Philadelphia, PA; Report - Incretins - Draft

Executive Highlights

Incretins were again a topic of significant enthusiasm and interest at this year’s ADA meeting. While there wasn’t much groundbreaking new data presented for GLP-1 agonists (topline results were previously reported for a number of the trials), there was a predominant focus on distinguishing the class from other anti-diabetic agents. In particular, several oral presentations highlighted the efficacy and safety of adding GLP-1 agonists (GlaxoSmithKline’s albiglutide and Sanofi’s lixisenatide) to basal insulin therapy (55-OR, 62-OR, 983-P). Four-year results from DURATION-1 for Amylin/Alkermes’ Bydureon (1156-P) and three-year results from EUREXA highlighted the durable effects of GLP-1 agonists on glycemic control and weight – this data is serving to make GLP-1 an even more established part of clinical care, rather than a “new” option, as it has been since its introduction in 2006. A pooled analysis of liraglutide’s (Novo Nordisk’s Victoza) LEAD development program found a significantly greater proportion of patients achieved a composite endpoint of A1c < 7.0%, no weight gain, and no hypoglycemia with 1.8 mg liraglutide (34%) and 1.2 mg liraglutide (30%) than with exenatide (Amylin’s Byetta, 24%), sitagliptin (Merck’s Januvia, 14%), sulfonylureas (9%), TZDs (3%), and insulin glargine (Sanofi’s Lantus, 9%) (1041-P). Several speakers, including Dr. Steven Marso (University of Missouri Kansas City, Kansas City, MO) and Dr. Ralph DeFronzo (University of Texas Health Science Center, San Antonio, TX), discussed the potential cardiovascular benefits of GLP-1 agonists and their potential utility as prediabetes treatments. We had been expecting to see Dr. DeFronzo’s trial using GLP-1, metformin, and TZDs that formed the basis of his Banting Lecture in 2008 – we found out that this was not accepted as a late breaker (presumably due to timing) and that it will be shown at EASD – good news for the EASD organizers, as many others will be looking forward to hearing this data. With three GLP-1 agonists currently marketed and several candidates in late-stage development, emphasis was also placed on comparing and contrasting the different drugs within the class. Dr. Filip Knop (Gentofte Hospital, Hellerup, Denmark) addressed the incretin competition topic head-on, emphasizing efficacy and tolerability differences based on duration of action, size, and structure – this was not new, but synthesized nicely. Additionally, further results from the HARMONY-7 trial comparing albiglutide to liraglutide were presented, which favored liraglutide in terms of glycemic efficacy and weight, but albiglutide in terms of GI tolerability. Finally, we were excited to get our first look at the PK/PD profiles of the exenatide once weekly suspension formulation, which appeared to closely resemble the PK/PD profiles of Bydureon. During its investor event at ADA, Amylin announced that the first phase 3 trial (named DURATION-NEO-1 – great name) for this new formulation was expected to initiate in 3Q12 (previously mid-2012), and that the trial would be similarly designed as DURATION-5 (head-to-head vs. Byetta).

In contrast to GLP-1 agonists, we felt that there was less new interesting data presented for DPP-4 inhibitors at ADA 2012. Overall, there appeared to be widespread agreement among KOLs that little differentiated the DPP-4 inhibitors on the market today. While there have been product advances in GLP-1 (twice daily to once daily to once weekly), there haven’t been as many changes with DPP-4 inhibitors, although there’s an additional combination available this year, Merck’s Juvisync, which combines DPP-4 inhibitor Januvia and with statin simvastatin. In discussing the class’s commercial success (the class sold over $5 billion in 2011, up from $42 million in 2005), speakers emphasized the class’s strong safety and tolerability profile, and several highlighted the potential use of DPP-4 inhibitors as prediabetes agents. Clearly, the next frontier for the DPP-4 inhibitor class will be once weekly dosing –it will be interesting to see how well this does since once-weekly dosing implies monotherapy as there are no combinations that offer once-weekly dosing. There was no new data presented for the once weekly DPP-4 inhibitors under development by Takeda (SYR-472; phase 3 in Japan) or Merck (MK-3102; phase 3 to initiate in 2012). With regards to new data that were presented, we were most eager to see data demonstrating the efficacy and safety of combination therapy with BMS/AZ’s dapagliflozin and Merck’s sitagliptin (Januvia; 1071-P). Still, we believe Lexicon’s dual SGLT- 1/SGLT-2 inhibitor LX4211 holds greater potential for combination use with DPP-4 inhibitors given the effects of LX411 on GLP-1 secretion (Lexicon recently released phase 2b data on Lx4211 – please see our Closer Look from June 25, 2012 that showed a 0.95% A1c reduction from an ~8% baseline A1c). We were also excited to see continued efforts in examining the effects of incretin therapies in the setting of type 1 diabetes. In particular, Dr. Bo Ahren (Lund University, Malmo, Sweden) reported results from a small (n=28) four-week study that showed a reduced glucagon response following a meal with vildagliptin treatment (Novartis’ Galvus), but no significant reduction in the glucagon response during hypoglycemia – potentially quite exciting. Finally, back on the GLP-1 front, Dr. Gayatri Sarkar (DEOB, NIDDK, NIH, Bethesda, MD) highlighted intriguing results from another small study (n=14) that found lower daily insulin requirements and enhanced insulin sensitivity with exenatide plus basal insulin therapy compared to insulin monotherapy in people with long standing type 1 diabetes. We wonder how complicated dosing would be – we have heard some serious enthusiasm to date from type 1 patients on GLP-1 agonists off label.

Incretins

Oral Sessions: Incretin Therapies

ONCE-WEEKLY GLP-1 RECEPTOR AGONIST ALBIGLUTIDE VS. TITRATED PRANDIAL LISPRO ADDED ON TO TITRATED BASAL INSULIN GLARGINE IN TYPE 2 DIABETES (T2D) UNCONTROLLED ON GLARGINE PLUS ORAL AGENTS: SIMILAR GLYCEMIC CONTROL WITH WEIGHT LOSS AND LESS HYPOGLYCEMIA (55-OR)

Julio Rosenstock, MD (University of Texas Southwestern Medical School, Dallas, TX)

Dr. Rosenstock presented additional results from the phase 3 study Harmony 6 for GSK’s once weekly GLP-1 agonist albiglutide. As a reminder, the study randomized participants to receive either albiglutide or thrice-daily insulin lispro added onto insulin glargine with or without metformin and/or a TZD for 52 weeks. Topline data announced in March reported: 1) non-inferiority with regard to A1c reduction at week 26 with albiglutide (0.82%) vs. insulin lispro (0.66%, p <0.0001 for non-inferiority); 2) weight loss with albiglutide (1.61 lbs) vs. weight gain (1.79 lbs) with insulin lispro at week 26; and 3) an increased rate of nausea (13% vs. 2.1%) and vomiting (7% vs. 1.4%) with albiglutide vs. insulin lispro. (For our coverage of this topline data, please see the April 6, 2012 Closer Look at http://bit.ly/Id8Oeo). The new data provided today by Dr. Rosenstock revealed that the A1c reductions achieved at week 26 were sustained through week 56, more participants in the albiglutide arm achieved an A1c <7.0% and <6.5%, weight changes continued to diverge between the groups through week 56, hypoglycemia rates were reduced in the albiglutide arm (2.12 vs. 1.01 events per patient year), injection site reactions were slightly higher in the albiglutide arm (9.5% vs. 5.3%), and antibody formation was low with albiglutidetreatment in the trial. During Q&A, Dr. Rosenstock remarked that there were no significant changes in lipids, blood pressure, or pulse rate with albiglutide treatment.

• The Harmony 6 trial was a 52-week, randomized, open-label, active comparator controlled study that randomized individuals with type 2 diabetes to receive 30 mg of once weekly albiglutide (n=279) or thrice-daily insulin lispro (n=278) added on to insulin glargine with or without metformin and/or a TZD. The primary efficacy endpoint of the study was A1c reduction at 26 weeks. At baseline, average age was 55 years, weight was 92 kg, BMI was 33 kg/m2, duration of diabetes was 11 years, A1c was 8.5%, and FPG was 153 mg/dl. Approximately 70% of participants continued to receive metformin therapy and 2% continued to receive TZD therapy in the study. Insulin glargine treatment was titrated to a target FPG of 80- 130 mg/dl. Insulin lispro therapy was adjusted per a pre-specified algorithm based upon BG monitoring. Albiglutide therapy could be up-titrated at week eight to 50 mg if an A1c of <8.0% was not achieved. An ITT-LOCF analysis was employed.
• Non-inferior improvements in glycemic control were demonstrated in the albiglutide arm in comparison to the insulin lispro arm at weeks 26 and 52. A1c reductions at week 26 were 0.82% in the albiglutide arm vs. 0.66% in the insulin lispro arm (p<0.0001 for non-inferiority). Dr. Rosenstock indicated that the result was close to demonstratingsuperiority for albiglutide (p=0.053). These reductions in A1c were largely maintained through week 52, with a change in A1c of 0.75% in the albiglutide arm and 0.66% in the insulin lispro arm. Changes in FPG at week 26 were also not significantly different between the arms (-17.9 mg/dl for albiglutide vs. -12.9 mg/dl for insulin lispro), and these changes were maintained out to week 52. Finally, more individuals in the albiglutide arm achieved an A1c <7% (30% vs. 25%) and <6.5% (11% vs. 8.5%) at the end of 52 weeks than individuals in the insulin lispro arm. Interestingly, the mean insulin glargine dose was increased in comparison to baseline in both the albiglutide (+5 units to 52 units) and insulin lispro (+7 units to 50 units) arms.
• On average, individuals in the albiglutide arm experienced weight loss while individuals in the insulin lispro arm experienced weight gain. At the end of 26 weeks, weight loss in the albiglutide arm was 0.73 kg (1.61 lbs) and weight gain in the insulin lispro arm was 0.81 kg (1.79 lbs). The resultant treatment difference was 1.54 kg (3.40 lbs; p <0.0001). At the end of 52 weeks, the treatment difference was even greater at 2.61 kg (5.75 lbs), with a weight loss of 0.96 kg (2.12 lbs) with albiglutide and weight gain of 1.66 kg (3.66 lbs) with insulin lispro.
• Hypoglycemia occurred less frequently while GI side effects occurred more frequently in the albiglutide arm. The number of hypoglycemic events per patient year were doubled in the insulin lispro arm (2.12 vs. 1.01 events per patient year). However, the occurrence of severe hypoglycemia was reported to be negligible in both arms. No major imbalance was observed between the arms with regards to adverse events, except for an increased rate of GI side effects in the albiglutide arm (41.8% vs. 21.4%). More specifically, 13% of participants experienced nausea in the albiglutide arm vs. 2.1% in the insulin lispro arm. Vomiting occurred in 7% of the participants in the albiglutide arm vs. 1.4% of participants in the insulin lispro arm. Dr. Rosenstock remarked that these rates for albiglutide, while relatively higher than insulin lispro in the study, were lower than rates observed with other GLP-1 agonists in separate studies. A slightly higher rate of injection site reactions were also observed in the albiglutide arm (9.5% vs. 5.3%), although the majority were deemed to be mild in intensity (83.7% vs. 95.6%, respectively). Few systemic allergic reactions occurred with both albiglutide (1.4%) and insulin lispro (0.7%) treatment, and the treatment difference was not statistically significant. Additionally, antibody formation to both therapies was noted to be low and similar between the groups.

Questions and Answers

Q: Can you comment on whether there were any changes in lipids, blood pressure, and pulse rate?

A: There were no changes in the lipid profile. In terms of blood pressure, there was nothing major there. There were also not major changes in heart rate. There were initial minor changes in heart rate, but nothing overall.

EFFICACY AND SAFETY OF ONCE-DAILY LIXISENATIDE ADDED ON TO TITRATED GLARGINE PLUS ORAL AGENTS IN TYPE 2 DIABETES: GETGOAL-DUO 1 STUDY (62-OR)

Julio Rosenstock, MD (University of Texas Southwestern, Dallas, TX)

Dr. Rosenstock presented results from the phase 3 study GetGoal-Duo 1 for Sanofi’s once daily GLP-1 agonist lixisenatide. As a reminder, the study evaluated the safety of efficacy of adding lixisenatide to recently initiated and optimally titrated insulin glargine therapy in individuals with type 2 diabetes. Topline results reported for the trial in December 2011 highlighted that lixisenatide led to further reductions in A1c over placebo and minimized the weight gain associated with basil insulin therapy, but was associated with increased rates of GI adverse events and hypoglycemia – although the hypoglycemia rate remained low. In today’s presentation, Dr. Rosenstock discussed additional safety and efficacy data from the trial. Of greatest note, he revealed: 1) the specific A1c reductions observed in each treatment arm (-0.71% with lixisenatide vs. -0.40% with placebo); 2) that significantly more participants in the lixisenatide arm were able to achieve the composite endpoint of A1c <7.0%, no hypoglycemia, and no weight gain (28% vs. 18%); 3) that injection site reactions were elevated in the lixisenatide arm (6.7% vs. 2.2%); and 4) that the discontinuation rate due to adverse events was higher in the lixisenatide arm (8.5% vs. 3.6%), largely driven by GI side effects.

• The GetGoal-Duo 1 study evaluated the safety of efficacy of adding lixisenatide to recently initiated and optimally titrated insulin glargine therapy in individuals with type 2 diabetes. The randomized, double-blind, placebo-controlled study included a 12-week run in period in which insulin glargine therapy was initiated and titrated to a target FPG of 80- 100 mg/dl. Following this 12-week period, participants (n=446) who had not achieved an A1c<7.0% despite achieving the FPG target were randomized to receive lixisenatide once daily orplacebo for 24 weeks while continuing on insulin glargine therapy (continuously titrated) and background metformin and/or TZD therapy. The primary endpoint of the study was change in A1c at week 26. At baseline, patient demographics were similar in both groups. Average age was 56.2 years, type 2 diabetes duration was 9.2 years, BMI was 31.8 kg/m2, and A1c was 8.6%.

• Lixisenatide treatment improved glycemic control over placebo when added onto insulin glargine treatment. During the run in period, A1c was reduced in both treatment groups from 8.6% to 7.6%. At week 26 of the treatment period, lixisenatide (-0.7%) provided further improvements in A1c over placebo (treatment difference of 0.32%; p <0.0001). The percentage of individuals achieving an A1c <7.0% (56% vs. 39%) and <6.5% (32% vs. 16%) was statistically greater in the lixisenatide arm than the placebo arm, respectively. Additionally, two hour OGTT values were significantly improved with lixisenatide over placebo (mean treatment difference of 56 mg/dl; p <0.0001). Dr. Rosenstock noted that insulin glargine doses were only minimally titrated in the treatment period, increasing from 44 units to 50 units per day in both arms.

