European Association for the Study of Diabetes

48th Annual Meeting September 30, 2012 – October 5 2012; Berlin, Germany – Incretin Therapies

Executive Highlights

We were heartened to see advancements on efforts to improve patient experience with incretins through progress in once-weekly GLP-1 therapy, a yearlong- implantable GLP-1 device, a once-weekly DPP-4 inhibitor, a more selective DPP-4 inhibitor, and GLP-1/basal insulin combination therapy. We learned from Dr. Michael Nauck (Diabetes Centre, Bad Lauterberg im Harz, Germany) that the highest dose tested of Novo Nordisk’s once-weekly GLP-1 agonist, semaglutide, performed better than the highest dose of Victoza in terms of A1c reduction and weight loss, but with a worse nausea profile that resulted in the decision to carry forward a lower dose to phase 3. Additionally, we paid close attention to Intarcia’s ITCA-650, an implantable extended-release device for exenatide that would be implanted once at a low titration dose for three months and then replaced every six to 12 months thereafter. Promisingly, in phase 2 studies ITCA-650 provided superior A1c reduction, similar weight loss, and less nausea at 12 weeks compared to the equivalent dose of Byetta (exenatide twice-daily); as we understand it, implantation is an easy process and we hope explantation can become so too. Merck’s once-weekly DPP-4, MK-3102, demonstrated significant improvements in A1c over placebo at all six doses tested in a phase 2b trial; a once-weekly DPP-4 certainly may offer an adherence benefit as a first-line option for patients who are not tolerant of metformin and we believe would even be appealing to patients (and payors) for those on metformin, since we know that plenty of patients forget to take even easy-to-use daily medicine. We also attended a presentation by Dr. Jonathan Rosenblum (ActivX Biosciences) on preclinical pharmacodynamics data for KRP-104, a more selective DPP-4 inhibitor that is currently in phase 2 trials. Interestingly, Dr. Rosenblum asserted that he would refuse to take sitagliptin because of its impact on the liver – a notable statement given the general consensus about the safety of the DPP-4 class – and that ActivX seeks to make KRP-104 the best-in-class DPP-4 inhibitor based on functional differentiation, something that no other DPP-4 inhibitor has shown. Additionally, we learned that four- year data from the DURATION-1 follow-up study for Bydureon (exenatide once-weekly; the longest- term GLP-1 data we have seen to date) demonstrated a solidly durable A1c reduction and moderate weight-loss durability out to four years – durability was always mentioned even in the early days as an advantage of GLP-1 and this view was certainly reinforced by this data.

GLP-1/basal insulin combination therapy continues to be a topic of interest when discussing attractive options for the treatment of type 2 diabetes. Dr. Tina Vilsboll (University of Copenhagen, Copenhagen, Denmark) strongly advocated for this combination at the Lilly corporate symposium, and panelists at a round-table discussion during Sanofi’s corporate symposium agreed with this sentiment – it’s now a foregone conclusion from our view that this combination is widely used and will become ever more so when there are combination applications. Speaking of, we attended an oral presentation on the GetGOAL-L study for Sanofi’s lixisenatide/Lantus (insulin glargine) that demonstrated that the combination lowered reduced placebo-adjusted A1c beyond Lantus alone – although not as big as the placebo-adjusted A1c reduction conferred by a combination of linagliptin and basal insulin as reported in a different oral presentation (0.36% vs. 0.65% placebo-adjusted reduction for lixisenatide/Lantus vs. linagliptin/basal insulin, respectively). We found this result noteworthy even though the lack of head-to- head data makes a true comparison impossible at this point. Still, whatever turns out to be the best formulation, it’s certainly clear at this point that combining incretins and basal insulin has become quite popular. Titles highlighted in yellow are new additions to the report that were not initially included in our daily updates from Berlin. Additionally, titles highlighted in blue belong to our list of top 12 talks.

Table of Contents 

Incretin Therapies

Oral Presentations: Incretin-Based Therapies

THE ONCE-WEEKLY HUMAN GLP-1 ANALOG SEMAGLUTIDE PROVIDES SIGNIFICANT REDUCTIONS IN HBA1C AND BODY WEIGHT IN PATIENTS WITH TYPE 2 DIABETES

Michael Nauck, MD, PhD (Diabetes Centre Bad Lauterberg, Harz, Germany)

Dr. Michael Nauck presented new phase 2 data for semaglutide, Novo Nordisk’s once-weekly GLP-1 agonist (expected to advance into phase 3 trials in the first half of 2013; for more details on semaglutide development, see our Novo Nordisk 2Q12 report at http://bit.ly/PCq8dD). In this 12-week dose-ranging trial, 411 patients were randomized to receive semaglutide once weekly, liraglutide (Victoza) once daily, or placebo. Semaglutide produced a dose-dependent reduction in A1c from a baseline of 8.1%. The 1.6 mg dose of semaglutide provided superior A1c reduction (1.7% [1.2% placebo-adjusted]) than the highest dose of liraglutide (1.3% [0.8% placebo-adjusted]). A dose-dependent effect of semaglutide on weight loss was also observed, with patients on the 0.8 mg, 0.8 mg titrated, and 1.6 mg titrated semaglutide doses achieving better weight loss (2.2 kg [4.8 lbs], 2.4 kg [5.3 lbs], and 3.6 kg [7.9 lbs] placebo-adjusted weight loss, respectively) than those taking the highest dose of liraglutide (1.4 kg [3.1 lbs] placebo- adjusted weight loss). Notably, titration of semaglutide reduced nausea while maintaining the same A1creduction and weight loss. Results from this trial will allow Novo Nordisk to define the dose range for phase 3 trials to optimize the balance between efficacy and side effects; Dr. Nauck stated that the highest dose of semaglutide tested in this trial (1.6 mg titrated) would not be carried forward to phase 3 due to its side effect profile (31% of patients in the 1.6 mg titrated semaglutide arm withdrew from the study, with most citing GI adverse events as the reason).

  • Dr. Nauck explained that the structure of semaglutide is generally similar to that of liraglutide. Both have a free fatty acid attached via a spacer molecule at Lys-26, but semaglutide has an amino acid substitution at position 8 (Ala à AiB [alpha-aminoisobutyric acid]) that prevents DPP-4 degradation. Semaglutide has about a 150-hour (6.25-day) half-life).
  • In this 12-week trial, 411 patients were randomized to receive semaglutide once- weekly, liraglutide (Victoza) once-daily, or placebo. Patients on semaglutide received 0.1 mg, 0.2 mg, 0.4, mg 0.8 mg, 0.8 mg titrated or 1.6 mg titrated semaglutide once weekly; patients given liraglutide received 1.2 mg titrated or 1.8 mg titrated liraglutide (n=43-50 per treatment arm). In the 0.8 mg titrated semaglutide group, patients were given 0.4 mg semaglutide for the first week and moved up to 0.8 mg for the second week. In the 1.6 mg titrated semaglutide group, patients were titrated from 0.4 mg the first week to 0.8 mg the second week, and 1.6 mg the third week. Patients had an average baseline A1c of 8.1%, BMI of 30.9 kg/m2, and weight of 87.5 kg (193 lbs). Patients had an average age of 55 years, were 35% female, and had a very short duration of diabetes (2.6 years). Interestingly, Dr. Nauck implied that the study purposely enrolled people with short disease duration, suggesting to us that Novo Nordisk may position the drug as anearly-stage treatment option.
  • Semaglutide produced a dose-dependent reduction in A1c from baseline, and the 1.6 mg dose of semaglutide provided superior A1c reduction (1.7% [1.2% placebo- adjusted] than the highest dose of liraglutide (1.3% [0.8% placebo-adjusted]). See the table below for full details. Additionally, more patients on the higher doses of semaglutide achieved A1c ≤6.5% or ≤7.0% than patients on liraglutide.
Treatment Dose Absolute A1c Reduction Placebo-Adjusted A1c Reduction % Achieving 

≤6.5% A1c

% Achieving 

≤7% A1c

Placebo   0.5% - 4% 15%
Semaglutide Once-Weekly 0.1 mg 0.6% 0.1% 13% 28%
0.2 mg 0.9% 0.4% 28% 45%
0.4 mg 1.1% 0.6% 20% 56%
0.8 mg 1.5% 1.0% 50% 73%
0.8 mg titrated  1.4% 0.9% 45% 69%
1.6 mg titrated 1.7% 1.2% 63% 81%
Liraglutide Once-Daily 1.2 mg titrated 1.2% 0.7% 34% 59%
1.8 mg 1.3% 0.8% 36% 57%
  • A dose-dependent effect of semaglutide on weight loss was also observed, with patients on the 0.8 mg, 0.8 mg titrated, and 1.6 mg titrated semaglutide doses achieving better weight loss than those taking the highest dose of liraglutide. Semaglutide 1.6 mg titrated produced a 3.6 kg (7.9 lbs) placebo-adjusted weight loss; 0.8 mg titrated a 2.4 kg (5.3 lbs) placebo-adjusted weight loss; and the 0.8 mg untitrated, a 2.2 kg (4.8 lbs) placebo-adjusted weight loss. For comparison, liraglutide 1.8 mg produced a 1.4 kg (3.1 lbs) placebo-adjusted weight loss.
  • Mild nausea was the most common side effect, and was ameliorated by titration (60% of patients on the 0.8 mg untitrated semaglutide experienced nausea [68% of whom described it as mild] vs. 39.5% of patients on the 0.8 mg titrated semaglutide). However, 31% of patients on the highest dose of semaglutide (1.6 mg titrated) withdrew from the study, with most of them citing GI adverse events as the cause. 57.4% of those on the highest dose reported nausea (59% described it as mild, 34% as moderate, and 7% as severe). Dr. Nauck stated that Novo Nordisk would not carry the 1.6 mg dose forward to phase 3 due to the high rate of GI side effects. Serious adverse events (SAEs) were rare, and adverse events (AEs) increased with dose in both semaglutide and liraglutide. As expected, no major hypoglycemic events were reported, and minor hypoglycemia was uncommon.

Questions and Answers:

Q: Did nausea or GI side effects decrease over time?

A: Not that I’m aware of; it’s a good question and maybe we should look whether this was the case.

Q: Did you study the effects of oral contraceptives on the pharmacokinetics of semaglutide?

A: We did not study those effects; it was not the topic studied in this phase 2 trial.

Q: Any data on antibodies?

A: No but the molecule is very similar to liraglutide and is very much like GLP-1 so I wouldn’t expect any antibody formation.

Q: I think this study nicely shows that getting to somewhat higher GLP-1 levels increases efficacy beyond what we see with use of currently available GLP-1 analogs today. Couldn’t one think about different methods of slowly ramping up dose initially to retain the beautiful A1c-lowering effects of the highest doses rather than going forward with low doses?

A: I think this is what should be done for phase 3; there is no hurry, and in principle this and other studies show that ramping up helps with GI side effects and so we’ll keep doing it carefully and slowly – that is fine for treatment of a chronic disease.

Q: You have reported a significant proportion of withdrawal. When you presented the reduction in A1c, was it based on the ITT population or per-protocol population?

A: That was as assigned with last observation carried forward.

EFFICACY AND SAFETY OF ONCE-DAILY LIXISENATIDE IN TYPE 2 DIABETES INSUFFICIENTLY CONTROLLED WITH BASAL INSULIN METFORMIN: GETGOAL-L STUDY

Ronnie Aronson, MD (LMC Diabetes & Endocrinology, Calgary, Canada)

This 24-week study examined the efficacy and safety of once-daily 20 g lixisenatide in patients with longstanding type 2 diabetes inadequately controlled on basal insulin (with or without metformin). Patients were randomized to receive lixisenatide (n=329) or placebo (n=167) in a 2:1 fashion. Lixisenatide treatment brought about a significant reduction in A1c beyond placebo over the 24-week treatment period (0.74% vs. 0.38% from a baseline of 8.4%; p<0.001), and also led to significant improvements in two-hour postprandial glucose, glucose excursions, seven-point profiles, body weight, and basal insulin dose. Side effects with lixisenatide were mainly gastrointestinal; there was no significant increase in hypoglycemia versus placebo.

  • In this 24-week study, patients with longstanding type 2 diabetes inadequately controlled on basal insulin (metformin) were randomized to receive lixisenatide 20 g once daily (n=329) or placebo (n=167). Main inclusion criteria were: 1) type 2 diabetes known for at least one year; 2) the use of basal insulin at a stable dose (≥30 U/day20%) for at least three months; and 3) A1c between 7.0-10.0% at screening. Main exclusion criteria were fasting plasma glucose above 13.9 mmol/l (250 mg/dl) and BMI ≤20 kg/m2. No concurrent antidiabetic medications were permitted other than metformin at a stable dose of ≥1.5 g/day for at least three months. Patients were titrated in a two-step process (10 g at baseline, 15 g at one week, and 20 g at the two-week mark). At baseline, patients had an average age of 57- 58, diabetes duration of 11 years, A1c of 8.4%, two-hour PPG of 16.1-16.5 mmol/l (290-297 mg/dl), fasting plasma glucose of 8.1 mmol/l (146 mg/dl), BMI of 31.9-32.6 kg/m2, and duration of insulin use of 1.7-1.8 years. Approximately 80% of patients were on metformin at baseline.
  • Patients receiving lixisenatide treatment experienced significant reductions in A1c, two-hour postprandial glucose, glucose excursions, seven-point profiles, body weight, and basal insulin dose versus placebo. Over the course of 24 weeks, patients on lixisenatide experienced a significantly greater reduction in A1c than patients on placebo (0.74% vs. 0.38%; p<0.001). A higher percentage of patients on lixisenatide achieved A1c targets of <7% and ≤6.5% than placebo – 28.3% of patients on lixisenatide and 12.0% of patients on placebo achieved an A1c of <7% (p<0.0001), while 14.5% of patients on lixisenatide and 3.8% of patients on placebo achieved an A1c ≤6.5% (p=0.0003). The lixisenatide arm also achieved a significant reduction in two-hour postprandial glucose versus placebo (5.5 mmol/l [99 mg/dl] vs. 1.7 mmol/l [31 mg/dl]; p<0.0001) and in glucose excursion (4.1 mmol [73.8 mg/dl] vs. 0.3 mmol/l [5.4 mg/dl]). In addition, patients on lixisenatide experienced a significant reduction in seven-point profile versus placebo (1.49 mmol/l [27 mg/dl] vs. 0.61 mmol/l [11 mg/dl]; p<0.0001). The lixisenatide arm achieved an average reduction in body weight of 1.3 kg (2.9 lbs), compared to a reduction of 0.1 kg (0.2 lbs) with placebo. Patients in the lixisenatide arm reduced their basal insulin dose an average of 5.6 units, versus 1.9 units with placebo (p=0.012).
  • During the study, patients on lixisenatide experienced a higher rate of gastrointestinal adverse events than those on placebo. Most nausea with lixisenatide occurred during the first three weeks of treatment; by the fourth week the frequency of nausea was reduced (please see table below).

Type of adverse event, n (%)

Basal insulin ±MET + lixisenatide  (n=328) Basal insulin ±MET + placebo (n=167)
Nausea                   86 (26.2)                14 (8.4)
Vomiting                    27 (8.2)                 1 (0.6)
Diarrhea                     24 (7.3)                  9 (5.4)
Dizziness                     17 (5.2)                  7 (4.2)
  • Dr. Aronson commented that the incidence of hypoglycemia was comparable between treatment arms. 27.7% of patients receiving lixisenatide experienced symptomatic hypoglycemia, compared to 21.6% of patients receiving placebo; 1.2% of patients receiving lixisenatide experienced severe symptomatic hypoglycemia, whereas no patients on placebo experienced severe symptomatic hypoglycemia.

