European Association for the Study of Diabetes — 49th Annual Meeting

September 22-27, 2013; Barcelona, Spain — Incretin Therapies – Draft

Executive Highlights

In keeping with previous years’ meetings, this year’s EASD featured a substantial number of sessions on incretin therapies. We heard a great deal of commentary on the DPP-4 inhibitor CVOTs SAVOR-TIMI 53 (for BMS/AZ’s Onglyza [saxagliptin]) and EXAMINE (for Takeda’s Nesina [alogliptin]). Overall, we do not believe that these 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). In our view, the question of whether BMS/AZ’s Onglyza (saxagliptin; SAVOR trial) or Takeda’s Nesina (alogliptin; EXAMINE trial) are cardioprotective has not been definitively answered – most speakers also appear to agree that the trial design and patient enrollment (extremely short trials enrolling high-risk patients) essentially precluded the possibility that the trials would turn out cardioprotective, and it is a shame that we may never know the truth about DPP-4 inhibitors and cardioprotection since no one has the financial incentive to fund a long-enough and large-enough trial in a newly-diagnosed patient population. 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, a signal which multiple KOLs believed deserves further study.                                   

We noticed less talk on the subject of incretin therapies and pancreatitis this year, and what we did hear was more reassuring than what has been heard at conferences earlier this year. The general consensus among most speakers at this year’s EASD was that current data is insufficient to support an increased risk of pancreatitis and pancreatic cancer. This was due, in large part, to better data on the issue. Neither SAVOR-TIMI 53 nor EXAMINE showed a statistically significant association between DPP-4 inhibitors and pancreatitis, a point that was brought up multiple times during the conference. Dr. Peter Boyle (International Prevention Research Institute, Lyon, France) presented the results of a meta-analysis of 70 independent studies, which indicated no evidence of any increased risk of pancreatitis with incretin therapies (summary relative risk = 1.08; 95% CI: 0.87-1.34).

We were very excited to see more data on the use of incretin therapies in type 1 diabetes. We feel that progress on this front is imperative, given that type 1 diabetes patients have relatively few options at their disposal when it comes to pharmacotherapy. Dr. Urd Kielgast (University of Copenhagen, Copenhagen, Denmark) delivered a terrific review of studies of GLP-1 agonists and DPP-4 inhibitors in this patient population. Dr. Simon Heller (University of Sheffield, Sheffield, UK) and his research group featured an oral presentation and poster on the use of liraglutide (Novo Nordisk’s Victoza) in type 1 diabetes patients, which indicated that the drug is effective and (very importantly) does not impair patients’ counterregulatory response to hypoglycemia. Combination therapies involving incretins received a substantial amount of attention this year. The star of the show, so to speak, was basal insulin/GLP-1 agonist co-therapy, a combination that Dr. John Buse (University of North Carolina, Chapel Hill, NC) characterized as potentially “unparalleled” in terms of efficacy and that Dr. Stephen Gough (University of Oxford, Oxford, UK) termed the “most exciting area of current development” in the future of GLP-1 agonists. Both KOLs specifically mentioned Novo Nordisk’s IDegLira, a fixed-ratio combination of Victoza (liraglutide) and Tresiba (insulin degludec).

In our report below, talks highlighted in yellow are on our list of our ten favorite talks of the entire conference, while those highlighted in blue are new additions to the report that were not included in our daily updates from Barcelona.

 

Table of Contents 

 

Incretin Therapies

Oral Presentations: Individualizing the Choice Among GLP-1 Receptor Agonists

Positive Effects of Liraglutide as Adjunct to Insulin in Type 1 Diabetes: Glycemic Control and Safety in a Randomized, Double Blind, Placebo Controlled Crossover Trial

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

After noting that GLP-1 agonists have promising potential for use in type 1 diabetes because of their ability to suppress glucagon release, inhibit gastric emptying, and lower weight (relative to insulin), Dr. Simon Heller discussed secondary results from a randomized, single-center, placebo-controlled crossover trial investigating the effects of liraglutide (Novo Nordisk’s Victoza) on the counterregulatory response to hypoglycemia, when used as an adjunct to insulin. The study enrolled 45 participants with type 1 diabetes, and allocated them to either a 0.6, 1.2, or 1.8 mg daily dose of liraglutide, and placebo for four weeks of treatment (with a two-to-three week washout period in between). At baseline, participants had an average age of 35 years, weight of 74 kg (163 lbs), BMI of 24 kg/m2, and duration of diabetes of 17 years. Given the short duration of the trial, there were no significant differences in A1c between liraglutide and placebo. Other findings, however, were promising: the 1.2 and 1.8 mg doses of liraglutide significantly reduced daily insulin dose by 27% and 24%, respectively, versus placebo. The two top doses also reduced patients’ glucagon secretion. Even though treatment only lasted four weeks, liraglutide led to weight loss of up to 3.3 kg (7.2 lbs) (whether the investigators considered this a safety issue arose – they did not). There was no significant difference in hypoglycemia seen between the groups – this was a bit surprising. GI side effects were more common with liraglutide; none of these adverse events were severe. Dr. Heller mentioned that some patients in the study tested positive for C-peptide; during Q&A, a number of attendees suggested analyzing the data to see if these patients responded more positively to liraglutide. We are glad to see that Novo Nordisk is investigating this use of GLP-1 agonists — as a reminder, the phase 3a ADJUNCT ONE trial of liraglutide in type 1 diabetes is expected to begin this coming December. 

Questions and Answers

Q: Did you measure the C-peptide levels at follow-up?

A: We did measure C-peptide in all patients at the start, and we found that a few tested positive.

Q: Do you have more data on the number of hypoglycemia episodes across the three liraglutide doses?

A: We measured the hypoglycemia in terms of percentages. About 18% had symptomatic hypoglycemia, but we didn’t see any major difference in terms of daytime episodes or nighttime episodes.

Q: Did baseline C-peptide levels discriminate between responders and non-responders?

A: It’s a good question. I think our numbers are too small, but that should be looked into.

Q: Might you elaborate on the last item in your slide that said that larger trials are needed to establish the clinical benefit? How large should the numbers be, and what would you define as enough of a clinical benefit?

A: That’s a challenging question for me to answer in this short period of time. I’d say it would need to be far longer than one month. In terms of numbers, I’d say we would need to treat a few hundred patients, and it would be interesting to see if people with C-peptide positivity would see a greater impact.

 

Glycemic Control and Hypoglycemia in Metformin-Treated T2DM Patients with Exenatide BID vs. Insulin Lispro TID Added to Titrated Insulin Glargine QD: The 4B Trial

Bruce Wolffenbuttel, MD, PhD (University of Groningen, Groningen, Netherlands)

Dr. Bruce Wolffenbuttel presented the results of a 30-week study comparing the efficacy and safety of exenatide BID versus insulin lispro TID as an add-on to insulin glargine therapy and metformin (with or without sulfonylurea). In the trial, participants were randomized to exenatide BID (per protocol n=247) or insulin lispro TID (n=263); respectively, 84% and 86% of participants completed the trial. At baseline, participants were on average 60 years old, had diabetes duration of 13 years, A1c of 8.2-8.3%, fasting glucose of 7.0-7.1 mmol/l (126-128 mg/dl), weight of 89-91 kg (196-200 lbs), and BMI of 32-33 kg/m2. After 30 weeks of treatment, there was no significant difference in A1c change (both treatments lowered A1c by an average of 1.1%); however, when looking at weight change, there was a significant difference (-2.5 kg [5.5 lbs] with exenatide, and +2.1 kg [4.6 lbs] with insulin lispro; p<0.0001). Though similar percentages of participants (~49-50%) achieved an A1c of ≤7% in both arms, a significantly higher percentage of participants on exenatide (44.6%) achieved the target with ≤1 kg (2.2 lbs) increase in body weight than those on insulin lispro (22.9%). In addition, patients on exenatide achieved a significant reduction in systolic blood pressure versus those on insulin lispro, as well as improvements in Diabetes Treatment Satisfaction Score (DTSQ) and Impact of Weight on Quality of Life (IWQoL). The incidence in minor hypoglycemia was significantly lower with exenatide versus insulin lispro (29.5% versus 40.7%; p=0.004), mainly attributed to a lower incidence of daytime hypoglycemia (15.2% versus 33.7%; p<0.001). A higher percentage of patients in the exenatide arm discontinued treatment (5.4% versus 2.6%), mainly due to nausea and vomiting at the beginning of the trial. Based on the results of the study, Dr. Wolffenbuttel concluded that the addition of a short-acting GLP-1 agonist instead of mealtime insulin is a novel and effective treatment strategy for patients for whom basal insulin does not provide optimal control.

Questions and Answers

Q: In the group of exenatide patients, did they continue with metformin, or did they stop metformin?

A: Both treatment arms continued on metformin, two grams daily. Sulfonylureas were stopped at the beginning of randomization.

Q: I think the GI symptoms that you mentioned probably were pertaining to metformin rather than exenatide. Do you think that was true, or do you think they were caused by exenatide?

A: I think that’s a good question. Most of all those patients were already on metformin. I think most of the side effects we saw were to the new treatment, exenatide; however, I don’t know how the combination may affect underlying small intolerances to metformin. We don’t have an answer to that.

Q: Do you have any data about glycemic variability?

A: We have some research on postprandial glucose. When you look at the blood glucose curve of a day, you see that during the day, postprandial glucose is similar. Only after lunch is it lower with lispro than exenatide, which has to do with the fact that those on lispro had a lunchtime injection.
 

Sustaining HbA1c Control Over Three Years During Treatment With Exenatide Once Weekly Compared With Insulin Glargine

Jaret Malloy, PhD (Bristol Myers Squibb, Princeton, NJ)

Dr. Jaret Malloy presented the final three-year results and an additional sub-analysis of the DURATION-3 trial, which compared once-weekly GLP-1 agonist Bydureon (exenatide once-weekly [EQW]) to insulin glargine (IG) in people with type 2 diabetes. Patients in the study were on background metformin or metformin + SFU (SFU was discontinued at the beginning of the study), had a mean baseline A1c of 8.3%, ~8 years diabetes duration, and a baseline BMI of 32 kg/m2. After three years, patients on EQW had better glycemic control (A1c reduction of 1.0% vs. 0.8% on IG) and weight loss (-2.5 kg [-5.5 lbs] vs. +2.0 kg [4.4lbs] on IG), whereas IG conferred better reductions in fasting plasma glucose (-2.7 mmol/L [-49 mg/dl] vs. -1.7 mmol/L [31 mg/dl] on EQW). For our full coverage of DURATION-3 three-year results at ADA 2013, please see our ADA 2013 Incretins report at http://www.closeconcerns.com/knowledgebase/r/6001b62d). The sub-analysis that Dr. Malloy presented today examined characteristics of people who were able to maintain glycemic control through all three years (A1c ≤7%) vs. those who did not maintain control (A1c >7% at two consecutive visits or A1c ≥9% at any one visit). A greater proportion of EQW patients achieved and maintained A1c control compared to IG patients (50% vs. 43% of the ITT population and 43% and 33% of the three-year completer population). This was despite a steady increase in mean insulin dose in the IG group throughout the three years. At baseline, for both the EQW and IG treatment groups, those who achieved and maintained glycemic control had a lower baseline A1c, lower FPG, and less SFU use than the group that lost glycemic control. Regardless of “goal achievement” status, EQW patients reported lower exposure-adjusted minor hypoglycemia events compared to IG patients.

Questions and Answers

Q: My experience with once-weekly exenatide is that the weight and A1c go down very nicely after one month. But after one year, despite the fact that weight goes up by two-to-three kg, the A1c is maintained and does not get worse. I think this suggests an improvement in beta cell function. What is your view?

A: We saw weight loss over the first 26 weeks to one year, which was maintained over the three year period such that you have a 2.5 kg decrease on exenatide after three years compared to a 2.0 kg increase with glargine, resulting in a 4.5 kg difference. Other long-term studies have shown maintenance of that weight loss out to five years, for example in the DURATION 1 trial. In relation to your question about beta cell function, at this point we don’t have any hard data in change in beta cell function with long-term treatment.

Q: Do you have any information about postprandial glucose profile after three years? Or is it all about FPG? What is the nature of the excellent glycemic control?

A: We don’t have postprandial measures out to three years. But what you see with insulin glargine is the maintenance of the FPG reduction and still you get gradual increases in A1c. So you could then speculate that it’s the deterioration in postprandial glucose control in that group, and at that those patients might be ones you would target with postprandial treatment. It’s similar to data you saw in the previous talk – looking at a short-acting GLP-1 agonist or mealtime insulin for those patients.

 

Efficacy and Safety of Dulaglutide vs Metformin in Type 2 Diabetes (AWARD-3)

Santiago Tofe Povedano, MD (Clinica Juaneda, Palma de Mallora, Spain)

Dr. Santiago Tofe Provedano presented results of Lilly’s phase 3 AWARD-3 trial for its once-weekly GLP-1 agonist dulaglutide. The primary objective was to show non-inferiority compared to metformin in people with newly diagnosed type 2 diabetes (3 months – 5 years), with superiority as a secondary objective. The same results were also presented at ADA 2013 – please see page 7 of our ADA 2013 Incretins report at http://www.closeconcerns.com/knowledgebase/r/6001b62d for our full coverage. In short, both 1.5 mg and 0.75 mg doses of dulaglutide conferred superior A1c reductions after 26 weeks, and this advantage was maintained out to 52 weeks. The high dose conferred similar weight loss as metformin, while weight loss on the low dose was lower. GI side effects were comparable between the dulaglutide and metformin arms.