• Lixisenatide had a beneficial effect on body weight, but was associated with an increased risk for hypoglycemia. In the lixisenatide arm, there was 0.3 kg (0.7 lbs) of weight gain vs. 1.2 kg (2.6 lbs) of weight gain in the placebo group (p=0.0012). Meanwhile, the number of hypoglycemic events per patient-year was 0.98 for lixisenatide vs. 0.44 for placebo – although Dr. Rosenstock argued that this was still a very low rate of hypoglycemia. Significantly more participants in the lixisenatide arm were able to achieve the composite endpoint of A1c <7.0%, no hypoglycemia, and no weight gain (28% vs. 18%).
• As expected, GI side effects were the most frequently reported adverse events in the lixisenatide arm. In particular, the rates of nausea (27.4% vs. 4.9%) and vomiting (9.4% and 1.3%) were elevated with lixisenatide treatment over placebo, respectively. On average, nausea appeared to subside after six to eight weeks of treatment. The percentage of participants discontinuing from the trial due to adverse events was also higher in the lixisenatide arm (8.5% vs. 3.6%), which was driven by nausea and vomiting (4% vs. none). Injection site reactions occurred in 6.7% of individuals in the lixisenatide arm in comparison to 2.2% in the placebo arm. However, injection sites reactions did not play a major causal role in study discontinuation (0.9%). Only one pancreatitis case was reported in the study, and it occurred in the placebo arm.

Questions and Answers

Q: Was there any effect on heart rate, blood pressure or lipids?

A: There were no lipid changes in this study. There doesn’t appear to be a signal for pulse increases with lixisenatide. There was no change in blood pressure either.

Q: The effects of lixisenatide were quite impressive. When was the drug administered?

A: Lixisenatide was administered in the morning. The mixed meal tests were conducted in the morning.

Q: Do you have any data for PPG following other meals?

A: No, we don’t in this study.

EXENATIDE TREATMENT FOR SIX MONTHS IMPROVES INSULIN SENSITIVITY IN ADULTS WITH TYPE 1 DIABETES MELLITUS (58-OR)

Gayatri Sarkar, MD (DEOB, NIDDK, NIH, Bethesda, MD)

Dr. Sarkar presented the results of a small study that explored the effects of exenatide on glucose metabolism in adults with type 1 diabetes with a focus on insulin sensitivity. The cross over study randomized 14 adults with long-standing, well-controlled type 1 diabetes to receive either insulin or insulin and exenatide (dose gradually increased to 10 mcg four times daily) for six months before switching treatments. Exenatide provided decreases in weight and postprandial plasma glucose levels, an increase in fasting plasma glucose levels, and no change in A1c (data presented in Table 1, below). While taking exenatide and insulin, participants had lower daily insulin requirements and enhanced insulin sensitivity compared to treatment with insulin monotherapy. Dr. Sarkar reviewed several potential explanations of the results, which are summarized in Table 2 below. In particular, she noted that while exenatide’s mechanism of enhancing insulin sensitivity in humans is currently uncertain, results from preclinical studies have suggested some possibilities, including increased vagus nerve activity and altered cytokine production. Dr. Sarkar concluded by stating that the results from this study should prompt further investigation into whether insulin sensitizing effects can also be achieved with other GLP-1 agonists in people with type 1 diabetes.

 

Table 1. Study Results

Measurement	On Exenatide	Off Exenatide	P value
Weight (kg)	74.2	78.4	p=0.0003
A1c (%)	6.6	6.8	p=0.388
Fasting plasma glucose (mg/dl)	136.9	129.7	p=0.0002
Postprandial plasma glucose (mg/dl)	135.5	142.5	p=0.0005
Insulin requirement (units/kg/day)	0.48	0.55	p=0.0062

Insulin Sensitivity Index* (SI) (mg/m2/min per U/ml)7.155.21p=0.0039* The Insulin Sensitivity Index (SI) is defined as the glucose disposal rate normalized for body surface area and plasma insulin concentration. It was determined using hyperinsulinemic euglycemic clamp studies lasting 180 minutes with an insulin dose of 120 U/m2/min.

Table 2: Potential Explanations of Results

Observed Result	Potential Explanation
Decreased body weight	Suppressed appetite
Lack of lowering fasting plasma glucose levels	Lack of inhibition of glucagon
Decreased postprandial plasma glucose levels	Slower gastric emptying
No change in A1c	Net effect of fasting and postprandial plasma glucose levels
Lower insulin requirement	Improved insulin sensitivity

Improved insulin sensitivity mechanism is not entirely clear in humans. Results of preclinical studies suggest three possibilities: 1. Increased insulin-stimulated glucose uptake in muscle and fat cells via a PI-3 kinase dependent mechanism 2. Centrally increased vagal activity 3. Anti-inflammatory effects and altered cytokine production.

Questions and Answers

Q: With respect to the increased fasting plasma glucose levels, you said it may be due to a lack of glucagon inhibition. Do you have any data on postprandial glucagon measurements?

A: No, our group didn’t see any difference in glucagon. However, other groups have shown inhibition of glucagon after exenatide use. So this remains controversial. Now there are postulates for some mechanisms for the lack of glucagon suppression. Because there is no ability to produce insulin in type 1 diabetes patients, the cross talk between glucagon and insulin may be lost. Also, there is no postprandial expression of amylin in people with type 1 diabetes, and amylin has been shown to suppress glucagon. So the topic is controversial.

VILDAGLIPTIN REDUCES GLUCAGON DURING HYPERGLYCEMIA AND SUSTAINS GLUCAGON COUNTER-REGULATION IN TYPE 1 DIABETES (59-OR)

Bo Ahren, MD, PhD (Lund University, Malmo, Sweden)

Dr. Ahren presented results from a small (n=28), randomized, placebo-controlled, crossover study in people with type 1 diabetes that examined the effects of vildagliptin treatment on glucagon responses during meal induced hyperglycemia and insulin-induced hypoglycemia. Following four weeks of treatment with vildagliptin or placebo, a mixed meal test and a subsequent hyperinsulinemic hypoglycemic clamp were used to measure glucagon responses to a meal and induced hypoglycemia. Overall, the study found that vildagliptin treatment was associated with a reduced glucagon response following a meal (73% reduction; p=0.022), but no significant reduction in the glucagon response during hypoglycemia (11% reduction; p=0.895). Changes to other counter-regulatory hormones (i.e., epinephrine, norepinephrine, and cortisol) were also not observed. Interestingly, despite no detected alterations in counter-regulatory responses to hypoglycemia, glucose levels remained lower in the vildagliptin arm (6.4 mmol/l [115 mg/dl]) than in the placebo arm (7.6 mmol/l [136.8 mg/dl]; p=0.040) during recovery from hypoglycemia. Dr. Ahren was unclear of why this result occurred, but hypothesized that it might have been related to the lower average blood glucose achieved by participants treated with vildagliptin in the study. Vildagliptin treatment led to a 0.3% reduction in A1c vs. no change with placebo (p <0.001). Finally, vildagliptin therapy was reported to be safe and well tolerated, with no differences in rates of adverse events in comparison to placebo, including hypoglycemia. Based on this data, Dr. Ahren concluded that vildagliptin could serve as an effective adjunct to insulin therapy in people with type 1 diabetes and called for more extensive studies to more robustly examine DPP-4 treatment in this patient population.

• This placebo-controlled, crossover study examined the effects of vildagliptin treatment on glucagon response during meal-induced hyperglycemia and insulin- induced hypoglycemia in people with type 1 diabetes. 28 individuals with type 1 diabetes with no measurable C-peptide response, an A1c of 6.5% to 8.5%, and a diabetes duration between two and twenty years were randomized to receive 50 mg of vildagliptin twice daily or placebo for four weeks. All participants continued with their previous insulin therapy. Following a four-week wash out period, trial participants received the alternative study treatment for an additional four weeks. A mixed meal test and subsequent hyperinsulinemic hypoglycemic clamp at 2.5 mmol/l (45 mg/dl) were used to measure glucagon responses to a meal and induced hypoglycemia at the end of both treatment periods. Blood glucose values, intact GLP-1 levels, and other counter- regulatory were also measured (i.e., epinephrine, norepinephrine, and cortisol). At baseline, average age was 30 years, BMI was 24.8 kg/m2, A1c was 7.7%, and diabetes duration of 11 years.
• Vildagliptin treatment was associated with a reduced glucagon response following a meal, but no significant reduction in glucagon response during hypoglycemia. Following the consumption of the mixed-meal, glucose levels were observed to be higher in the placebo arm than the vildagliptin arm. This result was at least partly attributed to a 73% reduction in glucagon levels in the vildagliptin arm (p=0.022). During hypoglycemia (induced using the hyperinsulinemic hypoglycemic clamp) the glucagon counter-regulatory response was not found to be significantly impaired with vildagliptin treatment (11% reduction, p=0.895). Similarly, the counter-regulatory responses in epinephrine, norepinephrine and cortisol were also not different between the groups. Interestingly, despite no detected alterations in counter-regulatory responses to hypoglycemia, glucose levels remained lower in the vildagliptin arm (6.4 mmol/l [115 mg/dl]) than in the placebo arm (7.6 mmol/l [136.8 mg/dl]; p=0.040) during recovery from hypoglycemia.
• Vildagliptin treatment provided statistically significant reductions in A1c over placebo but no change in insulin dose requirements. After four weeks of treatment, average A1c reduction in the vildagliptin arm was 0.3% in comparison to no change in placebo (p<0.001).

Oral Sessions: The Clinical Management of Diabetes

COMPARISON OF 24-WEEK TREATMENT WITH EXENATIDE, INSULIN AND PIOGLITAZONE IN NEWLY DIAGNOSED AND DRUG-NAÏVE T2DM (12-OR)

Wen Xu, MD (Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China)

In the CONFIDENCE trial (clinicaltrials.gov ID: NCT01147627; study conducted at 25 sites in China), newly diagnosed and drug-naïve patients with type 2 diabetes (n=416) were randomized to receive exenatide (5ug BID; titrated up to 10 ug BID after four weeks), mixed protamine zinc recombinant human insulin lispro 25R injection (initial dose 0.4 IU/kg/day), or pioglitazone (30 mg; titrated to 45 mg as appropriate) for a 48-week period in order to compare the efficacy of exenatide versus the other agents on glycemic control and β-cell function. In this preliminary analysis of 24-week data available as of November 2011 (n=127), the exenatide group (n=40) and the insulin group (n=43) experienced significantly greater (p=0.036) reductions in A1c (1.8% from baselines of 8.0% and 8.2%) compared to the pioglitazone group (n=44) (1.3% from a baseline of 8.0%). Exenatide treatment resulted in significantly more weight loss (5.0 kg [11 lbs]) than with insulin treatment (0.7 kg [1.6 lbs]) or pioglitazone treatment (2.6 kg [5.7 lbs]). No cases of severe hypoglycemia were reported during the 24-week period. In the exenatide group, GI side effects were the most commonly reported adverse event (60%); one case of acute pancreatitis was reported in this treatment arm. The trial is expected to complete later this year. (Editor’s note – we didn’t catch baseline weights.)

• In the CONFIDENCE trial, 416 newly diagnosed, drug-naïve individuals with type 2 diabetes were randomized to exenatide, insulin, or pioglitazone treatment. These patients were enrolled from 25 centers in China, were 30-70 years of age, had a BMI of 20-35 kg/m2, had baseline A1c between 7.0% and 10.0%, and had stable body weight (≤10% fluctuations for at least three months). In this analysis of the available 24-week data as of November 2011 (n=127), patients were on average 52 years old, with a BMI of 26 kg/m2.

Questions and Answers

Q: Nearly 60-65% of patients with exenatide experienced GI side effects. What was the discontinuation rate in this group?

A: Only five patients withdrew from the study because of severe GI effects. Most were able to tolerate these adverse events. About 20% of patients had to go back to the 5 ug BID dose; at that dose, they could tolerate the adverse events, and had very good glucose control at that dose.

Q: Could you comment on the rationale behind your insulin choice, and tell us how it was titrated?

A: We chose it because multiple daily injections would not have been practical, since all patients were treated for 48 weeks. So, we used a twice-daily insulin. We didn’t have a standard titration algorithm; we just asked investigators to titrate insulin according to their experience.

Q: Was the dose of pioglitazone increased to 45 mg?

A: Yes, it was – if patients had A1c greater than 9%, pioglitazone was titrated to the maximum dose of 45 mg.

Q: Some of the results you presented seemed surprising, just based on what I think I know from previous trials – you observed a 1.8% decrease in A1c with exenatide, and you didn’t see any weight gain with pioglitazone or insulin, right?

A: It is not common to see weight reduction with pioglitazone. In this preliminary data, we showed that patients treated with pioglitazone lost weight. Two potential explanations are the lifestyle modification program, and the small sample size in this analysis. Only 127 patients had 24-week data available for analysis at the time – just 40 patients in each group. Before I came here, I analyzed all the most recent data we could get from the database, and patients treated with exenatide had about a 3.5 kg (7.7 lb) weight reduction, patients treated with pioglitazone had about a 0.5 kg (1.1 lb) reduction, and patients treated with insulin had a 0.17 kg (0.37 lb) increase. We think that with a larger sample size and longer follow-up period, these weight changes may reflect what previous trials have shown; maybe patients treated with pioglitazone will have weight gain.

