous human insulin is indistinguishable from that administered exogenously. Once has to argue that it’s the same molecule, same receptor, doing the same thing. When you change the root of delivery, all you change are the pharmacokinetics. With these subtle differences, there isn’t much of a reason to believe that they would have differences in outcomes. Insulin is insulin, and I would be shocked if we didn’t find that at the end of the day. If it is human insulin, it's the same drug given in different forms. If we want to go this route, where every new formulation undergoes a CV trial, I’m just not sure if that’s in society’s best interest.
Private Corporate Symposium: Scientific Exchange and Expert Opinions on CV Outcomes in Diabetes (Sponsored by Sanofi)
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.
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.
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.
Workshop: Which Glucose-Lowering agent Do I Add Next?
Vivian Fonseca, MD (Tulane University, New Orleans, LA) and Angelo Avogaro, MD, PhD (University of Padova, Padova, Italy)
In this case-based workshop, Drs. Vivian Fonseca and Angelo Avogaro prompted attendees to select the most appropriate second-line treatment. The session benefitted from a remarkably diverse group of attendees — the providers in the room shared background and treatment guidelines from their respective countries, and at times jokingly referred to each other by their home countries (almost giving the room the aura of a United Nations conference). Attendees from Eastern Europe and Latin America seemed somewhat more eager to utilize basal insulin, whereas those from Western Europe and the United States seemed to favor incretin therapies slightly more. Dr. Fonseca recommended waiting for more data on the SGLT-2 inhibitor class before prescribing them early as a second-line therapy for most patients. He also expressed optimism about the 5,000-patient GRADE study (ClinicalTrials.gov Identifier: NCT01794143), which will provide much-needed head-to-head data on the use of four different diabetes therapies (glimepiride, sitagliptin, liraglutide, and insulin glargine) when added to metformin. An attendee from Mexico hypothesized that the largely neutral results from both the SAVOR and EXAMINE CVOTs might detract from Onglyza and Nesina’s popularity, but another attendee quickly countered that these two studies’ major aim was to establish the drugs’ basic safety (which they successfully did), and thus should have the potential to only help the DPP-4 inhibitor class.
Corporate Symposium: Cardiovascular Risk Control: The Critical Aim of T2D Management (Sponsored by Lilly/BI)
The Importance of CV Outcome Trials
Julio Rosenstock, MD (Dallas Diabetes and Endocrine Center, Dallas, TX)
Building off his presentation “CV Outcomes Trials with New Glucose Lowering Agents: What are We Learning?” at the previous day’s Sanofi event, Dr. Julio Rosenstock underscored the importance of CVOT, in his view. He began by noting that the “best that we can say” about currently available data on diabetes therapies and cardiovascular risk protection “is that it is suggestive but clearly is not conclusive.” Turning to SAVOR-TIMI 53, BMS/AZ’s CVOT for Onglyza (saxagliptin), Dr. Rosenstock expressed surprise and some concern at the agent’s association with higher rates of hospitalization due to congestive heart failure. Notably, he also implied that the numerical imbalance against saxagliptin in pancreatitis events could be indicative of a broader pancreatitis risk among incretin mimetics, remarking that pooled analysis of the CVOTs “may find something interesting” in terms of pancreatic events. More broadly, Dr. Rosenstock voiced strong support for the safety trials the FDA has required, cataloguing the many research questions it enables investigators to pursue.
- Dr. Rosenstock voiced strong support for the safety trials the FDA has required of late. He acknowledged that “industry may not like it” but that he sees the CVOTs are a great research opportunity to 1) learn more about the natural history of type 2 diabetes, 2) test drug effectiveness rather than just efficacy, 3) assess long-term durability, and 4) better define a drug’s cost:benefit profile.
- The ideal situation, Dr. Rosenstock believes, would be for CVOTs to continue beyond their primary outcome so that researchers can see a drug’s legacy effects. Also due to his curiosity in legacy effects, Dr. Rosenstock hopes to see more people with CV risk factors but not CVD enrolled in CVOTs. He thinks a greater representation of this population would give trials a better chance of demonstrating CV protection, since people will not enter with negative metabolic memory. We suspect that companies have tended to avoid enrolling this healthier population in large numbers, because trials would likely have to be larger, longer, and therefore more expensive to ascertain the needed number of CV events.