Questions and Answers:

Q: Looking at the meal test and your seven-point profile, lixisenatide seemed to bring about the greatest reductions in postprandial glucose with the morning meal. Do you think it would be helpful to do the meal test after the evening meal, or do you think that it suggests lixisenatide should be a twice-daily injection?

A: Lixisenatide once daily and BID has been studied, and there was no significant difference between the two, and that’s why it’s being presented as a once-daily medication in all phase 3 studies. There also has been a study looking at dosing with the morning meal and with the evening meal versus placebo, and both had identical benefits. There is a study underway (or about to start) comparing morning meal dosing to the largest meal of the day dosing, and that will be interesting to investigate in particular.

Q: Do you have any data on antibodies?

A: Across the phase 3 studies, about 20% were antibody positive at the end of the protocol. There were no differences in efficacy related to antibody positivity or negativity.

Q: It’s been suggested that lixisenatide increases heart rate. Do you have the heart rate and blood pressure data?

A: There was no difference in heart rate in this study, or in the phase 3 studies overall. There was a small reduction in systolic blood pressure of 2-3 mm Hg across the phase 3 program.

Q: There was one death in the study of a patient on lixisenatide. Could you comment on that please?

A: The death was related to sudden cardiac death, and not related to the study protocol or medication as far as investigators were aware.

Q: Did you see statistically significant differences in postprandial glucose after lunch and dinner as you saw after breakfast? (I’m assuming the data you showed us was for the breakfast meal.)

A: I can’t recall the exact statistical analysis. I think the standard errors of mean were sufficiently separated that it would be statistically significant, but I can’t say for certain.

Q: In this study, was basal insulin dosed in the morning or during the evening?

A: In this study, it was dosed in the morning.

Q: What about metformin?

A: Metformin was continued as before, most typically BID.

LONG-TERM SAFETY AND EFFICACY OF LINAGLIPTIN AS ADD-ON THERAPY TO BASAL INSULIN IN PATIENTS WITH TYPE 2 DIABETES: A 52-WEEK RANDOMIZED, PLACEBO-CONTROLLED TRIAL

Hannele Yki-Jarvinen, MD, PhD (University of Helsinki, Helsinki, Finland)

This study evaluated the efficacy after 24 weeks and safety after 52 weeks of linagliptin as an add-on therapy to basal insulin, alone or in combination with metformin and/or pioglitazone. At the 24-week mark, patients on linagliptin achieved an average A1c reduction of 0.58%, compared to an average increase of 0.07% with placebo (p<0.0001), from a baseline of 8.3%. Linagliptin treatment was shown to be effective independent of renal function or type of insulin used. There were no significant differences in the rate of adverse events between groups; linagliptin was not associated with an increased risk of hypoglycemia.

  • In this study, patients with type 2 diabetes on basal insulin (alone or in combination with metformin and/or pioglitazone) were randomized to receive linagliptin 5 mg once daily (n=631) or placebo (n=630). Efficacy was assessed at 24 weeks, and safety at 52 weeks. For the first 24 weeks, patients remained on a stable insulin dose; following this period, basal insulin was titrated as appropriate. At baseline, patients were on average 60 years of age, with BMI of 31 kg/m2, A1c of 8.3%; over 80% had diabetes duration of five or more years. Those on linagliptin had average baseline fasting plasma glucose of 8.2 mmol/l (148 mg/dl) and insulin dose of 41.5 U/day, compared to 8.4 mmol/l (151 mg/dl) and 40.1 U/day for placebo. Approximately 75% of patients were on metformin monotherapy, 1% were on pioglitazone therapy, and 7% on metformin plus pioglitazone at baseline.
  • At the 24-week mark, patients on linagliptin achieved an average A1c reduction of 0.58%, compared to an average increase of 0.07% with placebo (p<0.0001). Linagliptin treatment was shown to be effective independent of renal function or type of insulin used. Patients on linagliptin experienced a slight reduction in body weight (<0.2 kg [<0.4 lbs]) at the 24-week mark, compared to a slight increase (<0.2 kg [<0.4 lbs]) with placebo.

Questions and Answers:

Q: Was basal insulin titrated during the study? My impression was that only a small proportion of patients reached an A1c below 7%.

A: The ideal study in a way would be to first titrate basal insulin properly, and then add linagliptin. In the first 24 weeks, we did not allow for any changes in insulin dose.

Q: During the second period of the study, how was insulin titrated?

A: The instructions were to titrate to fasting plasma glucose below 6.0 mmol/l by increasing the basal insulin dose, but I don’t think that this really happened, at least judging from the results.

Q: In the linagliptin group, patients used less insulin, yet the hypoglycemia rate was similar to the placebo group. How do you explain that? One would expect less hypoglycemia in the linagliptin group.

A: The insulin dose was the same – it was 40 units at baseline. During the first 24 weeks of the study, the insulin dose did not change; it was similar between groups. The similar hypoglycemia rates observed is consistent with the idea that linagliptin does not increase the risk of hypoglycemia.

Q: Did you measure serum amylase on a regular basis during the study? Was there any change in the risk of pancreatitis in the two groups?

A: There were no hints of pancreatitis being more common in the linagliptin or placebo group. We didn’t measure amylase.

EXENATIDE ONCE WEEKLY RESULTED IN SUSTAINED IMPROVEMENT IN GLYCEMIC CONTROL WITH WEIGHT LOSS THROUGH FOUR YEARS

Leigh MacConnell, PhD (Amylin Pharmaceuticals, San Diego, CA)

Dr. MacConnell presented four-year results of the DURATION-1 follow-up study for exenatide once weekly – the longest-term data we have seen to date. The original DURATION-1 study compared exenatide once weekly (Bydureon) to exenatide twice daily (Byetta) over 30 weeks. After trial completion, all patients were put on Bydureon. Of the original 295 patients in the intent-to-treat population (ITT), 176 (60%) completed the four-year extension. At the end of four years, patients sustained an A1c reduction of 1.7% from a baseline of 8.2% (generally similar to the 1.9% reduction observed at the end of 30-weeks for DURATION-1; notably, Dr. MacConnell stated during Q&A that the A1c reduction in the ITT population using the last observation carried forward was 1.4% and the A1c reduction for patients who did not complete the trial was 1.1%). With regard to weight, patients sustained, on average, a 2.5 kg (5.5 lbs) weight loss from baseline after four years, compared to the ~4 kg (8.8 lbs) weight loss observed after the 30 weeks of DURATION-1. Safety analyses were performed on the ITT population; during four years 20% of patients experienced a serious adverse event (SAE), and three patients died. Dr. MacConnell stated that the causes of death were unrelated to treatment, and no pattern of SAEs was reported. No major hypoglycemia episodes were reported, and minor hypoglycemia only increased over four years in patients taking a concomitant sulfonylurea (n=116). Improvements in blood pressure, total cholesterol, LDL, and triglycerides were also observed. Overall, we believe this represents strong evidence of Bydureon’s durability in terms of efficacy and safety – four years is much longer than the average patient expects to take a given compound and expect it to work..

  • The four-year DURATION-1 follow-up study examined long-term safety and efficacy of exenatide once weekly (EQW). The original DURATION-1 study compared exenatide once weekly (Bydureon) to exenatide twice daily (Byetta) over 30 weeks. After trial completion, all patients were put on Bydureon. Of the original 295 patients enrolled in the study, 176 (60%) completed the four-year extension. Most withdrawals were due to “withdrawal of consent” (n=62; 21%) with no reason specified; 10% (n=29) withdrew due to an adverse event, and Dr. MacConnell stated that there was no clear trend in the type of adverse event leading to withdrawal. Baseline characteristics between the ITT and four-year completer populations were consistent (average age of 54 years, A1c 8.2%, BMI 35 kg/m2, diabetes duration of 7 years, and the majority on a background of metformin [33%] or a sulfonylurea metformin or TZD [39%]). Efficacy data presented were for the four-year completer population, and safety data presented were for the intent-to-treat (ITT) population.
  • Patients sustained an average 1.7% A1c reduction from baseline after four years of treatment. FPG at four years was reduced by 2.1 mmol/l (~38 mg/dl) from baseline, compared to the 46 mg/dl FPG drop observed in DURATION-1. A1c and FPG plotted every year over thefour years show that most of the rise in A1c and FPG between the end of the trial and the end of the four-year extension occurred from year one to two, with a slight upward trend from year two to three, and stabilization from year three to four. The majority of patients (55%) achieved the ADA recommendation of A1c <7%, and 36% achieved the AACE guideline of A1c <6.5%. At year four, patients also demonstrated improvements in HOMA-B and HOMA-S from baseline (26% and 13% improvement, respectively). Dr. MacConnell acknowledged during Q&A that the completer population is likely biased toward patients achieving better results on Bydureon (she stated during Q&A that the A1c reduction in the ITT population using the last observation carried forward was 1.4%, and the A1c reduction for patients that did not complete the trial was 1.1%).
  • Weight loss was fairly durable; after four years, patients sustained an average 2.5 kg(5.5 lb) weight loss from baseline, compared to the ~4 kg (8.8 lb) weight loss observed in the first 30 weeks of DURATION-1. However, weight tends to increase with age anyway, and without a control group, it is hard to say whether these patients would have gained more weight had they not been taking Bydureon. After four years, 71% of patients had lost weight from baseline, and 61% saw both a weight reduction and A1c reduction.
  • No unexpected safety concerns arose over four years. No pattern of serious adverse events (SAEs) was reported; 20% of patients experienced a SAE, and three patients died. Dr. MacConnell stated that the causes of death were unrelated to treatment. Withdrawal rate due to adverse events was low (8%); 2% withdrew due to GI adverse events. Hypoglycemia was nearly nonexistent in patients who were not using a concomitant sulfonylurea (SFU; n=179) and remained stable over four years in this group. In patients using a concomitant SFU (n=116), incidence of minor hypoglycemia increased slightly during the first year (~20% of patients experienced a minor hypoglycemic episode during the first year). No major hypoglycemic events were reported over four years. The most common side effects reported were nausea and injection site irritation, as expected (15 and 6 per 100 patient years, respectively), but they largely subsided after the first 20 weeks, and Dr. MacConnell indicated they were mild or transient.
  • Cardiometabolic risk factors also improved after four years. Improvements in blood pressure were observed (no significant difference in systolic blood pressure, but a 2.7 mmHg reduction in diastolic blood pressure was recorded); improvements were most marked in those with abnormal baseline blood pressure (systolic and diastolic reductions of 0.7 mmHg and 5.3 mmHg from a baseline of 140 mmHg and 82 mmHg, respectively). Total cholesterol, LDL, and triglycerides also improved. Maximum improvement in all of the aforementioned cardiometabolic risk factors was observed at two years and remained stable thereafter.

Questions and Answers:

Q: I am most interested in the time course of what happened to A1c. It appeared that durability did not set in until after year three. Does it take three years to achieve durability, or was it just the selection process and those that stuck with it after three years had a durable effect?

A: Certainly a limitation to this open-ended open-label assessment is that of course it doesn’t have a control arm. I think there is also bias in that patients in the completer population are enjoying their experience with exenatide once weekly.

Q: What additional therapies were added over the four years?

A: The protocol required they maintain their stable doses, but over the long term there was more fluctuation in therapy. 20% of patients either added or increased dosage of medications, but about 20% also dropped a medicine or decreased their dose.

Q: Did blood glucose control deteriorate in the patients that withdrew? What would the analysis look like if they had been included?

A: We have an ITT analysis using last observation carried forward. In that population, the A1c reduction was 1.4% vs. 1.7% in the completer population; we also looked specifically at those patients that did withdraw early and looked at A1c upon withdrawal, and they saw an about 1.1% reduction. So patients terminated early aren’t seeing as robust of an effect as those remaining on therapy, which was not surprising.

Q: Were there any heart rate data?

A: We see an increase in heart rate of about three to four beats per minute. It happens fairly early on and remains stable thereafter so there is no continued increase.

Q: Were patients on concomitant blood pressure or antihypertensive agents?

A: The majority of patients were on lipid-lowering drugs or antihypertensive agents. Most remained stable in their dosage and about 10% of patients increased or added lipid-lowering or antihypertensive agents.

LIRAGLUTIDE TRIAL IN PEDIATRIC SUBJECTS WITH TYPE 2 DIABETES: SAFETY, TOLERABILITY AND PHARMACOKINETICS/PHARMACODYNAMICS

Tadej Battelino, MD, PhD (University Children’s Hospital Ljubljana, Ljubljana, Slovenia)

Dr. Tadej Battelino detailed his group’s dose escalation study of liraglutide in pediatric patients with type 2 diabetes. He began by noting that though the prevalence of type 2 diabetes in children is increasing in the US, Asia, and Europe, metformin and insulin remain the only two treatments available to these patient populations. His group’s five-week trial assessed the safety, tolerability, and PK/PD profile of liraglutide in 21 pediatric participants (baseline age 14-16 years, A1c 7.8-8.3%, and average BMI 40 kg/m2). The study randomized seven participants to placebo and 14 to ascending doses of liraglutide (starting at 0.3 mg and increasing by 0.3 mg/week until reaching 1.8 mg in the fifth week; dose escalation was based on tolerability and levels of fasting plasma glucose). Adverse events were mild with liraglutide and mild/moderate with placebo, with no observed serious adverse events. Hypoglycemia was uncommon in both study groups and no major hypoglycemic episodes were reported. Participants did not experience any clinically significant shifts in calcitonin levels, and an external hormonal safety board found no evidence of hormonal disruption. The PK profiles for liraglutide in pediatric patients were similar to those reported in adults with type 2 diabetes. Interestingly, liraglutide provided a significant reduction in A1c (-0.86%) compared to a slight A1c increase with placebo (+0.04%), though no statistically significant effects on fasting plasma glucose or body weight were observed.

Questions and Answers:

Q: Were you not a little surprised that you didn’t see a difference with respect to body weight? I know it’s only a five-week study and patients were only on liraglutide 1.8 mg for a short period of time, and not all patients reached that dose. But were you surprised?

A: Yes, we were surprised. I think for good reason. I believe a bigger study of a longer duration, especially in an obese population, is needed in this age group because this could be a very important indication.

Q: Can you explain why you saw an important difference in A1c but no difference in fasting plasma glucose?

A: I appreciate that this looks difficult, however, as you know, in early onset type 2 diabetes, it’s mainly post-prandial glucose that contributes to A1c rather than fasting plasma glucose. So if we understand the natural course of type 2 diabetes and take into account the very young age of this population, I don’t think it’s very surprising.

Q: I think to prove safety you need a considerably larger group of patients.

A: There’s no question about it. It’s not proof that liraglutide is very safe. We wanted to start in a small patient group to see if there’s a major problem. There was no major problem, so a larger phase 3 trial is ongoing in Europe.

Q: Did you see any changes in pulse or blood pressure?

A: Nothing major. The truth is, that higher dose was used only for one week, and if you combine the three highest doses, patients were on them for only three weeks. We plan to plot individual graphs, but there is no major issue.