Questions and Answers

Q: I’m surprised to see is that the glycemic control is almost comparable in both dulaglutide doses, but in the 1.5 mg dose, there are more GI side effects. Can you comment on that?

A: It did not affect glycemic control because most of the GI symptoms were mild to moderate and transient – by week two or four, most patients were relieved of the symptoms.

Q: There is an analysis of metformin where they claim that the maximal effective dose is achieved with 3,000 mg/day, not 2,000. In your study maybe you did not use the highest level of metformin. So when you state that you have this comparison, I don’t know how valid that is.

A: This was the original design of the study. I don’t know if increasing to 3,000 mg/day could have achieved a further reduction in A1c level. I think there are studies that the optimal dose is 2,000 mg/day. So I don’t know. It could have been tested, but the original design of this study was 2,000 mg. I’m afraid I cannot answer this. There is one more thing. You might consider that a 0.5% reduction in A1c might be low for this metformin arm. You have to keep in mind that the patients had a pretty low baseline A1c of 7.6%. And the lower the A1c level is, the lower effect you can expect from any intervention. Secondly, 75% of patients were already treated with an oral antidiabetic agent, and as you can figure out, most were already treated with metformin. The washout period was fairly short (two weeks), so most of the patients randomized had been previously treated with metformin and likely had some effect of having already been treated by metformin.

 

HARMONY 3: 104 Week Efficacy of Albiglutide Compared to Sitagliptin and Glimepiride in Patients with Type 2 Diabetes Mellitus on Metformin

Murray Stewart, MD (GlaxoSmithKline, King of Prussia, PA)

HARMONY 3, part of GSK’s eight-part phase 3 program for albiglutide (the once weekly GLP-1 agonist Eperzan), assessed the safety and efficacy of 30 mg albiglutide versus 2 mg glimepiride and 100 mg sitagliptin (Merck’s Januvia). Dr. Murray Stewart presented the final study results, which were first presented as a poster at this year’s ADA. At baseline, participants had an average age of 55 years, BMI of 32.6 kg/m2, weight of 91 kg (200 lbs), A1c of 8.1%, and diabetes duration of six years. After 104 weeks, albiglutide demonstrated a 0.91% A1c reduction, a statistically significantly greater reduction than with sitagliptin (0.35%) or glimepiride (0.27%) treatment. The albiglutide group lost 1.2 kg (2.7 lbs) on average, similar to the weight loss seen with placebo (1.0 kg [2.2 lbs]) and sitagliptin (0.9 kg [2.0 lbs]), and significantly better than the weight gain with glimepiride. Notably, the incidence of nausea and vomiting seen in HARMONY 3 with albiglutide (10% and 6%, respectively) was lower than the rate seen with other GLP-1 agonists, especially during the early weeks of therapy — if this finding holds true in head-to-head trials or in clinical practice, it could be a most valuable differentiating factor for albiglutide. Albiglutide had a 17% incidence of injection site reactions (most of which were mild to moderate), compared to 8% with glimepiride, and 6% with sitagliptin. There were also two adjudicated cases of probable pancreatitis in the albiglutide group, one of which was “at least possibly related to the study drug” — we note that this number represents a very small percentage of the treatment group. As background, albiglutide is under regulatory review in the EU and US; this summer, the FDA decided to postpone the drug’s PDUFA date, likely to allow for more time to review recent HARMONY trial data.  

Questions and Answers

Q: I wonder about the very small weight loss you saw with [albiglutide]. Did you ask if they were having any trouble eating, or if they were eating as much as before?

A: Other than general diet instructions in the beginning, we did not impose any restrictions or ask any questions about what they ate.

Q: You mentioned that injection site issues happened, which were mostly mild and moderate. How many were severe, and what problems did you see?

A: There was only one case where there was some swelling; there were not systemic reactions. Less than 1% withdrew due to reactions.

Q: In this trial, albiglutide’s efficacy was better than that of glimepiride. With other GLP-1 agonists we have had mixed results — there was a liraglutide trial that showed that the drug was as effective as glimepiride. Why do you think you saw the efficacy difference you saw?

A: I think it may be partly related to the titration regimens. We could have maybe pushed the titration for both glimepiride and albiglutide a bit further.

 

Oral Presentations: State of the Art of Inhibiting DPP-4

Cardiovascular (CV) Safety of Linagliptin in Patients With Type 2 Diabetes: A Pooled Comprehensive Analysis of Prospectively Adjudicated CV Events in Phase 3 Studies

Odd Erik Johansen MD, PhD (Boehringer-Ingelheim, Ingelheim, Germany)

Dr. Odd Erik Johansen presented results of a prospectively defined pooled analysis of 19 randomized controlled trials (RCTs) between 12 weeks and 2 years in length to characterize the CV safety of linagliptin (Lilly/BI’s DPP-4 inhibitor Tradjenta). These results were first presented at ADA 2013 (see our ADA 2013 Incretin report at http://www.closeconcerns.com/knowledgebase/r/6001b62d for details of the presentation). The 19 trials encompassed 5,847 patients on linagliptin and 3,612 on placebo or active comparator. The HR for the primary outcome of four-point MACE (CV death, MI, stroke, and hospitalization for unstable angina), was 0.78 (95% CI 0.55-1.12), showing that linagliptin did not significantly increase or decrease CV events. Dr. Johansen also presented results of an analysis that included only trials that compared linagliptin to placebo (which included all but one of the trials included in the primary analysis, which was a two-year head-to-head comparison with glimepiride). In this 18-trial “placebo-cohort” analysis, the HR was 1.09 (95% CI=0.68-1.75) for the primary four-point MACE endpoint. In this cohort, the HR for hospitalization for heart failure was 1.04 (95% CI 0.43-2.47) – the wide confidence intervals reflect that very small number of events collected (21). Dr. Johansen concluded that in a diverse patient population ranging from low to high CV risk, linagliptin was not associated with increased risk for CV events or hospitalization for heart failure.

Questions and Answers

Q:  On the reduced risk of nonfatal stroke and TIA with linagliptin, how do you interpret that mechanistically? There have been some studies suggesting linagliptin may be neuroprotective.

A: I think it is nice hypothesis generating data. There are far too few events to arrive at any conclusions, but you alluded also to some preclinical trials conducted in collaboration with researchers from Sweden where we saw that brain injury following stroke was reduced. It’s very interesting, and we’re obviously encouraged to see the hard outcomes.

 

Comparison of the Pharmacokinetic and Pharmacodynamic properties of Dipeptidyl Peptidase-4 Inhibitors Saxagliptin, Sitagliptin, and Vildagliptin

Harvey Katzeff, MD (Merck, Rahway, NJ)

Dr. Harvey Katzeff presented results of a PK/PD analysis directly comparing the DPP-4 inhibitors saxagliptin (BMS/AZ’s Onglyza), sitagliptin (Merck’s Januvia), and vildagliptin (Novartis’ Galvus). Dr. Katzeff noted that there has never been a direct comparison of the DPP-4 inhibition provided by these agents using a single inhibition assay. The study sought to assess the difference in DPP-4 inhibition at 24 hours (trough levels) after the final dose following five days of administration in patients with type 2 diabetes. It was an open label, randomized, placebo-controlled, five-period cross over study (n=22; mean baseline A1c of 7.4%). Sitagliptin 100 mg once-daily (QD) and vildagliptin 50 mg twice-daily (BID) provided the best levels of inhibition 24 hours after the final dose (92% inhibition), followed by saxagliptin 5 mg QD (74%). Vildagliptin 50 mg once-daily provided the worst DPP-4 inhibition levels 24 hours after the final dose (29%) and placebo provided 4% inhibition. Looking at the time course of DPP-4 activity for 96 hours following the administration of each drug for five days, sitagliptin maintains its DPP-4 inhibition of ~92% over the course of 24 hours and then slowly declines. Vildagliptin 50 mg BID maintains ~90% inhibition over 24 hours but then falls rapidly from 24-48 hours to near zero levels. Saxagliptin maintains about 72% inhibition over 24 hours but also falls rapidly over the next 24 hours. Vildagliptin once-daily rises and falls rapidly such that by 24 hours it has very low inhibition levels. In summary, Dr. Katzeff concluded that the three DPP-4 inhibitors provided significantly different profiles of DPP-4 inhibition, with sitagliptin and vildagliptin BID providing the maximal levels of inhibition. However, as a couple audience members asked during Q&A, it is unclear if these PK data have clinical implications since the efficacy and safety of DPP-4 inhibitors appears to be largely similar.

Questions and Answers

Q: It would have been interesting to see if these differences in inhibition resulted in different GLP-1 levels.

A: That would be a nice start of a new study.

Q: Very clean data, but if you see these differences, why are there no clinical differences when you test these drugs? Does it matter?

A: For vildagliptin twice-daily, several small studies compared to it to sitagliptin and found virtually no difference in A1c, fasting glucose, or postprandial glucose. There is a one head-to-head trial for saxagliptin vs. sitagliptin. The A1c values are non-inferior, but the fasting glucose on saxagliptin was not as low as the fasting glucose on sitagliptin, numerically, and the 95% CIs did not match. So that might be considered a statistically significant difference, and that might be similar to what you see in the DPP-4 inhibition levels at 24 hrs.

Q: With Merck having done this study – is it prepared to do a clinical trial comparing the three prospectively?

A: That is certainly something to consider.

 

Improved Glucagon Dynamics During Hypoglycemia and Food-Rechallenge by DPP-4 Inhibition by Vildagliptin in Insulin-Treated Patients with Type 2 Diabetes

Bo Ahrén, MD, PhD (Lund University, Lund, Sweden)

Dr. Bo Ahrén presented data on the effect of Novartis’ DPP-4 inhibitor Galvus (vildagliptin) on glucagon secretion during meal ingestion and subsequent clamp-induced hypoglycemia in type 2 diabetes patients on insulin. Dr. Ahrén noted that this study addresses an important research question since DPP-4 inhibitors are increasingly used with basal insulin. The single-center, double-blind, crossover, placebo-controlled hypoglycemia clamp study enrolled 29 type 2 diabetes patients (mean age of 58 years; mean diabetes duration of 15 years; mean A1c of 7.7%). All patients were on basal insulin, and (notably) all but three were also on rapid-acting insulin. Patients were placed on vildagliptin (50 mg twice daily) and placebo for four-week periods, with a four-week washout in between. At the end of each four-week period, all subjects were fed a meal, subjected to a hyperinsulinemic hypoglycemic clamp, and subsequently re-challenged with a second meal. The investigators found that glucagon secretion was significantly reduced during the initial and final meals (as expected), but that glucagon levels rebounded during hypoglycemia, indicating an intact counterregulatory response. Plasma levels of GLP-1 and GIP were elevated throughout the test, while other counterregulatory hormones responses were preserved during hypoglycemia. The results, Dr. Ahrén concluded, indicate that vildagliptin preserves “glucagon dynamics” — in other words, it suppresses glucagon secretion via increased GLP-1 levels during hyperglycemia, but does not inhibit the counterregulatory glucagon response during hypoglycemia. These and previous results from clamp studies serve to strengthen the DPP-4 inhibitors’ safety profile, which (in our minds) is one of the class’ greatest strengths. 

Questions and Answers

Q: I want to challenge your conclusion that a DPP-4 inhibitor would actually enhance the counterregulatory response to hypoglycemia via glucagon. What is possible is that the plasma glucagon response was absolutely spontaneous due to the natural history of type 2 diabetes, and your model is a postprandial hypoglycemia model and not a fasting hypoglycemia model. That is important because amino acids levels have a big effect on glucagon secretion. I would propose that the increase in glucagon you saw was due to the amino acids from the meal.

A: My message was not that there would be an increase in the counterregulatory response; it was that it would be sustained. It’s important to be able to rely on a sustained glucagon response during hypoglycemia. Regarding the mechanism of counter-regulation, it could be the amino acids, the activation of autonomic nerves, or just the drop in glucose. The conclusion here is that DPP-4 inhibition does not impair this response.

Q: We know that GIP increases glucagon during hypoglycemia. Do you have data on GIP levels during the study?

A: That’s a very good point, because I think one of the protective elements of DPP-4 inhibition is the elevation in GIP. This study was not exactly designed to investigate a correlation between GIP and glucagon, but that would be interesting to investigate.

 

Durability of the Efficacy and Safety of Alogliptin Compared to Glipizide Over 2 Years When Used in Combination with Metformin

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

Dr. Stefano Del Prato presented data from one of the longer studies we have seen on Takeda’s DPP-4 inhibitor Nesina (alogliptin). Previous studies of shorter duration have established alogliptin’s efficacy and safety — Dr. Del Prato’s research group investigated whether these effects would last over longer periods of time. The 104-week, multicenter, double-blind, randomized trial enrolled 2,639 type 2 diabetes patients on metformin monotherapy, and randomized them to alogliptin 12.5 mg once daily, alogliptin 25 mg once daily, or glipizide 5 mg once daily (with the potential to titrate up to a 20 mg dose). By week 25, all three treatment arms saw an A1c decrease of approximately 0.8%; from then until week 104, each group saw a slight increase (glipizide more so than the alogliptin arms). The final A1c reductions were 0.59% for the glipizide arm, 0.68% for the alogliptin 12.5 mg arm, and 0.72% for the 25 mg alogliptin arm (the latter being statistically superior to glipizide). Both alogliptin groups experienced a significantly greater reduction in fasting plasma glucose than the glipizide. The glipizide group gained an average of 1 kg (~2 lbs) by week 104, while both alogliptin groups lost slightly under 1 kg (~2 lbs) (p<0.001). Glipizide led to a ten-fold higher incidence of hypoglycemia than either of the alogliptin doses. No worrying pancreatitis or MACE signal was seen, and there was no difference in the incidence of overall adverse events. Overall, the results indicate that alogliptin’s glycemic efficacy is durable over two years in patients also on metformin (the very slight increase in A1c in the alogliptin groups between weeks 25 and 104 could of course be attributable to the natural progression of the disease).   

