Background: Although early intervention to reduce hyperglycemia in patients with type 2 diabetes mellitus can improve macrovascular outcomes and may reduce microvascular complications, more than 50 percent of patients do not achieve A1C levels of less than 7 percent. Antidiabetic medical therapies based on glucagon-like peptide-1 (GLP-1) stimulate appropriate insulin secretion and suppress inappropriate glucagon secretion. The native peptide also slows gastric emptying and reduces food intake, but its short half-life and gastrointestinal (GI) side effects limit its therapeutic use. Albiglutide is a GLP-1 receptor agonist with a long half-life (approximately five days) and potentially fewer GI side effects. Rosenstock and colleagues explored a wide range of doses and administration schedules to assess the effectiveness, safety, and tolerability of albiglutide.
The Study: This phase II trial examined 10 treatment arms in a prospective randomized double-blind placebo-controlled study. Men and women 18 to 75 years of age with type 2 diabetes participated at 118 sites in the United States, Mexico, Chile, and the Dominican Republic between April 2007 and May 2008. Participants were eligible for the study if they were drug naïve or on metformin (Glucophage) only, had a body mass index between 20 and 40 kg per m2, and an A1C level between 7 and 10 percent. Participants were excluded if they were on any other oral antidiabetic drugs or insulin, had fasting triglyceride levels of more than 800 mg per dL (9.04 mmol per L), or had clinically significant end-organ disease. Lipid-lowering medications were allowed as long as the dosage had been stable for the three months preceding the study.
Participants were randomly assigned to albiglutide regimens at three different dosages: weekly at 4, 15, or 30 mg; biweekly at 15, 30, or 50 mg; or monthly at 50 or 100 mg. An open-label reference arm with exenatide (Byetta; a twice-daily GLP-1 agonist with a shorter half-life) and placebo matched for each treatment regimen were included. The doses of albiglutide were administered subcutaneously and given in physicians' offices for 16 weeks. A1C, fasting plasma glucose, fasting fructosamine, C-peptide, glucagon, insulin, and lipid levels were measured at baseline and at predetermined intervals throughout the study and during the 11-week follow-up phase after treatment. Adverse events were monitored throughout. The primary end point was the change in A1C level from baseline to week 16.
Results: Of the 774 participants screened, 361 were randomized and 255 completed the trial. Baseline demographics were similar in all groups. The intention-to-treat analysis found that albiglutide was effective; the highest dosage in each treatment group had similar, statistically significant reductions in A1C levels after 16 weeks compared with placebo (−0.87, −0.79, and −0.87 percent for 30 mg weekly, 50 mg biweekly, and 100 mg monthly, respectively).
Nausea and vomiting were the most commonly reported adverse events across the groups, and were more common with increasing dosage. However, in all groups the incidence of nausea decreased throughout the course of the study.
Conclusion: Albiglutide effectively lowers A1C levels 0.8 to 0.9 percent, on average. Further large-scale studies are needed to determine optimal dosing.