REAL-WORLD OUTCOMES OF INITIATING INJECTABLE THERAPY WITH INSULIN GLARGINE OR LIRAGLUTIDE AMONG PATIENTS WITH TYPE 2 DIABETES (11-OR)

Philip Levin, MD (Mercy Medical Center, Baltimore, MD)

Dr. Levin presented the results from a retrospective analysis of the IMPACT managed care database that assessed and compared the real-world clinical outcomes (at one-year) and costs associated with injectable treatment initiation with liraglutide or insulin glargine among people with type 2 diabetes. Inclusion criteria for the study included age over 18, initiation of either therapy between January and June 2010, and A1c over 7%. Stringent propensity score matching (1:1 ration) was used to minimize any differences among baseline characteristics between the two study groups. A total of 336 individuals were included in the final study (168 individuals in each group). Overall, differences in treatment persistence, A1c reductions (1.02% vs. 0.95%), prevalence of overall hypoglycemia (7.7% vs. 4.7%), and prevalence of severe hypoglycemia (1.1% for each) were found to be non-significant between the insulin glargine and liraglutide groups, respectively. However, insulin glargine was associated with lower yearly study drug costs ($1198 vs. $2784; p <0.0001), which also drove lower diabetes related drug costs ($2958 vs. $3988) and lower total diabetes related costs ($5600 vs. $7900) for insulin glargine. Dr. Levin concluded that these results suggest that among people with type 2 diabetes, the initiation of injectable therapy with insulin glargine in comparison to liraglutide is associated with similar clinical outcomes but lower diabetes care costs in a real-world setting. Still, he noted that there were several notable limitations to the study, including a small sample size, a lack of weight loss data, the short time span of the study, the observational and retrospective nature of the study, and the use of clinical data from a claims database that may contain errors regarding diagnosis and treatment codes. Further details from the study will be presented in poster 1108. We note that in the LEAD-5 study, liraglutide was demonstrated to provide statistically significant improvements in A1c (1.33% vs. 1.09%; p=0.0015) and weight (treatment difference -3.43 kg; p <0.0001) over insulin glargine when added onto metformin and glyburide therapy. Rates of major and minor hypoglycemia were reported to be similar between the two arms.

Oral Sessions: Human Immunology and Diabetes

GLUCAGON-LIKE PEPTIDE-1 – A KEY REGULATOR OF INNATE IMMUNE FUNCTION WITH CLINICAL EFFICACY IN A RANGE OF INFLAMMATORY DISEASES (90-OR)

Andrew Hogan, PhD (St. Columcille’s & St. Vincent’s Hospitals, Dublin, Ireland)

Dr. Hogan explored the role of GLP-1 as a regulator of innate immune function. In particular, he highlighted the anti-inflammatory effects of GLP-1, which he suggested were mediated by the hormone’s effects of on invariant natural killer T (iNKT) cells. As background, iNKT cells are a subset of lymphocytes that possess potent immunoregulatory activities, with the ability to modulate biological processes ranging from inflammation, autoimmunity, and tumor rejection to antimicrobial immunity. Consequently, iNKT cells are thought to play a role in the pathology of a number of different inflammatory, autoimmune, and infectious diseases. Dr. Hogan highlighted results from both rodent and human studies to detail the known impacts of GLP-1 on iNKT cells. In mice, liraglutide at 50 ug/kg (a significantly higher dose than currently approved for use in humans [1.2 or 1.8 mg]) had no effect on weight and food intake, but did decrease fat pad mass and white adipose tissue adipocyte size. Liraglutide was also found to increase the number of circulating and thymic iNKT cells, and it exhibited several anti-inflammatory effects, including the modulation of white adipose tissue macrophage polarization. These effects were conferred in an initial, very small human study, which examined the effects of liraglutide treatment in two people with type 2 diabetes and psoriasis (an inflammatory disease). After six weeks of treatment, the Psoriasis Area and Severity Index improved in both patients. These improvements were associated with increased numbers of iNKT cells in circulation and decreased numbers in psoriatic plaques. Separately, in vitro studies showed that the GLP-1 receptor was expressed on iNKT cells, and that GLP-1 could induce dose-dependent inhibition of iNKT cell cytokine secretion. While acknowledging the need for much further investigation in this area, Dr. Hogan concluded that GLP-1 appears to directly interact with the immune system, potentially raising the possibility for therapeutic applications of GLP-1 in inflammatory diseases.

 

Oral Sessions: Diabetic Dyslipidemia

EXENATIDE, A GLUCAGON-LIKE PEPTIDE RECEPTOR AGONIST, ACUTELY INHIBITS INTESTINAL LIPOPROTEIN PRODUCTION IN HEALTHY HUMANS (49-OR)

Changting Xiao, PhD (University of Toronto, Toronto, Canada)

Dr. Xiao described the effects of exenatide on triglyceride-rich lipoprotein (TRL) production and clearance in healthy men. A cohort of normolipidemic, normoglycemic men (n=15) was administered 10 ug of exenatide while a pancreatic clamp was used to mitigate exenatide-induced changes in insulin and glucagon production. During the study, a fed state was also maintained by infusing a high-fat, mixed macronutrient, liquid formula at a constant rate into the duodenum. No significant differences were observed in plasma triglyceride, TRL, or free fatty acid levels. Exenatide did, however, acutely inhibit intestinal lipoprotein (apoB-48) production, but not hepatic lipoprotein (apoB-100) production. While exenatide administration did result in a transient rise in insulin and C-peptide levels, Dr. Xiao indicated that the prolonged suppression of apoB-48 observed in the trial was thought to be a direct result of exenatide. Previous clinical trials have demonstrated the ability of GLP-1 agonists to improve plasma lipid profiles and postprandial lipemia; yet, the mechanisms underlying these effects have remained unclear. Based upon these results, Dr. Xiao suggested that these effects could be mediated by the direct effects of GLP-1 agonists on intestinal lipoprotein production independent of any effects on gastric emptying, weight loss, and satiety.

Questions and Answers

Q: You ran into an issue of lack of complete suppression with the pancreatic clamp – it could be that the intestine is more sensitive than the liver is. Could a change in the site of absorption be a factor?

A: This is possible, however we can’t tell if adsorption site changed with GLP-1 based on the current data.

Posters

EFFICACY AND SAFETY OF ONCE-DAILY LIXISENATIDE IN TYPE 2 DIABETES INSUFFICIENTLY CONTROLLED WITH BASAL INSULIN METFORMIN (983-P)

Matthew Riddle, Ronnie Aronson, Philip Home, Michel Marre, Elisabeth Niemoeller, Lin Ping, Julio Rosenstock

The 24 week, double-blind, placebo controlled phase 3 trial (n=495) randomized participants with type 2 diabetes previously treated with basal insulin with or without metformin to add placebo or 20 g of lixisenatide, Sanofi’s once daily GLP-1 agonist. Lixisenatide in addition to basal insulin led to significantly greater reductions in A1c compared to placebo (-0.74% vs -0.38%, p=0.0002), post- 0prandial glucose after breakfast (-75 mg/dl vs -6 mg/dl, p<0.0001), and mean seven-point self- monitored blood glucose (-27 mg/dl vs -11 mg/dl, p <0.0001). However, no significant change in fasting plasma glucose levels were observed. Additionally, after 24 weeks, participants on lixisenatide lost 1.8 kg (3.97 lbs) of weight on average compared to 0.5 kg (1.10 lbs) with placebo (p <0.0001). Gastrointestinal disorders accounted for the majority of adverse events in the lixisenatide arm, and were significantly more frequent (40.2%) than in the placebo arm (20.4%). Treatment with lixisenatide resulted in no significant increases in hypoglycemia compared to placebo. A double-blind extension study of at least 52 weeks is currently underway.

• In this 24 week, double-blind, randomized and placebo controlled trial, people with type 2 diabetes were randomized to receive placebo (n=167) or 20 g of lixisenatide (n=328) in addition to their previous basal insulin treatment, with or without metformin. Lixisenatide was added in a two-step dose increase regimen (i.e., 10 ug at trial start, 15 ug at week one, and 20 ug at week two). The study drug was delivered subcutaneously once daily, less than an hour before breakfast. Participants had diabetes for an average duration of 11 years, were on basal insulin at a stable dosage (>30 U/day) for at least three months, and received diet and lifestyle coaching every three months.
• Lixisenatide led to significantly improved glycemic control compared to placebo in terms of A1c, postprandial glucose, and seven-point self-monitored blood glucose. Lixisenatide reduced A1c from a mean 8.4% baseline significantly more than placebo (-0.74% vs. - 0.38%, p=0.0002). Additionally, a greater proportion of participants achieved a 7% A1c target at 24 weeks on lixisenatide (28.3%) compared to placebo (12%, p <0.01). Lixisenatide also led to significantly greater reduction of postprandial glucose increment following breakfast (-75 mg/dl from 138 mg/dl at baseline) than placebo (-6 mg/dl from 130 mg/dl at baseline, p <0.0001) and greater mean reduction of seven-point self-monitored blood glucose (-27 mg/dl vs. -11 mg/dl, p<0.0001). Change in fasting plasma glucose was not significantly different between the twogroups (-11 mg/dl with lixisenatide vs. -10 mg/dl with placebo, baseline of 145 mg/dl, p=ns). With regards to weight, significantly greater reductions were observed with lixisenatide (1.8 kg [4.0 lbs], baseline of 87.4 kg [192.7 lbs]) compared to placebo (0.5 kg [1.1 lbs], baseline of 89.1 kg [196.5 lbs], p<0.0001).
• The most common side effects associated with lixisenatide treatment in combination with basal insulin were gastrointestinal in nature. The incidence of gastrointestinal disorders was higher in the lixisenatide treatment arm (40.2%) compared to placebo (20.4%), and discontinuation due to GI adverse events was also higher with lixisenatide (4.3% vs 1.2%). The most common adverse events in the lixisenatide arm, excluding hypoglycemia, were nausea (26.2%), vomiting (8.2%), and diarrhea (7.3%). In contrast, 8.4% experienced nausea, 0.6% vomiting, and 5.4% diarrhea in the placebo arm. The study also reported one sudden cardiac death in the lixisenatide arm unrelated to the study treatment. Finally, while symptomatic hypoglycemia was r elevated in the lixisenatide arm over the placebo arm (27.7% and 21.6%, respectively), the difference was not found to be statistically significant.

IDENTIFYING PREDICTORS OF RESPONSE TO LIRAGLUTIDE IN TYPE 2 DIABETES USING RECURSIVE PARTIONING ANALYSIS (1041-P)

Robert Ratner, Jason Brett, Naum Khutoryansky, Vanita Aroda

Analyzing pooled data from the six LEAD trials and Lira-DPP-4 study, this study identified characteristics that predict the likelihood of responding to therapy, defined as achieving an endpoint A1c of <7%, with no weight gain and no hypoglycemia over 26 weeks. Overall, 34% of individuals on liraglutide 1.8 mg achieved this composite endpoint (n=1,530), compared to 30% of those on liraglutide 1.2 mg (n=1075), 24% on exenatide (n=221), 14% on sitagliptin (n=210), 9% on sulfonylureas (n=475), 9% on glargine (n=224), and 3% on TZDs (n=226). The most significant predictor of response to therapy was baseline A1c, as 46% of individuals with a baseline A1c <8.5% achieved the composite outcome compared to only 19% of individuals with baseline A1c ≥8.5% (p <0.0001). Recursive partitioning analysis was then used to identify a total of six homogenous subgroups with varying probabilities of achieving the composite endpoint with liraglutide 1.8 mg treatment. The subgroup consisting of female participants with baseline A1c <8.5%, previous treatment with diet or monotherapy, and diabetes duration <4.9 years had the highest likelihood of achieving the composite outcome (74%). Individuals with a baseline A1c ≥8.5% who were previously on combination oral antidiabetic therapy had the lowest likelihood of achieving the endpoint (14%). In general, the type of analysis used in this study may be valuable for guiding clinicians in individualizing treatment approaches.

PHARMACOKINETICS AND PHARMACODYNAMICS OF A NEW EXENATIDE FORMULATION, EXENATIDE SUSPENSION (1099-P)

Leigh MacConell, Stephen Flore, Brenda Cirincione, Matthew Zierhut, Christopher Biwald, Wenying Huang, T.K. Booker Porter, Lisa Porter

This phase 2, randomized, controlled, 2-cohort clinical trial examined the PK/PD profile of exenatide suspension (EQWS). EQWS utilizes the same extended release microspheres as once weekly exenatide (EQW), but is reformulated with a medium chain triglyceride (MCT) vehicle. As a pre-suspended product, EQWS would be compatible with a pen device and would reduce the initial release that appears to affect gastrointestinal tolerability. In an in vitro release assay, EQWS was shown to have a blunted initial release compared to EQW, but a similar release profile overall. This trial’s first cohort of 30 healthy volunteers, which was given a single 10 mg dose of EQWS, confirmed the release profile seen in vitro. This profile was characterized by exenatide concentrations increasing gradually over time and peaking at weeks six to seven. The extent and duration of exposure following one dose of EQWS was similar to what has been seen with EQW, suggesting that EQWS could provide similar efficacy with improved delivery. This trial’s second cohort included 35 individuals with type 2 diabetes who received weekly injections of 2 mg EQWS or MCT-only as a control. Those on EQWS achieved mean steady-state concentrations by eight to ten weeks. At week 12, there was a significant difference in mean A1c between those receiving EQWS compared to MCT-only (-0.9% versus 0.1%, p<0.05; mean baseline A1c ~ 8%). EQWS was generally well tolerated; the majority of observed treatment-emergent adverse events were of mild intensity, and no major or minor hypoglycemia was observed. Overall, the safety profile, release profile, and improvements in glycemic control seen with EQWS were comparable to EQW, supporting development of exenatide suspension.

• At twelve weeks, participants receiving 2 mg EQWS experienced an A1c reduction of 0.9% compared to a 0.1% A1c increase in the control group. Significantly more participants reached an A1c goal of <7% on EQWS (61%) compared to MCT-only (17%). EQWS treatment also led to a significant reduction in fasting plasma glucose (32 mg/dl) in comparison to MCT-only, which led to an 8 mg/dl increase after 12 weeks. Additionally, individuals on EQWS lost an average of 1.4 kg (3.1 lbs), compared to 0.4 kg (0.9 lbs) with MCT-only.
• Apart from injection site reactions, EQWS was generally well tolerated, with no major or minor hypoglycemia events observed. Injection site reactions accounted for the majority of adverse events, with 52.2%, 47.8%, and 39.1% of participants on EQWS experiencing erythema, pruritus, and haematoma, respectively. In comparison, participants on MCT-only experienced these reactions at rates of 8.3%, 8.3%, and 50%, respectively. Patients treated with 2 mg EQWS also reported decreased appetite, injection site pain, and nausea (21.7% each). In contrast, nausea, injection-site pain, and diarrhea rates were 8.3%, 0.0%, and 0.0%, respectively in control patients. Overall, the adverse event profile of EQWS was similar to that previously seen with EQW.