- On SAVOR-TIMI 53, Dr. Rosenstock remarked that it was “surprising” saxagliptin was associated with a higher rates of hospitalization due to congestive heart failure (CHF). We note, however, the heart failure risk was not accompanied by an increase in any CV outcomes, including overall or CV mortality. Dr. Rosenstock remarked that “[the CHF trend] raises a number of questions.” He noted that this finding could be by chance or that it could be real. During the subsequent panel discussion, Dr. Bernard Zinman (University of Toronto, Toronto, Canada), hypothesized that DPP-4 inhibitors could cause CHF by preventing the degradation of peptides other than GLP-1 or GIP (Dr. Rosenstock had left for another symposium he was speaking at, so we was unable to answer questions on SAVOR-TIMI or CVOTs). One of the peptides, circulating at a higher level, due to its breakdown being inhibited, could have a deleterious effect on the CV system. Dr. Zinman pressed that providers should be careful not to believe that the CHF association is a class effect, since they are metabolized differently and have varied impacts on different peptides.
- Dr. Rosenstock stated that the SAVOR-TIMI 53 “authors claim that there was no difference in pancreatitis.” He noted, however, that while there was no statistical difference in the rate of pancreatitis, there was a numerical difference. He continued to suggest that when the CVOT results are pooled “we may find something interesting there.”
- Dr. Rosenstock was “a bit disappointed” that SAVOR did not find a greater difference in A1c improvement between saxagliptin and placebo. Physicians were asked to treat both the saxagliptin and the placebo arms to an A1c target; however, Dr. Rosenstock does not believe the placebo group received an intensive glycemic intervention when the subjects were seen every 6 months for study visits and no specific directions were given to the physicians taken care of their diabetes. He explained this was, in part, due to cardiologists providing much of the care.
- Similar to his comments at the Sanofi event on Sunday (we are finalizing these notes), Dr. Julio Rosenstock pressed that while the data “very, very clearly” demonstrate that good control reduces microvascular complications, they are not conclusive on macrovascular complications. Regarding macrovascular risk, Dr. Rosenstock remarked that “UKPDS gave us a little reassurance [about glucose control’s impact on CV outcomes] but not enough.”
- Additionally, he noted that the majority of data that we have on diabetes therapies and CVD are on combination therapies rather than on specific drugs. The limited data available on specific therapies, he thinks, are insufficient to draw convincing conclusions. As an example, he told attendees that many people’s belief that metformin is certainly CV protective is largely unfounded. He explained that in the study often cited, a secondary analysis of metformin therapy from UKPDS, metformin did seem to reduce patients’ risk of CVD; however, it was insufficiently powered to draw definitive conclusions (n=342 people on metformin).
- Overall, Dr. Rosenstock believes that among the ongoing CVOTs, the one with the better chances of finding CV protection is CAROLINA because it has enrolled type 2 patients with earlier diabetes as suggested by lower A1C levels (and the fact that none are on insulin), contrasting with the study populations in the other CVOTs. Furthermore, CAROLINA also has less percentage of subjects with established CVD and more subjects with only CV risk factors and it is the only CVOT with an active comparator (linagliptin vs glimepiride). We look especially forward to seeing the results of a CVOT with an SFU.
Is Early Intervention the Best Intervention?
Stephen Gough, MD (University of Oxford, Oxford, UK)
Dr. Stephen Gough artfully described the molecular biology underpinning landmark trial demonstrations of metabolic memory in people with type 1 and type 2 diabetes. He opened by reminding attendees how large-scale trials like UKPDS and DCCT/EDIC showed that achieving metabolic control early in the course of diabetes reduce a person’s progression through the disease’s natural history and his/her development of complications. Dr. Gough proceeded to explain that atherogenic and inflammatory mediators are elevated even prior to the onset of diabetes, and that they contribute to the development of microvascular complications, even if glycemic control is later achieved. One explanation could be that poor glycemic control leads to elevated oxidative stress and the non-enzymatic glycation of cellular proteins and lipids, resulting in an increased risk of tissue and organ damage. In his view, epigenetic mechanisms likely also play a central role in this metabolic memory. Dr. Gough concluded that early intervention is needed to establish a positive metabolic memory, slow a person’s disease progression, and risk for complications. Reflecting on this, we are encouraged by the growing number of technologies and therapies that can empower the average patient to pursue tight glycemic control beginning at diagnosis. For example, Abbott’s newly introduced Flash Glucose Monitoring System might remove several barriers (e.g., hassle, poor strip reimbursement, etc.) previously deterring patients from checking their blood glucose more often.
- A potential pathway for the epigenetic “regulation” of metabolic memory is that hyperglycemia leads to excess oxygen and nitrogen free radicals. These free radicals, in particular, originate at the level of glycated-mitochondrial proteins. The presence of these free radicals can result in an increased risk of mitochondrial DNA damage. As a result, proteins encoded by the damaged mitochondrial DNA also become abnormal. Preclinical studies, according to Dr. Gough, suggest that the hyperglycemia-induced abnormalities in mitochondria continue even when euglycemia is restored.