Questions and Answers

Q: When you said you were monitoring pancreatitis, did you mean that you have been measuring amylase systematically?

A: No we have not been.

Q: Regarding the differences in fasting plasma glucose and postprandial glucose, do you think that the small A1c difference you saw was solely due to fasting plasma glucose?

A: I think it is a combination of both, although we don’t have any data on the contribution of each.

Q: If you look carefully at the design of all these studies comparing DPP-4 inhibitors and sulfonylureas, they are set up from the beginning to support the superiority of the DPP-4 inhibitors — all trials choose baseline A1cs that are low. If you want to be fair, you need to choose higher A1c, 8% to 9%, or test them as monotherapies.

A: These studies are meant to explore second-line options on top of metformin. Also they are not intended to investigate efficacy, but rather durability. The important thing is that the doses of both were fixed. This does not prove anything about efficacy.

Q: But the average dose for the sulfonylurea was only 5.2 mg, which isn’t a high dose at all.

A: That’s true, but if you have to continue up-titrating your dose of sulfonylurea, you are not getting at durability. The question is not how much sulfonylurea you need to add over time, it’s a question of the response over time on a constant dose.

 

Gemigliptin Added to Ongoing Metformin Therapy Provides Sustained Glycemic Control Over 52 Weeks and Was Well Tolerated in Patients with Type 2 Diabetes

Eun-Jung Rhee, MD, PhD (Kangbuk Samsung Medical Center, Seoul, Korea)

Dr. Rhee presented 52-week results of a study comparing the efficacy and safety of LG Life Science’s DPP-4 inhibitor gemigliptin to sitagliptin (Merck’s Januvia). In the multicenter, multinational (Korea and India), active-controlled, parallel group, double-blind trial, participants on metformin monotherapy were randomized to 50 mg gemigliptin QD (24-week completers n=124), 25 mg gemigliptin BID (n=127), or 100 mg sitagliptin QD (n=120) for 24 weeks of treatment, followed by a 28-week extension during which all participants were given 50 mg gemigliptin QD. At baseline, patients were on average 52-55 years of age, with diabetes duration of 6-7 years, BMI of 26 kg/m2, and A1c of 7.9-8.1%. All treatment arms brought about a significant reduction in A1c from baseline to the 24-week mark, with no significant differences between arms (DOM 2013); over 52 weeks, all three treatments demonstrated sustained efficacy (~1.1% A1c reduction). Efficacy was fairly consistent across subgroups when stratified by age, duration of diabetes, gender, and BMI. Dr. Rhee noted that patients originally on sitagliptin (through 24 weeks) had greater DPP-4 inhibition after switching to gemigliptin (when measured at the 52-week mark). There were no significant differences in weight and waist circumference change between treatment arms. Gemigliptin was well tolerated for 52 weeks, with a low risk of hypoglycemia and no weight gain.

Questions and Answers

Q: You mentioned that when looking at the extent of DPP-4 inhibition you saw a difference. Do you think the difference is genuine, or was it due to the way the assay was performed?

A: We actually did not expect the result, but we could just see the difference between gemigliptin and sitagliptin. We could also see the higher increase in GLP-1 levels when gemigliptin was prescribed instead of sitagliptin. There might be some differences between those two DPP-4 inhibitors, but more studies have to be performed.

Q: Did you measure any other parameters – blood pressure, lipids?

A: Yes. For lipids profiles from phase 2 and other phase 3 trials, all treatments of gemigliptin lowered total cholesterol, LDL, and triglycerides, consistent with other DPP-4s. I don’t exactly remember changes in blood pressure, but it at least did not increase, I think.

 

Oral Presentations: Impact of Treatment and Genetic Susceptibility to Comorbidities and Mortality

Diabetes, Incretin Therapy, Pancreatitis, and Pancreatic Cancer: Meta-Analyses

Peter Boyle, PhD (International Prevention Research Institute, Lyon, France)

Dr. Peter Boyle explored the potential associations between diabetes, incretin therapies, pancreatitis, and pancreatic cancer through a series of meta-analyses. His presentation was a condensed version of the talk he gave during Sanofi’s corporate symposium on Sunday; for our coverage of the Sunday event, please see page 20 of our EASD Day #2 Report at http://www.closeconcerns.com/knowledgebase/r/f517afa8. Pooling the results of randomized control trials and observational studies produced a strong correlation between diabetes and pancreatitis (an unsurprising finding). A separate meta-analysis of 70 independent studies (including RCTs and observational studies), however, showed no evidence of increased risk of pancreatitis with incretin therapies (summary relative risk=1.08; 95% CI, 0.87-1.34). Dr. Boyle took issue with the over reliance on databases such as the FDA-AERS, which cannot provide information on potential confounding factors and may be subject to significant reporting bias. Dr. Boyle concluded by noting that, at this time, poor data quality precludes the possibility of drawing definitive conclusions about pancreatitis risk with incretin therapy and that large prospective studies are urgently needed to provide satisfactory answers. Dr. Boyle, however, hypothesized that if any risk for pancreatitis exists with incretin mimetics, it probably is small.

Questions and Answers

Q: I had found the data from Peter Butler’s study convincing. Is it possible that there are some sort of subclinical changes caused by these agents that don’t immediately manifest as clinical symptoms?

A: What we are here to discuss is the risk of pancreatitis and pancreatic cancer. I don’t agree that the work of Peter Butler is very robust. I had a privilege to attend a NIDDK meeting in June on this issue [for our coverage of this meeting, please see http://www.closeconcerns.com/knowledgebase/r/8326d0dd and http://closeconcerns.com/knowledgebase/r/e90a832d], and there was strong criticism of Dr. Butler’s study. There is still lot of doubt about the reliability of that work, and it is based on a very small sample size.

Q: You mentioned that we need large population-based studies. Have you worked out what sample size and duration we would need to resolve the issue of pancreatitis and cancer?

A: We would love population studies of about 15 million people followed for four to five years, but we’re not going to get that. I think that a 3,000-4,000 patient trial lasting four to five years should suffice, assuming 100 events per 100,000 patients. Databases are inadequate; we need more direct, clinical information about the etiology of pancreatitis.

Q: Could you comment on the reporting system through which data makes its way into studies? Sometimes databases use passive reporting, and sometimes this data makes its way into scientific papers. As a scientific community, should we be limiting ourselves to randomized control trials and better observational studies?

A: We’ve got to be careful — these database studies are fraught with difficulties, and you have to pay attention to get them right. I think the FDA database has some problems. The databases in England, Denmark, and the Swedish registry are fairly rigorous. Generally, you have to be careful about where data come from.

 

Oral Presentations: Insulin in Type 2 Diabetes – Earlier? Dangerous? Stronger?

IDegLira, a Novel Fixed-Ratio Combination of Insulin Degludec and Liraglutide, is Efficacious and Safe in Subjects with Type 2 Diabetes: A Large, Randomzied Phase 3 Trial

Stephen Gough, MD (University of Oxford, Oxford, UK)

Dr. Stephen Gough presented and discussed the results of the phase 3 DUAL-1 study of Novo Nordisk’s IDegLira, a fixed-ratio combination of the company’s once-daily GLP-1 agonist Victoza (liraglutide) and ultra-long acting basal insulin Tresiba (insulin degludec). As a reminder, these very impressive data were first unveiled at this year’s ADA — read our coverage of the original presentation on page 4 of our ADA 2013 Incretins Report at http://www.closeconcerns.com/knowledgebase/r/6001b62d. The DUAL-1 study included 1,663 patients, randomized in a 2:1:1 ratio between IDegLira, insulin degludec, and liraglutide. IDegLira demonstrated a remarkable 1.9% A1c drop from a mean baseline of 8.3%, compared to drops of 1.3% and 1.4% (from the same baseline) for liraglutide and insulin degludec, respectively. The combination product also led to significantly less weight gain than insulin degludec (0.5 kg of weight loss compared to 1.5 kg of weight gain, respectively), and a 32% risk reduction for hypoglycemia compared to insulin degludec alone. IDegLira patients experienced significantly less nausea at trial onset than patients on liraglutide (3% compared to 10%), an effect that Dr. Gough partly attributed to the titration protocol in the IDegLira arm. During Q&A, Dr. Gough mentioned that there were a few small yet statistically significant differences between the treatment arms regarding lipid profiles, but did not elaborate on the subject — we would certainly be very interested in seeing that data.

Questions and Answers

Q: One would need to administer approximately 30 units of IDegLira to reach a meaningful dose range for liraglutide of 1 mg or more. Did the majority of patients use more than 30 units, and have you looked at patients who used fewer than 30 units to see whether a dose of liraglutide below 1 mg had a meaningful effect?

A: This here is the first data we have, and more data will be available once we do further analysis. I don’t think we need to hit a certain dose of liraglutide to see a certain benefit — the mean dose was 1.4 mg, but we’ll have to analyze this further.

Q: Did you look at lipid profiles before and after the trial?

A: We did — there were some small changes in terms of total cholesterol and triglycerides from the beginning to the end. There were some small statistically significant changes, but it’s hard to interpret those and disentangle them from the weight change.

 

Oral Presentations: Defining Strategies for The Treatment of Type 2 Diabetes

Initiation of New Injectable Treatment Introduced After Anti-Diabetic Therapy With Oral-Only Regimens (INITIATOR) Study: An Interim Analysis

James Chu MD (Monterey Endocrine and Diabetes Institute, Monterey, CA)

This work presents the interim results of an observational study on the real-world effects of prescribing insulin glargine (Lantus, Sanofi) and liraglutide (Victoza, Novo Nordisk) for patients with type 2 diabetes who are failing oral therapy. The study was sponsored by Sanofi. Dr. Chu examined two large US healthcare databases (Optum and HealthCore) and found ~1,400 patients who had enough data available for analysis. At baseline, the patients who were prescribed glargine appeared to be sicker – they had a much higher A1c, tended to be older and had more comorbidities. On the other hand, the liraglutide group tended to be better controlled, on more oral agents and heavier – implying that the two drugs are prescribed for different things. Insulin glargine demonstrated a greater reduction in A1c, but baseline A1c was so different that a comparison is difficult. As might be expected, hypoglycemia was lower with liraglutide and patients lost rather than gained weight. Patients taking liraglutide discontinued more. The databases did not show a significant net drug cost increase with glargine (with no clear explanation), but there was an observed increase with liraglutide of $950-$1,150/patient year (causing Dr. Chu to call for cost-effectiveness studies). Finally, the average baseline A1c ranged from 8.6% to 9.8% across the four cohorts – definitely well past time to add insulin or GLP-1 agonists to oral agents. Next step for the investigators is to increase the number of subjects and to assess outcomes by accounting for differences in the patient groups.

  • The purpose of the INITIATOR  study is to compare outcomes in a real world setting for patients with type 2 diabetes insufficiently controlled on oral agents starting insulin glargine (Lantus, Sanofi) or liraglutide (Victoza, Novo Nordisk). This is an observational, longitudinal cohort study, using databases from commercial health insurers in the USA – Optum and HealthCore.  The presentation represents interim data. The final analysis hopes to achieve n>4,000. Patients selected were previously taking OADs only with A1c >7%. They initiated glargine or liraglutide between 2010 and 2011, and had continuous health coverage 6 month before and 12 months after initiation.  These criteria narrowed the set of subjects to 1,417 across both databases.
  • Physicians appeared to prescribe glargine and liraglutide in different situations. Glargine patients tend to be older, with more comorbidities, higher A1c, on a lower number of OADs. On the other hand, liraglutide patients are younger, more are women, they have higher BMI and lower A1c. One interpretation is that glargine patients are sicker, and liraglutide patients are more concerned about losing weight. The database also tells us that more glargine patients persisted with their medicine refills compared with liraglutide.
  • Both groups had decreases in A1c, although it is hard to compare differences because of differences in baseline A1c. Baseline A1c was roughly 8.6% for liraglutide patients versus (a massive) 9.8% for glargine patients. (Remember that they were already treated with oral agents). Patients taking glargine reduced their A1c by 1.3%-1.4% in the follow up period, compared to a reduction of 0.5%-0.6% in the liraglutide group. In the next phase of the study, the team will attempt to match patients to compare outcomes.
  • As might be expected, weight increased (by about 1kg) for those taking glargine and decreased (by about 2kg-3kg) for those taking liraglutide. Hypoglycemia was also lower for the liraglutide cohort (with big differences in the data reported in each database).
  • A cost analysis (of medical and pharmacy costs compared to baseline) yielded a non-significant and confusing result for glargine (one database had a large increase, the other a large decrease), and a statistically significant cost increase in the range $950-$1,150/patient year for liraglutide. Dr. Chu claimed that this result warranted further analysis of the cost-effectiveness of liraglutide.

