SAN FRANCISCO — An investigational once-weekly formulation of exenatide resulted in superior improvements in glucose control at 30 weeks, compared with the current twice-daily version, and elicited sustained glycemic control and weight loss at 1 year in patients with type 2 diabetes.
The phase III data were presented in two separate sessions at the annual scientific sessions of the American Diabetes Association. Known commercially as Byetta, the twice-daily injectable incretin mimetic is comarketed by Amylin Pharmaceuticals Inc., Eli Lilly & Co., and Alkermes Inc. An application for approval of the long-acting release formulation was filed with the Food and Drug Administration in the first quarter of 2008, according to a statement issued by the three companies, which funded the study.
Dr. Daniel J. Drucker, professor of medicine and director of the Banting and Best Diabetes Centre at the University of Toronto, presented the 30-week data from an open-label study in which 295 patients with type 2 diabetes were randomized to receive either the twice-daily formulation (10 mcg twice a day) or the once-weekly version (2 mg/wk). At baseline, about 15% of the patients were drug-naive, while the rest were being treated with one or more oral glucose-lowering agents. They had a mean hemoglobin A1c (HbA1c) of 8.3%, fasting plasma glucose (FPG) of 169 mg/dL, body mass index (BMI) of 35 kg/m
Withdrawals prior to 30 weeks were not significantly different between the groups: 13.5% of the 148 patients with the once-weekly formulation, vs. 11.6% of the 147 patients in the twice-daily group. At 30 weeks, the mean HbA1c had dropped by 1.9 percentage points in the once-weekly group, compared with 1.5% in the twice-daily group. The proportion of patients in the entire cohort achieving an HbA1c of less than or equal to 7% was 77%, while 49% reached an HbA1c of 6.5% or below and 25% dropped to 6% or lower. Improvements in HbA1c were significantly greater among the patients in both formulation groups who had baseline values of 9% or higher, Dr. Drucker reported.
Fasting plasma glucose levels also dropped to a greater degree in the once-weekly group, by 42 mg/dL, compared with 25 mg/dL for the twice-daily patients. Despite the improved glycemic control, weight loss occurred in both groups, with an average loss of 3.6 kg for patients taking the once-weekly formulation and 3.7 kg for patients taking the twice-daily formulation—not significantly different. Reductions in total cholesterol, triglycerides, and systolic and diastolic blood pressure were also seen and were predominantly due to the weight loss, he said.
No major hypoglycemia occurred in either group, and mild hypoglycemia was seen only in the patients taking concurrent sulfonylureas. Injection-site bruising was more common in the twice-daily group than in the once-weekly group (10% vs. 5%). Nausea was less frequent in the once-weekly group (26% vs. 35% for the twice-daily group), but was predominantly mild and transient. And although the patients reporting nausea did lose more weight, those without nausea also experienced weight loss, Dr. Drucker noted.
American Diabetes Association president John Buse presented the 52-week data in a special “Late-Breaking Clinical Studies” session. Following the 30-week study, a total of 120 patients from the once-weekly group continued on that formulation for another 22 weeks, while 121 who had been on the twice-daily version switched to the once-weekly formulation for the next 22 weeks.
Improvements in glycemic control were sustained in the group that stayed on once-weekly exenatide (mean 2.0-percentage point drop from baseline in HbA1c and FPG reduction of 47 mg/dL), while further improvements from baseline occurred among those who switched to the long-acting formulation (2.0% and 43 mg/dL). The mean HbA1c in both groups at 52 weeks was 6.6%, said Dr. Buse, professor of medicine, director of the Diabetes Care Center, and chief of the division of endocrinology at the University of North Carolina at Chapel Hill.
Again, the results were far more dramatic among the patients who started with worse glycemic control. Among those with a baseline HbA1c of 9% or above, the group that took the once-weekly formulation for the entire 52 weeks had dropped by 2.8 percentage points, and those who switched formulations dropped by 2.6. In contrast, those drops were just 1.3% and 1.2%, respectively, among those with baseline HbA1c levels less than 9%.
Weight loss was similar in both groups at 52 weeks, with the group that stayed on once-weekly exenatide sustaining a 4.1-kg loss from baseline, while those who switched had a mean weight loss of 4.5 kg. Both groups also had clinically significant reductions in both systolic blood pressure (5.7 mm Hg in the once-weekly group and 4.0 mm Hg among those who switched) and diastolic blood pressure (2.2 and 2.1 mm Hg, respectively). Improvements in serum lipid profiles were similar in the two groups at 52 weeks, Dr. Buse said.