 

EFFICACY AND SAFETY OF LIXISENATIDE ONCE DAILY VERSUS PLACEBO IN PATIENTS WITH TYPE 2 DIABETES INSUFFICIENTLY CONTROLLED ON PIOGLITAZONE (GETGOAL-P) (1010-P)

Michel Pinget, Ronald Goldenberg, Elisabeth Niemoeller, Isabel Muehlen-Bartmer, Ronnie Aronson

This randomized, double-blind, placebo-controlled, multicenter study evaluated the efficacy and safety of lixisenatide (20 g), a once-daily selective GLP-1 receptor agonist, compared with placebo in patients with type 2 diabetes (n=484) insufficiently controlled with pioglitazone (≥30 mg daily) metformin. At the end of the study’s 24-week treatment period, lixisenatide produced a significantly greater reduction in A1c from baseline (-0.90%) than placebo (-0.34%) (p <0.0001). Furthermore, 52% of the lixisenatide treatment population achieved an A1c level of less than 7.0% compared with only 26% of the placebo population (p <0.0001). Overall, lixisenatide was well tolerated, and significantly fewer participants on lixisenatide vs. placebo required rescue therapy (3.8% vs. 11.3%). Incidence of adverse and severe side effects was comparable in both groups, and there were no cases of severe hypoglycemia in either group. This data suggests that lixisenatide effectively and safely improves glycemic control in patients with type 2 diabetes experiencing insufficient control with pioglitazone metformin.

• Lixisenatide (n=323) and placebo (n= 161) treatment arms were well matched for A1c, fasting plasma glucose, and body weight at baseline. Baseline A1c, fasting plasma glucose, and body weight were 8.08%, 164.5 mg/dl, and 92.9 kg (204.8 lbs), respectively, in the lixisenatide group. In the placebo group, baseline A1c, fasting plasma glucose, and body weight were 8.05%, 164.2 mg/dl, and 96.7 kg (213.2) lbs, respectively. About 51% of subjects in both groups had an A1c of ≥8%. Demographic characteristics, including average age (56.0 years (lixisenatide group) vs. 55.3 years (placebo group), gender (% male = 53.3% lixisenatide group) vs. 50.9% (placebo group)), and duration of diabetes (8.1 years), were also comparable between the two groups. Notably, over 80% of all participants in both populations were Caucasian.
• Compared with placebo, lixisenatide produced significantly greater reductions in A1c and fasting plasma glucose levels. At week 24, lixisenatide treatment lowered A1c by 0.90% versus 0.34% with placebo (p < 0.0001). A significantly greater proportion of patients in the lixisenatide arm vs. the placebo arm attained an A1c of ≤6.5% (28.9 vs. 10.1%; p <0.0001) and an A1c of <7.0% (52.3 vs. 26.4%; p <0.0001) at 24 weeks. Similarly, lixisenatide was associated with a significantly greater reduction in fasting plasma glucose vs. placebo (-20.9 mg/dl vs. -5.7 mg/dl). Significantly fewer lixisenatide vs. placebo-treated patients required rescue therapy during the study’s 24-week treatment period (3.8 vs. 11.3%; p = 0.0011).
• There was no significant difference in mean body weight reduction with lixisenatide vs. placebo treatment. From baseline to week 24, body weight decreased on average by -0.21 kg (0.5 lbs) in the lixisenatide group compared with an average increase of 0.21 kg (0.5 lbs) in placebo-treated patients.
• Incidence of adverse events and rates of discontinuation were comparable between both treatment arms. Rates of treatment emergent adverse events (72.4% with lixisenatide vs. 72.7% with placebo) and serious TEAEs (2.5% with lixisenatide vs. 1.9% with placebo) were similar between the study’s arms. Discontinuation rates due to TEAEs were also similar between groups (6.5% vs. 5.0% for the lixisenatide vs. placebo treated groups, respectively). Notably, symptomatic hypoglycemia rates were low in both groups, and there was no incidence of severe hypoglycemia in either treatment population.

 

EXENATIDE ONCE WEEKLY RESULTED IN SUSTAINED IMPROVEMENT IN GLYCEMIC CONTROL WITH WEIGHT LOSS THROUGH FOUR YEARS (1156-P)

Leigh MacConell, Yan Li, Rich Pencek, Christine Schulteis, Lisa Porter

The comparator-controlled, open-label, randomized DURATION-1 study examined the safety and efficacy of exenatide once-weekly (EQW) in patients with type 2 diabetes over 30 weeks. Persistence of glycemic control in patients receiving EQW was then studied in a four-year extension trial (n=258; 176 patients completed four years of treatment). Long-term EQW treatment was associated with a significant reduction in A1c (-1.7% [95% CI: -1.9, -1.5]). At four years, mean A1c was 6.9% 0.1% among those receiving EQW. Four year EQW treatment was also associated with clinically significant improvements in fasting plasma glucose (FPG) (-37 mg/dl), weight (-2.5 kg (5.5 lbs)), systolic blood pressure (-1.6 mmHg), total cholesterol (-10.9 mg/dl), LDL cholesterol (-8.0 mg/dl), and triglyceride levels (-13%). Nausea was the most common adverse effect associated with four-year EQW treatment; however, its incidence decreased substantially over time. 20% of patients experienced adverse events during the four-year study duration. However, there was no identifiable pattern of serious adverse events. No major hypoglycemia was observed, and minor hypoglycemia was mainly associated with SFU use.

• At baseline, the four-year completer population (n=176) were on average 56 years old, weighed 222 lbs, had a BMI of 35 kg/m2, an A1c of 8.2%, a fasting plasma glucose of 166 mg/dl, and an average duration of diabetes of 7 years. These values were comparable to baseline data for the intent-to-treat population (n=295).
• At the end of four years, 55% of patients receiving EQW achieved an A1c of less than 7.0%, and 36% achieved an A1c less than 6.5%, quite striking results, especially the percentage that got to an A1c of less than 6.5%, given the medium to high baseline A1c. We do note that 34% of the ITT population withdrew between weeks 30 and 212 and, presumably, their response to EQW might have not been as favorable; however, the results from those who did stay in the study are encouraging. Notably, improvements in beta cell function with EQW treatment were also observed after four years (HOMA-B and HOMA-S increased an average of 26% and 13%, respectively).
• Nausea and injection-site infection were the most common adverse side effects observed in the trial. Within the first 30 weeks of treatment, incidence of both nausea and injection-site events was ~30%. Subsequently, the incidence reduced dramatically, and during the second 30-week period of treatment, about 10% or less of patients reported either nausea and injection-site events. The annual event rate for nausea with EQW was 15/100 years patient exposure over the four-year study duration, while injection-site pruritus occurred at a rate of 6/100 years patient exposure. Rates of vomiting and diarrhea also declined over time. 20% of EQW patients experienced 89 serious adverse events during the study’s four years, without any pattern among these events.
• Notably, no major hypoglycemia was observed with EQW over the study’s four years. Minor hypoglycemic events occurred mainly in patients using concomitant sulfonylureas (event rate of 26/100 years patient exposure over four years). We find it very encouraging, though not surprising, that EQW’s favorable hypoglycemia profile persists with long-term treatment.

EFFICACY AND SAFETY OF ONCE-WEEKLY (QW) ALBIGLUTIDE VS ONCE-DAILY (QD) LIRAGLUTIDE IN T2D (TYPE 2 DIABETES) INADEQUATELY CONTROLLED ON ORAL AGENTS: HARMONY 7 TRIAL (945-P)

Richard Pratley, Anthony Barnet, Mark Feinglos, Ilana Harman-Boehm, Michael Nauck, Fernando Ovalle, Susan Johnson, Murray Stewart, June Ye, Julio Rosenstock

Harmony 7 was a 32-week, randomized, open-label phase 3 trial (n=841) in which participants on one to three oral anti-diabetic medications received GSK’s albiglutide once-weekly titrated to a maximum of 50 mg (n=404) or liraglutide once-daily titrated to a maximum of 1.8 mg (n=408). As previously reported (see our coverage at http://bit.ly/zBmUX8), albiglutide failed to meet the non-inferiority criteria of A1c reduction compared to liraglutide – compared to a 0.99% A1c reduction with liraglutide (baseline 8.15%), those on albiglutide experienced an average A1c reduction of 0.78% (baseline 8.19%). Additionally, participants receiving albiglutide lost less weight than those on liraglutide (0.64 kg [1.41 lbs] vs. 2.19 kg [4.83 lbs]). Fasting plasma glucose change from baseline was significantly greater with albiglutide than liraglutide (-22.1 mg/dl with albiglutide vs. -30.4 mg/dl for liraglutide; p = 0.005). Notably, fewer patients experienced nausea/vomiting on albiglutide than on liraglutide (9.9% vs. 29.2% nausea, and 5.0% vs. 9.3% vomiting) - this was a striking tolerability finding and makes us wonder about the dose of albiglutide used, especially since efficacy was lower. Hypoglycemia occurred more frequently in the liraglutide group than the albiglutide group (though was very low in both), while subjects on albiglutide experienced higher incidences of injection site reactions.

• Additional data on GI adverse events and A1c lowering support the strong tolerability but reduced A1c lowering efficacy of albiglutide compared to liraglutide. Although albiglutide significantly reduced A1c from baseline to week 32 (p <0.001), significantly more patients achieved an A1c of <7% at 32 weeks with liraglutide (51.7%) than albiglutide (42.2%) treatment (p=0.0323). Similarly, 19.6% vs. 28.1% (p=0.0009) of albiglutide vs. liraglutide treated patients achieved an A1c of <6.5% at 32 weeks. Additionally, there was a statistically significant difference between albiglutide and liraglutide for time to hypoglycemia rescue (p= 0.005), with a higher probability of hyperglycemia rescue from week 12 to 32 in those taking albiglutide vs. liraglutide. Notably, rates of GI adverse events were lower in the albiglutide vs. liraglutide group (35.9% vs. 49.0%) - if the efficacy had been as strong, this might have been quite a notable finding. The incidence of GI events was generally stable through the 32 weeks in the albiglutide group, compared to a high peak in GI events with liraglutide in the first two weeks followed by a plateau after 12 weeks. Rates of overall adverse events were similar between the two groups.
• Albiglutide showed a favorable tolerability profile in terms of pancreatitis and hypoglycemia, but was associated with a higher incidence of injection site reactions (12.9%) than liraglutide (5.4%). Pre- or post-rescue hypoglycemic events occurred more frequently in the liraglutide group than the albiglutide group (20.8% vs. 16.3%), with the majority of hypoglycemic events occurring in patients also taking sulfonylureas. Importantly, albiglutide was associated with no pancreatitis events, compared to five incidences of on-therapy pancreatitis in the liraglutide group (although one was likely not related to study drug).

Meet the Expert Sessions

NEWER AGENTS AND THEIR USE IN CLINICAL PRACTICE

John Buse, MD, PhD (University of North Carolina, Chapel Hill, NC)

In this very well attended Meet the Experts session (over 200 by our approximation!), Dr. Buse began by briefly lauding the use of DPP-4 inhibitors (because of their “extreme” tolerability) and GLP-1 agonists (because of their substantial glycemic efficacy and weight loss) in the treatment of type 2 diabetes. After highlighting the need for anti-diabetic agents that address beta cell function and cardiovascular risk, Dr. Buse opened the remainder of the session to questions from the audience. During the subsequent Q&A session, Dr. Buse touched on a number of hot topics in the pharmacological treatment of diabetes, including the prospects of SGLT-2 inhibitors, the safety of TZDs and GLP-1 agonists, the use of type 2 therapies to treat type 1 diabetes (i.e., GLP-1 agonists, SGLT-2 inhibitors), and the need for earlier treatment in the course of disease, including during prediabetes. Of particular note, Dr. Buse revealed that his default second line therapy for people with type 2 diabetes was a GLP-1 agonist, stating that, “if [he] had diabetes, that is what [he] would take.” He also voiced optimism regarding the SGLT-2 inhibitor class, noting that all drug classes have associated issues, and that SGLT- 2 inhibitors offer the powerful combination of glucose reduction, weight loss, and blood pressure lowering. While not appearing overly unconcerned with the potential bladder cancer risk associated with pioglitazone, Dr. Buse expressed hesitation regarding the early use of this therapy in the course of diabetes (including prediabetes) given the effects of the drug on bone loss.

Questions and Answers

Q: Can you tell us about the current status of SGLT-2 inhibitors?

A: This class is newer than new. Both dapagliflozin and canagliflozin are at one level of another under FDA review. From my understanding, dapagliflozin has received a preliminary approval decision from the EMA. It is not yet marketed in Europe, but it should be available soon. I personally think that this is an exciting class of medications, especially in the post ACCORD world, which found excess mortality in the intensively treated arm. There is some supposition, although no proof, that the mortality may have been related to adverse effects associated with the drugs used, such as hypoglycemia and weight gain. I really like the possibility of using metformin, GLP-1 agonists, SGLT-2 inhibitors, and maybe DPP-4 inhibitors to lower glucose levels without causing an increase in weight (potentially even providing weight loss) or hypoglycemia risk.

Q: I heard a rumor that sometime in our future there may be combo SGLT-2/SGLT-1 drug. These drugs would not only block reabsorption in the kidney, but also have an acarbose like effect and block the rate of carbohydrate absorption.

A: SGLT-1 is involved in glucose absorption in the GI tract and SGLT-2 is involved in glucose reabsorption in the kidney. There are several combined agents in development. If you inhibit the absorption of carbohydrates in the intestine, you might get flatulence and diarrhea like with acarbose. This is why many thought targeting SGLT-2 was more ideal. That said, there is some data around combined agents being effective with regard to weight loss and glucose lowering, at least from small studies. With acarbose, you are not getting a net malabsorption of carbohydrates, absorption is just delayed. With SGLT-1 inhibition, however, there would be malabsorption of carbohydrates.

Q: I find the mechanism of action of SGLT-2 inhibitors to be bizarre. Can you talk about your opinions on this class a little more?

A: It is bizarre. When I first heard the notion, I thought it was a bad idea. When I reflect back to when I was a fellow and graduate student, I remember seeing a publication on the use of phlorizin in rodents. I tried to hold back from my initial response. I looked at the rodent data and came to realize that there were humans with SGLT2 mutations. These individuals lived normal lifespans without kidney disease. In clinical trials, in general, people seem to tolerate SGLT-2 inhibitors quiet well. One of the issues that came up was that urinary tract and genital infections occur more frequently with treatment, particularly yeast infections in women. The severity of these side effects were reasonable modest. There were no patients in the development program for dapagliflozin who developed pyelonephritis. Like other classes of drugs, this class also has some associated issues. However, the ability of these drugs to lower glucose, blood pressure, and weight is very compelling in the field of diabetes. Another issue that may occur is that some patients may become dehydrated, especially those that develop flu like symptoms. There will lose an obligate loss of fluid. But again, all drug classes will have their issues.

Q: Is the pancreatitis observed with sitagliptin a class effect?