Questions and Answers

Q: How could adding insulin not result in a cost increase? Was Lantus given for free?           

A: I don’t know. The data represents different costs in many different situations.

Q: Since we went from 118,000 patients in the database to 755, is this really a real world study? I think there is a major impact of selection bias.

A: The selection attrition was related to data points we needed. With this data, there is a much broader range of clinical situations than in a randomized controlled trial, so we are trying to capture a real world situation.

 

Oral Presentations: Defining Strategies for The Treatment of Type 2 Diabetes

Initial Triple Combination Therapy Is More Effective and Safer Than Stepwise Add On Conventional Therapy in Newly Diagnosed Type 2 Diabetes Mellitus

Ralph DeFronzo, MD (University of Texas Health Sciences Center, San Antonio, TX)

Dr. Ralph DeFronzo re-presented the results of his group’s Triple Therapy study, which showed that metformin/pioglitazone/exenatide combination therapy led to significant improvements in glycemic control and lower rates of hypoglycemia versus conventional therapy in newly diagnosed type 2 diabetes patients. For our full coverage of the presentation, please see our ADA 2013 report at https://closeconcerns.app.box.com/s/xpjoerk8bam7mqqb5m9v.

Questions and Answers

Q: I have a question about the Kaplan-Meier survival curve on failure. It looks like the first occurrence of failure was around six months. But, in your study protocol, you start switching to sulfonylurea at month one and then insulin at month three. I seem a little confused about that difference.

A: You shouldn’t be confused. It’s exactly what you said. The point is that people fail very early, and metformin and sulfonylurea are not the end-all. Many ended on insulin glargine, which was titrated up to 60 units in the trial. When you get up to that point, you fail. After six months, there was a progressive failure rate. That’s what you can expect with metformin, sulfonylurea, and insulin. I can assure you that’s what Dr. Turner saw in UKPDS. Remember that at the end of 10 years, despite what Dr. Turner thought, that monotherapy would control everyone, he had to change the protocol to add metformin to sulfonylurea and vice versa, and some had to add insulin. People tend to forget that at the end of the study, people had an average A1c of 8.6%, and 65% were on insulin therapy. The data we see here in a much smaller group are really just reproducing what Dr. Turner showed 30 years ago. It’s exactly what you see in literature about sulfonylurea or metformin failure; I don’t think there’s anything inconsistent with the Kaplan-Meier plot.

 

Posters

Addition of Liraglutide vs. Addition of a Single Dose of Insulin Aspart to Insulin Degludec Plus Metformin in Patients with Type 2 Diabetes (Poster #1027)

Chantal Mathieu, Helena Rodbard, Bertrand Cariou, Yehuda Handelsman, Athena Philis-Tsimikas, Ann Marie Ocampo Francisco, Azhar Rana, Bernard Zinman

Dr. Bernard Zinman’s group compared the use of the GLP-1 agonist Victoza (liraglutide) and Novolog (rapid-acting insulin aspart) in patients inadequately controlled with metformin and the basal insulin Tresiba (insulin degludec). As background, all the products studied in this trial are made by Novo Nordisk. The 26-week study was designed to simulate the likely progression of therapy for a patient on basal insulin who might need help improving postprandial glucose. The investigators screened patients who were on metformin/insulin degludec combination therapy; those with an A1c at or above 7.0% were randomized to additional treatment with either insulin aspart (n=89; administered only once daily, before the largest meal) or liraglutide once daily (n=88; 1.2-1.8 mg). The addition of liraglutide reduced A1c 0.74% by week 26 while insulin aspart led to a 0.39% reduction from a baseline of 7.7% (p=0.0024). Mean fasting plasma glucose levels were unchanged in both treatment groups. Liraglutide addition led to 3 kg (~7 lbs) of weight loss, while aspart addition led to 1 kg (~2 lbs) of weight gain (p<0.0001) from respective baselines of 95 kg (209 lbs) and 91 kg (200 lbs). The degludec/liraglutide arm experienced an 87% lower incidence of confirmed hypoglycemia (86% lower incidence of nocturnal hypoglycemia) than the degludec/aspart arm. Approximately half (49%) of the degludec/liraglutide group, but only 7% of the degludec/aspart arm, achieved an A1c below 7.0% without weight gain or confirmed hypoglycemia (some may characterize the composite as “artificial” – we think it is a great way to present the results given all the problems with adherence). As expected, the addition of liraglutide led to an elevated incidence of adverse events (mostly nausea), but most were mild and transient. Liraglutide emerged as the winner of this study – the hypoglycemia and weight data was certainly impressive – but given that insulin aspart was administered only once a day, we don’t think it was truly “real-world”. That said, had aspart been given before every meal, there could well have been more weight gain and more hypoglycemia.

 

Treatment with Liraglutide as Adjunct to Insulin in Type 1 Diabets: Effects on Counterregulatory Response to Hypoglycemia: A Randomized, Double Blind, Crossover Trial (Poster #1007)

Thomas Pieber, Sigrid Deller, Martina Brunner, Lene Jensen, Erik Christiansen, Fumiaki Kiyomi, Simon Heller

Incretin therapies have been shown to reduce glucagon levels in type 1 and type 2 diabetes — a desirable effect in most cases, as glucagon contributes to higher blood sugar levels. However, a potential concern for use in type 1 diabetes is whether impaired glucagon secretion could hinder recovery from hypoglycemia, a process that is already partially compromised in type 1 diabetes patients. Dr. Simon Heller’s research group designed a hypoglycemic clamp study to test whether Novo Nordisk’s GLP-1 agonist Victoza (liraglutide) would affect the glucagon counter-regulatory response to hypoglycemia in 45 type 1 diabetes patients. In a plot of glucagon levels compared to plasma glucose level during the induced hypoglycemia sessions, liraglutide treatment downshifted the glucagon level curve compared to placebo (as would be expected), but patients in each liraglutide group responded to hypoglycemia with an increase in glucagon secretion. The poster also noted that baseline levels of glucagon were lower in the liraglutide treatment groups compared to the control. The secretion of adrenaline and cortisol in response to hypoglycemia (other counter-regulatory hormones for hypoglycemia) were also not impaired by any liraglutide dose. Significantly less insulin was needed in the three liraglutide groups during the hypoglycemic clamp than in the corresponding placebo groups, likely due to the overall repression of glucagon levels conferred by liraglutide. The investigators note that the potential benefit of this phenomenon merits further study. Overall, the results of this study were encouraging that liraglutide does not completely eliminate the glucagon counterregulatory response to hypoglycemia.

 

Effects of Six Weeks Treatment with Sitagliptin On Counterregulatory and Incretin Hormones during Acute Hypoglycemia in Patients with Type 1 Diabetes (Poster #599)

JE Schopman, JBL Hoekstra, BM Frier, MT Ackermans, JJ de Sonnaville, AM Stades, R Zwertbroek, JJ Holst, FK Knop, F Holleman

Because the glucagon response to type 1 diabetes is diminished in people with type 1 diabetes, and because incretin-based therapies are known to repress glucagon secretion, this study investigated whether use of the DPP-4 inhibitor sitagliptin (Merck’s Januvia) would diminish the counter-regulatory glucagon response to hypoglycemia in people with type 1 diabetes. In this single-center, randomized double-blind, placebo-controlled, three-period cross-over study, 16 male patients with type 1 diabetes and intact hypoglycemia awareness received 100 mg/day sitagliptin or placebo for six weeks and were monitored during three acute hypoglycemic events (at baseline, after sitagliptin, and after placebo). Glucagon and adrenergic counterregulatory responses were not changed by sitagliptin treatment.

 

Symposium: Risks and Benefits of Drugs

GLP-1 Based Therapies and Pancreatic Disease: What’s the Clinical Evidence?

Juris Meier, MD (St. Josef Hospital, Bochum, Germany)

In a balanced manner, Dr. Juris Meier detailed the issue of incretin therapy and pancreatic disease, tracing it from its early beginnings to the most recent and cutting-edge data. Dr. Meier analyzed the main trials that gave birth to the controversy. He explained that Elashoff et al.’s FDA-AERS analysis was weakened by a potential over-reporting bias, a lack of validation, and a dearth of information on potential confounders. Dr. Robert Butler’s 2013 morphological study, Dr. Meier noted, had small and poorly matched groups. Singh et al.’s retrospective population-based case-control study faces the same limitations as any retrospective study, according to Dr. Meier (i.e., the potential for residual confounders, etc.). A meta-analysis of incretin therapy randomized control trials conducted by Drs. Meier and Michael Nauck (Diabeteszentrum Bad Lauterberg, Harz, Germany) showed no significant safety signal. Due to the low incidence of pancreatitis, Drs. Meier and Nauck estimated that only a study with 40,000 patients in each group would be powerful enough to elucidate a statistically significant 20% risk signal — a likely unrealistic prospective study size. Dr. Meier concluded with a series of practical recommendations. He pressed not to use GLP-1 agonists in patients with chronic pancreatitis, a history of acute pancreatitis, or a family history of pancreatic cancer. However, he sees  their use being acceptable in patients with cholecystolithiasis or hypertriglyceridemia. Additionally, he recommended against routine surveillance of amylase or lipase levels unless symptoms of pancreatitis appear, because abnormal results may not be indicative of an adverse event.

  • Dr. Meier opened his presentation by walking attendees through the incretin and pancreatitis controversy while offering his own commentary. He noted that Elashoff et al.’s FDA-AERS database study in 2011 has been heavily criticized for its likely over-reporting bias, lack of validation, and incomplete information about confounding factors. More reliable case-control studies have been performed since, according to Dr. Meier; however, they are still limited by their retrospective nature. Dr. Meier brought up Dr. Peter Butler’s (in)famous pancreatic morphological study, which has been criticized for its small, poorly matched groups and likely accidental inclusion of type 1 diabetes patients. SAVOR-TIMI 53 and EXAMINE, the respective cardiovascular outcomes trials for BMS/AZ’s Onglyza (saxagliptin) and Takeda’s Nesina (alogliptin), both had statistically insignificant numerical imbalances in the number of pancreatitis cases. While these numbers may illustrate trends, Dr. Meier stated, they cannot prove or disprove the association.
  • To help clarify the issue, Dr. Meier and Dr. Nauck  conducted a meta-analysis of data from trials of all incretin therapies currently available in Europe. Some individual trials trended towards an increased thought insignificant risk, and the pooled estimate was neutral.
  • Dr. Meier next discussed mechanistic factors behind GLP-1 agonism, which in theory could impact the pancreas. For example, he pointed to the increase in lipase secretion seen during GLP-1 agonist therapy (Steinberg et al., Gastroenterology 2012) as a somewhat troubling phenomenon that merits further study. Dr. Meier worried that much of the data on lipase activity is not publicly available. Potential mechanistic explanations of the link between GLP-1 agonism and pancreatitis include the direct stimulation of pancreatic GLP-1 receptors in acinar tissue, the indirect effects of GLP-1 agonists on exocrine pancreatic function, and the activation of afferent neural pathways. These or other mechanisms could inhibit pancreatic outflow; inhibit bile motility; or lead to gallstones, which in turn could lead to pancreatitis. Dr. Meier discussed a smattering of early evidence from mechanistic studies that lend credence to these ideas. A study showed that exenatide reduced patients’ gallbladder ejection fraction, and radiolabeling data indicating that GLP-1 receptors are located near exocrine cells of the pancreas.
  • Dr. Meier ended with a series of practical recommendations. He suggested against the use of GLP-1 agonists in patients with chronic pancreatitis, a history of acute pancreatitis, or a family history of pancreatic cancer. He advocated the immediate discontinuation of treatment if pancreatitis is suspected. However, patients with cholecystolithiasis and hypertriglyceridemia, he said, can continue using the drug class. Dr. Meier dissuaded providers from conducting routine surveillance of amylase and lipase levels unless clinical symptoms manifest themselves (a recommendation which received attention during Q&A). Finally, he said, any and all recommendations should be reviewed after the publication of the ongoing outcomes trials. 

Questions and Answers

Q: I had a patient on Byetta [exenatide] with no symptoms, and I did an amylase test and found a nearly tenfold elevation. After discontinuing the drug, the results returned to normal. What would you say about those situations?

A: I think it is a very valid point. We don’t have a clear answer on how to proceed in such cases. I would concur that if a patient has a tenfold elevation, I would also withdraw treatment. I would probably not withdraw treatment if the elevation were below threefold.

Q: Why did you say that there is no use in screening for enzymes? I had two patients with an increase in those enzymes, and then I stopped the GLP-1 analog and they went back to normal. Chronic pancreatitis can have no symptoms.

A: I think the problem is that if you perform routine monitoring of amylase or lipase, you will see elevated levels in 20% to 30% of cases. If you have these abnormalities in the absence of clinical symptoms, what do you do? This may lead to ultrasounds, CTs, and even MRIs, which could be unnecessary in the absence of clinical symptoms. I would prefer performing lab studies only if we see symptoms.

Q: Just one point of clarification – I agree that we shouldn’t be measuring lipase and amylase in the clinical setting, but should we be measuring them in trials?

A: Definitely yes.