Oral Presentation: Novel Therapies (Incretins)

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

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

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

  • Dr. Henry opened by reasoning that presently, poor adherence to GLP-1 therapy is hindering patients’ ability to optimize glucose control. All currently approved GLP-1 agonists (Novo Nordisk’s Victoza, BMS/AZ/Amylin’s Bydureon, BMS/AZ/Amylin’s Byetta), and all late-stage candidates for that matter, require self-injection on a regular basis. Dr. Henry stated that adherence to GLP-1 therapy for patients with type 2 diabetes ranges from 30-70%, and that this has relegated this promising class to a third- or fourth-line position for treatment. He believes that reducing the burden of injections will lead to earlier and broader use along with better patient outcomes. ITCA 650 is a miniature osmotic pump system that delivers exenatide subcutaneously, eliminating the barrier of self-injection. The device is about the size of a matchstick and would be implanted subcutaneously. In in vitro tests, it demonstrated the ability to release fluid at a constant rate for 12 months.
  • A phase 2 dose-ranging study found that ITCA 650 provided better A1c reduction than the equivalent total daily dose of exenatide twice daily; higher doses of ITCA 650 conferred even greater A1c and weight benefits. The trial consisted of two stages. In the first stage, 155 patients were randomized to exenatide twice daily (n=53; total of 20 μg/day), ITCA 650 20 μg/day (n=51), or ITCA 650 40 μg/day (n=51) (patients had average baseline A1c’s of 8.0%, 7.9%, and 8.0%, respectively in the three treatment arms). After 12 weeks, exenatide twice daily produced a 0.7% A1c reduction, and both ITCA 650 20 μg/day and 40 μg/day produced a 1.0% A1c reduction. During stage two of the study, patients remained on the same dose of ITCA 650, or had the dose increased by 40 μg/day, and patients on exenatide were switched to ITCA 40 μg/day or 60 μg/day (overall, n=20 for 20 μg/day, n=42 for 40 μg/day, n=46 for 60 μg/day, and n=23 for 80 μg/day). Those on 20 or 40 μg/day achieved 0.9% and 1.0% A1c reductions, respectively, and those on 60 or 80 μg/day achieved 1.3% and 1.4% reductions, respectively. A1c lowering was durable out to week 48. Weight loss on the 20 μg/day dose was 0.8 kg (1.8 lbs) at week 24, and for all higher doses was greater than 3 kg (6.6 lbs). Weight loss at for exenatide at week 12 was not disclosed; as we recall, it was around 3-4 kg at about a year.
  • Additionally, ITCA 650 produced a lower rate and shorter duration of nausea than an equivalent dose of exenatide twice daily. The incidence of nausea was consistently lower for ITCA 650 20 μg/day compared to 20 μg/day of exenatide twice daily; the mean duration of nausea on ITCA 650 20 μg/day was 17 days, versus 47.7 days for exenatide injections. Another testament to ITCA 650’s favorable tolerability profile was the 93% completion rate for stage one and 95% completion rate for stage two of the trial; 89% of patients in the exenatide arm completed stage one of the study, which is also very high. In general, though this is great to see, we aren’t typically successful forecasting adherence or patient interest from trials since there is certainly an unrepresentative cohort of patients that are “early adopters” – too, some patients participate in trials because they are paid.
  • The 20 to ->->60 μg/day dose sequence was chosen as the best regimen to use in phase 3 trials. Since the 80 μg/day did not outperform the 60 μg/day dose and, as expected, exhibited worse tolerability, it was removed from consideration. The 20 μg/day dose was selected as the introductory dose given, its good initial efficacy and favorable tolerability. The 60 μg/day dose exhibited generally similar average A1c reduction to the 40 μg/day dose, but conferred better A1c reductions for those with higher baseline A1cs, and allowed a larger percentage of patients to achieve targets of ≤7.0% or ≤6.5%. Phase 3 trials investigating the use of ITCA 650 for six-to-12 months will start in 1Q13. We look forward to hearing details on physician comfort with explanting the device; implanting, as we understand it, has been very straightforward.

Questions and Answers:

Q: Were antibodies measured during these studies?

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

Q: Were they neutralizing antibodies?

A: They were not neutralizing.

Q: What was the incidence of pancreatitis?

A: There was no incidence of pancreatitis at all.

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

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

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

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

 

Outcome at Week 12

 

 

MK-3102 Doses

 

 

Placebo

 

0.25 mg

 

1 mg

 

3 mg

 

10 mg

 

25 mg

 

Mean Change in A1c (%)

 

0.14

 

-0.14

 

-0.36

 

-0.35

 

-0.53

 

-0.57

 

Placebo-adjusted  change

 

---

 

-0.28

 

-0.50

 

-0.49

 

-0.67

 

-0.71

 

Mean Change in 2-hour PMG (mg/dl)

 

7.2

 

-10.8

 

-25.2

 

-27.0

 

-34.2

 

-37.8

 

Placebo-adjusted  change

 

---

 

-18

 

-34.2

 

-34.2

 

-41.4

 

-45.0

 

Mean Change in FPG (mg/dl)

 

3.6

 

1.8

 

-16.2

 

-10.8

 

-9.0

 

-18.0

 

Placebo-adjusted  change

 

---

 

-1.8

 

-19.8

 

-14.4

 

-12.6

 

-21.6

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

Questions and Answers:

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

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

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

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

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

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

Dr. Jonathan Rosenblum presented results from in vitro and in vivo animal studies on KRP-104, a novel DPP-4 inhibitor, which Dr. Rosenblum stated ActivX is positioning as best-in-class by differentiating its functional selectivity and pharmacodynamic profile, as it has nearly 100% DPP-4 inhibition in humans.. Dr. Rosenblum noted that upon ingestion, KRP-104 is quickly converted into GIS-103, a DPP-4 inhibitor that cannot enter the intracellular space, in contrast to currently available DPP-4 inhibitors. Thus, because GIS-103 is confined within a small space, it has a relatively high potency due to its high maximum concentration. Additionally, since GIS-103 co-localizes with DPP-4 in the extracellular space, less administered drug is required to block DPP-4 action. Dr. Rosenblum thus argued that KRP-104  gives you “more bang for your buck” than its competitors. Enzymatic activity-based profiling assays revealed that GIS-103 inhibits almost no DPP-9 in an intact cell, while vildagliptin (Novartis’ Galvus) inhibits roughly 55% of DPP-9 when added to intact cells at its therapeutic Cmax (maximum concentration that a drug achieves). Similarly, after oral administration of KRP-104 to rats, the ratio of GIS-103 in tissues to plasma was significantly smaller than that of either vildagliptin or sitagliptin (see table below for more details). Though the data appears to indicate that KRP-104 has lower off-target action than currently marketed DPP-4 inhibitors. Dr. Rosenblum did not comment on whether this finding is clinically significant, even though KRP-104 has been studied in clinical trials. Phase 1 and phase 2 data indicate that KRP-104 provides comparable glycemic efficacy to other DPP-4 inhibitors; they have not at this stage shown better efficacy. Thus, most of the drug’s benefits, ActivX has described, seem to involve improvements in side effect profile (though we have not seen any data on differences in adverse event rates between KRP-104 and other DPP-4 inhibitors). If KRP-104 “differentiation” is characterized as primarily safety-related ,we are dubious how much of an impact this form of differentiation will have because safety is a minimal concern for most patients and providers using the therapeutic class. Notably, in a later conversation we had with Dr. Rosenblum he raised concerns about the long-term impact of potentially high levels of sitagliptin (Merck’s Januvia) in tissues, and that these drugs might not be as safe as they are commonly considered to be.

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

 

Compound

 

Lung

 

Heart

 

Pancreas

Sitagliptin

~13

~8

~19

Vildagliptin

~2

~2

~4

GIS-103

~1

~0

~0

Oral Presentations: Mechanisms of Incretin Action

MECHANISMS OF GLUCOSE LOWERING IN TYPE 2 DIABETES PATIENTS TREATED WITH SITAGLIPTIN ALONE OR IN COMBINATION WITH METFORMIN: A DOUBLE TRACER STUDY

Carolina Solis-Herrera, PhD (University of Texas Health Science Center, San Antonio, TX )

Dr. Carolina Solis-Herrera’s crossover study investigated the mechanisms underlying the action of sitagliptin and metformin. The study included 16 people with type 2 diabetes (mean age 47 years, BMI 33.5kg/m2, A1c 8.8%, and duration of diabetes 1.5 years). The participants underwent four treatment periods (six weeks on drug followed by a two-week washout period) during which they took metformin 2000 mg, sitagliptin 100 mg, sitagliptin/metformin combination therapy, or placebo in a randomized order. At the end of each six-week treatment period, the participants received a meal tolerance test (MTT) labeled with 14C-glucose, after which blood samples were taken regularly for six hours. Both sitagliptin and metformin significantly decreased post-meal plasma glucose and total glucose levels,   and sitagliptin/metformin combination therapy provided a larger reduction than either drug alone. The reduction in total glucose was not attributed to post-meal oral glucose levels, but rather to a decrease in endogenous glucose production, which was reduced with metformin and the combination therapy, and  to a lesser extent with sitagliptin. Notably, post-meal glucagon levels decreased by 26% with sitagliptin and 33% with the combination therapy compared to placebo, with no effect observed with metformin. In addition, sitagliptin and the combination therapy resulted in a ~2-fold increase in bioactive GLP-1 levels compared to placebo (metformin provided no change). Taken together, the results indicate that metformin and sitagliptin reduce post-meal glucose levels to the same extent, but through two different mechanisms: metformin suppresses hepatic glucose production while sitagliptin increases GLP-1 levels, thereby decreasing glucagon secretion.

Questions and Answers:

Q: You mentioned that you measured bioactive GIP – do you have data on GIP in this experimental set?

A: We did measure GIP, but it increased in all treatment arms so we didn’t include the data.

Q: So there was no change in GIP between the treatment groups?

A: No, GIP increased equally in all the treatment arms – a four-fold increase.

Q: I think you described that sitagliptin alone lowered glucose and had a little bit of a stimulation effect on insulin secretion that wasn’t statistically significant. For the assessment, and based on what sitagliptin does to insulin secretion and the beta cell’s response to rising glucose, wouldn’t it make sense to calculate the ratio of insulin secretion to the rise in glucose? I would assume that with sitagliptin, you would get a significant rise in how beta cells responds to an increase in glucose.

A: We did calculate several indexes that we didn’t show here because we wanted to show most of the data we have. We did measure C-peptide and other parameters, as well as the ratio of insulin secretion to glucose, and we did find that they all improved. We found a slightly greater improvement with the combination  therapy.

Oral Presentations: Metformin Action and Benefits

METFORMIN ENHANCES SECRETION OF GLP-1 BUT NOT GIP AND IMPROVES POSTPRANDIAL GLUCOSE EXCURSION IN JAPANESE PATIENTS WITH TYPE 2 DIABETES

Hitoshi Kuwata (Kansai Electric Power Hospital, Osaka, Japan)

Dr. Hitoshi Kuwata investigated metformin’s effect on GLP-1 and GIP insulin secretion in 29 patients with type 2 diabetes after one-day administration of metformin. Patients had a mean A1c of 7.6%, mean BMI of 27.7 kg/m2 (which Dr. Kuwata indicated was a bit higher than average for Japanese patients with type 2 diabetes), and a mean disease duration of 3.1 years. Patients were given metformin 500 mg at lunch and at dinner on day 1 of the study and at breakfast on day 2 of the study. GLP-1, GIP, insulin secretion, C-peptide, and glucagon secretion were measured at 30 minute intervals after breakfast on day 2. Metformin significantly lowered postprandial glucose area under curve (AUC) by about 200 mM*min and increased total postprandial GLP-1 AUC vs. control (increase of about 1000 pM*min), but had no effect on postprandial insulin secretion, C-peptide, or total GIP AUC. Intact GLP-1 AUC was also elevated to almost twice that of the control with no decrease in DPP-4 AUC, indicating that the increase in intact GLP-1 was due to enhanced GLP-1 secretion and not inhibition of DPP-4 degradation. Dr. Kuwata also stated that metformin improved beta cell function, presumably drawing these conclusions from measures of C-peptide (though this was not explicitly stated or written on the slide), and that the improved beta cell function correlated with enhancement of GLP-1 secretion. Therefore, he concluded that metformin’s selective enhancement of GLP-1 secretion improved beta cell function, though we believe this may be an overstatement given that a correlation cannot prove causation. Furthermore, the improvement in beta cell function was not accompanied by an improvement in postprandial insulin secretion, so the GLP-1 increase may be clinically irrelevant. We would have liked to see measurements taken of other downstream indicators of GLP-1 action (e.g., glucagon secretion).

Symposium: GLP-1 Beyond the Pancreas

GLP-1 AND CARDIOVASCULAR DISEASE

Mansoor Husain, MD (University of Toronto, Toronto, Canada)

In his fast-paced presentation, Dr. Mansoor Husain opened with a review of type 2 diabetes and cardiovascular (CV) disease before discussing the CV effects of GLP-1, DPP-4 inhibitors, and GLP-1 agonists in both animal and humans before ending with a brief overview of meta-analyses and CV outcome trials. He noted that animal models indicate that GLP-1 receptors are expressed in cardiac and vascular tissue. Furthermore, GLP-1 agonists have exerted cardiovascular and vasodilatory effects in isolated tissue, suggesting that their CV effects can occur independent of the central nervous system and of insulin. Both the absence or inhibition of DPP-4 improved survival in animal models of myocardial infarction. Dr. Husain then discussed several human studies and noted that GLP-1 agonists have been shown to improve blood pressure, endothelial function, and infarct size. While early results from human studies and meta-analyses appear positive, data from cardiovascular outcome studies are needed to confirm the effects of GLP-1 agonist therapy on cardiovascular disease.

  • Dr. Husain began his talk by showing data from 400 patients in UKPDS, which illustrated that higher A1c levels predict cardiovascular disease (Stratton et al., BMJ 2000). Dr. Husain noted that type 2 diabetes coexists with several risk factors of CVD (such as obesity and hypertension), and that hyperglycemia represents a robust biomarker for CVD. However, previous studies have found it difficult to demonstrate that lowering A1c using anti- diabetic therapies provides a reduction in macrovascular outcomes.
  • Dr. Husain then discussed the cardiovascular (CV) effects of GLP-1 in animal models. He first reminded the audience since only 10% of secreted GLP-1 reaches systemic circulation, researchers have begun to question whether and how GLP-1 can work at very low concentrations. Dr. Husain then reviewed prior studies, which demonstrated that GLP-1 receptors are present in cardiac and vascular tissue, and that GLP-1 and its metabolites protect the heart from ischemia reperfusion injury and increase coronary flow. He highlighted that studies in animals without a functional GLP-1 receptor have indicated that GLP-1’s CV effects are not  entirely dependent on the receptor.
  • Dr. Husain then turned to the CV effects of DPP-4 inhibition in experimental models. He first noted that a genetic mouse model lacking DPP-4 exhibited improved outcomes after experimental myocardial infarction (MI) compared to wild type mice (Sauve et al., Diabetes 2010). Previous studies have also shown that in mouse models of diabetes, the pharmacological inhibition of DPP-4 increases survival over untreated controls following MI.
  • Moving on to GLP-1 agonist therapy, Dr. Husain showed data illustrating a potential positive cardiovascular effect. In a mouse model of MI, pre-treatment with liraglutide reduced cardiac rupture, decreased infarct size, and increased survival through mechanisms independent of weight loss, but apparently dependent on the GLP-1 receptor. Before turning to human studies, Dr. Husain presented unpublished data from his lab showing that GLP-1 agonism appears to provide cardioprotection in a high-fat diet model of obesity and cardiomyopathy, potentially through several pathways.
  • Dr. Husain then reviewed several human studies to illustrate general effects of incretin therapy on cardiovascular-related outcomes. In addition to promoting weight loss, GLP-1 agonists have been shown to improve blood pressure, endothelial function, and lipids. Dr. Husain highlighted that GLP-1 agonists cause a potentially negative impact on heart rate, though he noted that the clinical significance of this effect is currently unclear: while an increase  in heart rate of roughly ten beats per minute has been correlated with cardiovascular morbidity, GLP-1 agonists such as liraglutide only produce an increase of two to three beats per minute. Dr. Husain stated that at the moment, physicians have not observed a rise in cardiovascular outcomes due to this increase in heart rate. On the contrary, studies have shown that exenatide reduces infarct size in patients with acute myocardial infarction (Lonborg et al., Eur Heart J 2011), and that GLP-1 agonists provide beneficial effects on max VO2, heart failure, and quality of life scores  in patients with heart failure, though the study cohort was small (Sokos et al., J Cardiac Fail 2006).
  • Dr. Husain ended his talk with a brief overview of some meta-analyses. One such analysis included 40 studies of DPP-4 inhibitors and found a 31% reduction in certain hard cardiovascular endpoints. Another meta-analysis of roughly 6,500 people on GLP-1 agonist therapy found a 50% reduction in major adverse cardiovascular events cardiovascular outcomes relative to placebo (Monami et al., Ex Diabetes Res 2011).

