OBJECTIVE -This study evaluates the ability of the incretin mimetic exenatide (exendin-4) to improve glycemic control in patients with type 2 diabetes failing to achieve glycemic control with maximally effective metformin doses. RESEARCH DESIGN AND METHODS-A triple-blind, placebo-controlled, 30-week study at 82 U.S. sites was performed with 336 randomized patients. In all, 272 patients completed the study. The intent-to-treat population baseline was 53 Ϯ 10 years with BMI of 34.2 Ϯ 5.9 kg/m 2 and HbA 1c of 8.2 Ϯ 1.1%. After 4 weeks of placebo, subjects self-administered 5 g exenatide or placebo subcutaneously twice daily for 4 weeks followed by 5 or 10 g exenatide, or placebo subcutaneously twice daily for 26 weeks. All subjects continued metformin therapy.RESULTS -At week 30, HbA 1c changes from baseline Ϯ SE for each group were Ϫ0.78 Ϯ 0.10% (10 g), Ϫ0.40 Ϯ 0.11% (5 g), and ϩ0.08 Ϯ 0.10% (placebo; intent to treat; adjusted P Ͻ 0.002). Of evaluable subjects, 46% (10 g), 32% (5 g), and 13% (placebo) achieved HbA 1c Յ7% (P Ͻ 0.01 vs. placebo). Exenatide-treated subjects displayed progressive dose-dependent weight loss (Ϫ2.8 Ϯ 0.5 kg [10 g], Ϫ1.6 Ϯ 0.4 kg [5 g]; P Ͻ 0.001 vs. placebo). The most frequent adverse events were gastrointestinal in nature and generally mild to moderate. Incidence of mild to moderate hypoglycemia was low and similar across treatment arms, with no severe hypoglycemia.CONCLUSIONS -Exenatide was generally well tolerated and reduced HbA 1c with no weight gain and no increased incidence of hypoglycemia in patients with type 2 diabetes failing to achieve glycemic control with metformin.

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 Ϯ 11 years, BMI 33 Ϯ 6 kg/m 2 , HbA 1c 8.6 Ϯ 1.2% [ϮSD]) and began 4 weeks at 5 g subcutaneous exenatide twice daily (before breakfast and dinner; arms A and B) or placebo. Subsequently, subjects in arm B were escalated to 10 g b.i.d. exenatide. All subjects continued sulfonylurea therapy.RESULTS -At week 30, HbA 1c changes from baseline were Ϫ0.86 Ϯ 0.11, Ϫ0.46 Ϯ 0.12, and 0.12 Ϯ 0.09% (ϮSE) in the 10-g, 5-g, and placebo arms, respectively (adjusted P Ͻ 0.001). Of evaluable subjects with baseline HbA 1c Ͼ 7% (n ϭ 237), 41% (10 g), 33% (5 g), and 9% (placebo) achieved HbA 1c Յ 7% (P Ͻ 0.001). Fasting plasma glucose concentrations decreased in the 10-g arm compared with placebo (P Ͻ 0.05). Subjects in the exenatide arms had dose-dependent progressive weight loss, with an end-of-study loss in the 10-g exenatide arm of Ϫ1.6 Ϯ 0.3 kg from baseline (P Ͻ 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.

OBJECTIVE -This study evaluated the effects of exenatide, a novel incretin mimetic, in hyperglycemic patients with type 2 diabetes unable to achieve glycemic control with metforminsulfonylurea combination therapy. RESULTS -Week 30 A1C changes from baseline (ϮSE) were Ϫ0.8 Ϯ 0.1% (10 g), Ϫ0.6 Ϯ 0.1% (5 g), and ϩ0.2 Ϯ 0.1% (placebo; adjusted P Ͻ 0.0001 vs. placebo), yielding placeboadjusted reductions of Ϫ1.0% (10 g) and Ϫ0.8% (5 g). In the evaluable population, exenatide-treated subjects were more likely to achieve A1C Յ7% than placebo-treated subjects (34% [10 g], 27% [5 g], and 9% [placebo]; P Ͻ 0.0001). Both exenatide arms demonstrated significant weight loss (Ϫ1.6 Ϯ 0.2 kg from baseline each exenatide arm, Ϫ0.9 Ϯ 0.2 kg placebo; P Յ 0.01 vs. placebo). Mild or moderate nausea was the most frequent adverse event. The incidence of mild/moderate hypoglycemia was 28% (10 g), 19% (5 g), and 13% (placebo) and appeared lower with MIN than with MAX sulfonylurea treatment. RESEARCH DESIGN AND METHODSCONCLUSIONS -Exenatide significantly reduced A1C in patients with type 2 diabetes unable to achieve adequate glycemic control with maximally effective doses of combined metformin-sulfonylurea therapy. This improvement in glycemic control was associated with no weight gain and was generally well tolerated.

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Despite the advent of new treatments, glucose control in the type 2 diabetes population is unsatisfactory. AC2993 (synthetic exendin-4; exenatide), a novel glucose-dependent insulinotropic agent, exhibited notable antidiabetic potential in two clinical studies in patients with type 2 diabetes. In study A, 24 subjects received sc injections of study medication (0.1 micro g/kg AC2993 or placebo) twice daily with meals for 5 d. Statistically significant reductions in mean postprandial circulating concentrations of glucose, insulin, and glucagon occurred following treatment with AC2993. In study B, 13 subjects receiving a single dose of study medication (0.05, 0.1, or 0.2 micro g/kg AC2993 or placebo) following an overnight fast had reduced fasting plasma glucose concentrations during the subsequent 8-h period. The relative glucose and insulin concentration profiles were consistent with glucose-dependent insulinotropism. AC2993 was well tolerated. Mild transient headache, nausea, and vomiting were the main adverse events. In conclusion, AC2993 acutely and markedly reduces fasting and postprandial glucose concentrations in patients with type 2 diabetes. During fasting, glucose-dependent enhancement of insulin secretion and suppression of glucagon secretion are the predominant mechanisms, and postprandially, slowing of gastric emptying is additionally operative. This robust antidiabetic effect warrants further evaluation of AC2993.