 

GLP-1 Based Therapies and Pancreatic Disease: Review of Potential Mechanisms

Fred Gorelick, MD (Yale University, New Haven, CT)

Dr. Fred Gorelick concluded the session with a discussion of potential mechanisms of the proposed link between incretin therapies and pancreatic disease. The majority of the talk was dedicated to a general discussion of pancreatitis and pancreatic cancer; although this information was enlightening, we wish that more of the presentation dealt with diabetes and diabetes drugs. In his conclusion, Dr. Gorelick noted that the mechanisms of drug-induced pancreatitis are largely unknown and that animal models are rarely useful for mechanistic investigations. He expressed agreement with the recommendations of previous speaker Dr. Juris Meier (St. Josef Hospital, Bochum, Germany; for details on his comments, please above) and added that HCPs should suggest avoidance of cigarette smoking and heavy alcohol consumption in patients taking GLP-1 agonists. He also noted that data on the timing of pancreatitis incidence would be informative in determining if incretins cause pancreatic disease.

 

Symposium: Incretin-based Medications – Areas of Active Research and Unanswered Questions

Potential Use of DPP-4 Inhibitors and GLP-1 Receptor Agonists in Type 1 Diabetes?

Urd Kielgast, MD (University of Copenhagen, Denmark)

Dr. Urd Kielgast provided a terrific review of studies of GLP-1 agonists and DPP-4 inhibitors in type 1 diabetes (comprehensive tables below). Our takeaway from all the studies was that there is very encouraging potential to use GLP-1 agonists in type 1 diabetes to improve A1c, reduce insulin dose, reduce glycemic variability, improve hypoglycemia (potentially), and reduce body weight. Dr. Kielgast only covered three DPP-4 studies in type 1 diabetes, and the results were inconsistent – Garg et al. showed no benefit, two studies showed an A1c benefit, and one showed a benefit on insulin dose. Encouragingly, neither GLP-1s nor DPP-4s appear to impair the counterregulatory response to hypoglycemia in type 1 diabetes. Dr. Kielgast concluded that large-scale clinical trials are now justified to elucidate the potential long-term benefits of GLP-1 agonists in type 1 diabetes – we agree. As a reminder, Novo Nordisk’s phase 3a trial for liraglutide in type 1 diabetes is expected to begin in December 2013 (ADJUNCT ONE, ClinicalTrials.gov Identifier: NCT01836523). 

  • Dr. Kielgast reminded the audience of the potential benefits of GLP-1 based therapies in type 1 diabetes: reduced fasting glucose, reduced postprandial glucose, reduced insulin dose, reduced body weight, reduced risk of hypoglycemia, improved glycemic control, and potentially improved beta cell function (an open question).
  • Lack of glucagon suppression contributes to postprandial hyperglycemia in type 1 diabetes and type 2 diabetes. Thus, Dr. Kielgast hypothesized that suppressing excess glucagon “should perhaps be considered as a future target in treating type 1 diabetes.” We completely agree.
  • Dr. Kielgast covered six studies testing GLP-1 receptor agonists in type 1 diabetes – the clear theme was a reduction in insulin dose, an improvement in glucose control, and a reduction in body weight.

Study

Drug/Size/ Length

A1c/Glucose

Insulin Dose

Body Weight

Notes

Kuhadiya et al., Endocrine Practice 2013

Liraglutide
24 weeks
n=27

A1c: -0.4% (Baseline: 7.9%)

-18%

-4.7 kg

Obese patients with type 1 diabetes

Harrison et al., J Investig Med 2013

20 weeks
n=11

A1c -0.4 and
-0.8%
(Baseline: 7.4%)

-19%

-4.2%

Retrospective chart review; nausea caused four patients to discontinue

Varanasi et al., Eur J Endocrinol 2011

Liraglutide
1-24 weeks
n=14

A1c: -0.4% (Baseline: 6.5%)

-34%

-4.5 kg

Pages 4-5 at http://www.closeconcerns.com/knowledgebase/r/5f9e5133

Kielgast Diabetes Care 2011

Liraglutide
Four weeks n=29

A1c: -0.3% and
-0.5%
(-0.2% w/ insulin alone); less hypoglycemia

-18% and 
-38%

-2.3 kg

Efficacy depended on baseline C-peptide

Kielgast Diabetes 2011

Meal study
n=24

Exogenous GLP-1 decreases peak postprandial glucose by 45%

-50% (bolus insulin)

NA

Benefits occurred regardless of residual -cell function

Rother et al, Diabetes Care 2009

Exenatide
Six months
n=16

A1c: No difference

-13%

-4.1 kg

Exenatide did not improve beta-cell function

 

 

  • Dr. Kielgast covered just a handful DPP-4 inhibitor studies in type 1 diabetes, which have shown inconclusive results. We hope there is still potential, since the once-daily oral administration would be warmly received.

Study/Size/ Length

Drug

A1c

Insulin Dose

Body Weight

Notes

Garg et al., Endocrine Practice 2013

Sitagliptin
16 weeks
n=123

No Difference

No Difference

No Difference

C-peptide positive patients had a non-significant trend towards decrease in A1c, mean glucose, and time spent in hyperglycemia

Farngren et al., JCEM 2012

Vildagliptin
Four weeks
n=28

A1c: -0.3% (Baseline: 7.5%)

No Difference

 

Inhibited glucagon secretion during hyperglycemia; did not compromise glucagon counterregulatory response during hypoglycemia

Ellis et al., Diabet Med 2011

Sitagliptin
Four weeks
n=20

A1c: -0.3%

 

 

“Further investigation is warranted in patients with type 1 diabetes”

 

 

Questions and Answers

Dr. Paolo Pozzilli (Universitario Campus Bio-Medico, Rome, Italy): Good presentation on what’s been done so far. But you are missing three abstracts presented at EASD last year. The data is quite encouraging with linagliptin and saxagliptin in patients with LADA. This data suggested increases in C-peptide in these patients. There’s a reduction of insulin dose that cannot be explained simply by the suppression of glucagon. Also, in measuring residual beta cell function in type 1 diabetes patients, the arginine test is not the best test. You need to either use a very specific test or a mixed meal test. Garg et al. is only one paper that showed no effect. In all other patients, there is an effect. This is quite encouraging for developing trials in this direction.

A: I completely agree that the reduction in insulin dose is not only due to glucagon suppression. There’s also suppression of gastric emptying and appetite. We asked our patients to eat the same and have the same level of physical activity to hopefully address the direct glucose lowering effects of liraglutide. That’s why the insulin dose parameter has to be interpreted very carefully.

Q: There is a theme emerging about the most consistent effect of incretin-based therapies in type 1 diabetes – a reduction in insulin dose. While obviously that's beneficial for type 2 diabetes, what is the benefit in type 1 diabetes? Is it worth pursuing if that’s the only benefit?

A: You are absolutely right. Patients were allowed to reduce their insulin dose as they felt was best. Perhaps they shouldn’t have been able to do that. Probably the glycemic effect may have been better.

Q: It’s a small tradeoff…

A: The beneficial effects of reducing the insulin dose may be in reducing hypoglycemia, but we have not shown that for sure.

Q: I’m wondering about the percentage of insulin dose reduction. In Poster #576 here, type 1 diabetes patients underwent a euglycemic clamp, and we gave them an oral glucagon receptor antagonist. They saw a 20% reduction in insulin dose. This is the effect of glucagon antagonism. What is the plus effect with gastric emptying?

A: I cannot go into the mechanisms in a four-week study. I think the combination of gastric emptying, glucagon suppression, and perhaps C-peptide levels is at work.

Dr. Michael Nauck (Diabeteszentrum Bad Lauterberg, Harz, Germany): What is the main endpoint for a study of GLP-1 in type 1 diabetes patients? Would it be weight loss, hypoglycemia?

A: A1c. In the studies performed here, for four weeks, it’s very difficult to see A1c. But A1c and weight loss would be primary endpoint I would choose. And it would be obese patients.

Q: Regarding the mechanism of action of how we decrease glucagon levels in patients with type 1 diabetes – is that through the delta cell and somatostatin? And is there any electrophysiological improvement of the rest of the beta cells?

A: It does not seem that intra-islet insulin is necessary for glucagon. It’s likely to be mediated through somatostatin, but it’s a matter of some controversy.

 

Towards a Better Exploitation of GLP-1’s Potential to Treat Type 2 Diabetes: Where do Current Developments of GLP-1 Receptors Aim?

Stephen Gough, MD (University of Oxford, Oxford, UK)

Dr. Gough provided a rousing presentation on the future of the GLP-1 agonist class to begin the symposium. He laid out a wish list for future GLP-1 agonists, which included normoglycemia with no hypoglycemia, sustained weight loss, few to no side effects, and improved long-term outcomes. He told the story of the class’ success over the past decade, both in terms of proven efficacy and their resultant entry into treatment guidelines, and argued that they should be used earlier in the course of treatment. He then highlighted the differences between short and long-acting GLP-1 analogues, and argued that providers should take advantage of these differences to individualize treatment for patients. For example, a short-acting GLP-1 agonist would be best in a patient in need of postprandial glucose control, while a longer-acting agent would be more suited to control fasting plasma glucose. A significant portion of the presentation was given to a discussion of GLP-1 agonist/insulin combination therapy, which Dr. Gough considered the best way to derive extra benefit from the GLP-1 agonist class in the short term. He highlighted the two class’ complementary characteristics and expressed enthusiasm about the combination of the two classes within one device, citing data on Novo Nordisk’s IDegLira (a fixed-dose combination of insulin degludec and liraglutide). Looking further into the future, he postulated that a significant advance could involve finding ways to introduce GLP-1 agonists directly into the bloodstream rather than subcutaneously (where they have been shown to have greater efficacy and cause fewer GI side effects). He mentioned the possibility of oral or even inhaled (!) GLP-1 agonists, although he acknowledged that these alternate forms of delivery lie farther in the future. During Q&A, Dr. Gough stated that longer-acting GLP-1 agonists are not necessarily better for every patient, and affirmed the growing consensus that pancreatitis concerns are not backed up by convincing data at present.

  • Dr. Gough began with a GLP-1 agonist wish list for the future, which included normoglycemia without hypoglycemia, better side effect profiles, and improved long term outcomes. He touched upon the growing interest in the scientific community in the extra-pancreatic effects of GLP-1 agonists (including their possible neuroprotective role), but explained that his presentation would keep its sights on the drug class’ metabolic effects.
  • GLP-1 agonists have shown impressive clinical results during their relatively short career, and as a result have come to occupy important positions in most type 2 diabetes treatment algorithms. Dr. Gough expressed his belief that this position is deserved, given the great efficacy, low hypoglycemia, and (most uniquely among diabetes drug classes) consistent weight loss they confer. He then called for the use of GLP-1 agonists earlier in the time course of diabetes treatment, suggesting that early treatment could help improve patients’ “metabolic memory” and reduce complications later in life.  
  • Dr. Gough emphasized that the heterogeneity of the GLP-1 agonist class can help individualize therapy for patients. He noted that the class can roughly be divided into short-acting agents (exenatide BID, lixisenatide) and long-acting agents (exenatide QW, liraglutide, albiglutide). There are clinically relevant differences between the categories that prescribers should consider: for example, longer-acting agents are more effective at controlling fasting plasma glucose, while shorter-acting agents exert a greater effect on postprandial glucose and gastric emptying. Further contributing to efforts to more intelligently target GLP-1 therapy, some scientists are searching for biomarkers that may be able to predict which patients will respond most effectively to which agents.
  • Dr. Gough was especially enthusiastic about the use of GLP-1 agonists alongside insulin therapy, terming it the “most exciting area of current development in this field.” Basal insulin/GLP-1 agonist combination therapy has been shown to preserve the benefits of each drug class while minimizing their respective side effect profiles. Dr. Gough explicitly mentioned Novo Nordisk’s IDegLira (a fixed-dose combination of insulin degludec and liraglutide), noting that the pen device allows the titration of both drugs together.
  • Gazing further into the future, Dr. Gough discussed different delivery methods for GLP-1 agonists. He cited studies showing that subcutaneous delivery of a GLP-1 agonist yields less glycemic efficacy and more severe GI side effects than intravenous delivery. Dr. Gough suggested that activation of subcutaneous GLP-1 receptors may be activating the autonomic nervous system, or that the drugs are being modified in interstitial space. In either case, the development of more direct and convenient delivery methods for these drugs would (in his mind) be an immensely important development. He mentioned that proof-of-concept studies on oral and even inhaled GLP-1 agonists are being looked into — interestingly, we learned during Q&A that Dr. Gough believes that inhalable GLP-1 may be more attainable than an inhalable insulin.

Questions and Answers

Q: All the novel GLP-1 agonists that are under development right now aim at once-weekly injection. Is that something that represents a real advantage over once- or twice-daily agents?

A: I’m not sure — this is related to my earlier point about treatment individualization. Some people may prefer a once-weekly injection: you can take care of it once and forget about it the rest of the week. Some may prefer a once-daily option that allows you to stay focused on your diabetes. Also, if you have a problem with the agent that you’re on, it takes longer for a long-acting to clear from your system. I know some biweekly agents are being looked into, but I’m not sure there are any benefits to moving beyond once a week.

Q: Could you speak about pancreatic effects of the GLP-1 agonist class?

A: The easiest answer is that there is an excellent presentation tomorrow by Juris Meier on the current state of the pancreatitis debate. Currently, a number of high-profile organizations that have made it clear that there is nothing right now that should change our prescription behavior. The studies aren’t giving us a decisive answer one way or another.

Q: Do you think that we could see a combined inhalable insulin and GLP-1?

A: No, I think it’s most unlikely. It’s unlikely that we’ll see inhaled insulin for obvious reasons, and right now inhaled GLP-1 is at proof-of-concept stage.