GLP-1 AND THE CENTRAL NERVOUS SYSTEM

Darleen Sandoval, PhD (University of Cincinnati, Cincinnati, OH)

Dr. Darleen Sandoval reviewed her preclinical findings on GLP-1’s role in regulating long-term energy balance in rodent models. She found that: 1) GLP-1 in the central nervous system (CNS) is necessary for regulating adiposity; 2) while peripheral GLP-1 (the GLP-1 produced in the intestine) acts as a neurotransmitter to control glucose homeostasis, it does not act in this way to regulate energy balance/total body weight; and 3) the GLP-1 receptor is not necessary for the full weight loss and insulin-sensitizing effects of vertical sleeve gastrectomy in rats. If preclinical findings about mechanism of GLP-1 action prove to be true in humans, perhaps an analog that produces less nausea or more weight loss could be developed.

  • GLP-1, aside from its well-known production in L cells and action on the pancreas, is also made in the brain and acts on receptors in the brain. It is produced in the brainstem and has receptors in the brainstem, hypothalamus, and amygdala. Using mouse models, Dr. Sandoval explored whether GLP-1 in the central nervous system (CNS) impacts long- term energy balance. This question was based on past research that had found a correlation between hindbrain pre-proglucagon (PPG; the precursor peptide to GLP-1) expression and fat mass.
  • Dr. Sandoval found that the GLP-1 receptor in the CNS was necessary for regulating adiposity. When Dr. Sandoval’s team selectively administered exendin-9 (a GLP-1 receptor antagonist) in the cerebral ventricle of mice, mice fed on a regular or high fat diet both gained roughly 2% more body weight after five weeks compared to those administered a saline control. Furthermore, selectively knocking out the GLP-1 receptor in the brain and feeding mice a high fat diet for three to four weeks resulted in mice with higher adiposity than wild type mice (~28% vs. ~20% adiposity).
  • She then examined whether there was an interaction between brain and peripheral GLP-1 in regulating energy balance. She stated that it was unlikely that intestinal GLP-1 acts as a hormone on the brain because it is cleared from circulation so quickly by DPP-4 and the liver. But GLP-1 receptors are found on neurons in the portal vein, suggesting GLP-1 might act as a neurotransmitter after being secreted from intestinal L cells. Studies suggested that GLP-1 receptor activity in the portal vein was responsible for regulating glucose homeostasis, but not  food intake. She then hypothesized that intestinal GLP-1 receptors act to stimulate neurons in the intestine as a means of interaction between the intestinal and central nervous systems. In mice that only expressed PPG (the GLP-1 precursor) in the intestine (and not the brain), no reduction  in body weight was observed compared to the whole body PPG knockout, suggesting that  intestinal activity of GLP-1 was not sufficient for regulating body weight.
  • Finally she examined the impact of GLP-1 on bariatric surgery, demonstrating that  in a rat model, the GLP-1 receptor was not necessary for full effects of vertical sleeve gastrectomy. Percent change in body mass after surgery was the same in GLP-1 whole body knockout mice and wild-type mice. Additionally, post-meal insulin response was the same in both wild-type and knockout mice.

GLP-1 AND METABOLIC LIVER DISEASE

Philip Newsome, PhD (University of Birmingham, Birmingham, UK)

In his presentation, Dr. Philip Newsome gave a valuable overview of the prevalence and pathology of non-alcoholic fatty liver disease (NAFLD), as well as a review of preclinical and clinical evidence supporting the use of GLP-1 agonists as a potential therapy. NAFLD is present in roughly 30% of  western populations and is strongly associated with excess weight– 80-90% of people who are morbidly obese suffer from the disease. NAFLD is an independent risk factor for cardiovascular disease, and it is  of particular concern for people with type 2 diabetes, as nearly 9% of patients die from liver disease. After briefly reviewing the pathology of NAFLD, including the “three-hit hypothesis”, Dr. Newsome discussed preclinical data showing that GLP-1 agonists can reduce hepatic lipogenesis, potentially through multiple mechanisms, some independent of the GLP-1 receptor. In addition, results from the LEAD trial of liraglutide (studying liraglutide for weight loss) indicate that the GLP-1 agonist lowers  ALT (alanine aminotransferase; a marker of liver damage) in patients, without increasing the risk of side effects. Looking forward, Dr. Newsome hoped that additional data from ongoing and future clinical trials will clarify the therapeutic potential of GLP-1 agonists in treating NAFLD.

  • Dr. Newsome began his presentation by discussing the prevalence of non-alcoholic fatty liver disease (NAFLD). He noted that FLD is often asymptomatic, with patients having only trivially abnormal liver function tests. However, obesity is a significant driver of the disease; as childhood obesity increases, the growing prevalence of NAFLD in youth and young adults has become a topic of increasing concern. Dr. Newsome reminded the audience that NAFLD is a common disease that affects roughly 30% of western populations along with 80-90% of people who are morbidly obese. He cited a study from Hong Kong that found that over a quarter of the population (27%) has NAFLD (Wong et al., GUT 2011) and noted that 10-15% of the US population has the disease.
  • NAFLD is a predominant cause of negative cardiovascular outcomes, and FLD is an independent risk factor for cardiovascular disease. Because the risk of death increases drastically as the disease progresses, Dr. Newsome recommended that patients with early-stage NAFLD (such as simple steatosis) focus on preventing CV events while those with advanced NAFLD focus on maintaining liver health. NAFLD is a significant concern for people with type 2 diabetes, as nearly 9% of patients die from liver disease; males have a higher risk than females.
  • Dr. Newsome briefly reviewed the pathology of NAFLD, noting that rather than being harmful, the conversion of free fatty acids to triglycerides inside the liver may represent a protective response, while the accumulation of unconverted free fatty acids could be an important driver of the disease (Yamaguchi et al, Hepatol 2007). Previous studies indicate that free fatty acids act in multiple pathways that can mediate liver damage (Parekh et al., Gastroenterology 2007) and that require further study. Dr. Newsome then succinctly described the “three-hit hypothesis,” which posits that NAFLD results from three sequential events: 1) fat accumulation (steatosis), which makes the liver more susceptible to damage; 2) enhanced lipid peroxidation, which accelerates the generation of reactive oxygen species; and 3) inadequate hepatocyte regeneration (Dowman et al., QJM 2010)
  • Dr. Newsome highlighted the lack of effective treatments and believes that GLP-1 agonist therapy may be a favorable option for obese people with an elevated A1c (>7.5%). GLP-1 analogs have been shown to reduce hepatic lipogenesis in preclinical models of NAFLD (notwithstanding the limitations of such models). The mechanism responsible for GLP-1 agonists’ effects is not clear – the beneficial outcomes may result from GLP-1-mediated weight loss, improved insulin sensitivity, or through other pathways. Previous studies show that human hepatocytes express the GLP-1 receptor, suggesting that GLP-1 may act directly on hepatocytes (Gupta et al., Hepatology 2010). Stimulation of GLP-1 appears to activate the insulin-signaling cascade though, as Dr. Newsome noted, GLP-1 agonists may have other effects independent of the GLP-1 receptor. Additional studies show that GLP-1 agonists modulate hepatic lipogenesis by suppressing the expression of lipogenic enzymes and transcription factors in primary hepatocyte cultures, suggesting that GLP-1 has beneficial effects independent of insulin signaling (Ben- Shlomo et al., JHep 2012). Data also suggest that GLP-1 may have anti-inflammatory properties.
  • Dr. Newsome then turned to clinical data, noting that GLP-1 analogs have shown promise and safety in patient cohorts with NAFLD. While a meta-analysis of GLP-1 agonists found no clear effect of the drugs on liver enzyme activity (Vilsboll et al., BMJ 2012),  data from the LEAD trials of liraglutide (which study liraglutide for weight loss) showed a significant reduction in alanine aminotransferase (ALT) with liraglutide. Dr. Newsome also noted that liraglutide treatment led to no increase in side effects in people with abnormal liver function tests, a result he found reassuring. Currently, assessments of NAFLD and NASH (nonalcoholic steatohepatitis, an extreme form of NAFLD) in clinical trials are performed via liver biopsies, though Dr. Newsome is hopeful that non-invasive procedures are imminent.

44th Claude Bernard Lecture

UNDERSTANDING INCRETIN HORMONE ACTION AND THE TREATMENT OF DIABETES

Daniel Drucker, MD (University of Toronto, Toronto, Canada)

The 44th Claude Bernard lecture, given by the inimitable Dr. Daniel Drucker, marked the end of a fantastic EASD 2012. Dr. Drucker comprehensively explored the roles of various proglucagon-derived peptides (including glucagon and GLP-1) based on his work in rodent models. He began by highlighting how wide-ranging the physiological effects of GLP-1 are. He then discussed his findings about, and potential clinical implications for, three peptides released from the cleavage of proglucagon: glucagon, GLP-1, and GLP-2. Glucagon antagonism has demonstrated robust glucose lowering capabilities and islet-enhancing effects in mice, but Dr. Drucker has also found that glucose plays important roles in  liver cell survival and liver lipid homeostasis. Therefore, any glucagon inhibiting effects must balance these positive and negative effects. He then discussed cardioprotective benefits of GLP-1 seen in mice studies and argued that we need more careful analysis to identify its mechanism of action. Finally, Dr. Drucker shared evidence of GLP-2’s role in controlling nutrient absorption and intestinal defense mechanisms. He ended his talk with a tribute to Claude Bernard and a moving dedication of the lecture to his parents.

  • The successful attenuation of glucagon to treat type 2 diabetes depends on understanding how to find the right balance when manipulating this system. While the importance of glucagon in glucose homeostasis is widely known, Dr. Drucker has also found an essential role of glucagon in cell survival and lipid homeostasis in the mouse liver. Additionally, he has found that glucagon receptor signaling in the mouse liver attenuates pancreatic alpha cell proliferation; glucagon receptor knockout mice exhibit increased alpha cell proliferation and beta cell function. He proposed that if human alpha cell proliferation is similarly repressed in response to hepatic glucagon signaling, that one might use this principle to generate   a treatment for type 1 diabetes by using a glucagon receptor antagonist to promote alpha cell proliferation and then differentiate those extra alpha cells into beta cells. But since glucagon is necessary for hepatocyte survival and hepatic lipid homeostasis, one must be certain to balance  the glucose-lowering and islet-enhancing effects against potential liver harm when determining  the desired level of glucagon inhibition. Indeed, Dr. Drucker cited the glucagon receptor  antagonist MK-0893 as an example – in human trials it produced robust glucose lowering effects but increased levels of hepatic transaminases and lipids (it was subsequently dropped from development).
    • As a side note, Dr. Drucker’s proposed type 1 diabetes therapy detailed above seems like a very creative approach to us, but still of course very early stage at this point – glucagon receptor antagonists are currently in clinical development, but as we understand it, differentiation of alpha cells into beta cells would likely first necessitate de-differentiation into a precursor cell before it could be turned into a beta cell. With the complexity of both dedifferentiation and differentiation, we imagine meticulous coordination would be required.
  • Dr. Drucker then turned his attention to the hot topic of potential cardioprotective effects of GLP-1; he argued that we need more careful analysis to identify the mechanism by which GLP-1 produces such robust cardioprotection in mice (indeed this may help us understand if we should expect to see cardioprotection in humans). We know   that activating the GLP-1 receptor (GLP-1r) increases survival in murine myocardial infarction, improves cardiovascular output, reduces accumulation and migration of macrophages in blood vessels, and has vasodilatory effects. Dr. Drucker stated that we don’t yet understand the relative contributions of direct vs. indirect actions of GLP-1 on the heart and blood vessels, but know there are contributions from both. Some have attributed GLP-1’s cardiovascular effects to a direct mechanism of action on the heart because they have detected GLP-1r on cardiomyocytes.  However, Dr. Drucker challenged this notion, noting that his lab has only found the receptor on arterial cardiomyocytes, and not in ventricular cardiomyocytes, and that other labs have used antibodies that give false positive readings in detecting GLP-1r.
    • Dr. Drucker then analyzed the mechanisms behind GLP-1 secretion from L cells, demonstrating that progesterone activates GLP-1 secretion even without having to enter the cell. This could have exciting therapeutic implications if we could stimulate GLP-1 secretion from the gut lumen without having a drug enter systemic  circulation.
  • Finally, Dr. Drucker shared evidence of GLP-2’s role in controlling nutrient absorption and intestinal defense mechanisms. GLP-2 enhances intestinal blood flow, enhancing the absorption of nutrients. GLP-2 also regulates the mucosal inflammatory response in the intestine and bacterial populations. GLP-2 is being investigated in clinical trials for short bowel syndrome.

Corporate Symposium: Diabetes Care Today: Individualizing Treatment Options (Lilly Diabetes)

WHEN TO COMBINE INSULIN WITH GLP-1 (INCRETIN-BASED THERAPIES)

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

Dr. Tina Vilsboll argued in favor of combining GLP-1 therapy with insulin. She reviewed their complementary effects: when used together, they produce an additive A1c reduction; GLP-1 offsets the weight gain associated with insulin; GLP-1 can reduce insulin dose; and GLP-1 can reduce  hypoglycemia associated with insulin use. Dr. Vilsboll also believes that GLP-1 agonists’ glucagon- suppressing effects are often under-emphasized. She stated that at least 50% of the benefit derived from GLP-1 agonist therapy is due to improved alpha cell function resulting in a reduction of glucagon secretion, as well as hepatic glucose production. She stated that patients with type 2 diabetes experience fasting hyperglucagonemia and inappropriate glucagon responses resulting in a doubling of post- prandial glucagon secretion compared to healthy people. The glucagon-suppressing effects of GLP-1 agonists stop when patients become hypoglycemic – the glycemic-dependent nature of GLP-1 is, of course, one of its biggest advantages..

  • Dr. Vilsboll highlighted the often under-emphasized effects of GLP-1 agonists on glucagon secretion, stating, “Glucagon is the neglected hormone” of type 2 diabetes. She noted that patients with type 2 diabetes have both fasting hyperglucagonemia and a doubling of the post-prandial glucagon response. GLP-1 suppresses glucagon secretion and most importantly, will not increase patients’ risk of hypoglycemia since the glucagon suppression stops once normoglycemia is reached. DPP-4 inhibitors, she said, also exhibit a glucagon effect.
  • Adding GLP-1 to existing insulin therapy or adding insulin therapy to existing GLP-1 therapy are both effective options. Dr. Vilsboll cited a Novo Nordisk trial which found that adding liraglutide to basal insulin plus metformin resulted in additional A1c reduction, no  increase in hypoglycemia, and only 1 kg (2.2 lbs) of weight gain after one year. Another trial demonstrated that adding exenatide to insulin glargine increased the number of patients meeting treatment targets (from 35% to 60%), produced a 3 kg (6.6 lbs) placebo-adjusted weight loss, did not increase the risk of hypoglycemia, and was insulin sparing. Dr. Vilsboll argued that data from clinical trials support the physiological and pharmacological rationale for combining GLP-1 and insulin therapy due to their complementary modes of action. While insulin is an effective and inevitably necessary treatment in most cases of type 2 diabetes, its efficacy is offset by weight gain (up to 4 kg [8.8 lbs] of weight gain, according to Dr. Vilsboll), and risk of hypoglycemia, which GLP-1 helps to mediate. Dr. Vilsboll also added that, in general, she favors earlier use of combination treatment, stating, “Why should we wait for one treatment to fail before moving on  to another?”