A: To be provocative, I will say that it is a class effect. However, the class effect will be that there is probably no increase in pancreatitis risk with these drugs. There have been three epidemiological studies published that have examined the incidence of pancreatitis requiring hospitalization. These were pharmacy benefit manager type data sets. Overall, the incidence of hospitalization due to pancreatitis associated with GLP-1 or DPP-4 therapy (most of the data was for exenatide and sitagliptin) appeared similar to the incidence with metformin and glyburide. That said, there were confidence intervals and there could be a small increased risk. However, the vast evidence seems to suggest right now that there is no increased risk.

Q: Can you discuss how you use colesevelam and bromocriptine in clinical practice?

A: With colesevelam, I use it with the occasional patient who is on high doses of statins or is statin intolerant and needs some additional LDL and A1c lowering. It provides both and is fairly well tolerated with no serious adverse effects. That said, I haven’t used it a lot. The A1c reductions achieved in clinical trials is modest, about 0.5%. You shouldn't think of it as something that will solve the diabetes problem, but it will provide you with some LDL and A1c lowering that might be beneficial for a minority of patients. Bromocriptine is a bit more of a mystery. It would provide any greater efficacy than colesevelam, maybe even a bit less. I have not tried this in my patients yet, but that doesn’t mean that I don’t wish to do so. I just haven’t had the occasion. You do need to take multiple tablets a day and there is only modest efficacy. I think bromocriptine might be a drug that begins to find its way as we get more data on efficacy and tolerability through studies other than company-sponsored studies. It does have a novel mechanism of action and is not associated with weight loss or hypoglycemia.

Q: Bromocriptine has had astonishing CV disease data published. Maybe the drug will have a special role in treating high CV risk patients?

A: My only concern is that the data is from a short-term study. It is really not equivalent to the data that is being collected from the CV outcomes studies that are being conducted today for DPP-4 inhibitors and GLP-1 agonists. In the short-term, it is suggestive of benefit. For many drugs, however, shorter studies have suggested potential CV benefit, such as the meta-analyses of development program data for DPP-4 inhibitors and GLP-1 agonists. Fundamentally, I just don't believe it. I believe that these short-term studies may be leading us astray. I’m not sure how, but I do believe they are leading us astray.

Q: Can you discuss the link between bladder cancer and pioglitazone?

A: We have a serious problem in the American society right now. Epidemiological studies are only hypothesis generating. Multiple datasets have looked at this issue, but we cannot conclude based on the results of one, two, or three such publications that pioglitazone causes bladder cancer. It is really only hypothesis generating. That said, there was a bit of an issue in rodents during the development program. My understanding of it, although this is not my area of expertise, the regulatory bodies decided that the rodent bladder cancer risk was different from what was expected in humans. In the PROactive study, which was an randomized controlled trial, there was an imbalance in bladder cancer risk. However, there weren’t routine urinalyses in the study. Pioglitazone can cause edema, so these individuals may have received urinalyses to evaluate edema more often than controls, leading to a possible detection bias for bladder cancer in the trial. There were two large pharmaco-epidemiology studies that examined bladder cancer risk with pioglitazone. The Kaiser study was very well conducted. The French study had less data on potential baseline confounding variables. They both come to similar conclusions – with long term use, there is a potential increased risk for bladder cancer with pioglitazone. This is by no means proof. The second thing is that bladder cancer is quite rare. The last time I reviewed this data, it was about 1 case per 20,000 individuals per year. If the elevated risk found in the epidemiological studies is proven accurate, then the incidence would increase to 1.5 cases per 20,000 patients per year. In comparison to the benefits of pioglitazone, that risk may not be terribly dangerous. The third issue is that in the French study, a reduction in risk for head, neck, and breast cancers and a trend toward reduced risk for other cancers. Patients don’t care what type of cancer they get. If there is an absence of increased risk for overall cancer or cancer mortality, the increased risk for bladder cancer may not matter that much. There may be an increased risk for some cancers and a decreased risk for others. It might be random. Basically, I don't think this is a big issue.

Q: What about the effect of pioglitazone on bone loss and osteoporosis?

A: I think this is a bigger issue. I believe there is a great opportunity for the earlier diagnosis and earlier management of type 2 diabetes. Pioglitazone has one of the best data sets available for prevention of beta cell failure or beta cell failure progression. However, the early use of pioglitazone is problematic for me. I usually use pioglitazone in patients that are already using agents that increase insulin levels and are inadequately controlled.

Q: Regarding SGLT-2 inhibitors, what study design would you like to see to discern whether SGLT2 inhibitors do no cause hypoglycemia exacerbation in people with type 1 diabetes or people with type 2 diabetes using insulin?

A: I do like the idea of using SGLT-2 inhibitors in people with type 1 diabetes. It almost certainly will work. I like the idea that there is an autoregulatory component of SGLT-2 inhibition. You will get more glucose excretion at higher glucose levels and less glucose excretion at lower glucose levels. What type of study would be best would entail a much longer discussion.

Q: What about cell therapy for type 2 diabetes?

A: Some companies are doing studies that are looking at cell-based therapies. I’m not wildly optimistic that they are going to work. That is me being skeptical in general. But I do think someone will learn to take advantage of cell therapy for type 1 and type 2 diabetes one day. I’m not sure we are there yet.

Q: What about the use of alpha-glucosidase inhibitors?

A: These just never worked out in the US. I’ve started hundreds of patients on these agents in my career. A few patients have thought it was great. They get lower blood glucose and not as much constipation. In the type 1 diabetes setting, I sometimes give a small dose to my patients for nighttime use alongside a small snack to avoid nocturnal hypoglycemia. But what I found over time is that very few patients continue on the drug. In my practice, I discuss the benefits and potential harms of each drug. My patients are deciding that they are not getting enough benefits given the drug’s side effects. I know that it is popular in other parts of the world. Regarding the ADA/EASD algorithm, we discussed including it the first, second, and third time. We decided to not put it in as a core recommendation. That said, my belief is that it will lower blood glucose in anyone if it is carefully titrated upward. If flatulence is not a major psychosocial issue for a patient, it could be good.

Q: If early treatment is desirable, is there a role for new drugs that are better than metformin in the early treatment or prevention of diabetes?

A: I do think that prevention is a tremendous strategy and a real opportunity in overall diabetes care. Lifestyle therapy applied early in the course of disease appears to have its advantages. Metformin doesn’t appear to work very well with really early prediabetes. Other agents may have greater benefit. I am still concerned about the use of pioglitazone in the early stages of diabetes or prediabetes given the effects of the drug on bone loss. Incretin-based therapies and SGLT-2 inhibitors could be compelling choices if we had data. The important issue here is that someone needs to do a study. The earlier we want to treat, especially during prediabetes when not everyone will progress to diabetes, the more clinical evidence we need that a therapy is safe and effective.

Q: In the new ADA/EASD position statement, there great leniency on which second line therapy to use. What is your drug of choice?

A: My default is a GLP-1 agonist. If I had diabetes, that is what I would take. It is a bit of an act of faith since we don’t have long-term data to guarantee its safety and efficacy. My sense of the data that we have available today is that these drugs are safe and effective. Liraglutide and exenatide once weekly are unparalleled in terms of glycemic efficacy. We wrote in the position statement that insulin had the highest efficacy, but you can also make the argument that GLP-1 agonists are just as powerful as basal insulin in reducing A1c. This is my personal bias. The maybe patients who would not prefer to use an injectable therapy as a second line option. Other orals are all fair game. Sulfonylureas are dirt-cheap. They can fill the need for those who have difficulty paying for more expensive therapies. DPP-4 inhibitors are ridiculously well tolerated. Many would prefer this as their second line therapy.

Q: What about the risk for C-cell carcinoma with GLP-1 agonists?

A: I think people have largely bought into the notion that the regulation of C-cells in humans is different from the regulation of C-cells in rodents. Medullary thyroid cancer occurs much more frequently in rodents than in humans. I’m not terribly worried about thyroid cancer with these agents. There will be studies to address this concern in the future. With regards to pancreatic cancer, the human data is remarkably bad. By that, I mean that the studies have not been conducted in a way that should be reported in medical literature. Pancreatic cancer risk will also be addressed with studies to come. I neither believe nor can I prove that GLP-1 agonists don't cause cancer. However, the evidence that they do is essentially zero.

Q: What about Afrezza and the use of GLP-1 agonists to treat obesity in people with type 1 diabetes?

A: I know very little about Afrezza. The pulmonary insulin route is interesting. It has both issues and possibilities. If it is approved, I would do my best to evaluate the drug. With regards to GLP-1 agonists in type 1 diabetes, there are many pieces of anecdotal evidence to support their use. In some individuals, blood glucose has stabilized and weight loss was achieved. Small studies have also suggested some benefit. My belief is that if we are considering using a $4,000 a year therapy for an already $10,000 a year condition, we need to conduct robust studies to clearly show benefit. We can spend an almost unlimited amount of money managing type 1 diabetes. This is an expensive therapy and we only have anecdotal evidence so far.

Q: Is it worth it to start with combination therapy to preserve beta cells?

A: We don't have a lot of data. It's a wonderful theory. It is based on better living through chemistry. I have had many hundreds of patient who were on 10-15 drugs for type 2 diabetes. I just wonder if 100 years from now, we’ll look back and say, “what did these people think they were doing?” We are basically creating a chemical swamp in people with diabetes to compensate for bad lifestyle. It is compelling, but I worry about the slippery slope of thinking that three therapies will be more effective than two therapies, etc. It doesn’t turn out that way most of the time. I understand the theory, but I am resistant to globally adopting it.

Q: What about the combination use of GLP-1 agonists and basal insulins?

A: I think this combination is great. I struggled to get Lilly and Amylin to apply for this indication for five years. I think it is a remarkable combination. We will have new drug therapies, but my default pathway is metformin, a GLP-1 agonist, then a basal insulin. The big question right now is whether long-acting GLP-1 agonists like liraglutide and exenatide once weekly will provide similar benefits when used alongside basal insulin therapy as exenatide twice daily. I believe that there might be a special niche for the short acting GLP-1 agonists to be used alongside basal insulins. Will have to see.

Q: What are the relative safety and efficacy issues among GLP-1 receptor agonists?

A: Exenatide twice daily is the most powerful post-prandial agent we have. Liraglutide is the most powerful A1c reducing agent we have. Bydureon is the best-tolerated GLP-1 agonist we have. The rest with cancer risk, antibodies, pancreatitis risk, etc., there are some small potential differences, but the clinical significance is what we just reviewed. Though there have been efforts to distinguish safety issues between the three, I do not think there are compelling issues in that comparison.

Symposium: Incretin-Based Therapies (Supported by an Unrestricted Educational Grant from Merck)

GLP-1 RECEPTOR AGONISTS – ARE THEY ALL THE SAME?

Filip Knop, MD, PhD (Gentofte Hospital, Hellerup, Denmark)

In front of a packed audience, Dr. Knop highlighted the similarities and differences between the GLP-1 agonists exenatide (Byetta), liraglutide (Victoza), exenatide once weekly (Bydureon), lixisenatide (Lyxumia), and albiglutide (Syncria). After reviewing the structures and pharmacokinetic profiles of each drug, Dr. Knop discussed results from several head-to-head studies that examined these agents, including DURATION-1, -5, and -6, LEAD-6, and HARMONY 7. Overall, Dr. Knop emphasized that: 1) longer-acting GLP-1 agonists (i.e., liraglutide, exenatide once weekly, albiglutide) tend to provide greater glycemic efficacy and fewer GI side effects than shorter-acting GLP-1 agonists (exenatide BID and lixisenatide); 2) exendin-based drugs (i.e., exenatide, exenatide once weekly, lixisenatide) are associated with a higher incidence of antibody formation (the clinical relevance of which remains unclear, although some studies have suggested minimal impacts on efficacy and safety); and 3) large GLP-1 agonists (i.e., albiglutide) have a reduced effect on weight as well as lower associated rates of GI adverse events potentially resulting from restricted movement across the blood-brain barrier. Thus, addressing the question posed by the title of his talk, Dr. Knop concluded that all GLP-1 receptor agonists are not the same.

Questions and Answers

Q: Based on your understanding of differences between GLP-1 agonists, would you expect there to be any differences with regards to more serious side effects?

A: That is a very hard question to answer, and I cannot back it up with any data, which is why I chose not to include this discussion in my presentation. Theoretically, since GLP-1 may help preserve or proliferate beta cells, a continuous acting dose may have a higher associated risk for malignancy. Yet, the short- acting agonists, because of their frequent exposure peaks, may have a higher associated risk for pancreatitis. Saying that, this is all theoretical.

DPP-IV INHIBITORS – ARE THEY ALL THE SAME?

Adrian Vella, MD (Mayo Clinic, Rochester, MN)

To open this Merck-supported session, Dr. Adrian Vella reviewed DPP-4 inhibitors in terms of their mechanism of action, effects (glucose- and non-glucose-related), and safety. He noted that most agents in the class have 24-hour effect with >80% DPP-4 inhibition (except for vildagliptin, which has a half- life of two-to-three hours), most have a large volume distribution and bind poorly to plasma protein (except for linagliptin), and most do not have metabolic activity with cytochrome P450 (other than saxagliptin). Compared to the field, vildagliptin and saxagliptin are somewhat less selective for DPP-4 inhibition relative to DPP-8 and -9, and linagliptin is less selective relative to fibroblast activation protein (FAP) – these differences have not yet been shown to have safety or efficacy effects, though Dr. Vella implied that the possibility has not been ruled out. Notably, he disputed the clinical relevance of linagliptin’s lack of renal clearance (or, as he framed it, the fact that 85% of linagliptin is excreted in the feces): he thinks that DPP-4 inhibitors are rarely appropriate in patients whose renal dysfunction is severe enough to require dose adjustment.

Questions and Answers

Q: One clinical difference is the lack of need to screen with creatinine to select a dose with linagliptin. Is that of clinical import to you?

A: No. It is true that due to linagliptin’s large volume distribution and the fact that 85% of the secretion is in the feces, there is no need for checking renal function. But it is the rare patient with diabetes and significant renal failure who would be on a DPP-4 inhibitor, at least in my practice. I will grant you that this is a difference among members of the class in pharmacokinetics.