SGLT2 Inhibition: Potential Impact on CV Risk Factors
Bernard Zinman, MD (University of Toronto, Toronto, Canada)
Dr. Bernard Zinman detailed the impact of SGLT-2 inhibitors on cardiovascular risk factors, which provide hints to the class’ potential impact on cardiovascular outcomes. With the exception of LDL cholesterol, these CV risk factors improve. Dr. Zinman noted that some variation in the magnitude of improvements appears to exist between agents; however, he view these disparities as small and, due to no head-to-head trials being preformed, not robust. Delving into the increase seen in LDL, Dr. Zinman described the effect as small but potentially a dose response, increasing the odds that it results from the SGLT-2 inhibitor given. He sighed, this is “not what we want to see,” but did not express great concern over its clinical significance, pressing, “the consequence remains to be demonstrated.” Dr. Zinman concluded that the field needs well-powered, long-term studies in which CV events are adjudicated. Thus, he believes results from the SGLT-2 inhibitors’ CV outcome trials (i.e., empagliflozin’s EMPA-REG OUTCOME, canagliflozin’s CANVAS, ad dapagliflozin’s DECLARE) will define the CV effects of SGLT-2 inhibitors.
- During Q&A, Dr. Zinman remarked that empagliflozin’s greater specificity for SGLT-2 than other SGLT-2 inhibitors does not appear to be clinically significant.
- Dr. Zinman noted that SGLT-2 inhibitors might improve beta cell function by reducing glucotoxicity. He explained that such an effect has been seen in preclinical studies; however, it is unclear if it also occurs in humans – Dr. Zinman hypothesized that it does.
Questions and Answers
Q: Can you explain the change in body composition or is it only water variations?
A: These compounds inhibit SGLT-2 so you actually have an excretion of glucose and of sodium – it basically acts as a diuretic in terms of lowering blood pressure. Patients do not experience excessive urination except for early on.
Q: Can you please comment on the effects of SGLT2s on improving beta cell function?
A: It was Ralph DeFronzo and his trainees. At the time they wanted to have a mechanism of reducing glucose independent of metformin. When you independently reduce glucose by in essence having a glucose sink, you get an improvement in beta cell function and insulin action. That was a seminal observation to prove the idea of glucose toxicity. Now, does that happen in people? I think it does but we will see.
Q: Can you comment on the increase in hospitalizations for heart failure seen in SAVOR?
A: The fact is that DPP-4 inhibitors inhibit the breakdown of compounds other than GLP-1 and GIP. One can postulate that there are some peptides that are circulating at a higher level because their breakdown was inhibited, and that could have a deleterious effect. We should be careful not to ascribe that response to all DPP-4 inhibitors. They are metabolized differently and have different side effects. We don't know if it is a class effect or unique to saxagliptin.
Q: Why don't you continue to lose weight when you are on an SGLT-2 inhibitor?
A: I think that there is a compensation effect and you eat more. The good thing is that the weight comes down and stays down.
Q: If you compare the three available SGLT-2 inhibitors, empagliflozin is the most specific for SGLT-2 of the three. Now it is not clear that we want that specific of inhibition. Can you comment on this?
A: I think that the reductions in A1c are pretty similar. It would be very interesting to do a head-to-head comparison between empagliflozin and one that is less selective. There may be some differences. Are they clinically meaningful? Doesn't seem to be.
Moderator: Julio Rosenstock, MD (Dallas Diabetes and Endocrine Center, Dallas, TX)
Panelists: Stephen Gough, MD (University of Oxford, Oxford, UK); Bernard Zinman, MD (University of Toronto, Toronto, Canada)
Q: Where do you see SGLT-2 inhibitors fitting in the current treatment paradigm?
Dr. Zinman: It can be used along the entire spectrum of diabetes. I think we are now entering the age where we should be using drugs that are not associated with weight gain or increased risk of hypoglycemia. We have enough options to do this. I would use these drugs early. As I mentioned, you can use them in type 1 diabetes, though that certainly is not a labeled indication.
Q: What do you make of SGLT-2 inhibitors’ cancer risk?
Dr. Zinman: With dapagliflozin there was a suggestion of a small number of additional bladder tumors. I don't think this has been demonstrated with the other agents. I don't think there is any evidence to suggest a risk.
Q: You think SGLT-2 inhibitors can be used in type 1 diabetes?
