Abstract

OBJECTIVE—This study evaluated the ability of the incretin mimetic exenatide (exendin-4) to improve glycemic control in patients with type 2 diabetes failing maximally effective doses of a sulfonylurea as monotherapy.

RESEARCH DESIGN AND METHODS—This was a triple-blind, placebo-controlled, 30-week study conducted at 101 sites in the U.S. After a 4-week, single-blind, placebo lead-in period, 377 subjects were randomized (60% men, age 55 ± 11 years, BMI 33 ± 6 kg/m², HbA_1c 8.6 ± 1.2% [±SD]) and began 4 weeks at 5 μg subcutaneous exenatide twice daily (before breakfast and dinner; arms A and B) or placebo. Subsequently, subjects in arm B were escalated to 10 μg b.i.d. exenatide. All subjects continued sulfonylurea therapy.

RESULTS—At week 30, HbA_1c changes from baseline were −0.86 ± 0.11, −0.46 ± 0.12, and 0.12 ± 0.09% (±SE) in the 10-μg, 5-μg, and placebo arms, respectively (adjusted P < 0.001). Of evaluable subjects with baseline HbA_1c > 7% (n = 237), 41% (10 μg), 33% (5 μg), and 9% (placebo) achieved HbA_1c ≤ 7% (P < 0.001). Fasting plasma glucose concentrations decreased in the 10-μg arm compared with placebo (P < 0.05). Subjects in the exenatide arms had dose-dependent progressive weight loss, with an end-of-study loss in the 10-μg exenatide arm of −1.6 ± 0.3 kg from baseline (P < 0.05 vs. placebo). The most frequent adverse events were generally mild or moderate and gastrointestinal in nature. No severe hypoglycemia was observed.

CONCLUSIONS—Exenatide significantly reduced HbA_1c in patients with type 2 diabetes failing maximally effective doses of a sulfonylurea. Exenatide was generally well tolerated and was associated with weight loss.