CARDIAC EFFECTS OF INCRETIN-BASED THERAPIES

Steven Marso, MD (University of Missouri Kansas City, Kansas City, MO)

Dr. Marso delivered an engaging lecture on the potential impact of incretin-based therapies on the cardiovascular (CV) system. Reviewing a series of results from preclinical and clinical studies, Dr. Marso highlighted the following observations as indications that incretin based therapies might have a beneficial impact on the CV system: 1) small clinical studies have demonstrated a potential benefit of native GLP-1 on endothelial function; 2) GLP-1 agonists have positive impacts on several established CV risk markers (LDL, total cholesterol, triglycerides, weight); 3) both native GLP-1 and GLP-1 agonists minimize myocardial ischemia/reperfusion injury and decrease infarct size in rodents and possibly in humans; and 5) meta-analyses have demonstrated a reduced risk for MACE with GLP-1 agonists and DPP-4 inhibitors (Ratner et al., Cardiovascular Diabetology 2011; Marso et al., Diabetes and Vascular Disease Research, 2011). Still, he expressed concern that GLP-1 agonists have been documented to increase pulse rate in humans and emphasized that it remains unclear whether these findings will translate into actual CV benefit. He concluded by notating that a number of dedicated CV outcomes studies were currently underway for GLP-1 agonists and DPP-4 inhibitors that would help clarify the CV impacts of these drugs. As a reminder, these CV outcomes studies include ELIXA (lixisenatide; expected completion in 2014); LEADER (liraglutide; 2016), EXSCEL (exenatide once weekly; 2017), ELIXA (lixisenatide; 2014), REWIND (dulaglutide; 2019), TECOS (sitagliptin; 2014), SAVOR-TIMI 53 (saxagliptin; 2014), EXAMINE (alogliptin; 2015), and CAROLINA (linagliptin; 2018).

Symposium: The Role of Pharmacology in Managing Prediabetes

LIFESTYLE CHANGES AND METFORMIN ARE NOT ADEQUATE

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

After making the case for why lifestyle alone is not sufficient to manage prediabetes (e.g., inevitable weight regain, the impracticality of implementing intensive lifestyle interventions in the real world, the body’s metabolic adaptation to reduced caloric intake), Dr. DeFronzo discussed the role of pharmacotherapies in managing prediabetes. In particular, he expressed enthusiasm for two classes of drugs – thiazolidinediones (TZDs) and GLP-1 agonists – as potent drugs that could be used to manage prediabetes. While TZDs have been proven to be effective in preventing the progression from prediabetes to diabetes in clinical trials, GLP-1 agonists remain unproven in this domain. Nonetheless, when taking the totality of currently available data for GLP-1 agonists into consideration, Dr. DeFronzo is quite convinced they’ll be effective. Highlighting that those in the highest tertile of IGT are already maximally insulin resistant and have lost 80% of their beta cell function, Dr. DeFronzo stressed that we must intervene with drugs earlier in dysglycemia to stop the progressive loss of beta cells and beta-cell function.

• Dr. DeFronzo highlighted that pharmacotherapies, especially thiazolidinediones, have been shown to be effective in preventing type 2 diabetes. In the IDPP and the DPP, metformin treatment decreased progression to type 2 diabetes by 26% and 31%, respectively. Meanwhile, thiazolidinediones were even more impressive, reducing progression to type 2 diabetes by 55-75% in clinical trials (55% with troglitazone in TRIPOD, 60% with rosiglitazone in DREAM, 72% with pioglitazone in ACT NOW, and 75% with troglitazone in the DPP). Other agents, including acarbose (36%; STOP-NIDDM), voglibose (40%), and orlistat (37%; XENDOS) have also been shown to reduce progression to type 2 diabetes.
• He further emphasized the effectiveness of pioglitazone in diabetes prevention, reviewing results from the ACT NOW trial. In the ACT NOW trial, pioglitazone treatment reduced the progression from IGT to type 2 diabetes by 72% (DeFronzo et al., NEJM 2011). Only 18 patients with IGT would need to be treated for one year with pioglitazone to prevent one case of type 2 diabetes; for comparison, 35-40 patients would need to be treated with a statin to prevent one myocardial infarction. Dr. DeFronzo noted that with all the recent emphasis on cardiovascular disease, we’ve forgotten about microvascular complications – each day, diabetes causes 55 people go blind and 120 to go on dialysis. He stated that given the fact that pioglitazone is soon going generic, one could probably extrapolate significant cost-benefit or cost savings.
• Dr. DeFronzo noted that data suggest that GLP-1 agonists would be very effective in preventing the progression from IGT to type 2 diabetes. He expressed excitement, because in overt diabetes, GLP-1 agonists lower A1c, promote weight loss, address many of the pathophysiological defects of diabetes, do not cause hypoglycemia, and have excellent safety profiles. In a study investigating the effects of liraglutide on weight in obese patients without diabetes, the vast majority of patients with prediabetes reverted back to normoglycemia; patients experienced noticeable reductions in weight, A1c, and blood pressure as well (Astrup et al., IJO 2011).

Questions and Answers

Q: I’m interested in your patient population. You said that a lot of them are over 100 kg (220 lbs). I’m really interested in your standpoint on bariatric surgery for prevention versus Victoza?

A: That goes a little bit beyond pharmacology. I think that there are several nice articles that came out back to back in the NEJM, and we have long-term data from the SOS showing a decrease in mortality over 20 years. If you are morbidly obese, whether you have diabetes or sleep apnea or some other disorder, bariatric surgery is really the only thing that works on a long-term basis. I think it’s a whole different situation for those with BMIs of 32-33 kg/m2 who have not taken metformin or intensive lifestyle interventions. I don’t want you to think that I disagree with Dr. Hamman. We have to try as best we can to intervene from a lifestyle standpoint. I like metformin; I just think we can do a lot better than that. Bariatric surgery is something I would look at much further down the line. What seems to be so effective about bariatric surgery and normalizing glucose tolerance is the astronomical levels of GLP-1 that you get in these people, and the marked improvements in beta cell function. It’s similar to what I tried to show you with liraglutide. I believe you would see this effect not only with liraglutide, but also with Bydureon or exenatide. GLP-1 agonists are a unique group of drugs. They should be considered not only in treatment but also in prevention.

Comment: I appreciated you saying that you don’t disagree much with Dr. Hamman. I don’t disagree much with you. I was a strong supporter of trying troglitazone in the DPP. I think there is a huge role for the right medicine for prevention. We may see the glass as half empty or half full right now, but regardless, we need to take cost effectiveness and safety into consideration. The physiological standpoint is where we need to start, but we don’t know where that will take us 5-10 years later. There are some concerning side effect data, especially for TZDs. GLP-1 may be the best way to go, but before we give it to a 20 year-old with a BMI of 30 kg/m2, who would take the medication for 30-40 years, we would want to know what it will do in the long term. Absolutely, we’re going to have to take some risk, but we should try to characterize the cost-effectiveness and safety as much as we can.

Q: You avoided mentioning DPP-4 inhibitors – was that intentional?

A: I avoided mentioning them because we don’t really have any data with them in terms of prevention of IGT. We have very nice studies with liraglutide. We have done a head-to-head study with exenatide and sitagliptin, and I’m sorry to say for DPP-4 lovers that exenatide just destroyed sitagliptin in anything you would want to look at. In my practice, I actually only use GLP-1 analogs because they have much more powerful effects on the beta cell. Probably the most important effect of DPP-4 is to inhibit glucagon, not to augment insulin secretion. But, I wouldn’t be opposed if someone wanted to conduct an intervention trial and get some serious data. I do believe that the earlier we start, when there is still significant beta-cell function, the more likely they will be effective.

Joint ADA/The Lancet Symposium

EXENATIDE TWICE A DAY VERSUS GLIMEPIRIDE FOR PREVENTION OF GLYCAEMIC DETERIORATION IN PATIENTS WITH TYPE 2 DIABETES WITH METFORMIN FAILURE (EUREXA)--AN OPEN-LABEL, RANDOMISED CONTROLLED TRIAL

Guntram Schernthaner, MD (Rudolfstifstung Hospital, Vienna, Austria)

Dr. Schernthaner presented efficacy data on EUREXA – “the longest GLP-1 study in the literature at the moment” – a three-year comparison of exenatide 10 mcg BID to glimepiride (titrated to a mean of 2 mg/day) in type 2 diabetes patients on background metformin therapy (Gallwitze et al., Lancet 2012 in press). At baseline, the study population (n=1,029) had a very low mean A1c (~7.4%), short diabetes duration (~5.5 years), and high BMI (~31 kg/m2). Exenatide was superior to glimepiride in the primary efficacy endpoint, time to treatment failure as defined by A1c (median 180 weeks for exenatide and 142 weeks for glimepiride). The favorable result for exenatide was certainly encouraging, though we think a median failure timeline of less than three years highlights the need more effective, durable, and easy-to- use therapies – still, SFUs can fail in less than a year as we understand it. Compared to glimepiride, exenatide caused more favorable change in body weight (3.9 kg decrease vs. 1.5 kg increase [-8.6 vs. +3.3 lbs]), higher prevalence of GI side effects (47% vs. 24%), and rarer hypoglycemia (1.5 vs. 5.3 episodes per year). Several questioners sought more granular data (e.g., on liver function and heart rate), but Dr. Schernthaner said we would all have to wait until his group’s presentation at EASD 2012 – which will also include results from a substudy of re-randomization to triple therapy (exenatide+metformin+TZD or exenatide+metformin+glimepiride).

• Mean baseline A1c was low at 7.42%-7.45% (inclusion criteria allowed baseline A1c between 6.5% and 9.0%), mean BMI was roughly 31 kg/m2, and mean fasting plasma glucose was 8.6-8.9 mmol/l (155-160 mg/dl) – a fairly low value that Dr. Schernthaner said may have been due to preservation of beta-cell function. Mean age was ~56 years old, mean diabetes duration was 5.5-5.6 years, and mean metformin dose was over 1.9 g/day. The population was mostly male (50-55%) and predominantly Caucasian (>90%) or Hispanic (7%).
• Rates of discontinuation were higher in the exenatide group (though the difference, due largely to GI side effects, was statistically significant only in the first six months of the study), and treatment failure was more common in the sulfonylurea group. The EUREXA investigators randomized 515 patients to exenatide and 514 to sulfonylurea. Of the intent to treat population (490 and 487), 174 and 128 patients discontinued, respectively, and 203 and 262 failed treatment, respectively. Thus at study end 138 patients remained in the exenatide group, compared to 124 in the sulfonylurea group.
• Exenatide was both non-inferior and superior to glimepiride in the study’s primary endpoint, time to treatment failure (median 180 vs. 142 weeks; p=0.032 by log-rank test). Along similar lines, rate of treatment failure at three years was lower with exenatide (41% vs. 54%; HR 0.748, p=0.002). (Treatment failure was defined as when a patient on the maximally tolerated dose of drug had either a) two consecutive A1c measurements >7.0% taken by at least three months apart or b) a single A1c measurement >9.0%.) Exenatide and glimepiride conferred similarly rapid glycemic improvements down to an A1c nadir of roughly 6.7% during the first few months of the study; Dr. Schernthaner noted that this was an earlier glucose normalization than seen in many previous exenatide studies. HOMA-B was not significantly different between groups at any of the three years, but HOMA-IR and disposition index were significantly better for exenatide at the end of each year in the study.
• Baseline A1c had a highly statistically significant relationship with time to treatment failure – i.e., faster at higher baseline A1c (p <0.001). Failure was rarest among those with A1c ≤7.3%, in whom rates were similar regardless of treatment (which Dr. Schernthaner said made sense, since these patients presumably tended to have sufficient beta-cell function). However, exenatide performed better than glimepiride in people with A1c >7.3% and ≤8.2%, and in those with A1c above 8.2%.
• Adverse event findings were in line with previous studies; Dr. Schernthaner noted that exenatide was not associated with any added risk of pancreatitis (one in each group), nor did any participants get pancreatic cancer. Gastrointestinal side effects were much more prevalent with exenatide (47% vs. 24%), and adverse injection site reactions were more common as well. However, the incidence of hypoglycemia was lower compared to sulfonylurea, across the range of hypoglycemia definitions studied: any events (36% vs. 67%), nocturnal (10% vs. 16%), glucose confirmed below <3.9 mmol/l (< 70 mg/dl) (20% vs. 47%), etc. Hypoglycemic events were less frequent with exenatide (1.5 vs. 5.3 episodes per year), and the time to first hypoglycemic event was longer.
• Dr. Schernthaner closed by discussing the study’s limitations, including the low baseline A1c and the relatively low rates of glimepiride, despite titration to the maximum protocol-recommended dose. However, during Q&A Dr. Schernthaner notedthat higher glimepiride doses might not have been much more effective; he referenced his own double-blind comparison of glimepiride and gliclazide (in which 3 - 6 mg doses did not seem more effective than 2 mg) and Dr. Alan Garber’s LEAD-3 trial (in which the efficacy of high-dose glimepiride was roughly in line with that seen in EUREXA). Another study limitation was the ethnic homogeneity of the enrolled population, most of whom came from Europe (with some also from Mexico and Israel). During Q&A Dr. Schernthaner tentatively forecasted that results would have been positive in East Asian patients as well, based on previous successful studies of GLP-1 receptor agonists in these patients.

Questions and Answers

Q: It looked from the graph like the earliest failure was at one year in either group. Usually treatment failure occurs sooner – did you look for treatment failure at three or six months?

A: There were very few failures this early. Probably this was because A1c was very low at the start, so you don’t see treatment failure at the beginning. The result could be totally different if starting with higher baseline.

Q: Did you monitor liver enzymes? With weight difference of more than 5 kg, perhaps Byetta has a direct effect on liver disease?

A: The data were accepted for presentation at EASD, so I cannot present them. But I can talk to you personally.

Q: The BMI was fairly high in your group. I just wonder if you tested this in a lower BMI or lower body-weight cohort that looks more like an Asian population. Do you suspect that exenatide would also be better then sulfonylurea in such a lower-BMI population?

A: I just returned from lecturing in Asian countries; I saw that the highest there was about 28 kg/m2. But there is much more visceral and liver fat in Asia. But GLP-1 receptor agonists are at least as effective in Asian vs. Western populations, so I wouldn’t expect to see a difference.

Q: 53% of the group failed glimepiride. How did you define maximum-tolerated dose in this study, in which obviously glimepiride was not the study drug.

A: I did a double-blind study of gliclazide vs. glimepiride that we cited in this paper; 3, 4, 5, and even 6 mg were not better than 2 mg. Alan Garber used up to 8 mg in LEAD-3, and the A1c-lowering was in line. Probably higher doses are not as beneficial as previously thought.

Q: Did you see geographic variation in how glimepiride was prescribed and up-titrated?