Dr. Zinman: Studies are ongoing that look at that. Bruce Perkins will report a very preliminary POC on SGLT-2 inhibitors for type 1 diabetes. This is a several week experience looking at A1c, renal function, and hypoglycemia.
Q: Do SGLT-2 inhibitors increase people’s heart rate?
Dr. Zinman: There is no increase in heart rate; don't ask me why. They are unlike the GLP-1 RAs, which are associated with an increase in heart rate.
Q: Regarding the elevation in LDL; what kind of isoforms are increased?
Dr. Zinman: I don't think there is enough data to talk about that at this stage.
Q: At the end of the day, is good glycemic control important for preventing macrovascular outcomes?
Dr. Rosenstock: I think it is not a question of whether good glycemic control is resulting in health benefits. In people with renal failure, at any stage, an improvement in glycemic control is transmitted into health benefits. Of course, don't over treat.
Dr. Gough: I am going to speak on the concept of metabolic memory and I am going to say that if you want to be able to see CV benefits, you have to start early.
Q: What is the mechanism of the cardioprotective effect in earlier stage patients?
Dr. Zinman: I think that when you look at DPP-4 inhibitors, you see that obviously GLP-1 is increasing and so is GIP. GLP-1 has all kind of effects on endothelial tissue. We don't really know what the logic would be. CAROLINA is a unique study, not so much because it has an active comparator, but because it answers a clinically meaningful question: you are on metformin and are starting to fail it, should you go on an SFU or a DPP-4 inhibitor?
Q: Why in CAROLINA was glimepiride used instead of glipizide?
Dr. Rosenstock: I don't think we should answer this question. The SFUs have a mode of action such that at any stage it would work. However, if you don't have the breaks you will get problems. With all SFUs there will be a risk of severe hypoglycemia.
Corporate Symposium: SAVOR Trial: How May the Largest DPP-4 Inhibitor CV Safety Study Influence Day-To-Day Clinical Practice? (Sponsored by BMS/AZ)
The Potential Impact of SAVOR on Clinical Practice
Chantal Mathieu, MD (Katholieke Universiteit Leuven, Leuven, Belgium)
Dr. Chantal Mathieu provided her interpretation of SAVOR results from a clinical perspective. As a reminder, SAVOR is the CVOT for BMS/AZ’s DPP-4 inhibitor Onglyza (saxagliptin), whose results were released earlier this month at ESC 2013. The trial confirmed the CV safety of Onglyza with a HR of 1.00 for MACE compared to placebo and did not achieve its secondary CV superiority endpoint – please see http://www.closeconcerns.com/knowledgebase/r/2a8925c5 for full results, including evidence that potentially supports its pancreatic safety. Dr. Mathieu had a glass half full perspective on SAVOR results – she remarked that we already know that glucose control prevents microvascular disease, and now we can also conclude that Onglyza is safe on the cardiovascular side. She stated that it was, of course, disappointing that the superiority endpoint was not met and explained why this may have been the case despite the suggestions from animal studies and pooled analyses of phase 2 and 3 trials that the drug might show benefit. First, compared to the phase 2/3 clinical trial program, the population studied in SAVOR had much more advanced diabetes and CVD risk (80% already had CVD present). Second, any effects of the 0.3% A1c difference between the treatment and placebo groups would almost certainly take more than 2 years to emerge (based on previous experience from UKPDS and STENO-2). She highlighted the fact that even though investigators were told to titrate the two arms of the trial equally, the Onglyza arm still performed 0.3% better in A1c reductions. Finally, she remarked that the safety findings for pancreatitis and pancreatic cancer were another big takeaway – while two years may have been too short a time to see any difference of pancreatic cancer due to the drug, she still thought the data showing no difference between the groups were reassuring.
Corporate Symposium: Glucose Lowering Approaches: Short Term and Long Term Safety Considerations (Sponsored by Sanofi)
Glucose Lowering Drugs and CV Outcomes: The Evidence
Hertzel Gerstein, MD (McMaster University, Hamilton, Canada)
Dr. Hertzel Gerstein provided a whirlwind overview of the currently available evidence regarding glucose-lowering and cardiovascular outcomes. He noted that in a meta-analysis of the UKPDS, ACCORD, ADVANCE, and VADT trials, intensive glycemic control showed a marginally significant 9% reduction in MACE beyond placebo, driven by a 15+% reduction in myocardial infarction for those who were intensively controlled (CONTROL Group, Diabetologia 2009). Subsequently, Dr. Gerstein stated that based on the results of the BARI-2D trial, the means by which glucose is lowered does not appear to have an effect on cardiovascular outcomes – insulin-sensitizing (e.g., rosiglitazone or metformin) and insulin-supplying (e.g., sulfonylureas, insulin) agents had comparable effects on mortality and cardiovascular outcomes (NEJM 2009). Dr. Gerstein then reviewed the available evidence on cardiovascular outcomes for individual type 2 diabetes medications, and displayed a comprehensive list of the ongoing cardiovascular outcomes trials, noting that there are approximately 115,000 people(!) who are being followed in such trials (Gerstein et al., Circulation 2013).