PANEL DISCUSSION

Peter Diem, MD (University of Bern, Bern, Switzerland); Rury Holman, MD (University of Oxford, Oxford, United Kingdom); Tina Vilsboll, MD (University of Copenhagen, Copenhagen, Denmark)

Q: What are determinants of metformin failure?

Dr. Diem: There are certainly patients for whom metformin doesn’t work. I think often times metformin failure may be that patients do not like the GI side effects and just don’t use it. It’s difficult to define.

Q: What is the place of long-acting GLP-1 agonists?

Dr. Vilsboll: There are a lot of trials that have evaluated different GLP-1 analogs. One head to head comparison trial was LEAD-6 (which compared exenatide twice daily with liraglutide), and in that trial, liraglutide was more efficacious in A1c lowering. Recently the DURATION-6 trial compared liraglutide to exenatide once-weekly. There, to my surprise, the results favored liraglutide. One could say they did not use enough exenatide once-weekly in that trial. From DURATION-1, exenatide once-weekly had beautiful results. From head to head trials, it seems like once-daily is at least as good and maybe a bit better. But  the GLP-1 agonists are a bit different: exenatide has a human backbone and a bit of immunogenicity.

Q: Peter, do sulfonylureas [SFUs] harm beta cells? Should this be taken into account and may it affect success from future therapies?

Dr. Diem: The ADOPT trial clearly shows a rise in A1c following the initial drop with SFUs. Whether the beta cells are really harmed irreversibly, I’m not really sure. If you look at HOMA analysis in UKPDS patients on SFU, it was even higher. Currently we do not have a good way to assess beta cell function once patients are treated with different options. Most analyses I’ve seen are speculations of true function of  beta cells in theses situations.

Dr. Holman: A recent study in Diabetes Care from someone working on a triple therapy in oral agents found that there are no differences. It’s interesting [Editor’s note: we believe he is referring to Dr. Ralph DeFronzo’s long-awaited triple therapy data, which will appear first in journal format in several months, according to Dr. DeFronzo].

Dr. Vilsboll: In mouse islets, if you add SFU in vitro you actually increase islet cell apoptosis, but if you add GLP-1 to human islets in vitro you see a decrease in apoptosis.

Dr. Holman: If I were treating mice, then that would be compelling.

Q: Glucotoxicity improves with any glucose lowering agent, not just GLP-1.

Dr. Vilsboll: Point taken.

Q: What about use of metformin in pregnancy?

Dr. Diem: We don’t use it. We use insulin during pregnancy.

Dr. Vilsboll: But you use it until they become pregnant – it’s not that it’s really dangerous because you use it in women with PCOS and then you stop it when they become pregnant.

Dr. Holman: Though reasonable data exists showing that it’s safe in pregnancy now.

Q: Can you speak to the use of metformin post-liver transplant?

Dr. Diem: I’d look at the reason for the liver transplant. Depending on the reason for liver deterioration, I might not use it at all. I’m not aware of any data that you need to use stricter criteria for kidney function post-liver transplant. As long as liver function is okay, we should use it. In general, I would tend to use lower doses. I very rarely use more than two grams per day.

Dr. Holman: I think we need to use it cautiously, and the guidelines now allow for an eGFR down to 30 with no evidence of increased lactic acidosis.

Q: Does GLP-1 have action on extra-pancreatic glucagon?

Dr. Vilsboll: There are quite a few things we don’t know about glucagon. The intestine might actually secrete some glucagon. Right now we’re conducting a study with biopsies of the GI tract of type 2 diabetes and healthy subjects to see if L cells actually secrete intestinal glucagon. So that’s a hot and interesting topic I’m not capable of addressing right now.

Q: Some people on metformin and DPP-4 inhibitors get hypoglycemia – why does this still happen when both have a low risk of hypoglycemia?

Dr. Diem: The risk is not zero. Perhaps it is also related to the fact that counter regulation in type 2 is not normal.

Dr. Vilsboll: Even placebo can induce hypoglycemia, and it depends on how hypoglycemia is defined. Additionally, other things like alcohol may be involved. But in general, GLP-1 works in a strictly glucose dependent manner and doesn’t push patients into hypoglycemia.

[Note: additional talks from this corporate symposium can be found in the “Insulin and Insulin Therapies” section of this report]

Corporate Symposium: A Comprehensive Therapeutic Approach to Diabetes Management (Sponsored by Sanofi)

ARE ALL GLP-1 AGONISTS THE SAME?

Michaela Diamant, MD, PhD (VU Medical Center, Amsterdam, The Netherlands)

Highlighting the differences between short- and long-acting agents, Dr. Diamant compared available and late-stage-investigational GLP-1 receptor agonists with regard to pharmacologic qualities and results of head-to-head trials. Long-acting GLP-1 receptor agonists (liraglutide, exenatide QW, albiglutide QW) have a more potent effect on fasting glucose, but short-acting agonists (exenatide BID, lixisenatide) more dramatically blunt post-meal spikes of glucose and glucagon. The greater postprandial effects of short-acting agents may reflect greater delay of gastric emptying: an effect that seems to be mediated by the vagus nerve (Veedfald et al., EASD 2012). With continuous stimulation of GLP-1, gastric emptying seems to re-acclimate and come back toward normal (Nauck et al., Diabetes 2011). Short-acting agents, by stimulating GLP-1 only intermittently, could lead to delayed gastric emptying that is more sustainable (though short-acting agents also lead to nausea that is more persistent than with long-acting agents). As for body-weight effects, Dr. Diamant suggested that these depend in part on the agonist’s ability to cross the blood-brain barrier. This hypothesis would explain why albiglutide QW (which is large due to binding with albumin) caused less weight loss than liraglutide in the Harmony 7 trial (Pratley et al., ADA 2012).

NEW EVIDENCE FOR LIXISENATIDE IN COMBINATION WITH BASAL INSULIN/LANTUS

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

After explaining the rationale for using GLP-1 agonists in combination with basal insulin, Dr.  Rosenstock reviewed results from several clinical trials of said combination therapy, focusing on the use of lixisenatide with insulin glargine. He noted that earlier trials demonstrated that GLP-1 agonists could further enhance glycemic control when added on to basal insulin therapy, and vice versa – exenatide improved glycemic control and weight when added to insulin glargine (Buse et al., AIM 2011), and insulin detemir improved glycemic control (without weight gain) when added to liraglutide (Rosenstock et al., Diabetes 2011). Dr. Rosenstock reviewed the results of the GetGoal-L and GetGoal-L-Asia trials, emphasizing that lixisenatide provided robust reductions in two-hour postprandial glucose levels  (earlier in his presentation he pointed out that lixisenatide has a stronger postprandial effect than liraglutide), and conferred incremental A1c reductions in combination with insulin glargine. Finally, he noted that it could be possible to combine longer-acting GLP-1 agonists with basal insulin as well – one recent trial compared once-weekly albiglutide versus three-times-daily insulin lispro as add-ons to insulin glargine (Rosenstock et al., Diabetes 2012). Dr. Rosenstock hoped that people would not waste energy debating whether a GLP-1 agonist or basal insulin should be initiated first; regardless of which is started first, eventually both will be needed. During the following panel discussion, he stated that as a rule of thumb, those with A1c above 8.5% should start on basal insulin, and those with A1c in the 7-8% range should start on a GLP-1 agonist first.

ROUND TABLE: BASAL INSULIN AND GLP-1 – A CONVINCING COUPLE?

William Cefalu, MD (Louisiana State University School of Medicine, Baton Rouge, LA), Michaela Diamant, MD, PhD (Diabetes Center, VU University Medical Center, Amsterdam, The Netherlands), Julio Rosenstock, MD (Dallas Diabetes and Endocrine Center, Dallas, TX)

Dr. Cefalu: In your clinical practice, do you use basal insulin in combination with GLP-1 agonists?

Audience: 57% yes; 43% no.

Dr. Cefalu: What would be the preferred order of combination therapy for a patient with an A1c less than 8%?

Audience: 35% basal insulin followed by a GLP-1 agonist; 53% a GLP-1 agonist followed by basal insulin; 12% immediate combination therapy.

Dr. Cefalu: What would be the preferred order of combination therapy for a patient with an A1c greater than 8%?

Audience: 59% basal insulin followed by a GLP-1 agonist; 25% a GLP-1 agonist followed by basal insulin; 16% immediate combination therapy.

Dr. Rosenstock: I agree with this. Whatever you choose is fine. Two things are very critical. We know that insulin works for almost everyone. GLP-1 does not work for everyone – it’s not that effective for 25-30% of patients, and 25-40% of patients don’t tolerate them. Also, GLP-1 agonists are more expensive than  insulin. But, if you want to base it on A1c, I think that if someone is above 8.5%, basal insulin is the way to go. For an A1c between 7-8%, GLP-1 can do very well. For an A1c of 8.0-8.5%, do whatever you want.

Dr. Diamant: At this point, more patients are being started on basal insulin, so the studies you presented with add-on of GLP-1 receptor agonist reflect a practice that will be more common.

Dr. Rosenstock: Plus, as Dr. Gerstein said, we’ve been using insulin for 90 years. We know what to expect. We don’t know what will happen after 10-15 years of GLP-1 receptor agonist use.

Dr. Cefalu: With regard to the mechanism of postprandial control, you discussed effects of time course. Can you comment on the differences in short- and long-acting GLP-1 receptor agonists?

Dr. Diamant: In an infusion study, researchers looked at the effects on gastric emptying, insulin secretion, glucagon secretion, and peripheral glucose disposal. They made some estimates of relative contribution and calculated that gastric emptying was responsible for about 50% and glucagon for another 30%. If you slow down gastric emptying in a way that doesn’t vein off over time, that effects postprandial glucose. This would be for the short-acting GLP-1 receptor agonists: both exenatide BID and lixisenatide.

Dr. Cefalu: You’ve shown a lot on A1c response to GLP-1 receptor agonists. Could you sum up who will respond best and discuss in which situations you would initialize patients to combination therapy with insulin and GLP-1 receptor agonist?

Dr. Diamant: I think that predicting responders is the million-dollar question. The data vary. Some suggest that if you start earlier in the course of disease you have more response, but how do you assess response: A1c response at three months? A combination of body weight and A1c change at three months? Some of my patients have been on two shots of exenatide for eight years, but I don’t know if from this we can get data on what predicts response.

Dr. Rosenstock: In our 12-week study we got a sense of what determines response. In randomized controlled trials we give drug the drug to everyone and then in a randomized comparison to a control group. Maybe the way to go in the future is to try, as we do in clinical practice, choosing cutoffs for continuation. In clinic it’s “the-n-of-one trial” you try it in a patient for 12-24 weeks and assess the response based on some predetermined criteria. If there is a response, continue; if not, don’t continue it. Likewise in the UK, liraglutide has to show a reduction of 1.5% in A1c and 3% body weight over six months. If the patient gets a response the health system pays for liraglutide use; if not, they don’t.

Dr. Cefalu: Would GLP-1 receptor agonists be more effective following basal insulin optimization, once you’ve broken glucotoxicity?

Dr. Diamant: It makes sense, I think. I think most clinicians would like to optimize insulin first and then afterward see what can be done, for instance, to lower postprandial hyperglycemia.

Dr. Rosenstock: Everything works better after you optimize insulin; for example, insulin sensitivity is improved. Indeed, sometimes you hear about GLP-1 deficiency, but it is just dysfunction. Once you optimize insulin you improve native GLP-1 secretion.

Dr. Cefalu: For a patient with an A1c of 9.5%, do you think there is any benefit of starting GLP-1 and insulin therapy at the same time?

Dr. Diamant: We don’t have data on this. It’s definitely an interesting issue, because you could say, well, we are advocating to start combination therapy in these patients because they have such poor control. It needs to be studied.

Dr. Rosenstock: It is an exciting area. I myself am not fond of premix insulin. I know it causes more hypoglycemia and weight gain and so on. But a coformulation of basal insulin plus a GLP-1 could be a very exciting area. As we speak, there are trials ongoing, with degludec and liraglutide, and glargine in combination with lixisenatide.

Dr. Cefalu: Where do we go from here? What do you want to see?

Dr. Rosenstock: I think we need to move further and intervene much earlier. We need better and more consistent organization in studies, especially with regard to insulin optimization. I think that patients should self-titrate, up by one-to-two units per week. We need long-term studies to show durability of effect. We should design long-term studies to find the responders. Not all therapies are good for everyone.

Dr. Diamant: I agree. Head-to-head studies with basal-bolus vs. basal-GLP-1 receptor agonists would be valuable, provided they are designed well with regard to titration and of sufficiently long duration to convince reimbursement authorities. I think they should be two-to-three years long, with combined endpoints and low rates of hypoglycemia, to show cost-effectiveness. I think the design of studies is still a major issue.

[Note: additional talks from this corporate symposium can be found in the “Insulin and Insulin Therapies” and “Type 1 Diabetes Therapies” sections of this report]

Corporate Symposium: Delivering Innovation in Type 2 Diabetes – Tailored Approaches with SGLT-2 and Incretin-Based Therapies (Sponsored by BMS/AZ)

WHAT CAN WE LEARN FROM RETROSPECTIVE CARDIOVASCULAR OUTCOME STUDIES?

Edoardo Mannucci, MD (Careggi Teaching Hospital, Florence, Italy)

Dr. Edoardo Mannucci began the second session of the symposium, which was focused on  cardiovascular risk and incretins. When the audience was asked, “How much do you think the improvement of glucose control reduces CV risk?” A) no effect; B) marginal decrease in risk; and C) significant decrease in risk. A slight majority of the audience (56%) voted that improving glucose control significantly reduces CV risk, while 37% voted that it marginally decreases risk. Dr. Mannucci said this split voting pattern is not surprising and representative of the literature, which overall seems to point to a moderate improvement (about a 10% drop in major adverse cardiac events [MACE] with a 1% drop in A1c) in cardiovascular risk with better glucose control, but that there have been mixed results  (sometimes even within the same trial). While reviewing the impact different therapies have on cardiovascular risk Dr. Mannucci noted that in the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) trial (n=4,447) found that there were no significant differences between rosiglitazone and sulfonylureas (SFUs) for MACE or cardiovascular mortality. He rosiglitazone was removed from the market because it increased cardiovascular risk, causing us to question why sulfonylureas have not faced the same fate. On the positive side, he reported that DPP-4 inhibitors reduced MACE by about 30% and all cause mortality by 40% in phase 3 trials.

INTRODUCING SAVOR, A PROSPECTIVE CARDIOVASCULAR OUTCOMES STUDY

Petra-Maria Schumm-Draeger, MD, PhD (Clinic Munich Bogenhausen, Munich, Germany)

Dr. Petra-Maria Schumm-Draeger detailed the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombosis in Myocardial Infarction (SAVOR-TIMI) 53 study being carried out by Bristol Myers Squibb and Astra Zeneca. The multicenter (523 sites), randomized, double- blind, placebo controlled, multinational (25 countries), phase 4 trial is comparing cardiovascular risk and outcomes of saxagliptin vs. a placebo, and has a primary endpoint that is a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. The study has completed enrollment (n≈16,500) of people with type 2 diabetes (A1c between 6.5-12.0%) who either have established cardiovascular disease or cardiovascular risk factors, and will run for about five years. Results are expected for mid 2014, which will make this one of the first CV outcomes studies to report. (Canagliflozin’s CANVAS trial will end in April 2013, and lixisenatide’s ELIXA trial in May 2014).

