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/m(2), HbA(1c) 8.6 +/- 1.2% [+/-SD]) and began 4 weeks at 5 microg subcutaneous exenatide twice daily (before breakfast and dinner; arms A and B) or placebo. Subsequently, subjects in arm B were escalated to 10 microg 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-microg, 5-microg, and placebo arms, respectively (adjusted P < 0.001). Of evaluable subjects with baseline HbA(1c) > 7% (n = 237), 41% (10 microg), 33% (5 microg), and 9% (placebo) achieved HbA(1c) <or= 7% (P < 0.001). Fasting plasma glucose concentrations decreased in the 10-microg 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-microg 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.