A: The highest risk of hypoglycemia was seen at the 1-2 mg doses. This confirms previous research in which the most events were seen at lower doses –probably because there is more beta-cell function remaining in these patients.

Q: Do you have the information about effect on heart rate?

A: Yes, or course. We will present this data at EASD in Berlin; since the manuscript is already accepted I cannot bring this data today.

Corporate Symposium: Long-Acting GLP-1 Receptor Agonist Therapy: Improving Efficacy, Adherence, and Weight in T2DM (Sponsored by Amylin)

A HOLISTIC VIEW OF TYPE 2 DIABETES PATHOPHYSIOLOGY AND MANAGEMENT

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

Dr. DeFronzo reviewed the basic physiology and epidemiology of diabetes to set the stage for discussing GLP-1 agonist therapy. Driving home the impact of diabetes in the US, he noted that every 24 hours there are 4,000 new cases of diabetes, 810 deaths from diabetes, 230 amputations, 120 kidney failures, and 55 blinded from the disease. He expressed particular sympathy for individuals with diabetes suffering from the microvascular complications of the disease due to the lifelong debilitation with which they are afflicted. A theme of Dr. DeFronzo’s talks is that the treatment of diseases should be based on their pathophysiology, and that a multifactorial disease like diabetes will require a combination of therapies to address its various etiological facets. On this note, he reminded us of his “ominous octet” of dysfunction in diabetes (he first introduced this term at his Banting lecture during ADA 2008): decreased insulin secretion, increased glucagon secretion, increased hepatic glucose production, neurotransmitter dysfunction, decreased glucose uptake, increased glucose reabsorption, increased lipolysis, and of course, decreased insulin effect. He emphasized that GLP-1 agonists address aspects of the ominous octet uniquely from any other class – in addition to reducing A1c, they preserve beta-cell function, promote weight loss, and do not cause hypoglycemia. He said that, in his opinion, the most dramatic study carried out in people with type 2 diabetes was one in which liraglutide (7.5 ug/kg) drastically increased the rate of insulin secretion in a glycemic-dependent manner almost to the extent where they were indistinguishable from normal controls (Chang et al. Diabetes 2003).

LONG-ACTING GLP-1 RECEPTOR AGONIST CLINICAL TRIAL DATA

John Buse, MD, PhD (University of North Carolina, Chapel Hill, NC)

Dr. Buse reviewed some of the landmark trials involving GLP-1 agonists to support their clinical utility. The currently approved GLP-1 medications are exenatide (Amylin’s Byetta), exenatide once weekly (Amylin/Alkermes’ Bydureon), and liraglutide (Novo Nordisk’s Victoza). He began with a recap of the DURATION-1 trial, which compared exenatide once weekly versus the twice-daily formulation. The once-weekly formulation reduced A1c significantly more than the twice-daily formulation; switching all patients to the once-weekly formulation halfway through the study allowed both groups to achieve a ~2.0% A1c reduction after 52 weeks of treatment (we did not get the baseline A1c). Nonetheless, he noted that exenatide twice-daily is the most powerful postprandial glucose lowering drug available today. He also emphasized that liraglutide is the most powerful GLP-1 receptor agonist, based on the surprising DURATION-6 study result that showed a 0.2% greater A1c reduction in liraglutide compared to exenatide once-weekly. Importantly, he emphasized that longer-acting formulations are associated with less nausea than the shorter-acting exenatide; in addition, they are also associated with less hypoglycemia. In summary, Dr. Buse concluded that GLP-1 agonists are unparalleled in their A1c- lowering abilities, that they improve a variety of endpoints relevant to diabetes, and that the safety profile includes some risks but for most patients is safe and appropriate. Profiling the individual drugs, he said that exenatide showed the best postprandial control, that exenatide once weekly is the best tolerated, and that liraglutide has the best glycemic efficacy and weight loss.

• Dr. Buse elaborated on the safety issues associated with GLP-1 agonists. Although he said that pancreatitis isn’t a huge worry, he always tells his patients to stop their therapy if they experience vomiting or other worrying symptoms like back pain. Another potential concern with GLP-1 agonists is their use with renal impairment. There is not enough clinical experience in patients with stage 4/5 kidney disease, since nausea/vomiting can exacerbate an already unstable hemodynamic clinical picture. He briefly overviewed the C-cell tumor black box warning for theGLP-1 agonist class, noting that the human relevance to animal trials could not be determined with clinical or nonclinical studies, and that the only real consequence was that this class is contraindicated in patients with multiple endocrine neoplasia 2 (a genetic condition predisposing patients to thyroid cancer) or personal family history of medullary thyroid cancer. Moving on to cardiovascular risk, Dr. Buse noted that DURATION-2 showed roughly similar risk factor changes (HDL, LDL, systolic blood pressure, C-reactive protein) with exenatide, sitagliptin and pioglitazone treatment. The exceptions were that exenatide showed superior systolic blood pressure improvement compared to sitagliptin and superior HDL improvement compared to pioglitazone.

EXTRAGLYCEMIC EFFECTS AND CLINICAL APPLICATIONS OF LONG-ACTING GLP-1 RECEPTOR AGONISTS

David D’Alessio, MD (University of Cincinnati, Cincinnati, OH)

Dr. D’Alessio discussed the physiology of GLP-1 in the body and how the basic science correlates to the clinical effects of GLP-1 agonists. Overall, the most clinically notable central nervous system effects of GLP-1 agonists are decreased food intake and nausea. Dr. D’Alessio broke this down by the effects of GLP-1 in individual areas of the brain. Subsequently, he explained that despite the fact that proteins and peptides don’t cross the blood-brain barrier, there are areas in which the blood-brain barrier is leaky called circumventricular organs, which typically function to detect toxins and allow for peptide sensing of the bloodstream. These are the areas in which GLP-1 agonists can exert their greatest effect. He described how changes in food intake are partially due to a decrease in gastric emptying that promotes satiety and lower peak blood glucose. In addition, Dr. D’Alessio also described the direct impacts of GLP-1 agonists on the cardiovascular system, and the potential for GLP-1 agonists as weight-loss drugs. He highlighted that liraglutide 3.0 mg has demonstrated a ~9 kg (~20 lb) weight loss after 20 weeks. In closing, he advocated for greater use of GLP-1 agonists and commented that novel applications may expand the clinical utility of this class.

• Dr. D’Alessio broke this down by the effects of GLP-1 in individual areas of the brain. If GLP-1 is injected into the brainstem and paraventricular nucleus of the hypothalamus, a consistent decrease in food intake is always observed. A moderate aversive response is observed when GLP-1 is injected into the central amygdala, an area associated with fear and stress. Administration to the arcuate nucleus decreases hepatic glucose production. An autonomic and cognitive stress response is seen with injection into any of these areas.
• Subsequently, he described the direct impacts of GLP-1 agonists on the cardiovascular system. The GLP-1 receptor is expressed in vascular endothelial cells, arterial muscles, myocardium and the endocardium. GLP-1 knockout mice show increased septal and posterolateral wall thickness but a decreased cardiac size with an impaired response to stress hormones. It seems that GLP-1 serves to increase insulin sensitivity in the heart, while improving myocardial relaxation and protecting from ischemia. After a myocardial infarction, GLP-1 has been shown to increase left ventricular ejection fraction (a measure of cardiac performance) and to cause beneficial vasodilation, reducing the cardiac burden that can exacerbate future CV events.

PANEL DISCUSSION

Ralph DeFronzo, MD (University of Texas, San Antonio, TX); John Buse, MD, PhD (University of North Carolina, Chapel Hill, NC); David D’Alessio, MD (University of Cincinnati, Cincinnati, OH)

Q: Does it make sense to use exenatide BID three times a day, with each meal?

Dr. Buse: It hasn’t been studied that way, but one well-known clinician (who has type 1 diabetes himself) does prescribe exenatide that way.

Q: How are patients doing on exenatide once weekly? Are there problems with the injections?

Dr. Buse: We’ve been experimenting with this for years and we don’t really have any problems, but people in other centers say that they do have problems with the injection kits. I think the important thing is education to make sure that your patients know how to use the kit.

Q: Do you recommend a combo of GLP-1 agonists and DPP-4 inhibitors?

Dr. Buse: There is a rationale for this, but the cost is too great to support this regimen currently. There are other hormones that are broken down by DPP-4, and those may be involved.

Q: What do we know about preservation of beta-cell function on a long-term basis with GLP-1 agonists?

Dr. DeFronzo: With exenatide the effects are maintained past three years. But shortly after discontinuing therapy, the protection was lost.

Q: What is the evidence for DPP-4 and beta-cell dysfunction?

Dr. DeFronzo: It’s relatively weak. With sitagliptin we couldn’t show an improvement in beta-cell function. If you go through the literature you can find varying effects. The strongest effect was seen with vildagliptin. But with GLP-1 analogs you always see a powerful effect.

Q: How do you explain bladder cancer to your patients on pioglitazone?

Dr. DeFronzo: I tell them it’s not solidly shown what the relationship is between pioglitazone and bladder cancer. If you look at the incidence of people off pioglitazone the incidence was 7/10,000; on any dose of pioglitazone it was 8/10,000. That’s pretty minimal. When you compare that to a 2-3% decrease in myocardial infarction, it’s not even comparable in terms of risk-benefit. And for many cancers there’s actually a decrease.

Q: Do you have a follow-up of your triple therapy study?

Dr. DeFronzo: Yes I do. We submitted that study as a late-breaker at ADA. And let me say that it just destroyed the ADA algorithm. Better weight loss, better hypoglycemia, better everything. But mysteriously it wasn’t accepted as a late-breaker at ADA this year. I found that rather strange considering the late- breakers I saw, but apparently they didn’t think that it was worth showing.

Q: Is the vasodilation effect of GLP-1 agonists receptor mediated?

Dr. D’Alessio: It seems to be specific to acetylcholine-mediated vasodilation as opposed to nitric oxide- mediated vasodilation.

Q: Is the insulin-GLP-1 combo cost effective?

Dr. D’Alessio: We don’t have enough data yet to say either way.

Q: What’s happened to the CV studies?

Dr. D’Alessio: The last one I showed you was from 2004, so why haven’t they done a big clinical trial? I’ve wondered that. I think there are going to be some studies. GLP-1 agonists have been studies in clinical trials with heart failure. It is a curiosity why this hasn’t been studied more.

Q: What’s the mechanism of GLP-1-associated nausea, and is it related to gastric emptying?

Dr. D’Alessio: We’re not sure how it happens in humans. We can inject it into an area of mouse brains to make them sick, but we still can’t extrapolate an exact mechanism from those studies.

Q: Is liraglutide on the road to a once-weekly formulation?

Dr. Buse: They’re developing a modified version of liraglutide that’s longer acting, but it’s going to be a different compound so I don’t think it’s actually fair to call it liraglutide any more.

Corporate Symposium: Role of GLP-1 and DPP-4 in Type 2 Diabetes (Sponsored by Novo Nordisk)

ROLE OF GLP-1 AND DPP-4 IN TYPE 2 DIABETES (SPONSORED BY NOVO NORDISK)

Richard Pratley, MD (Florida Hospital Diabetes Institute, Orlando, FL)

Dr. Pratley’s promotional presentation focused on the mechanism of action of GLP-1 analogs, and the advantages of Victoza (liraglutide) over sitagliptin (Merck’s Januvia). After reviewing the method of action of the GLP-1 hormone and DPP-4 enzyme, he explained that the incretin effect is seriously diminished in people with type 2 diabetes. Dr. Pratley then reviewed Victoza’s structure, effects on various glycemic metrics, safety data, and performance in a head to head trial with sitagliptin. He noted that from average baseline A1c levels of 8.4, participants in the trial on the 1.2 mg and 1.8 mg doses of Victoza showed larger declines in A1c than taking sitagliptin (A1c declines were -1.2%, -1.5%, and -0.9%, for the Victoza 1.2 mg, Victoza 1.8 mg, and sitagliptin groups, respectively) . He also emphasized Victoza’s positive effects on fasting plasma glucose and weight loss compared to sitagliptin. For more details on this study, see our April 10, 2012 Closer Look at http://bit.ly/KU36Az. Audience questions mainly focused on choosing among therapies, reducing nausea and injection site reactions, and the underlying mechanism in the observed weight loss and nausea.

Amylin Investor Reception

Daniel Bradbury (CEO) and Christian Weyer, MD (Senior Vice President, R&D)

Amylin CEO Daniel Bradbury led the company’s investor presentation, which focused heavily on its exenatide franchise. Reviewing data presented at ADA 2012, management emphasized Bydureon’s robust and durable effects on glycemic control, associated weight loss, low risk for hypoglycemia, improved tolerability, and convenience. In the DURATION-1 study, participants receiving Bydureon treatment for four years maintained strong glycemic control (average A1c of 6.9%) and exhibited improvements in beta cell function markers and weight (1156-P). A 26-week study found significantly greater improvements in A1c and weight with Bydureon vs. Levemir as well as low rates of associated hypoglycemia (40-LB). Furthermore, in the DURATION program, participants treated with Bydureon exhibited similar reductions in A1c and weight regardless of baseline weight (1152-P). Turning to Byetta, management highlighted the results of the EUREXA study, which demonstrated a greater durability of glycemic effect with Byetta vs. glimepiride at the end of three years (CT-SY22). Finally, regarding Symlin, data was reviewed from an in silico study that suggested a Symlin to insulin ratio of 9 mcg to 1 U in a coformulation would maintain 90% of the study’s virtual patients within optimal glycemic control without hypoglycemia (1057-P). Subsequently, management provided several updates regarding the company’s development pipeline. Most notably, management revealed that Amylin was pursuing a line extension regulatory approach for their exenatide once weekly suspension formulation, building upon already available data for Byetta and Bydureon – a similar strategy was used in the development of Bydureon. The first phase 3 trial for the new formulation (named DURATION-NEO-1) is expected to initiate in 3Q12 (previously mid-2012), and the trial will be similarly designed as DURATION-5 (head-to-head vs. Byetta). During the Q&A session, management reaffirmed that the submission timeline for Bydureon’s dual chamber pen had been delayed until early 2013 because of requests from the FDA for additional test data and longer stability data for the device. Amylin confirmed with the agency, however, that it could file an sNDA for the pen, allowing for a four-month review. Separately, management indicated that the first clinical study to test various co-formulations of pramlintide and insulin would commence in 3Q12. Particular excitement was expressed for the use of this coformulation in an artificial pancreas device.