 

Understanding the Mode of Action of DPP-4 Inhibitors: Recent Insights

Bo Ahrén, MD, PhD (Lund University, Lund, Sweden)

Dr. Bo Ahrén concluded the session with a discussion of recent mechanistic data on DPP-4 inhibitors. He pointed out that the DPP-4 enzyme is not distributed evenly throughout the body; rather, it is localized in high concentrations immediately adjacent to the intestinal L cells that produce GLP-1, leading to rapid deactivation of GLP-1 before it can enter the hepatic portal system. The significance of this mechanistic insight is that inhibition of DPP-4 has a particularly strong positive impact on GLP-1 levels in the portal system, and thereby an especially strong effect on the pancreas and liver (key target areas for the reduction of blood glucose). Dr. Ahrén also hypothesized that the increased level of GLP-1 in the portal circulation could activate autonomic nerves in the gut, which in turn stimulate the secretion of insulin in the pancreas. He next noted that GLP-1 enters the lymphatic system in addition to blood vessels, and that the hormone’s lymphatic effects deserve further study. Dr. Ahrén next addressed DPP-4’s effects on targets other than GLP-1. He cited evidence that DPP-4 inhibition increases plasma levels of GIP, which likely protects against hypoglycemia. He also brought up early evidence that DPP-4 inhibitors increase the secretion of neuropeptides such as PACAP that act at acetylcholine terminals to directly stimulate pancreatic insulin secretion. Another beneficial effect of DPP-4 inhibition being studied is its potential inhibition of the pancreatic islet inflammation seen in type 2 diabetes. Dr. Ahrén’s talk certainly broadened our understanding of the effects of DPP-4 inhibition, and we look forward to seeing data from future studies of DPP-4 inhibitors’ non-GLP-1-mediated effects.

Questions and Answers

Q: In my practice, we had a patient that had substantial hepatic adiposity that decreased after we prescribed a DPP-4 inhibitor. Is there evidence that DPP-4 inhibitors may have an effect on fat in the liver?

A: That would be an important mechanism, as the reduction of fat in the liver could reduce insulin resistance. There are studies right now investigating DPP-4 inhibitors in patients with fatty livers; it will be interesting to see the data that results from those studies.

Q: Would the PACAP neuropeptide explain the reduction in glucagon seen with DPP-4 inhibition?

A: No, we measured glucagon excretion and we did not see a change. The PACAP effect would explain the insulin effect.

 

Corporate Symposium: Glucose Lowering Approaches: Short Term and Long Term Safety Considerations (Sponsored by Sanofi)

Diabetes, Incretin Therapy, Pancreatitis, and Pancreatic Cancer

Peter Boyle, PhD (International Prevention Research Institute, Lyon, France)

Looking at available prospective trials (as well as several observational studies) and following the PRISMA guidelines for meta-analyses, Dr. Peter Boyle explored the potential associations between: 1) diabetes and pancreatic cancer; 2) diabetes and pancreatitis risk; 3) pancreatitis and pancreatic cancer risk; 4) the use of incretin therapies and pancreatitis risk; 5) the use of GLP-1 receptor agonists and pancreatitis risk; and 6) the use of DPP-4 inhibitors and pancreatitis risk. From his meta-analysis of 70 independent studies, Dr. Boyle concluded that there is no evidence of increased risk of pancreatitis with incretin therapies (overall summary relative risk [SRR]=1.08; 95% CI: 0.87-1.34). Dr. Boyle proceeded to discuss two analyses of the FDA Adverse Event Reporting System (AERS) database, cautioning the audience how such analyses could be misinterpreted or blown out of proportion by the media. Dr. Boyle noted that Raschi et al. highlighted the severe limitation of the FDA AERS database in drawing conclusions about the causal nature of any signal found, given various biases (the Weber effect, the ripple effect, and notoriety bias, described below), and he pointed out fact that 90% of those identified in the FDA AERS database had other risk factors for pancreatitis. After removing this analysis from Dr. Boyle’s meta-analyses, the point estimates of the SRRs for incretin therapies, GLP-1 agonists, and DPP-4 inhibitors all tended even closer to neutrality. Dr. Boyle commented that the poor quality of data available precludes drawing any definitive conclusions apart from observations that any potential increased risk of pancreatitis associated with incretin therapies is likely to be small. As such, carefully designed, large, prospective, population-based registries with good follow-up collecting key clinical and epidemiological information are urgently needed to answer these critical safety questions and provide reassurance to diabetes patients and their clinicians.

  • Diabetes is associated with an increased risk of pancreatitis and pancreatic cancer. In a meta-analysis of a number of prospective studies, Dr. Boyle found an overall summary relative risk (SRR) of 1.68 (95% CI: 1.56-1.82) for pancreatic cancer for those with diabetes. Meanwhile, he found diabetes to have an SRR of 1.90 (95% CI: 1.56-2.33) for pancreatitis. Not surprisingly, Dr. Boyle found pancreatitis (all forms) to have an SRR of 10.52 (95% CI: 6.34-17.47) for pancreatic cancer in a meta-analysis of 27 independent studies. Chronic pancreatitis had an even higher SRR for pancreatic cancer – 13.24 (95% CI: 5.66-30.96). 
  • From his meta-analysis of 70 independent studies, Dr. Boyle concluded that there is no evidence of increased risk of pancreatitis with incretin therapies (overall summary relative risk [SRR]=1.08; 95% CI: 0.87-1.34). He noted that there is some evidence of publication bias based on the Egger and Macaskill tests, but that the overall risk of bias is quite low. Looking only at observational studies, incretin therapies had an SRR of 1.17 (95% CI: 0.87-1.57) for pancreatitis. In separate meta-analyses, Dr. Boyle found GLP-1 agonists (based on 28 independent studies) and DPP-4 inhibitors (based on 42 independent studies) to have SRRs of 1.09 (95% CI: 0.79-1.52) and 1.15 (95% CI: 0.85-1.54) for pancreatitis, respectively (both had some evidence of publication bias based on the Egger and Macaskill tests).
  • Dr. Boyle called it “terrifying” that the BMJ stated that incretins had a 25-fold increased risk of pancreatitis (featuring the article on the front cover of an issue), based on the results of an analysis of the FDA Adverse Event Reporting System (AERS) database. He clarified that this 25-fold risk could not be used as an odds ratio, because the analysis conducted was a disproportionality analysis (as background, disproportionality analysis measures the rate of events between those on drug versus off drug). Based on his calculations, if there actually were a 25-fold increase in acute pancreatitis with incretin therapies, they would cause 68,250 cases of acute pancreatitis in the US in one year (a quarter of all cases). If this happened, Dr. Boyle commented, “Gastroenterologists would be banging on doors.” As such, Dr. Boyle cautioned members of the audience about this flawed interpretation.
  • Dr. Boyle stated that he thought Raschi et al.’s analysis of the FDA AERS database provided a lot of great insight into what was going on regarding incretins and pancreatitis risk (Acta Diabetologia 2013). Raschi and colleagues used a case/non-case method, and reported an odds ratio with a corresponding confidence interval calculated as a measure of disproportionality between two groups. Looking at 2,625 cases and 156,601 non-cases, Raschi et al. found a significant association between exenatide and sitagliptin with pancreatitis. Specifically, there was disproportionality in pancreatitis risk in the first quarter of 2008 with exenatide soon after the FDA issued an alert (notoriety bias), and in the second quarter of 2008 with sitagliptin (the ripple effect). In addition, disproportionate numbers of adverse events were reported during the first two years the medications were on the market (the Weber effect). Dr. Boyle thought the authors of the paper drew a good conclusion, that “temporal analysis found a striking influence of relevant FDA warnings on reporting of pancreatitis (the so-called notoriety bias), and is, therefore, recommended to avoid a transforming pharmacovigilance signal of alert automatically into an alarm.”

Panel Discussion

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.

 

Corporate Symposium: Insights into Advancing the GLP-1 Experience (Sponsored by Lilly)

Long Acting GLP-1 Receptor Agonist: Clinical Impact and Individualized Care

Francesco Giorgino, MD, PhD (University of Bari Aldo Moro, Bari, Italy)

Dr. Francesco Giorgino reviewed the phase 3 AWARD program for Lilly’s GLP-1 receptor agonist dulaglutide. In particular he relayed results from the AWARD-1, AWARD-3, and AWARD-5, whose detailed results were presented at ADA 2013 (66-OR, 69-OR, and 71-OR, respectively). Reflecting on these trials’ results, he concluded that dulaglutide is associated with superior glycemic control (as measured by change in A1c or percent of users reaching A1c target) when compared to metformin, sitagliptin, or exenatide BID. In terms of weight, he remarked that dulaglutide causes more weight loss than sitagliptin, and similar weight loss to metformin and exenatide BID. He acknowledged, however, that only dulaglutide 1.5 mg (not 0.75 mg) caused comparable weight loss to metformin and exenatide BID. At the BMS/AZ Corporate Symposium, Dr. Michael Nauck (Diabeteszentrum Bad Lauterberg, Harz, Germany) explained that dulaglutide 0.75 mg’s association with less weight loss than other GLP-1 receptor agonists could be because dulaglutide does not cross the blood-brain barrier as readily as other agents. Thus, it might not impact a patient’s appetite as significantly. Turning to dulaglutide’s safety, Dr. Girogino described its safety profile as determined by the overall AWARD program’s results to date. He underscored that safety signals have not been found for either pancreatitis or a new adverse event.

  • In the AWARD program so far, as expected, the most common adverse events are GI related. Among the participants on dulaglutide, 11-28% have experienced nausea and 6-17% have vomited. Researchers have not identified a pancreatitis signal and the pancreatitis rate has been 1.4 cases per 1,000 patient years. Dr. Girogino, however, noted that it is very difficult to draw conclusions from the low number of pancreatic events. The rate of hypoglycemia has been one or fewer events per patient per year. Systolic blood pressure has dropped a mean of 1-3 mmHg and heart rate has increased 2-4 bpm. Less than 5% of dulaglutide users have experienced an injection site reaction, and no nodules have been observed.
  • AWARD-1 compared dulaglutide at two doses (1.5 mg and 0.7 5mg) to exenatide twice daily (BMS/AZ’s Byetta) and placebo on a background of maximal doses of metformin and pioglitazone (Takeda’s Actos). After 26 weeks, dulaglutide 1.5 mg provided an A1c reduction of 1.5% from baseline (compared to a reduction of 1.0% with exenatide), which was roughly 1% lower than the placebo group. For more details on AWARD-1’s results, please see page 6 of our ADA 2013 Report – Incretin-Based Therapies at http://www.closeconcerns.com/knowledgebase/r/6001b62d. Dr. Carol Wysham (University of Washington, Spokane, WA), who presented AWARD-1’s results at ADA, also has a poster at EASD 2013 (919-P) on AWARD-1’s results.
  • AWARD-3 compared dulaglutide monotherapy to metformin, for patients with an average type 2 diabetes duration of 2.6 years, and an A1c of 7.6%. The trial’s results indicate that dulaglutide had a superior A1c reduction at 26 weeks (around 0.2% better than metformin, but statistically significant), together with a higher percentage of patients reaching target. More details on AWARD-3’s results can be found on page 7 of our ADA 2013 Report – Incretin-Based Therapies at http://www.closeconcerns.com/knowledgebase/r/6001b62d. Dr. Santiago Tofé Povedano will be presenting the results at EASD 2013 in OP-004 on Tuesday at 11:30 AM in Bernard Hall.
  • AWARD-5 compared dulaglutide 1.5 mg and 0.75 mg to sitagliptin and placebo in 1,098 type 2 patients. At 52 weeks, both dulaglutide doses provided superior A1c reductions compared to sitagliptin (1.11%, 0.86%, and 0.39%, respectively), as well as larger improvements in body weight (-3.22 kg [-7.1 lbs], -2.7 kg [-6.0 lbs], and -1.63 kg [-3.6], respectively). For more information on AWARD-5’s 52-week results, please see page 8 of our ADA 2013 Report – Incretin-Based Therapies at http://www.closeconcerns.com/knowledgebase/r/6001b62d. Dr. Giorgino noted that Dr. Nauck is presenting full 104-week results from AWARD-5 in a poster at EASD (921-P).

 

Panel Discussion

Moderator: Bruno Guerci MD, PhD (Hospital Jeanne d’Arc, Nancy, France)

Panelists: John Jendle, MD, PhD (Örebro University Hospital, Örebro, Sweden); Francesco Giorgino, MD, PhD (University of Bari Aldo Moro, Bari, Italy)

Q: How is dulaglutide excreted from the body?

Dr. Jendle: With a very large molecule like dulaglutide – 60,000 Daltons – the clearance from the kidneys will be very low, if any. It is believed that as far as liraglutide  is concerned, the clearance is by proteolytic pathways with the molecular being degraded into amino acid components.

Q: Do you have concerns regarding the pancreatitis seen in animal studies?

Dr. Giorgino: This is a very hot topic in diabetes care. It does not only apply to dulaglutide but also other incretins as well. With regard to the AWARD program, the incidence comes out to be the same in all arms. There is also evidence of a very slight increase in amylase and lipase enzymes – this is a biochemically significant change but it does not appear to be clinically significant. It is not demonstrated that this change will lead to pancreatitis. We do not see a specific signal for the pancreatitis issue.

Q: Do you have information on AWARD-2 or AWARD-4?

Dr. Giorgino: The safety profile is maintained as we have seen on the other AWARD studies, particularly with regards to pancreatitis. In both studies, dulaglutide was found to be more efficacious than glargine.

