Once-weekly exenatide reduced hemoglobin A1c to a significantly greater degree than did either sitagliptin or pioglitazone in DURATION-2, a 26-week randomized, double-blind trial of 491 patients with type 2 diabetes who had baseline HbA1c levels of 8.5% or higher despite metformin treatment.
The study, funded by Amylin Pharmaceuticals and Eli Lilly, was published online to coincide with a presentation of its results by lead author Dr. Richard M. Bergenstal at the annual scientific sessions of the American Diabetes Association (Lancet 2010 June 26 [doi:10.1016/S0140-6736(10)60590-9]).
Patients received treatment in 72 sites in the United States, India, and Mexico. All had been treated with a stable metformin regimen for at least 2 months before screening and continued to take metformin throughout the study. The patients were randomized to one of three regimens: 2-mg exenatide injection once weekly plus oral placebo once daily, 100 mg oral sitagliptin once daily plus placebo injection once weekly, and 45 mg oral pioglitazone once daily with placebo injections once weekly.
Patients and staff in DURATION-2 (A Study to Compare the Glycemic Effects, Safety, and Tolerability of Exenatide Once Weekly to Those of Sitagliptin and a Thiazolidinedione in Subjects With Type 2 Diabetes Treated With Metformin) were all blinded to treatment allocation during the 26 weeks of treatment, said Dr. Bergenstal of the International Diabetes Center at Park Nicollet, Minneapolis, and his associates.
Of the 514 participants randomized to treatment, those who received at least one treatment (491) were included in the intention-to-treat analysis. Fewer patients withdrew from treatment with sitagliptin (13%) than did those receiving exenatide once weekly (21%) or pioglitazone (21%).
At 26 weeks, mean HbA1c values were 7.2% for exenatide, 7.7% for sitagliptin, and 7.4% for pioglitazone. From baseline to week 26, reduction in HbA1c with once-weekly exenatide was significantly greater than with the other two drugs, at 1.5 percentage points, compared with 0.9 and 1.2 percentage points with sitagliptin and pioglitazone, respectively.
When the data were stratified by baseline HbA1c, once-weekly exenatide was associated with a significantly greater reduction in HbA1c than was sitagliptin in all patients, but for exenatide versus pioglitazone the difference was significant only in patients with baseline HbA1c of 9% or higher, the investigators reported.
All three treatments improved fasting plasma glucose, but once-weekly exenatide resulted in a significantly greater reduction than did sitagliptin—32 vs. 16 mg/dL—but not pioglitazone, which produced a reduction in fasting plasma glucose of 27 mg/dL. Fasting insulin was significantly increased at week 26 with once-weekly exenatide compared with both sitagliptin and pioglitazone, they said.
Weight loss at 26 weeks was significantly greater with exenatide than with sitagliptin, 2.3 vs. 0.8 kg, while the pioglitazone group gained an average of 2.8 kg. Over 75% of the patients on once-weekly exenatide lost body weight, compared with 61% of those on sitagliptin and 21% of those on pioglitazone.
Reductions in systolic blood pressure were significantly greater with once-weekly exenatide than with sitagliptin, but did not differ from those seen with pioglitazone. Change in diastolic pressure at week 26 did not differ between the three groups. Significant improvement in HDL cholesterol was recorded with all treatments, and improvement was significantly greater with pioglitazone than with exenatide. Pioglitazone was the only treatment associated with a significant reduction in triglycerides and total cholesterol, Dr. Bergenstal and his associates noted.
The most common treatment-emergent adverse events for patients on exenatide and sitagliptin were nausea and diarrhea, whereas pioglitazone patients' most common adverse events were upper respiratory tract infection and peripheral edema. Vomiting was more common with exenatide than with sitagliptin or pioglitazone.
Adverse events leading to withdrawal from the study drug occurred in 10 patients on exenatide, 5 on sitagliptin, and 6 on pioglitazone. Of the 26 serious adverse events during treatment, one was fatal but the others resolved.
Dr. Bergenstal's institution has received consultancy fees or research grant support, or both, with receipt of travel and accommodation expenses in some cases, from Abbott Diabetes Care, Amylin, Bayer, Eli Lilly, Intuity Medical, Hygieia Medical, LifeScan, Mannkind, Medtronic-Minimed, National Institutes of Health, Novo Nordisk, ResMed, Roche, Sanofi-Aventis, United Health Group, and Valeritas; all research activity, and advisory or consultancy services were done under contract with the nonprofit International Diabetes Center at Park Nicollet. Dr. Bergenstal also owns stock in Merck. One coauthor has similar disclosures, six are employees of Amylin Pharmaceuticals, and one is an employee of Eli Lilly.