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Background: Exenatide is the first of a new class of agents known as incretin mimetics that are in development for the treatment of type 2 diabetes. Exenatide has been shown to reduce fasting and postprandial glucose in patients with type 2 diabetes, as well as provide sustained reductions in hemoglobin A_1c (HbA_1c). This study was designed to assess the dose dependencies of the glucoregulatory effects and tolerability of exenatide when added to diet and exercise or metformin monotherapy in patients with type 2 diabetes.

Methods: In this randomized, triple-blinded, placebo-controlled Phase 2 clinical trial, 156 patients were randomized to placebo or exenatide at 2.5, 5.0, 7.5, or 10.0 µg administered b.i.d. for 28 days.

Results: After 28 days of therapy, exenatide was associated with significant (P < 0.0001, linear contrast testing), dose-dependent reductions in HbA1c (0.1 ± 0.1%, –0.3 ± 0.1%, –0.4 ± 0.1%, ±0.5 ± 0.0%, and –0.5 ± 0.1% for placebo and 2.5, 5.0, 7.5, and 10.0 µg b.i.d. exenatide, respectively) and significant (P = 0.0006, linear contrast testing) reductions in fasting plasma glucose (+6.8 ± 4.1, –20.1 ± 5.2, –21.2 ± 3.9, –17.7 ± 4.8, and –17.3 ± 4.4 mg/dL for placebo and 2.5, 5.0, 7.5, and 10.0 µg b.i.d. exenatide, respectively) by Day 28. These reductions were similar for patients treated with diet/exercise and those treated with metformin. In addition, patients receiving exenatide exhibited dose-dependent reductions in body weight (0.0 ± 0.3, –0.7 ± 0.3, –0.7 ± 0.2, –1.4 ± 0.3, and –1.8 ± 0.3 kg for placebo and 2.5, 5.0, 7.5, and 10.0 µg b.i.d. exenatide, respectively; P < 0.01 for 7.5 and 10.0 µg b.i.d. exenatide doses compared with placebo) at Day 28. The most common adverse event was mild-to-moderate nausea that was dose-dependent (seven of 123 patients randomized to exenatide withdrew from the study because of gastrointestinal effects).

Conclusions: Exenatide dose-dependently improved glycemic control and reduced body weight over 28 days in patients with type 2 diabetes treated with diet/exercise or metformin.