PANEL DISCUSSION

Kamlesh Khunti, MD, PhD (University of Leicester, Leicester, United Kingdom); Paola Fioretto, MD, PhD (University of Padova, Padova, Italy); Samy Hadjadj, MD, PhD (Poitiers University Hospital, Poitiers, France); Andreas Pfeiffer, MD (Charité University Hospital, Berlin, Germany); Edoardo Mannucci, MD (Careggi Teaching Hospital, Florence, Italy); Laurie Baggio, PhD (Samuel Lunenfeld Research Institute, Toronto, Canada); Petra-Maria Schumm-Draeger, MD, PhD (Clinic Munich Bogenhausen, Munich, Germany); Jiten Vora, MD (Royal Liverpool University Hospital, Liverpool, United Kingdom)

Q: If there is a 40% reduction in all-cause mortality for people on DPP-4 inhibitors, shouldn’t we stop ongoing studies comparing DPP-4 inhibitors to placebo?

Dr. Mannucci: The data I presented was showing reduced mortality in the first year; we don’t know what happens after fiver or ten years. So we need a longer study to determine that.

Q: For the SAVOR-TIMI 53 study, do you think having an A1c range from 6.5% to 12% is too large and could result in bias?

Dr. Schumm-Draeger: It is true that this is a large range. I think we have to include this whole spectrum in order to get a full answer on cardiovascular risk. It is a large study so that it will be representative for well and not well patients.

Dr. Mannucci: If this trial had a metabolic endpoint then this range would have been too wide, but what we are looking at here is cardiovascular outcomes. It is correct to have a range as wide a range as possible to have it be applicable to as big a population as possible.

Dr. Khunti: We can’t just go for tight A1c targets for everyone, and this study will give us more information on what patients – and A1cs – should be taking a DPP-4 inhibitor.

Dr. Vora: Looking into the future do you think we will see differences between DPP-4 inhibitors and GLP-1 agonists in terms of cardiovascular risk?

Dr. Baggio: That is a very good question. Based on the preclinical data and the ongoing clinical trials I think there will be differences. One thing that sticks out in my mind is that with some of the GLP-1 agonists there were reports of small increases in heart rate, but to my knowledge DPP-4 inhibitors have not been associated with any increase in heart rate. So I do think we will see some difference. Also GLP-1 agonists works through the GLP-1 receptor but the DPP-4 inhibitors have a number of potential substrates. The problem is they are hard to measure in vivo. It is not clear if they will be physiologically relevant, we just have to wait for the studies.

Q: What do you think of using dapagliflozin in type 1 diabetes patients who may become pregnant?

Dr. Fioretto: I think that dapagliflozin can be used in type 1 patients, particularly patients who are overweight. We have emphasized that the mechanism of action is totally insulin independent. As far as pregnancy is concerned, I do not know the data on that so I cannot address that question.

Q: Could you please elaborate on the clinical importance of the 2-3 kg [4.4-6.6 lbs.] weight loss? If you are continuously losing glucose in your urine why do you not continue to lose weight?

Dr. Hadjadj: Even if losing two to three kg does not do a lot in terms of medical practice it does do a lot in terms of the relationship you have with your patient. Any type 2 diabetes patient is involved in some body weight control program. If we can move their weight in the right direction and give them that motivation then that is probably more important than any clinical benefit.

Dr. Fioretto: I think that losing several kilos is hugely important for motivation. Getting sustained weight loss like this is not easy in people with type 2 diabetes.

Dr. Vora: Do you know the epidemiological benefits of 3 kg [6.6 lbs.] of weight loss?

Dr. Mannucci: Losing 5% of your body weight produces clinically relevant improvements in glycemic control and many other factors. The difference between the weight loss on dapagliflozin and the weight gain on an SFU is five kg and that is more than 5% of the body weight of most of our patients.

Dr. Pfeiffer: Why do they not continue to lose weight? Is it because they eat more? It needs more studying.

Dr. Fioretto: There is not a clear answer to that. I think that the glucosuria is not the only reason for the weight loss. We hypothesize that patients get reset and eat more. But there may also be something going on at the liver level. I think we need to do more studies to find out why they do not continue to lose weight.

Dr. Pfeiffer: Do you think that the ADA/EASD guidelines are realistic? They say we have to put our patient in the drivers seat. So do you think we can really do this?

Dr. Mannucci: I don’t find it unrealistic. What we are really missing right now are studies with good subgroup analysis.

Dr. Vora: What do you think the guidelines are based on?

Dr. Mannucci: For the personalization guides, I would say nothing. For the other parts I would say expert opinion.

Corporate Symposium: Asking The Tough Questions in Type 2 Diabetes Treatment! (Sponsored by Boehringer Ingelheim / Lilly Diabetes)

SESSION 1A: CAN TREATMENT BE RELIABLE?

The intention of this session was to challenge conventional wisdom – particularly in the earlier use of DPP-4s. The key messages appeared to be that DPP-4 inhibitors should be used as second line therapy after metformin instead of sulfonylureas (SU), and that linagliptin (BI/Lilly’s Tradjenta) offered an advantage over other DPP-4s because it can be used in patients with chronic kidney disease, whereas all other DPP-4s are contraindicated in those with renal impairment. The audience seemed to be aligned with the first point – in a later poll, 58% of them said they already prescribed DPP-4 after metformin compared to 28% preferring a SU.

Perspective 1: Optimizing Glycemic Control –Putting the Guidelines and Latest Evidence in Context

Melanie Davies, MD (University of Leicester, UK)

  • Evidence from large-scale outcomes trials generally promotes maintaining a low A1c while minimizing hypoglycemia and weight gain. The UKPDS showed that intensive therapy leads to better outcomes (both micro- and macro-vascular). But the ACCORD trial led to some confusion. Even though the intensive arm successfully reached an A1c of 6.4%, there was increased mortality. In the ADVANCE trial, the intensive group also reached 6.4% A1c, but with no detrimental effects. The difference was hypoglycemia and weight gain – which should ideally be minimized.
  • The ADA/EASD guidelines have been recently changed to allow many options of second line therapy after metformin, including insulin and the incretin based therapies. We should also be taking individual patient characteristics more into account.
  • A large meta-analysis of metformin showed no reduction in all-cause mortality or cardiovascular mortality, so the evidence base for its use as a platform is not clear- cut. There is also no particular mortality benefit with metformin in combination with insulin. On the other hand, DPP-4s showed A1c reduction with little adverse effects. However, we need more evidence to establish DPP-4s as first line therapy.

 

Perspective 2: The Effect of Patient Characteristics on Treatment Outcomes

Brian M Frier, MD (University of Edinburgh, Scotland);

  • Dr. Brian Frier reiterated that there are many factors that should influence therapy choices for patients. These include: A1c targets, age, duration of diabetes, hypoglycemia, renal function, co-morbidities, psycho-social and cognitive status, and socio-economic status.
  • Very strict control is not appropriate for certain groups. The only major intensive therapy trial that started close to the date of diagnosis is UKPDS – the others start around a decade after diagnosis – so we can’t generalize their results to all patients. It seems that strict control is good for patients in the early stages in diabetes, but could even be harmful in the more advanced stages, depending on your interpretation of ACCORD.
  • Hypoglycemia is probably underestimated as a cause of cardiovascular mortality in type 2 diabetes. Hypoglycemia is also related to fracture risk (from falls) in older women. The risk of hypoglycemia increases greatly with chronic kidney disease (CKD). Metformin, SUs and insulin should be discontinued in CKD.
  • Linagliptin (Tradjenta, BI/Lilly) is the only diabetes drug that is suitable for patients on dialysis, and only pioglitazone (Takeda’s Actos) and linagliptin are suitable for patients with eGFR <30 mL/min/1.73 m2.
  • Intensive therapy is contraindicated in patients with advanced age, limited life expectancy, a less motivated attitude, higher risk of hypoglycemia, longer disease duration, those with more co-morbidities and those with established vascular complications.

 

Perspective 3: Do Patient Characteristics Influence Choice of DPP-4 Inhibitor?

Bernard Zinman CM, MD, FRCPC, FACP (University of Toronto, Canada)

  • The ideal drug for diabetes has many aspects. These include: safe, efficacious, durable control, well tolerated, low risk of hypoglycemia, weight neutral or weight loss, can be used at all stages of the disease, provides complimentary mode of action with other medication.
  • There are some differences between the five available DPP-4 inhibitors, although the efficacy is quite similar. The most cut-and-dried difference that we are aware of, though, is that the share of renal excretion is different – linagliptin has only 5%, versus 87% for sitagliptin (Merck’s Januvia) and 85% for vildagliptin (Novartis’ Galvus). This means that linagliptin can be used in patients with greater degrees of renal impairment.
  • There are many advantageous aspects of linagliptin in efficacy, safety, and convenience. The long term durability of linagliptin is not firmly established but data suggest that it works out to at least two years. Efficacy seems unaffected by patient age, or duration of diabetes. A meta-analysis of all the linagliptin studies shows a 0.7% reduction in A1c, which is similar to the other DPP-4s. Adverse events are low – there were only two events of pancreatitis in 2,566 patients receiving linagliptin versus zero in the control group.
  • Prof. Zinman stated that “unless there is a financial reason, for me, DPP-4s seem a superior choice than sulfonylureas. I am bold enough to go to a DPP-4 inhibitor after metformin rather than a sulfonylurea.”

SESSION 1B: DOES LOWER HBA1C ALWAYS MEAN LOWERING CARDIOVASCULAR RISK?

Again this session, we emphasized the use of DPP-4s as a replacement for SUs, but also got into an interesting discussion of how prescriptive the guidelines should be. Should physicians be told exactly when to use a DPP-4, or do we trust them to make the correct individualized patient decisions?

Perspective 1: Hypoglycemia and Cardiovascular Risk

Brian M Frier MD (University of Edinburgh, Scotland)

  • The heart already has several problems in diabetes, so the effects of hypoglycemia are superimposed on top of a weakened organ. Existing problems from diabetes include coronary artery disease (e.g. atherosclerosis), autonomic dysfunction, and a diseased cardiac muscle  (cardiomyopathy).
  • Hypoglycemia is associated with cardiac ischemia. There is a very high release of adrenaline (similar to a major trauma or heart attack) in hypoglycemia, which magnifies the symptomatic response. In hypoglycemia, studies show that the heart has to do a lot of extra work. This is fine if you have a young, healthy heart, but if the heart is diseased there is a bigger risk of ischemia. Hypoglycemia is also associated with negative ECG changes. Studies also show that during hypoglycemia, coronary blood flow is compromised in patients with diabetes compared to healthy patients. The normal autonomic reflex response to stress is blunted by antecedent hypoglycemia.
  • Hypoglycemia is also associated with endothelial dysfunction, blood coagulation abnormalities, and inflammation, as well as the sympatho-adrenal response mentioned above. The effect on the vasculature may persist a lot longer than the hypo episode–ihsetprel.
  • Remember that 80% of people with type 2 diabetes die of heart related issues – the ‘smoking gun’ here may well be hypoglycemia. In ACCORD, the cause of excess mortality was not established, but clearly intensive therapy leads to higher hypoglycemia. In VADT severe hypoglycemia was a predictor of death. A retrospective cohort study of patients with type 2 diabetes on oral medications showed that the cohort with higher hypoglycemia had the higher mortality.
  • “Is the recommended target of 6.5% A1c appropriate for all patients? Because of hypoglycemia, we have to be very cautious”.

 

Perspective 2: DPP-4 Inhibitors vs. Sulfonylureas  

Bernard Zinman CM, MD (University of Toronto, Canada)

  • Not all therapies are created equal, and some are associated with more weight gain and hypoglycemia.” Comparing linagliptin and sulfonylurea (SU) over time, we see similar A1c lowering out to two years, with possibly a little bit better durability for linagliptin. But the SUs have much worse weight gain and hypoglycemia than linagliptin (and all the other DPP-4s and GLP-1s).
  • There is some suggestive (but not definitive) data showing a lower relative risk for adjudicated cardio-vascular events with linagliptin versus glimepiride, particularly for non fatal stroke. In a prospective small-scale study, linagliptin was associated with reduced cardiovascular risk, but it was again not definitive.
  • However, the ongoing CAROLINA study is designed to conclusively evaluate the cardiovascular safety of linagliptin versus an active comparator (glimepiride). CAROLINA will study 6,000 patients with or without a metformin background over a six to seven year follow up period. The primary endpoint is the time to first occurrence of the primary composite endpoint. There is no placebo group, but this study addresses the clinically relevant question ‘which drug is better as second line therapy?’
  • Prof. Zinman applauded the FDA for insisting on a comprehensive post-approval cardiovascular study for new diabetes drugs. He feels that the evidence suggests that linagliptin, like other DPP-4s, are not associated with increased cardiovascular risk.

 

Panel Discussion

Brian M Frier, MD (University of Edinburgh, Scotland); Bernard Zinman CM, MD (University of Toronto, Canada)

Q: Is there any evidence that metformin is toxic?

A: No, we don’t think it is toxic at all. But we need to avoid it in certain circumstances, such as in renal impairment.

Q: What is the risk of hypoglycemia with linagliptin when used in patients with cardiac failure.

A: The risk of hypoglycemia with linagliptin is very low, not zero, but extremely low.

Q: Can we use linagliptin in a patient that already has pancreatitis?

A: I would avoid using DPP-4 and GLP-1 in those patients. Not because we believe they cause it, but we should just be cautious.

Q: Hypoglycemia unawareness is not uncommon in patients on intensive insulin therapy. Do we have electrophysiological studies of the heart in these patients?

A: No, not on this group. It’s less common in type 2 diabetes. I don’t believe that they have any enhanced risk, since the adrenal response is minimized. There is a lot of asymptomatic hypoglycemia going on, and we still need to learn if this can trigger the same symptoms. I suspect that it will and this is an area that needs a lot of further explanation. We can’t show cause and effect in ACCORD unfortunately.

Q: Aren’t the current ADA/EASD guidelines too vague, and give the physician too much room to make errors given the breadth of options they are given by the algorithms?

Dr. Zinman: I couldn’t agree with you more. What PCPs need is not a longer and longer list of drugs. We can be more prescriptive, using the latest evidence. I am critical of the current round of guidelines.

Dr. Ferrannini: Yes, but we can’t tell physicians that we know more about the situation than they do. There just isn’t good enough evidence to support one track versus another given the large numbers of drugs available.

Dr. Davies: The big barrier to improvements is clinical inertia. More and more patients are being treated in primary care. Fewer physicians read the guidelines carefully. We need a clear scenario for when we should use a DPP-4. This would be better than giving every patient every choice.

Dr. Ferrannini: But there is no evidence that this would improve compliance. Guidelines aren’t being followed anyway. The desire is to put the treatment in the hands of the doctors rather than the trialists. Diabetes is a very complex disease, but now we want an algorithm that fits all patients, all over the world, in all circumstances. We thought that this was just too ambitious.

Q: Audience Poll - What is your typical drug choice after metformin?

A: SU 28%, insulin 3%, GLP-1 7%, DPP-4 58% (!), TZD 4%

[Note: additional talks from this corporate symposium can be found in the “Novel Therapies” section of this report]

Corporate Symposium: 25th Anniversary of the Discovery of GLP-1 (Sponsored by the Samuel Lunenfeld Research Institute)

GLP-1, HISTORY AND CRITICAL PROOF OF CONCEPTS OVER 25 YEARS

Jens Hull Holst, MD, PhD (University of Copenhagen, Copenhagen, Denmark)

Dr. Jens Holst presented a history of GLP-1 discovery (calling his presentation “a personal account, the way [he] feel that it happened”) starting from the initial search to identify the hormone in the distal small intestine involved in the incretin effect and ending with GLP-1’s various therapeutic benefits  today. He focused specifically on proving how endogenous GLP-1 stimulates insulin and reduces glucagon secretion in healthy subjects. In particular, Dr. Holst identified sustained weight loss over two years and restoration of glucose tolerance in individuals with prediabetes as indicative that the discovery of GLP-1 was not just of physiological importance, but also had great clinical potential – we were keen to hear this influential researcher talk about the potential for pre-diabetes. He then highlighted the importance of GLP-1 in the efficacy of glucose tolerance improvement almost immediately after Roux-en-Y gastric bypass surgery. Finally, Dr. Holst addressed why GLP-1 therapy might be appropriate in type 1 diabetes. Dr. Holst argued that, due to its inhibitory effects on gastric emptying and glucagon secretion, GLP-1 could help patients with type 1 diabetes that have no residual beta cell function. He presented data suggesting that, while GLP-1 did not appear to awaken silent beta cells, its glucagon lowering effects were independent of insulin secretion. Furthermore, after four weeks of treatment with liraglutide in patients with and without beta cell function, patients saw a major reduction in insulin dose and a decrease in hypoglycemia. During Q&A, Dr. Holst said there were other incretins that could be valuable to patients, including gastrin and secretin.