Q: These two papers are not yet published?

Dr. Giorgino: No, only press releases.

Q: Does dulaglutide need to be refrigerated? When can we expect to use it?

Dr. Jendle: It is best to keep it in the refrigerator; however, there are investigations and discussions surrounding how long it can be kept at room temperature. Regarding when we can anticipate to use it – that is always a difficult question. Submission is on track and is expected to the FDA before the end of this year.

Q: What is the rate of antibody formation with dulaglutide?

Dr. Jendle: Throughout the program antibodies have been assessed. This molecule has very low immunogenicity – less than 0.5% of patients all together have developed antibodies.

Dr. Giorgino: In the design of the molecule there was one amino acid substitution to reduce the immunogenicity. Of course the structure is very similar to that of GLP-1 overall.

Q: Are you planning to conduct a study comparing liraglutide and dulaglutide?

Dr. Giorgino: I know this study has been planned and is developing. Clearly the comparison in the AWARD program that I have presented – AWARD-1 – was with exenatide BID, because at the time this was the GLP-1 that was available. Liraglutide came later.

Q: Are you planning to look at dulaglutide in people with renal impairment?

Dr. Giorgino: That is another topic that needs to be addressed. I am aware that there is a study being planned in people with impaired kidney function. I do not anticipate that status having much of an effect, since the drug is not excreted through the kidney.

Q: How many patients were included in all of the AWARD program?

Dr. Giorgino: It is about 5,000 patients. We have shown these data.

Q: Can you comment on the CV study? What is the objective of the study?

Dr. Jendle: The REWIND Study was commenced in 2011. It is an event driven study with 9,600 patients and 1,000 MACE events. It is anticipated to end in 2018.

Dr. Giorgino: After the publication of the SAVOR and EXAMINE studies, we know these agents had no effect on CV outcomes. I think we have seen in the dulaglutide program that there is an effect on body weight and SBP, and I think there is a very low rate of hypoglycemia. Also, GLP-1’s non-mimetic effects might potentially contribute to the CV outcomes.

 

Corporate Symposium: Pathophysiology and Glycemic Control in T2D: Focusing on the Underlying Defect to Improve Treatment Outcomes (Sponsored by Sanofi)

Contribution of New GLP-1 Receptor Agonists in Type 2 Diabetes

Francesco Giorgino, MD, PhD (University of Bari Aldo Moro, Bari, Italy)

After emphasizing the importance of factoring in patterns of glucose abnormalities (e.g., elevated fasting glucose versus elevated postprandial glucose) in therapy choice, Dr. Francesco Giorgino reviewed the differences between short-acting and longer-acting GLP-1 agonists and highlighted the stronger postprandial effect of the short-acting agents. In a 28-day, randomized, open-label, parallel group, multicenter phase 2 trial, lixisenatide brought about a greater reduction in postprandial glucose than liraglutide did (Kapitza et al., DOM 2013). Similarly, in a 30-week, randomized, non-inferiority study, exenatide BID brought about a greater reduction in postprandial glucose than exenatide once weekly did (Drucker et al., Lancet 2008). Dr. Giorgino also noted that short-acting agents have the ability to delay gastric emptying, which correlates with reductions in postprandial glucose levels – in one study, changes in postprandial glucose with lixisenatide were inversely correlated with the magnitude of gastric emptying inhibition (Lorenz et al., Regulatory Peptides 2013). In addition, Dr. Giorgino reviewed data from lixisenatide’s phase 3 GetGoal program, highlighting its ability to reduce postprandial hyperglycemia across a wide breadth of treatment regimens, and its lower incidence of hypoglycemia and nausea compared to exenatide in the GetGoal-X study.

 

Treatment Intensification Using the Combination of Basal Insulin and GLP-1 Receptor Agonists

Melanie Davies, MB ChB, MD (University of Leicester, Leicester, UK)

Dr. Melanie Davies discussed the rationale and evidence for the use of GLP-1 agonists in combination with basal insulin. She noted that adding basal insulin to a GLP-1 agonist and adding a GLP-1 agonist to basal insulin are both good options. Dr. Davies emphasized that a short-acting GLP-1 agonist should be used in combination with basal insulin, given their stronger effect on postprandial hyperglycemia compared to longer-acting GLP-1 agonists (Kapitza et al., DOM 2012). Looking within the short-acting GLP-1 agonist category, Dr. Davies highlighted that lixisenatide had reduced rates of nausea and hypoglycemia compared to exenatide in the head-to-head GetGoal-X trial. In addition, Dr. Davies stressed the importance of optimizing basal insulin dosing, noting that in a post hoc analysis from GetGoal-L, the therapeutic effect of lixisenatide when used in combination with basal insulin is greater when fasting glucose is well controlled (Vidal et al., to be presented at EASD).

 

Panel Discussion

Moderator: Julio Rosenstock, MD (University of Texas Southwestern Medical Center, Dallas, TX); Anthony Barnett, MD (University of Birmingham, Birmingham, United Kingdom); Matthew Riddle, MD (Oregon Health Sciences University, Portland, OR); Melanie Davies, MB ChB, MD (University of Leicester, Leicester, United Kingdom)

Dr. Rosenstock: We dealt a lot with early intervention, and discussing time of intervention. Is there any way to define phenotypes of who should go first with basal insulin or with a GLP-1 agonist?

Dr. Davies: I think it would be fantastic if there was an easy answer to that. Some data suggests that if a patient is more obese and has a higher A1c, it may drive you one way or another. I think the predictors have been a little disappointing. If you look at some of the GLP-1 data, you would think they would work better early, but some people who have had diabetes for decades also respond. It hasn’t been as easy as we would like to pick out clear predictors of who would respond and who won’t. We have to look at the overall profile of the patient, and look at them in terms of their priorities and what treatments are acceptable to them.

Dr. Riddle: I agree with what Melanie said, that we don’t have very good predictors for the right first injectable. At least in the US, it’s strongly influenced by ease of access to one or the other. The barriers are greater to injectable GLP-1 drugs. Health insurance plans are less willing to pay for it. In addition, there is an evidence base of long experience of insulin. We know the benefit/risk profile better for insulin. So, people are more often beginning with insulin. It’s true that we need to know who will have a better response, and we will have to discover that.

Q: How much should we consider family history of cancer before initiating any patient on a GLP-1 agonist?

Dr. Barnett: If you look at recently published studies – SAVOR, and EXAMINE – which included a large number of high-risk patients, there was no signal whatsoever for pancreatic cancer or pancreatitis. If you look at large meta-analyses, you do not see any evidence of increased risk of pancreatic cancer. There are some concerns about histological studies and animal data. In general, it’s not something that would mitigate my use of GLP-1 agonists or DPP-4 inhibitors. Others may disagree.

Q: What is the decision-making process of selecting a GLP-1 agonist when you combine it with basal insulin? Which one would you use?

Dr. Davies: I think that for adding a GLP-1 agonist to basal insulin, a short-acting GLP-1 agonist – exenatide or lixisenatide – should be used. If you look, there are more studies with lixisenatide. In a head-to-head of lixisenatide with exenatide, lixisenatide showed equivalent A1c lowering, but less nausea and less hypoglycemia than exenatide. In the UK, the cost of lixisenatide is cheaper than exenatide, which is another consideration. For many patients, they may want to limit the number of injections, and take a drug that is once daily compared to twice daily.

Q: With all the different treatment options, how much do you keep adding, rather than switching [therapies]?

Dr. Barnett: The trouble is, if we wait until patients achieve an A1c of 9-10%, we’ve missed the boat. For most these patients, I really think the emphasis should be on early treatment appropriate for each individual patient. I don’t think it’s good enough that GPs target an A1c of 7.5%. For those, we need to be getting down to 6.5% and maintaining it as long as possible. The earlier you do it, the longer you’ll have good glycemic control. We should stop drugs that are clearly not working. And, with new drugs, the rule of thirds seems to hold true – with GLP-1 agonists, a third do brilliantly, a third do well, and for the last third they don’t seem to make a difference. We need to have stopping rules in place in addition to starting rules.

 

Corporate Symposium: Catalysts for Change? How Can GLP-1 Receptor Agonists and SGLT-2 Inhibitors Help Us Reshape Individualized Diabetes Care? (Sponsored by BMS/AZ)

The symposium opened with a short video on “transformational thinking” and change, quoting world leaders in transformational thinking such as Aristotle, Heraclites, Martin Luther King, Jr., John F. Kennedy, and Steve Jobs. Panelists overviewed clinical trial data and clinical experience with GLP-1 receptor agonists and SGLT-2 inhibitors. Full coverage of the symposium will come in our EASD 2013 full report.

 

Clinical Experience: How Can GLP-1 Receptor Agonists Improve Daily Life for Patients?

Tina Vilsboll, MD (University of Copenhagen, Copenhagen, Denmark)

Dr. Tina Vilsboll discussed clinical considerations for using GLP-1 receptor agonists.  She shaped her argument around the three major factors she considers when facing a diabetes patient: A1c-lowering efficacy, effect on body weight, and risk of hypoglycemia. She noted that GLP-1 receptor agonists were the only agent in the ADA/EASD 2012 position statement that had a positive effect on all three factors. She emphasized that weight and hypoglycemia effects have a large bearing on adherence, which in turn impacts effectiveness. She relayed that a minority of patients adhere fully to insulin treatment, according to a prescription re-fill study (Donnelly et al, Q J Med 2007) that found that only 33% of patients take ≥80% of the insulin prescribed by their physicians. Finally, Dr. Vilsboll addressed pancreatitis, stating that it has been well established that type 2 diabetes increases the risk of pancreatitis by two-to-three fold. She suggested that GLP-1 receptor agonists do not change this risk, as the odds ratio for pancreatitis on GLP-1 receptor agonists compared to other glucose-lowering agents has consistently been found to be around 1.0 (though she cautioned that the CIs were quite wide).

  • Notably, in her discussion of DURATION-6 results (a head-to-head of BMS/AZ’s Bydureon and Novo Nordisk’s Victoza), while Victoza slightly edged out Bydureon in A1c-reducing efficacy (1.5% vs. 1.3% reduction) and body weight, Victoza resulted in substantially more nausea and vomiting. With regard to patients achieving an A1c <7.0% with no weight gain and no hypoglycemia, she presented results from two separate posters presented at EASD 2012 and EASD 2013 with one showing that 46% of patients achieve this composite endpoint on Bydureon vs. the other poster that showed only 34% of patients achieving this composite endpoint on Victoza (Aroda, EASD 2013 Poster #893 and Ratner, EASD 2013 2012 Poster #806).

 

Panel Discussion

Michael Nauck, MD, PhD (Diabetes Zentrum Bad Lauterberg, Harz, Germany); Tina Vilsboll, MD (University of Copenhagen, Copenhagen, Denmark); Peter Rossing, MD (Aarhus University and University of Copenhagen, Copenhagen, Denmark); Samy Hadjadj, MD (Poitiers Medical University Hospital, Poitiers, France)

Q: Why does the efficacy of dapagliflozin depend on renal function, and where is a meaningful cutoff where you should not use SGLT-2 inhibitors anymore?

Dr. Rossing: It seems that the lower the filtration rate, the lower the effect, because you need a filtration of glucose in order for this mechanism to be active. Based on the data that Samy showed, if your estimated glomerular filtration rate (eGFR) is below 60 ml/min/1.73 m2 then the effect is so small that, actually, it’s advised against. I think to some extent it depends on the studies. For canagliflozin, the data are in a larger trial, and it found that if you have GFR between 45-60 ml/min/1.73 m2 there might be a meaningful effect.

Q: What proportion of the type 2 diabetes population falls under these criteria? Sixty ml/min/1.73 m2 doesn’t seem to be too low.

Dr. Rossing: The prevalence of patients with GFR in the range of 30-60 ml/min/1.73 m2 depends very much on age group. In the elderly, it is a considerable population – I would think around 15-20% that are below this eGFR of 60. The older you are, the higher the fraction of low GFR. It is not a trivial problem, and it’s also relevant for other classes of drugs.

Q: Do we know the exact mechanisms that cause the genitourinary infections? And more importantly, do we know the risk factors for these infections so that we can sort patients at especially high risk and better treat them with other agents?

Dr. Hadjadj: The mechanism is probably due to the glycosuria – more glucose is good fuel for bacteria in general. Females have twice or three times greater risk than men. Females who are sexually active also have more risk than when not sexually active. This has been proven in studies with nuns. One very simple and effective thing is to tell female patients to go to the toilet after sexual intercourse.

Q: For dapagliflozin, is any patient profile considered high risk for tumors? And why is dapagliflozin contraindicated for use with pioglitazone?

Dr. Rossing: I would say, as Samy has showed you, the concern was whether this increases bladder tumors. The experimental data did not show increased risk of bladder or other tumor types. But we would all be a little concerned with a drug that acts on the kidney and increases outflow of urine that then shows potential signs of bladder cancer. On the other hand, when you go into the data, you will find that many were early cases, making it unlikely that it was the drug causing it. I think at this moment we have to be open-minded and consider it carefully. These are very small numbers – there are no experimental data to suggest caution related to cancers. So maybe for a patient with a history of bladder cancer, this drug would not be my choice but I don’t have any data to support that. Regarding pioglitazone, I think that it’s just that there are no studies demonstrating the effect. People say basically that SGLT-2 inhibition is a way of lowering glucose that should work in any patient.