PANEL DISCUSSION

Moderator: David Maggs, MD, MRCP (Vice President for R&D Strategic Relations, Amylin, San Diego, CA); Virginia Valentine, CNS, CDE (University of New Mexico, Albuquerque, NM); Anne Peters, MD (Keck School of Medicine, Los Angeles, CA); Carol Wysham, MD (University of Washington, Seattle, WA)

Dr. Maggs: Have you seen patients with lipodystrophy? What do you think about the potential of metreleptin?

Dr. Wysham: Traditionally, we have thought of lipodystrophy as a very rare condition, something we only read about in textbooks. Only when the metreleptin studies and the NIH reports came out to give some guidance on partial forms of lipodystrophy did I find out that it occurs much more commonly. On several occasions, I’ve taken the advice of my colleagues to ask my patients to show me their calves or give me a view of what their arms look like, and recognized that I have those patients in my practice. Although metreleptin will come out as an agent for what we think is a rare disease, I suspect we have a significant number of patients with partial lipodystrophy for which this agent will be very helpful.

Dr. Maggs We’re excited about the pramlintide/insulin coformulation at Amylin. What are your thoughts about the coformulation?

Dr. Peters: Everybody who is on insulin, particularly people with type 1 diabetes, should be on the coformulation product once it’s available. I can’t wait, could you hurry up?

Dr. Maggs: What would this mean for your patients on insulin pumps?

Ms. Valentine: It’d be huge to have physiological replacement of both hormones. The limiting factor for patients on pumps or using injections is the hassle factor. So, having a pump automatically deliver both insulin and pramlintide would make it more usable, and way more utilized than it is now.

Dr. Peters: And maybe better than insulin alone in many ways.

Dr. Maggs: Could you reflect on the type 2 diabetes epidemic and what type 2 diabetes currently looks like in your clinic?

Dr. Wysham: I have been in this field for 30 years now. I’m currently working in a county hospital taking care of many people with diabetes. I’m very astounded by how little we had to offer patients thirty years ago. The advance we have made in glucose testing and treatment have had a dramatic impact on patients. I keep wondering to myself how my patients got so old, and I’m thrilled that they are doing well. My biggest concern is with my younger patients. Some of these patients come in and have several risk factors for type 2 diabetes. They develop diabetes in their 30s. They are in their reproductive age. These are patients we hope enjoy a normal life expectancy. But if they are not well controlled, they will exhibit disease characteristics in their 40s that are typically present in 60-year olds. We need agents that not only help our patients achieve good glycemic control, but also alter their long term risk for progression to complications.

Dr. Maggs: Regarding the new ADA/EASD position statement, Anne, you were one of the key authors. Can you describe what this position statement means? What do you mean by patient-centered approaches to diabetes care?

Dr. Peters: That concept didn’t come up until later in the committee’s discussions. If patients don't use the their therapies, they are not going to work. There are a lot of drugs that we give our patients that they don’t take. It is import to consider the patient when making treatment recommendations. What is the patient going to want to do? How do we guide them to individualized targets? From ACCORD, we learned that the one size fits all approach might not be that good. There should be individualized targets and individualized treatment protocols. I may use drugs in different orders and in different places given different patient factors. The algorithm was meant to capture that. Some people wanted a more prescriptive algorithm. As an organization, the ADA wants to give more options for the patient and the provider. It wants what is best for the patient.

Dr. Maggs: What has your early experience been like with Bydureon? What do your patients think of it?

Ms. Valentine: It has gone extremely well. In my experience, people have been very positive about it. They are taking it, and they are loving not having to take multiple injections. Having had diabetes for 32 years myself, I of course immediately went on it too. I’m amazed how you really don’t have to think about it, that it’s only once a week. Patients are expressing the same feeling. It was easier to start than I thought it would be. The injection is amazingly easy, and what I’ve discovered is that after learning how to use Bydureon, it takes minimal effort afterwards. With the other GLP-1 agonists, the work up front is lower, but then it keeps going up because of titration and side effects. It’s just been amazingly smooth, people are liking it, and I’ve been very impressed with the persistence. People are sticking with it. That’s been wonderful.

Dr. Wysham: I agree with everything Virginia said. I participated in an earlier trial before the current device was available, and back then, it was a little bit more burdensome, so I was somewhat concerned. I have an older population so you’d think it’d be more challenging, but Bydureon has been well accepted by my patients. I gave myself a dry injection with the needle, and was not uncomfortable at all. I expected it to be worse, and that’s what most physicians are concerned with – the difference in the size of the needle. But it’s not an uncomfortable injection. Persistence is an important issue – when we look at persistence with some of the previously available GLP-1 agonists, levels are less than 50%. Insulin wasn’t much better than that. It is very important to measure and beware of what the persistence data is for Bydureon.

Dr. Peters: I agree entirely. I’m a cynic. I actually thought that I wouldn’t like Bydureon because I thought my patients would hate the whole fiddling thing with dosing as well as the huge needle. Not only did my patients like it, I’m sold as well. The product really just sold itself. My patients have had great experiences. They hate insulin. It has this taboo around it. But this is so different from insulin. They only have to take it once a week. For some patients that I wasn’t able to control on insulin, they’ve been willing to try it and they are getting amazing results. Yes, we all do the same thing. We all try shots. It is bigger and thicker, but it doesn’t hurt. I have been pleasantly surprised about my experience with Bydureon.

Dr. Maggs: We no have three products in the GLP-1 space. Is there such a thing as short- acting and long-acting GLP-1 agonists?

Dr. Peters: Absolutely. I have some patients on Byetta who tried Bydureon and wanted to switch back. They like Byetta more. They feel that Bydureon is more stealth. They get more of an immediate post- prandial effect with Byetta. Bydureon provides a slower effect. I think that there is a role for both. If you combine Byetta with a long acting insulin, you get a great response. We need more studies, however, to look at all the possible GLP-1 agonist/basal insulin combinations. We don't know yet what combination will work best. I like that there is more than one available. We’ll just have to see how it plays out clinically.

Ms. Valentine: I’ve had one patient who went back from Bydureon to Byetta. How come? My patient said, “Byetta speaks to me, whereas Bydureon whispers.”

Dr. Maggs: The GLP-1 agonist class as a whole seems pretty potent, and now we’re seeing that it’s durable, with three-year data for Byetta, and four-year data for Bydureon. Any thoughts on this?

Dr. Wysham: If you asked us all what we want, it’s to start a patient on a therapy and not have to worry about them for as long as possible. Durability is really key. Primary care is going to have a lot of difficulty trying to keep up with new medicines, titration, et cetera. Having something that you can just start patients on and have a durable effect is very important. One interesting observation from my own practice is that in the original Byetta clinical trials, the patients who were only on metformin are still only on metformin and Byetta. We had to stop prescribing metformin to a few patients with renal insufficiency, but they are doing just fine on Byetta, and they’ve been taking it for about eight years now. That’s something we just don’t see. I think it really points to the fact that these agents are extraordinarily effective early on in disease, and may very well change the natural history of the disease. If managed care insists on trying one or two additional agents before using GLP-1 agonists, we might lose the durability effect.

Ms. Valentine: What I hear from primary care doctors is that they don’t have to do any titration. In the diabetes club, we want to see our patients every three months or so. But for primary care doctors, however, they like that they don’t have to see their patients every three months in order to help them with titrations.

Dr. Maggs: I want to ask a little bit more about the comparison to basal insulin therapy. We’ve seen some nice data going out to three years comparing Bydureon to Lantus. What do these results mean to you as you make clinical decisions in your practice?

Dr. Peters: I prefer not to use insulin in people with type 2 diabetes. They seem to do less well on insulin than anything else. If I don't have to go to insulin, I prefer GLP-1 agonists because, similar to Carol’s experience, I’ve found that initiating these therapies early leads to sustained benefit. I’ve been in clinical practice for 30 years, and after three months of treatment, it’s really those on insulin who have a lot of issues. Clinical trials are the best-case scenarios for inulin. I think GLP-1 agonists can have a huge role in delaying insulin therapy or to be used in combination with insulin therapy. When I think about the pathophysiology of diabetes, GLP-1 therapy seems to make a lot of sense, whether or not it is used in combination with insulin.

Dr. Wysham: And we do it. Patients are able to get control with insulin with endocrinologists, but that just doesn’t happen in the primary care arena, and that’s who’s taking care of most of diabetes.

Ms. Valentine: Everybody in my practice with type 2 diabetes is going to be on an incretin of some sort or other until proven otherwise. The benefits so outweigh any issues. My patients really don’t like to go on insulin because of weight gain and fear of hypoglycemia.

Dr. Maggs: There is now quite some literature looking at the wider cardiometabolic effects of GLP-1 receptor agonism. What are your thoughts on the cardiovascular effects of GLP-1 agonists?

Dr. Wysham: I find myself thinking back to my discussions with primary care academic colleagues, who in 1992 said there was no proof that good glycemic control changed microvascular or macrovascular outcomes. I felt like there was so much data we accumulated between animal data and what we understood about the effects of good control that it was just inconceivable to me that primary care docs didn’t get it. We’re in the same situation with GLP-1 agonists and cardiovascular effects. The animal studies, the meta-analyses, the markers that we have of oxidative stress – that’s overwhelming evidence to me that it really looks like this is going to be a changer in terms of cardiovascular disease. But, we really need the outcomes studies to prove that, and to push that towards our payers to say that this is why these drugs need to be preferred over less expensive medications that solely lower glucose and don’t have an impact on cardiovascular risk factors.

Dr. Maggs: Any last comments?

Dr. Peters: I think our ability to take care of patients has really improved and will get better over time. I think GLP-1 agonists will help, and I am really looking forward to seeing data on how this class impacts outcomes.

Questions and Answers

Q: There has been a lot of controversy around Byetta since you launched Bydureon. Byetta sales have remained relatively flat. I’d like to know from your market research, is the universe of prescribing physicians expanding? Are prescriptions expanding? How do these factors explain the dynamics of Bydureon vs. Byetta prescriptions?

Vincent Mihalik (Senior Vice President, Sales and Marketing, Chief Commercial Officer): As you can expect, there has been some erosion for Byetta from patient switches. Our data lags by about two months, but we are seeing some erosion from Victoza and from Bydureon. Yet, we are seeing nice growth of Byetta on top of insulin. The Byetta market share is very dynamic right now. Looking at patient data, about 50% of Bydureon prescriptions are from patient switches. The other 50% are naïve to GLP-1. In terms of prescribers, if you look at total prescriptions, there is continual growth in the prescriber base. It is up from the first year of Byetta’s launch. It is even up from Victoza due to Bydureon’s launch. We are seeing very good productivity from Bydureon compared to Victoza with endocrinologists.

Q: How much impact do you think the pen will have beyond the current formulation and dosing process? I went to your booth and saw a demo on how to inject yourself, and it seemed pretty simple to me.

Ms. Valentine: I think for the diabetes club it won’t make any difference because we’ve just jumped right in. I think that for primary care, it might make a difference for some people.

Dr. Wysham: The perception of any injectable therapy – insulin, pens, et cetera – is way worse in the primary care office than in reality. So, anything that decreases the complexity in their minds is going to improve the likelihood of prescription. I think the pen is really important. Again, for those of us who feel really comfortable with the current formulation, I’ve had literally no problems when presenting Bydureon to patients. They’re very excited. We unfortunately cannot take care of all patients with diabetes, so we really have to address the concerns of primary care.

Dr. Peters: The lack of titration is key no matter how it is given. One of the real barriers for primary care physicians is that they can sometimes have difficulty communicating to patients what to do with their medications. This needs to be a point of stress. I tell providers who are hesitant to start prescribing Bydureon that once you teach a patient how to use it for the first time, you will know how to dose the drug. The guide is very easy to use, and I find it fun to teach patients how to use the drug. The pen may make it more easily accessible, but the fact that it requires no titration, is administered once weekly, and is not associated with hypoglycemia will make it a pretty well accepted therapy.

Mr. Mihalik: I would just like to build on Anne’s point. One thing that I keep hearing from primary care physicians and endocrinologists is that they like the increased tolerability. They keep telling us that they are getting no call backs from patients, and that they are not used to that with GLP-1 agonists. This is not just with the medication, but the kit too. It’s the increased tolerability that is really helping acceptance. That bodes very well for the primary care community. They want a simple drug that does not require blood glucose monitoring or titrations. Providers appear to like the simplicity that Bydureon offers.

Q: Can you compare how teaching patients to use Bydureon versus insulin (e.g., starting a Lantus regimen) are in terms of time and ease in physicians’ practices?

Ms. Valentine: With Bydureon, all the work is up front, and then there is nothing after that. Teaching a patient how to inject insulin is maybe a few minutes shorter. But then there is teaching them what their dose is, teaching them about hypoglycemia, teaching them how to check blood sugar, and teaching them how to titrate. You’ve got to teach them to titrate, or they have to call you about their blood sugars, or come in to the practice and have you titrate insulin for them. And then you have to deal with side effects – hypoglycemia and weight gain. With Bydureon, it’s very simple to teach, and they’ve done an extraordinary job of designing a very simple system that is well supported.

Dr. Wysham: Probably the most important part of insulin titration is that even though we teach patients and give ideas on how to do it, it’s not uncommon for half of the patients not to titrate insulin at home by themselves, because they don’t feel comfortable doing so.

Ms. Valentine: I’d say in my practice it’s more than half.

Dr. Wysham: When this happens, the efficacy of medications is reduced because patients are not able to take the steps necessary to make the medicine work. Whereas, with Bydureon, we tell our patients that we’ll step them through their next injection if they have problems, but we haven’t had any patients come back to us for help.

Ms. Valentine: They never call, they never write.

Dr. Wysham: They never take us up on that even though we offer. We’re happy to go through the next injection. I have a patient who is 80 years old – one of my original Byetta patients, who just needed a bit more A1c reduction. We taught him one time in five minutes, and he felt like he could do it after that. It’s not difficult, and it doesn’t affect our workflow whatsoever.

Q: Can you give us more granularity about what the FDA is requiring that led to the delay for Bydureon’s pen?

Mr. Bradbury: We announced last week that we now plan to submit the pen in 2013 and that we expect an approval in 2013. Regarding the application itself, we received clarity from the FDA that we would be able to submit an sNDA, allowing for a four-month review. The FDA asked for additional testing and stability data for the device. The stability data they asked for was a little bit longer than what we already had in place. These activities are already ongoing and will allow us to submit in 2013 with an expected approval in 2013.

 

-- by Hannah Deming, Ben Kozak, Nina Ran, Lisa Rotenstein, Joseph Shivers, Mark Sorrentino, Katrina Verbrugge, Nick Wilkie, Vincent Wu , and Kelly Close