- Dr. Gerstein reviewed the available evidence on cardiovascular outcomes for individual drug classes. Though no one can say for sure what metformin’s pleiotropic effects on cardiovascular outcomes might be, the data to date suggest a potential cardioprotective effect. As for meglitinides, there was absolutely no effect on cardiovascular outcomes for patients with impaired glucose tolerance in NAVIGATOR. For TZDs, rosiglitazone had a neutral effect in RECORD, and pioglitazone suggested cardioprotective benefit in PROACTIVE. Meanwhile, ORIGIN showed that insulin glargine had a long-term neutral effect on cardiovascular outcomes. In addition, an exploratory analysis of the STOP-NIDDM trial suggested cardiovascular benefit for acarbose. Most recently, two cardiovascular outcomes trials for DPP-4 inhibitors reported. EXAMINE showed no effect on MACE or death from cardiovascular causes for alogliptin, while SAVOR-TIMI showed no effect on MACE or MACE+. However, Dr. Gerstein noted that there was an intriguing heart failure signal in the SAVOR-TIMI trial, which remains to be explained (he commented that it could potentially just be a chance finding).
Moderator: Vivian Fonseca, MD (Tulane University, New Orleans, LA); Hertzel Gerstein, MD (McMaster University, Hamilton, Canada); and Peter Boyle, PhD (International Prevention Research Institute, Lyon, France)
Dr. Fonseca: Hertzel, could you comment on a few things regarding the FDA? One was the controversy about rosiglitazone. Also, recently Sanofi withdrew their NDA for lixisenatide to await results from clinical trials. Could you explain the rationale there?
Dr. Gerstein: First of all, one can never understand what a regulatory agency does. It’s not a scientific agency. Regulators are there to regulate drugs, their audience is the public, and they will tend to make decisions based on all sorts of considerations, including politics, what is in the media, and the general public’s perceptions. They do consider the science, but they are there to regulate, which is an important principle. The rosiglitazone issue came up a few years ago, as there were allegations it caused cardiovascular and all sorts of other harms, based on problematic meta-analyses. There were politically charged discussions, including Congress and Senate hearings, and the decision was made several years ago to suspend large trials of rosiglitazone. Re-adjudication of the results vindicated the initial studies. As such, the FDA is now appropriately reconsidering its initial decision. But unfortunately, as a result, the TZD class is gone (pioglitazone for other reasons). Any other potential benefits that would have came out, we will never know. Regarding the second issue, the FDA wanted to review ongoing results from the trial. Large, international outcomes trials are designed so that data safety boards review emerging safety issues in confidence. The reason is because if anyone had an event and the whole world knew, people would make decisions and judgments based on very little data, and those judgments become entrenched, and before you know it, a drug would become haloed as a wonderful drug or damned as a bad drug on very little data That’s why safety is reviewed by the DSMB – their job is decide when safety signals emerge and to alert the world. When Sanofi submitted its file, the FDA wanted to review ongoing results of this large ELIXA outcomes trial. Initially, there was hope that they would do this confidentially, but when it became clear that confidentiality could not be guaranteed, I personally think Sanofi did the right thing to get the right results from this trial rather than risk poisoning the trial by having the results presented publicly. The investigators and the steering committee don’t know the result. People at Sanofi didn’t know the results. The decision [to withdraw the NDA] was made blind of the results. This is the right thing to do, to not expose the results of an ongoing trial until the DSMB says you do it or until a trial is finished. The best example is that canagliflozin made that mistake – its interim CV results were presented to the FDA, and it’s now universally viewed as crippling to their outcomes trial.
Dr. Fonseca: Why do people say drugs are causing cancer three months [after they start taking them]?
Dr. Boyle: I don’t think they understand what carcinogenesis is all about. In the majority of human cancer in adults, there are large delays. I do not know of a good example of a quick response to a carcinogen. Generally it takes years or decades.
Satellite Session: 6th 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.
-- by Adam Brown, Poonam Daryani, Hannah Deming, Jessica Dong, Hannah Martin, Manu Venkat, Vincent Wu, and Kelly Close