Major Finding: At 26 weeks, HbA_1c in patients treated with long-acting exenatide had dropped 1.5 percentage points, compared with a 1.3-point reduction in those treated with daily insulin glargine.

Data Source: DURATION-3, a phase III, 26-week open-label randomized trial of 456 patients with type 2 diabetes who had suboptimal control despite use of metformin with or without sulfonylureas.

Disclosures: The study was funded by Amylin Pharmaceuticals and Eli Lilly.

A once-weekly formulation of exenatide reduced hemoglobin A_1c level to a greater degree than did once-daily insulin glargine in DURATION-3, a phase III, 26-week open-label randomized trial of 456 patients with type 2 diabetes who had suboptimal control despite use of metformin with or without sulfonylureas.

The overall greater lowering of HbA1_c with exenatide was due to significantly lower postprandial glucose excursions, since fasting plasma glucose was actually lower among the patients randomized to insulin glargine. DURATION-3 (Efficacy of Once-Weekly Exenatide Long-Acting Release and Once-Daily Insulin Glargine in Patients With Type 2 Diabetes Treated With Metformin Alone or in Combination With Sulfonylurea was conducted in 72 sites around the world, funded by Amylin Pharmaceuticals and Eli Lilly and Co. (Lancet 2010;375:2234-43).

Patients randomized to exenatide received a 2-mg dose injected once a week. Those in the insulin glargine group started with 10 IU per day injected at bedtime, and were instructed to adjust insulin doses to achieve target fasting glucose values of 72–99 mg/dL TMetformin doses were kept constant, but patients taking sulfonylureas were advised to reduce that dose. The study design did not allow for blinding, noted Dr. Michaela Diamant, of VU University, Amsterdam, and her associates.

Mean doses of insulin glargine rose from 10 IU to 31 IU per day, and nearly one in four patients reduced their sulfonylurea dose. Metformin doses were about 2,000 mg/day throughout the study.

At 26 weeks, hemoglobin A1_c in the exenatide group had dropped 1.5 percentage points, compared with 1.3 in those receiving glargine, and 60% of the exenatide patients achieved an HbA1_c of less than 7%, compared with 48% for the glargine group, both significant differences. The proportions achieving HbA1_c values less than 6.5% were 35% and 23% respectively.

Mean fasting serum glucose concentrations were reduced in both groups, but to a significantly greater degree with insulin glargine (38 vs. 50 mg/dL), Dr. Diamant and her associates noted.

Whereas exenatide was associated with a progressive decrease in body weight, those taking insulin glargine had progressive increases. At 26 weeks, the exenatide group had lost an average of 2.6 kg, while the glargine group had gained 1.4 kg. In the exenatide group, reductions in body weight occurred in both those who reported nausea (3.5 kg) and those who did not (2.2 kg), they said.

Gastrointestinal events including nausea and diarrhea were among the most frequently reported adverse events in the exenatide group. Nausea was reported by 13% with exenatide vs. 1% with glargine, and diarrhea by 9% and 4%, respectively. All were mild or moderate in intensity. No serious adverse events were reported by more than one patient except for chest pain in two patients. No deaths occurred in either group. Discontinuations owing to adverse events were greater with exenatide (5% vs. 1%), due in part to injection-site reactions (2% vs. 0%).

At 26 weeks, five exenatide and no glargine patients had elevated amylase or lipase concentrations and one patient taking exenatide had edematous pancreatitis, an adverse event that has been reported previously with the currently available twice-daily exenatide. That patient was fully recovered by 2 months.

In an accompanying editorial, Dr. Anoop Misra and Dr. Shashank Joshi pointed out that the nausea, although less common with once-weekly exenatide versus the twice-daily formulation, could still be troublesome in patients who are taking multiple drugs, including metformin, and in those who have diabetic gastroparesis. They also noted that cardiovascular safety data are still needed for this drug, and strict monitoring of pancreatic effects will be necessary.

Both the long-acting and the twice-daily exenatide formulations have been linked to renal dysfunction, and to attenuation of the response among the 6%–9% who develop antibodies to the drug, Dr. Misra and Dr. Joshi said (Lancet 2010;375:2198-9).

Nonetheless, this or other drugs in the glucagon-like peptide-1 receptor analogue class might be suitable for patients with type 2 diabetes who are obese or those in whom hypoglycemia is a clinical concern. “Currently, there is more promise, few disadvantages, and some unknowns about treatment with long-acting exenatide for diabetes,” they concluded.

Dr. Diamant is a consultant and speaker for Eli Lilly, Novo Nordisk, and Merck, Sharpe, and Dohme, and a consultant for Sanofi-Aventis. The VU University has also received research grants from those companies as well Amylin Pharmaceuticals, Novartis, and Takeda. Three of the coauthors are employees of Lilly, and one works for Amylin.

Dr. Misra has received lecture fees and research funding from Sanofi-Aventis, Merck, Novo Nordisk, and Eli Lilly. Dr. Joshi stated that he had no conflicts of interest.

Weekly Exenatide Topped Daily Insulin Glargine : In exenatide patients, 60% had an HbA1c of less than 7%, compared with 48% of glargine patients.

Weekly Exenatide Topped Daily Insulin Glargine : In exenatide patients, 60% had an HbA1_c of less than 7%, compared with 48% of glargine patients.