Q: Even for type 1 diabetes?

Dr. Rossing: Even for type 1 diabetes. I’ve seen some studies initiated, but I haven’t seen the data. I think it’s exciting that this could be of value even in type 1 patients. We don’t have the data so it’s not something I’m recommending, but theoretically yes.

Q: I’m a bit surprised no one has mentioned this so far – this is the first class of oral glucose-lowering agents that lowers body weight. We have never had that. My question is: how much of this weight loss is negative fluid balance, and how much is loss of adipose tissue?

Dr. Hadjadj: There were some body composition studies performed before and after dapagliflozin treatment. After six months you have a decrease in fat mass – so you don’t lose that much water. In addition, you can initially lose some water, but at certain point you reset your body fluid at another level. Otherwise you would completely run out of fluids! I tried to show in the weight loss data that you have some great stability. So you have reset everything at another level. This reset is associated with a decrease in fat mass and particularly visceral fat mass. There is a preferential loss of visceral fat. We don’t know why.

Dr. Rossing: I think initially it was debated because the weight loss is quite a quick response, so some suspected that there might be some fluid loss initially. You can calculate that you’re losing about 300 calories per day due to glucose you’re excreting so you could consider the continuous negative energy balance. However, patients also compensate for the energy balance when weight stabilizes.

Dr. Nauck: But your energy expenditure is lower when body mass is reduced, and usually you lose a little muscle mass when you lose fat mass, leading to a new balance.

Q: I am curious about the triple combination of metformin, DPP-4, and SGLT-2 inhibitors. Besides in the US, where triple combinations have been popular, could this be attractive to Europeans?

Dr. Vilsboll: Absolutely, which is why companies developing SGLT-2s are working on these combinations. Some companies are even working on combining it in one pill.

Q: Are there studies telling us whether there will be weight loss with that combination, and what kind of glycemic control it confers?

Dr. Vilsboll: I haven’t seen the data, but I think they’re very close to being final. There are trials that have been ongoing for a while. Another interesting approach would also be the combination of metformin, GLP-1 and an SGLT-2 inhibitor. It might not be as convenient as one tablet, but combining GLP-1 with SGLT-2 would also be an interesting approach. What you see in body weight with this combo would be interesting in the future.

Q: What is the predicted reduction in insulin dose if you add dapagliflozin to insulin?

Dr. Hadjadj: the answer is a little hard to give. In the trials we ran, you were not expected to modify insulin dose. You could modify it if you had hypoglycemia or bad glucose control. In the study with add-on to insulin, the point was to have no change in insulin dosage (and baseline dose was 70-something units per day) and still show an A1c decrease of about 1%. I’m not sure you can expect any clear decrease in insulin dose. To the best of my knowledge, I don’t know any study performed that used SGLT-2 inhibitors as insulin sparing agents. Everything was done in another way, so I cannot answer this question properly.

Q: Which is the best option among the GLP-1 agonists? Is there one best option?

Dr. Vilsbøll: It is a question that we are often asked. Right now, in Denmark, I can prescribe five different DPP-4 inhibitors; I don't really need to have five to prescribe but it is nice to have because then the companies compete on price. For GLP-1 agonists there are also a couple options. There are long acting and short acting options. The two compounds that are mainly used are liraglutide as a once-daily injection and exenatide as a once-weekly. There are benefits to a one-daily; the efficacy is slightly more pronounced but the patients have more nausea. In contrast, you could say that with the once-weekly approach only one-third of patients do what they are told and take it as prescribed.

Dr. Nauck: So you tell them to take it on Sunday on the way back from church?

Dr. Vilsbøll: [Laughter] That is a good idea. It also looks like GLP-1s in the future might be even better.

Q: Why are some people responding to GLP-1s and others do not respond?

Dr. Nauck: I think Tina gave us some idea why weight reduction is induced. It has to do with your sense of satiety. This is something that is regulated by the hypothalamus. GLP-1 has a chance even when infused into the greater circulation to cross the blood-brain barrier and interact with these regions. One thought for why dulaglutide does not generally cause as much weight loss as other GLP-1s because it does not cross the blood-brain barrier as readily. There is some question of whether slowed stomach emptying might also contribute, and I don't think that is it. Between the different long-acting agents there is no difference in body weight despite them having different impacts on gastric emptying.

Dr. Vilsbøll: Some doctors say that they have 25% non-responders. That has not been my experience. There are some, maybe 5-7%. Remember that patients may not be doing what you believe they are doing.

Dr. Nauck: I think this very much depends on how you define a non-responder. Usually we define non-responders by looking at clinical trials lasting 26 weeks or longer and seeing who got to a certain A1c target. I think when you look at type 2 diabetes, GLP-1 studies in general have a lot of non-responders. But that is true for SFUs, metformin, TZDS; they sum up to 30-40% in most of the studies. I think this is important to learn from. You might need to be more sensitive to whether or not a person is a responder. To your question of what is behind it, I find it interesting that there might be some mechanistic nonresponse. We know that there are polymorphisms of the GLP-1 receptor that are highly prevalent in the Caucasian population, and if you do GLP-1 studies they do not respond as well as those with the wild type receptor. I think that genotype testing could be helpful at some point on this.

Dr. Vilsbøll: Some people have a lot of impact on body weight but not A1c, or A1c but not body weight. It is not a cure for type 2 diabetes.

 

Corporate Symposium: The Evolution of Diabetes Management in the 21st Century — The Role of Sitagliptin (Sponsored by Merck)

DPP-4 Inhibitors and Incretin Based Therapy Differentiation

Carolyn Deacon, PhD (University of Copenhagen, Copenhagen, Denmark)

Dr. Carolyn Deacon provided a detailed comparison of several DPP-4 inhibitors: Merck’s Januvia (sitagliptin), Novartis’ Galvus (vildagliptin), BMS/AZ’s Onglyza (saxagliptin), Takeda’s Nesina (alogliptin), and BI/Lilly’s Tradjenta (linagliptin) [LG Life Science’s gemigliptin, Daiichi Sankyo’s tenegliptin, and Kowa’s anagliptin were among the agents mentioned but not included in the analysis due to their limited geographic availability.] Dr. Deacon acknowledged that most DPP-4 inhibitors have similar mechanistic efficacy (i.e., DPP-4 enzyme inhibition above 80%) and low hypoglycemia incidence – the differentiating factors are largely their PK/PD profiles, drug interactions, and metabolism pathways. Sitagliptin, alogliptin, and linagliptin have relatively long half lives (upwards of 12 hours), while vildagliptin and saxagliptin have shorter half lives (2-3 hours), although saxagliptin’s primary metabolite also has DPP-4 inhibitory activity. Linagliptin is the only major DPP-4 inhibitor not cleared via the kidneys, allowing it to be used without dose adjustment in patients with end-stage renal disease. Given the prevalence of kidney disease in people with diabetes, we think this is an underappreciated advantage. Vildagliptin has been shown to lead to small increases in liver transaminases, requiring dose changes and liver function tests in the hepatically impaired. Dr. Deacon characterized the DPP-4 inhibitor class as safe, and noted that there has not been convincing data connecting the class to increased CV risk or pancreatitis.

Questions and Answers

Q: Which drugs do you use or adjust in terms of renal impairment? Also is one better than the other in terms of reducing albuminuria?

A: The reduction in dose in patients with renal impairment isn’t for renal safety; it is just to keep the blood levels of the drug constant. In terms of the effect on albuminuria, it seems to be a class effect. We haven’t had much data on this, but we’ve seen it with sitagliptin, linagliptin, and vildagliptin, so I think it’s a class effect. We don’t know, however, whether this is just an outcome of glycemic control, or an effect on endothelial function or blood pressure.

Q: You mentioned the potential effect of linagliptin on arrhythmias. Based on the registration trials, do you think it is because of its Xanthine-based structure?

A: Well yes, linagliptin is related to caffeine, so it’s a good question. The arrhythmias are generally being seen at doses higher than the normal dose. I don’t think it translates into cardiovascular risk. It would be interesting to know the actual mechanism behind that.

Q: Can you compare the addition of a DPP-4 inhibitor or a sulfonylurea to metformin?

A: We see similar efficacy in terms of glycemic control with sulfonylureas and DPP-4 inhibitors, but there is a definite hypoglycemia advantage with the latter.

Q: Do you have any thoughts on the potential differences in activity of the DPP-4 inhibitor class in Asians versus other ethnic groups?

A: I have seen two studies showing that we’re seeing slightly greater A1c reductions in Asian populations compared to Caucasians. Perhaps it is due to the etiology of the disease – in Asians, diabetes is due more to beta cell deficit than insulin resistance, which could be behind it.

Q: Do you know if there is any difference in DPP-4 activity at different sites that could be therapeutically beneficial?

A: The data here is very confusing, and it largely comes down to the way that we measure DPP-4 activity. As far as I’m aware, we haven’t really looked to see if there are different sites of enzyme activity. I don’t think it would be a useful thing to measure in clinical practice.

 

Potential Cardiovascular Effects of DPP-4 Inhibitors

Mansoor Husain, MD (University Health Network, Toronto, Ontario, Canada)

Dr. Mansoor Husain spoke on the hot topic of DPP-4 inhibitors and cardiovascular risk, which heated up even further this month with the presentation of SAVOR-TIMI 53 (BMS/AZ’s CVOT for Onglyza [saxagliptin]) and EXAMINE (Takeda’s CVOT for Nesina [alogliptin]) at ESC’s annual meeting — read about the presentations in our ESC 2013 Day #1 Report for at http://www.closeconcerns.com/knowledgebase/r/2a8925c5. Regarding EXAMINE, Dr. Husain noted that the investigation team decided not to pursue superiority, as the incidence of cardiovascular outcomes was nearly identical in the treatment and comparator arms. He pointed out that the enrolled patients in both arms were “well taken care of” (the vast majority were on aspirin and statins, among other medications), and postulated that this may have blunted any potential cardioprotective effect Nesina might have had. Turning to SAVOR-TIMI 53, Dr. Husain highlighted the 27% increase in hospitalization for heart failure seen in the saxagliptin arm, and emphasized the need for further investigation of the issue. On the bright side for the two CVOTs, he noted, neither of the trials showed a significant pancreatitis signal. To conclude, he believes that DPP-4 inhibitors are safe based on the vast majority of RCT data, and could potentially have cardioprotective effects based on early data.

  • Dr. Husain provided appreciable background on the issue of DPP-4 inhibitors and cardiovascular disease. He began with the basics, citing a preclinical study that demonstrated that DPP-4 knockout mice had significantly better survival rates after an induced myocardial infarction. Turning to small, mechanistic studies of incretin therapies, he highlighted evidence that DPP-4 inhibitors might have cardioprotective potential. He did mention evidence (Pratley et al., Lancet 2010) showing that sitagliptin slightly elevated patients’ heart rate, but stated that the clinical significance of this phenomenon is likely low.
  • The “heart” of Dr. Husain’s presentation was a discussion of the results of EXAMINE and SAVOR-TIMI 53. Regarding EXAMINE, he highlighted that nearly all the enrolled patients were on aspirin and statins, and many were on other cardioprotective medications (Editor’s Note: almost all patients in SAVOR were also on statins by the end of the trial). He used this fact to explain the lack of cardiovascular benefit seen in the alogliptin arm — tightening glycemic control in patients that otherwise are so well taken care of, he said, may not have been able to cause a measurable CV benefit in 18 months (the mean patient follow-up in the study). He did not believe that the data on pancreatitis indicated any safety issues.
  • Turning to SAVOR-TIMI 53, Dr. Husain stated emphatically that the 27% increase in hospitalization for heart failure seen in the Onglyza group deserves further attention. The fact that the outcome was pre-defined and adjudicated, in his mind, likely means that the signal is real rather than the result of random chance. He expressed a desire for the study data to be re-analyzed in order to better explain the troubling signal — we heard at another session today that subgroup and baseline risk analyses may be ready to present at AHA in November. As with EXAMINE there was no significant pancreatitis signal seen in SAVOR. To conclude, Dr. Husain expressed his confidence in the DPP-4 inhibitor class, reminding the audience that a plethora for RCT data has suggested that the class is safe.

Questions and Answers

Q: Regarding the DPP-4 knockout mouse experiment, in which a lack of DPP-4 reduced infarct size and improved survival, aren’t there no GLP-1 receptors in the myocardium?

A: There are GLP-1 receptors in the atria. And in Dan Drucker’s beautiful Nature Medicine paper, these receptors were shown to be important for GLP-1-mediated release of ANP, which is released by the heart in conditions of increased pressure. I would imagine that after an MI, anything that promotes the release of ANP would be beneficial.

Q: Does the result of SAVOR-TIMI change your recommendations about Onglyza?

A: It’s a very unexpected and very unexplained result. I can think of three or four mechanisms that would have explained the opposite, but this I am truly at a loss to explain mechanistically. One always has the hazard, even in a large study, of having an outlier emerge. If we are to believe the early presentations, it may be occurring in patients at risk of heart failure. The only caveat may be to avoid Saxagliptin in patients at risk for heart failure.

Q: Ultimately, would you recommend the use of DPP-4 inhibitors in patients with cardiovascular disease?

A: I think the takeaway message is that if you need to use a blood-sugar-lowering drug in patients with either recent acute cardiac syndrome or who are at high risk for cardiovascular events, these drugs are safe. How many drugs classes have the same level of data as DPP-4 inhibitors are getting?

 

 

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