Questions and Answers:

Q: I noticed in the study after bariatric surgery that the pattern of what you saw with exendin 9-39 [a GLP-1 receptor antagonist] was consistent on insulin secretion but it appeared to have an even larger effect on glucose concentrations pre-operatively. How is that consistent with over secretion of GLP-1 after the operation, which should give you more substrate for the exendin 9-39 GLP-1 receptor antagonist to work on?

A: This does raise a question of using exendin 9-39 as a tool. I suppose the interference of glucagon function is important here as well, and I didn’t show you that. The glucagon behavior in these people and with exendin after operation, is something we don’t understand right now.

Q: Although those patients don’t have a stomach, I guess we assume there is an effect of GLP-1 on the small intestine. Does that interfere with the absorption process?

A: That’s possible.

Q: For GLP-1 targets such as gastric emptying, GLP-1 is a major player, but there are other players that are GPR receptors. What is your view on those targets in medication and therapy in the future?

A: This is a beautiful field for others to cover in this room. I’ll just throw a bit of salt in the wound and say that one of the studies we did involved looking at the twenty-fold, at least, GLP-1 induction in response to meal intake, and in those meals, there was no fat.

Q: So you told us about the situation around 1987 and 1988 that there were reasons to believe that there are new incretins to be discovered. So how about today? Is there still some room for incretins that haven’t been discovered so far?

A: I know that my own mentor has published a paper where we say a focus has been on GLP-1, but what about gastrin and secretin? What about them? Is there room still? I could add that the double incretin knockout mice suggest that if you take away most GIP and GLP-1, they aren’t terribly sensitive bodies.

Q: What do you think we should make of improvements in insulin resistance? Is that related to gut hormones or just pure caloric restriction?

A: Several groups have studied this, showing caloric restriction of the kind we’re looking at here acutely will improve hepatic insulin sensitivity. Peripheral insulin sensitivity is not changed shortly after bypass; that takes months and is probably related to loss of fat, particularly intramuscular fat and possibly liver fat. I’m quite sure it is not just related to the gut hormone.

GLP-1 SYNTHESIS AND SECRETION

Fiona Gribble, PhD (Cambridge Institute for Medical Research, Cambridge, United Kingdom)

Dr. Fiona Gribble detailed findings from an L cell model that she developed to investigate mechanisms   of GLP-1 synthesis and secretion. As a reminder, L cells are located in the intestine and secrete the GLP-1 hormone. Her major finding was that nutrients in the intestinal lumen modulate L cell GLP-1 secretion by depolarization of the cell upon nutrient transport from the lumen into the L cell cytosol.

  • Dr. Gribble reviewed the gut’s role as an endocrine hormone, as well as the synthesis of GLP-1. While endocrine cells account for only ~1% of the gut lining, in total they make up the largest endocrine organ of the body thanks to the gut’s substantial length. GLP-1 is a cleavage product of the proglucagon peptide that, in the pancreas is cleaved to release glucagon, but in the L cells of the intestine is cleaved to release GLP-1 and GLP-2.
  • Dr. Gribble described the transgenic mouse L cell model that her team developed to investigate the mechanisms of GLP-1 secretion. Dr. Gribble’s team engineered a transgenic mouse expressing the GLU-Venus construct in which every cell that expressed proglucagon (i.e., L cells in the intestine and alpha cells in the pancreas) also glowed fluorescent yellow. This allowed for the visualization and identification of L cells in the intestine, which otherwise would not have been possible since L cells represent a small percentage of all gut cells.
  • Dr. Gribble then explained that the mechanism for GLP-1 secretion from L cells involves nutrient-induced depolarization. Glucose from the intestinal lumen enters L cells through sodium-coupled glucose transporters (primarily through SGLT-1) along the gut border. Each glucose molecule that enters is coupled with a Na+ ion. Therefore, glucose stimulation increases the inward flow of positive ions into the cell, depolarizing the cell and allowing for an action potential to signal (mediated by an increase in intracellular Ca2+ concentration) for the release of GLP-1. In SGLT-1 knock-out (KO) mice, GLP-1 is not secreted when the mouse is challenged with glucose by oral gavage. Additionally, Ca2+ concentration within L cells from SGLT-1 KO mice did not increase in response to the addition of glucose. Based on these findings, Dr. Gribble stated that there is a strong body of evidence suggesting that a major way in which L cells sense glucose in the gut lumen is through the activity of SGLT-1. She also presented data demonstrating that amino acids, as well as certain di- and tri-peptides, can similarly trigger GLP- 1 release from L cells via ion-coupled transport that results in L cell depolarization.

Questions and Answers:

Q: Is there a possibility that GLP-1 could beget GLP-1? Have you tested this, or do we know if there are GLP-1 receptors directly on L cells or those of any of other hormones that positively feed back onto themselves like GLP-1 does on beta cells?

A: We don’t find GLP-1 receptors on L cells themselves, but if you give GLP-1 to animals or humans, you affect endogenous GLP-1 secretion. So we think that there is cross talk, but not directly through L cells.

Q: Would SGLT-2 inhibitors have some cross reactivity on SGLT-1?

A: I haven’t seen the data. I would predict that if you partially block SGLT-1, then you could deliver more glucose lower along the GI tract, where there is a higher concentration of L cells, and have a pharmacologic bypass experiment.

Q: Since we estimate the half-life of L cells to be two to three days, would it be possible to drive stem cells to produce more GLP-1? And which transcription factors are involved?

A: There is a whole list of transcription factors in a paper we published. We did a microarray of these cells; we recognized a lot of ones that came up, and there were also a heap of ones we did not recognize. The conclusion was that we didn’t think it would be easy to generate more L cells without generating more I and K cells at the same time because it would be difficult to pull out a transcription factor that would actually specifically produce L cells and not other cell types. There is a lot of potential and we haven’t tried everything yet.

Q: When we eat, we are bombarding L cells with hundreds or thousands of ligands at the same time. So the way it integrates those nutrient responses is different from when we give a lot of glucose or a lot of peptides alone. Have you had a chance to look at L cell response  to a combination of nutrients? To enhance GLP-1 response, would it be best to stimulate with a lot of one type of nutrient, or would it be optimally increased in a combinatorial manner?

A: I think you need more than one stimulus to get a lot out of an L cell. We haven’t fully defined the synergy but it looks like more than an additive effect when you combine stimuli. At least in vitro you can start to add these signals together, and the very effective action of glutamine you see in vitro illustrates the strength of putting transporter systems together. I think elevating cAMP is the most obvious way to try to increase secretion in vitro. I think combined with food intake arriving at right place, you can have the best effect.

Diana Williams, PhD (Florida State University, Tallahassee, FL)

Dr. Diana Williams’ study focused on GLP-1 neurons in the nucleus of the solitary tract and investigated whether the projection of these neurons to the nucleus accumbens (NAc) mediates the anorexic effects of meal-related GI signaling. In her lab’s study, rats received intra-NAc injections of saline or exendin [9- 39] (a GLP-1 receptor antagonist) 15 minutes before a preload of saline or condensed milk, after which rats were able to feed ad lib on chow. Exendin [9-39] reduced food intake following the preload by decreasing meal size rather than the number of meals consumed or the frequency of meals. To Dr. Williams, this finding suggests that NAc GLP-1 neurons play a physiologic role in the control of food intake. Results also showed that GLP-1 appears to reduce the palatability of food, indicating a possible mechanism through which GLP-1 projections to the NAc may regulate food intake. Dr. Williams then detailed her investigation of GLP-1 action in the context of a high-fat diet. Previous data show that overconsumption of a high fat diet is due in part to endogenous opioid activity in the NAc, leading Dr. Williams to examine whether NAc GLP-1 receptors interact with μ-opioid receptors. GLP-1 agonists affected the consumption of a high-fat meal only when given in combination with a μ-opioid antagonist (Naltrexone), suggesting that endogenous opioid activity in the NAc may impair the anorexic effects of GLP-1 signaling.

Questions and Answers:

Q: Do you think that rats are the same as mice in regard to this response? Are they the  same as larger animals and humans? Because rodents are completely different in terms of periodicity and their 24 hour cycle, and the way they eat, etc. Do you have any sense of how applicable the learnings are from the rodent studies to humans?

A: This is an issue with GLP-1 neurons because even mouse and rat are relatively different, although the neuronal projections are similar. We don’t know if the details, such as the behavior effects, are the same. We don’t know how GLP-1 affects palatability. As far as humans go, no one has had GLP-1 injected intracranially. We only have to go on peripheral injection. Anecdotally, there’s discussion on the effect of GLP-1-based therapy on food reward. People are saying that they’re less excited about palatable food such as junk food. But there has to be more studies done because it’s hard to tease out the details on what is happening. There is some reason to think that these types of effects are going on in humans, but we need more studies.

Q: Though I think you’ve looked at this before, you didn’t speak today on whether you can separate an aversive response from a more selective satiety response. How do you view the separation between a highly specific responses vs. just sensing a massive aversive response?

A: That’s certainly an issue with looking at GLP-1 in the brain. We know that global administration will give you taste aversion, such as nausea. I think that GLP-1 is part of the aversive response. That’s been found to be part of the response. I don’t think that’s going on a meal-to-meal basis. We have shown that for some brain areas, injection of GLP-1 at the same doses that affect food intake doesn’t produce a taste aversion. And injection of exendin-9 at this site doesn’t reduce nausea. So there are sites where you don’t get that effect. Injection of GLP-1 into the amygdala shows an effect. So I think there’s a lot of functional segregation throughout the nervous system.

THE EFFECT OF GLP-1 ON FOOD INTAKE IS LOST IN TRUNCALLY VAGOTOMISED PARTICIPANTS.

Astrid Plamboeck, MD (University of Copenhagen, Copenhagen, Denmark)

Dr. Astrid Plamboeck opened by noting that because native GLP-1 is rapidly degraded by DPP-4 (only 10% of intact peptide reaches systemic circulation), it may act locally to confer its biological effects, possibly via the vagus nerve. Dr. Plamboeck’s lab studied participants who had undergone truncal vagotomy (surgical cutting of the vagus nerve) to investigate GLP-1’s effects on plasma glucose, gastric emptying, insulin secretion, and food intake. Ten vagotomized participants and controls received GLP-1 infusion or saline 30 minutes before a liquid meal and four hours before an ad lib meal (where participants could eat as much as they desired). Vagotomized participants exhibited accelerated gastric emptying compared to controls (when both were given saline) and GLP-1 had a slight effect on gastric emptying in vagotomized participants compared to a significant effect in controls. Vagotomized  patients also exhibited altered glucose homeostasis, with a higher level of glucose following the liquid meal compared to controls. Glucagon levels were similarly elevated in vagotomized participants. GLP-1 infusion lowered post-prandial glucose and glucagon levels to a much lesser extent in vagotomized vs. control participants, perhaps due to the loss of GLP-1 signaling via the vagus nerve. Furthermore, greater insulin secretion, decreased food intake, and less appetite sensation was observed in vagotomized participants, with GLP-1 infusion having no effect on these parameters.

Questions and Answers:

Q: Regarding the pathways that you’re identifying that may be lost, do you think that they are highly selective GLP-1 pathways? Or are they relaying all kinds of information, and maybe the loss of GLP-1 responsiveness is secondary to multiple defects in these people? Because this is not a selective ablation of GLP-1 pathways, it’s a massive ablation of communication.

A: I think a value of this experiment is that we examined them with or without the GLP-1 infusion. I can’t speculate on the rest of the action.

Q: Did you have a chance to treat these people with a DPP-4 inhibitor, which we speculate is a more gentle method, but perhaps also very important for communication signals, perhaps from the same pathway? So you get much lower levels of GLP-1, but more direct engagement of that nerve communication.

A: We didn’t do it in this study, because it doesn’t look like DPP-4 inhibitors affect food intake or weight in a clinical setting. We did that in another study where we gave an OGTT, but we haven’t analyzed these data yet.

GLUCAGON-LIKE PEPTIDE-1 RECEPTOR ACTIVATION PROTECTS CARDIOMYOCYTES FROM HIGH GLUCOSE-INDUCED CELL DEATH

Julio Ayala, PhD (Sanford-Burnham Medical Research Institute at Lake Nona, Orlando, FL)

Dr. Julio Ayala presented results from his research on potential mechanisms of GLP-1 agonists on cardioprotection by examining the effects of exendin 4 (the active ingredient in exenatide) on cardiomyocyte loss in neonatal rat ventricular myocytes. Previous studies had established that incubating cardiomyocytes in high glucose promotes apoptosis. Dr. Ayala found that incubating cells with exendin 4 reduced hyperglycemia-induced cell death in a dose-dependent manner. He then investigated the mechanism for this cardioprotective effect. He first hypothesized that exendin 4 might mediate oxidative stress, one cause of cardiomyocyte death. However, exendin 4 did not reduce markers of oxidative stress. Endoplasmic reticulum (ER) stress occurs downstream of oxidative stress, and Dr. Ayala found that markers of ER stress (CHOP and GRP78) were down regulated with the addition of exendin 4. In examining exendin 4’s effects on ER stress, Dr. Ayala identified a potential therapeutic target: SERCA2a. He found that exendin 4 protected cardiomyocytes from thapsigargin-induced death; thapsigargin is a known inhibitor of calcium homeostasis that acts by inhibiting SERCA2a (a pump that moves Ca2+ from the cytosol into the sarcoplasmic/endoplasmic reticulum and is important for cell viability). Specifically, exendin 4 enhances the phosphorylation of phospholamban, a protein that, only when phosphorylated, enhances SERCA2a affinity for Ca2+. Additionally, SERCA2a is also inhibited by hyperglycemia; since Dr. Ayala had already demonstrated that exendin 4 protects cardiomyocytes from hyperglycemia-induced death, he concluded that exendin 4’s ability to enhance SERCA2a activity would be especially relevant to preventing loss of cardiomyocytes in the context of diabetes.

Questions and Answers:

Q: You used a high glucose model, and for some of your stressors you don’t really need glucose. So do you have a sense of the interactions preserved under normoglycemic conditions, or do you require high glucose to get the good effects?

A: Yes, so we’re doing some of those controls right now to look under normal conditions. One of the key targets for GLP-1 receptor agonist activation is PKA and we don’t know if we want to be activating PKA under normal conditions. So this might be an example where hyperglycemia produces a defect that GLP-1 restores.

Q: You only showed results for exendin 4, so I would be curious to compare these effects to other GLP-1 receptor agonists.

A: We are interested in doing that, and there is even interest in using the GLP-1 9-36 molecule.

Q: I saw two or three posters at ADA that said many actions of GLP-1 on the heart in terms of glucose uptake or vascular reactivity were lost in older patients with diabetes. Do you have thoughts about making animals, even for 24 hours, hyperglycemic first, and then examining whether you get preserved responses?

A: We’re establishing methods for isolating cardiomyocytes from mice but that’s certainly an interesting study to see if this is a preventative or intervention type effect.

GLP-1 SECRETION IN JAPANESE PATIENTS WITH TYPE 2 DIABETES: RESPONSE TO ANTI-DIABETIC DRUGS METFORMIN, AND ALPHA-GLUCOSIDASE INHIBITOR

Daisuke Yabe, MD, PhD (Kansai Electrical Power Hospital, Osaka, Japan)

Dr. Daisuke Yabe presented data on methods to enhance GLP-1 secretion. He reported that metformin and alpha-glucosidase inhibitor therapy (specifically, Acarbose) increased both intact and total circulating GLP-1 post-prandially compared to control, but had no effect on levels of DPP-4. Therefore, Dr. Yabe suggested that use of metformin or Acarbose in combination with a DPP-4 inhibitor would be an especially potent combination for enhancing endogenous GLP-1 activity. Additionally, past research had indicated that A1c reduction with the use of DPP-4 inhibitors correlated with fish intake in Japanese patients. Efforts are currently underway to identify which nutrients in fish may potentiate this effect,  but Dr. Yabe hypothesized that the fish nutrients may actually potentiate GLP-1 secretion. In addition,   he found that when Japanese patients with type 2 diabetes eat fish before rice, total GLP-1 levels  increase more after the meal than if rice is eaten before fish, and post-prandial glucose excursions are also improved. Therefore, he concluded that the nutrients in fish enhance GLP-1 secretion and that metformin or Acarbose in combination with eating fish could be another viable treatment option.

Questions and Answers:

Q: Your results about the order of fish and rice were quite intriguing. Did you consider the possibility that rice empties faster from the stomach than fish? Could that explain parts of results?

A: Yes, I believe some of the effect might be explained by that.

GLP-1 EFFECTS ON PANCREATIC ISLET CELLS

Juris Meier, MD (Ruhr-Universität Bochum, Bochum, Germany)

Dr. Juris Meier reviewed several studies in discussing GLP-1’s pancreatic effects, including its influence on beta cell function, insulin secretion, and glucagon concentration. He began by reasoning that since people’s capability for beta cell proliferation go down as they age, incretins likely preserve beta cell function by inhibiting beta cell death rather than stimulating cell replication. Native GLP-1 also promotes glucose homeostasis, primarily through increasing insulin secretion. Dr. Meier emphasized that GLP-1 also influences the “rhythm” of insulin secretion, namely the frequency and amplitude of insulin pulses. Dr. Meir then turned to GLP-1 agonists and explained that short-acting agonists inhibit gastric emptying, delay the absorption of intestinal glucose, and decrease post-prandial insulin levels while long-acting GLP-1 agonists stimulate insulin and reduce glucagon concentration, and thus act primarily on fasting glucose. Dr. Meier also highlighted that GLP-1 agonists stimulate insulin biosynthesis in addition to insulin secretion, and thus appear to help prevent a chronic degranulation of beta cells. GLP-1 agonists also increase the glucose sensitivity of beta cells and inhibit glucagon  secretion by increasing somatostatin. Dr. Meier closed his presentation by reviewing data showing that GLP-1 agonists’ effects on insulin and glucagon contribute equally to the drugs’ ability to lower glucose.

  • Dr. Meier explained that while several in vitro and in vivo studies of GLP-1 agonists and DPP-4 inhibitors indicate that incretins can stimulate beta cell proliferation, investigators have not seen a large clinical impact of incretins on the progression of type 2 diabetes. To Dr. Meier, the discrepancy is attributed to the fact that rodent studies have used young animals at an age equivalent to human infants. Subsequent studies that investigated beta cell proliferation in young and older animals found an effect of exendin-4 (the active ingredient in exenatide) on beta cell mass and replication only in the younger animals. Researchers have associated the decline in beta cell proliferation with the accumulation of the cell cycle inhibitor p16, which is increasingly expressed with age. Studies using pancreatic specimens from children show that Ki67 – a marker of beta cell replication – is abundantly expressed in pancreases from six-month-old infants but not 15-year-old adolescents, indicating that the rate beta cell replication declines drastically with age. The expression of p16 shows an inverse trend – nearly no expression in young pancreases but high expression in older specimens – suggesting that P16 may be one of many factors that restrict beta cell replication as people age.
  • In discussing GLP-1 agonists, Dr. Meier pointed out an interesting postprandial effect – acute administration of GLP-1 agonists in the postprandial state appears to lower, rather than raise, insulin levels. Dr. Meier explained this observation by noting that glucose  concentration drives insulin secretion and that several GLP-1 agonists delay gastric emptying and thus reduce the absorption of intestinal glucose. He stated that since the effect on gastric   emptying is dependent on tachyphylaxis (the decrease in response to a drug following its administration), long-acting GLP-1 agonists, which maintain a prolonged, elevated level of GLP-1 in the body, have little effect. Thus short-acting GLP-1 agonists inhibit gastric emptying, delay the absorption of intestinal glucose, and decrease post-prandial insulin levels while long-acting GLP-1 agonists act primarily on fasting glucose by stimulating insulin secretion and reducing glucagon concentration.

Questions and Answers:

Q: You may have seen a paper published two weeks ago from Dr. Accili’s lab in New York. He used multiple different models – lineage tracing, genetic models, etc.– and found that it’s not apoptosis, it’s dedifferentiation. He doesn’t see apoptosis as a consistent procedure in diabetes, but he always sees dedifferentiation. So beta cells go away, but they go away to become other endocorine cells, and if we can switch that process back, that may be an effective approach. So we can look at these markers from the same sections of the pancreas and there’s data – it’s not great data–that suggests that GLP-1 affects the differentiation of beta cells. Do you want to comment?

A: It’s certainly intriguing, but it’s extremely difficult to prove or disprove in human models. We can’t do this experiment of GLP-1 stimulation, because we don’t have access to the pancreas. I think the story for the plasticity of beta cells is an old story, but there’s no proof in humans. What we do have is evidence of beta cell death in humans and animal models. Using markers of beta cell apoptosis, we do see apoptosis. That doesn’t exclude the fact that there might be some dedifferentiation. There’s also this hypothesis that some beta cells lose insulin expression. Maybe some beta cell death might be beta cell dedifferenition and the loss of insulin expression. Again, we can’t exclude this based on the models we use, but it’s an interesting thought.

Q: I wanted to challenge your view on the difference between short-acting and long-acting drugs. I think you neglected the glucose dependence of GLP-1 action in the way you looked at the data. There’s clearly a difference in their effect on gastric empyting. But I strongly believe there’s no difference in their effects on insulin and glucagon secretion. You have to take into account the effect of glucose. GLP-1 acts in a glucose-depedent manner. Fundamentally, the only difference I see is the effect on gastric emptying. All other effects seem to me to be exactly the same if you normalize for different glucose concentrations.

A: I don’t think we are in disagreement. I think that the difference in glucose concentration results from the difference in gastric empyting. That’s why I said that the major driver of insulin secretion is not GLP-1 itself, but the concentration of glucose. So the abiltiy of GLP-1 to stimulate insulin is glucose dependent. Clinically, what we see when we inject these drugs is a stimulation on one hand and a reduction on the other hand, but other than that, I agree with you.

EXTRA-PANCREATIC ACTIONS OF INCRETIN HORMONES: WHAT DO WE KNOW, WHICH AREAS ARE UNCLEAR AND NEED MORE INVESTIGATION?

Daniel Drucker, MD (Samuel Lunenfeld Research Institute, Toronto, Canada)

Dr. Daniel Drucker presented his view on various extra-pancreatic actions that have been proposed for GLP-1 agonists. Most of his presentation focused on the hot-topic of GLP-1 agonists’ potential cardioprotective effects. He reviewed several mechanisms for how GLP-1 agonists might exert positive cardiovascular effects; specifically, he identified blood pressure reduction as his favorite mechanism because it has been validated in humans. In turn, his favored putative mechanisms for how GLP-1 agonists reduce blood pressure are by diuresis and vasodilation. Dr. Drucker also discussed the lipid- lowering effects of GLP-1, but he cautioned that, based on currently available data, lipids could not be identified as an independent risk factor for cardiovascular disease that is modified by GLP-1. While preclinical studies have shown powerful cardioprotective effects of GLP-1 receptor activation or DPP-4 inhibition, Dr. Drucker stressed that little clinical data exists suggesting that these therapies will produce cardioprotection in elderly human patients with diabetes. He expressed hope that ongoing outcomes studies will be able to establish the cardiovascular effects of incretin-based therapies, but also warned it will be difficult to directly compare treatments due to differences in study design.

  • Dr. Drucker reviewed potential means by which GLP-1 agonists could act on the cardiovascular system; he identified blood pressure reduction as his favored mechanism by which GLP-1 agonists may provide beneficial cardiovascular effects. In humans, validated effects of GLP-1 therapy include weight loss, blood pressure reduction, heart rate increase, decreased post-prandial lipids, reduced post-prandial glucose, and improved vascular flow-mediated dilation (FMD). Dr. Drucker presented data demonstrating that both GLP-1 agonists and DPP-4 inhibitors are associated with rapid and sustained reductions in blood pressure (liraglutide produced ~2.5 mmHg reduction in systolic blood pressure within two weeks over 26 weeks).
    • Dr. Drucker believes that diuresis and vasodilation are the most likely mechanisms by which GLP-1 agonists reduce blood pressure. GLP-1 agonists and DPP-4 inhibitors both increase urine sodium excretion, though preclinical data suggest that DPP-4 inhibitors also act through a separate mechanism independent of GLP-1 that may involve the kidney. Dr. Drucker believes that endogenous GLP-1 does not act directly to induce vasodilation, but that this effect may be mediated through the GLP- 1 (9-36) cleavage product. With regards to potential GLP-1 effects on heart rate, Dr. Drucker believes that a substantial number of questions remain in this area including what parameters should be measured, whether the central or peripheral nervous systems are involved, if the effect persists over time, and whether mean heart rate or outliers should be the key endpoint.
    • Dr. Drucker also discussed the lipid-lowering effects of GLP-1, though he cautioned that lipids could not be identified as an independent risk factor for cardiovascular disease that is modified by GLP-1. In humans, DPP-4 inhibition reduces post-prandial total serum triglycerides (TGs) after four weeks of treatment. Additionally, in healthy humans, exenatide reduced the production of ApoB48, but not ApoB100 at a very low dose. However, he warned that the extent to which lipid lowering affects diabetes complications has not been well established, and the mechanisms coupling GLP-1 signaling to Apo-protein secretion are not well understood.
  •  While preclinical studies have shown powerful cardioprotective effects of GLP-1 receptor activation or DPP-4 inhibition, Dr. Drucker stressed that there is little clinical data to suggest that these therapies will produce cardioprotection in older human patients with diabetes. An interesting incongruity in the argument that GLP-1 agonism produces cardioprotective effects is that when one compares the number substrates in  the cardiovascular system that are responsive to DPP-4 to the number responsive to GLP-1, the  list is much longer for DPP-4, suggesting that DPP-4 inhibition might also act independently of the GLP-1 axis. Additionally, many metabolites generated by DPP-4 also have independent effects on the cardiovascular system (he did not specify what types of effects). Dr. Drucker stressed that, with regards to GLP-1 action in the cardiovascular system, we have very little idea of where the hormone works (whether the cardiomyocyte, nervous system, immune system, or blood vessel is the actual target of therapy). Furthermore, mice used in preclinical studies are often young and healthy as opposed to old and diabetic or atherosclerotic. He hopes that the ongoing long-term outcomes studies will be able to establish the cardiovascular effects of incretin-based therapies, but also warned it will be difficult to directly compare treatments due to differences in study design.

Questions and Answers:

Q: Normally the active GLP-1 is a peptide sequence from amino acids 7 to 36, and the inactive one is amino acids 9 to 36. From your experience, is there a way to convert the 9- 36 peptide to the 7-36 peptide?

A: I’m sure you could do that chemically in the lab, but I’m not aware of a biologic process that would re- anneal those amino acids back to their previous form.

Q: If you have pharmacologically characterized some hints that there must be another receptor for GLP-1, why is it so difficult to nail it?

A: Let me clarify the concept of a second receptor: for years, people have asked me, “Is there a second GLP-1 receptor?” When we give a GLP-1 receptor agonist to our GLP-1 knockout mice, we never see glucose lowering, insulin secretion, or a reduction in food intake and body weight. I think those actions are mediated by the classic GLP-1 receptor. Once you start going into cardiomyocytes, liver, muscle, adipocytes and blood vessels, I think you can have GLP-1 dependent and independent effects, and I think some of those cells don’t express the classical receptor. I don’t think we know what that other mechanism might be. Others are trying to look at this to see what it is that recognizes the GLP-1 receptor agonist or a degradation product. It’s not an impossible task, it just hasn’t been done elegantly enough.

Q: Do you think GLP-1 is really the system that is mediating the complexities that result in metabolic  syndrome?

A: I think all benefits of GLP1 are pharmacological. You get a little improvement in insulin secretion at the upper ranges of the physiological range, but I don’t think it’s as important of an endogenous system that taking it away would cause dysregulation.

Q: What percentage of metabolic syndrome do you think is attributable to [endogenous] GLP-1 and its antagonists?

A: Close to zero.

Q: You emphasized the use of old and young animals. I’d like to know also when you continue with elevation of active GLP ligand, what happens to the receptor? It’s also important because as far as I understand, when we treat patients with a DPP-4 inhibitor, if active GLP-1 level goes up then total GLP-1 release might go down. When we continue with high levels of GLP-1 what happens to the receptor?

A: There are some very small limited studies saying that treatment of animals for a few weeks does not decrease receptor expression. I think most of those studies are done with antibodies that don’t recognize the GLP-1 receptor. I don’t think we have good data to answer that question. What chronic therapy in diabetic models does to receptor expression and signaling is not very well understood.

Q: Could you speculate about the potential cardioprotective role of reducing postprandial hyperglycemia? In ApoE knock out mice, if you produce intermittent hyperglycemia, you exacerbate atherosclerosis compared to those subject to chronic hyperglycemia. And alpha-glucosidase inhibitors appeared to be cardioprotective.

A: There is an abundance of biomarker data: post-prandial glucose correlates with ROS [reactive oxygen species], coronary artery calcification, and much more. To date, when you look at human intervention studies designed to target post-prandial glucose and then look at CV events, you don’t see convincing data. Acarbose does not only have one mechanism of action either – it increases GLP-1 in some studies and not in others, so we will have a hard time attributing its effects.

GLP-1 AND INCRETIN BIOLOGY IN THE CLINIC: CURRENT STATUS AND FUTURE CONSIDERATIONS

Michael Nauck, MD (Diabeteszentrum Bad Lauterberg, Bad Lauterberg im Harz, Germany).

Dr. Nauck, who has researched GLP-1 for the past 25 years and whose studies were repeatedly cited throughout the symposium, gave a straightforward overview of current and future GLP-1 agonists and DPP-4 inhibitors. He first compared short-acting vs. long-acting GLP-1 agonists, explaining that short- acting agonists have a greater effect on gastric emptying and post-prandial glucose while long-acting agents more significantly reduce A1c and fasting plasma glucose levels. Dr. Nauck then compared several GLP-1 agonists with respect to their differing effects on fasting glucose, A1c, post-prandial glucose, and weight. Specifically, he noted that long-acting GLP-1 agonists provide similar glycemic control compared to basal insulin, a fact clinicians should consider when choosing a diabetes treatment. In contrast, short-acting agents may be especially well-suited for combination with basal insulin therapy. Dr. Nauck then turned to DPP-4 inhibitors, first noting that some agents differ pharmacologically with respect to their pharmacokinetic profile, specificity, mechanism of DPP-4 inhibition, and interaction with CYP450. After comparing the effectiveness of DPP-4 inhibitors vs. sulfonylureas, Dr. Nauck ended by noting that not all of the effects of DPP-4 inhibitors appear to be mediated by GLP-1, leaving room for the existence of other mediators, which could be favorable targets for diabetes therapies.

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