OBJECTIVE:To evaluate available literature characterizing the pharmacology, pharmacokinetics, drug interactions, efficacy, and safety of exenatide in patients with type 2 diabetes. DATA SOURCES:A PubMed database search (1966-May 2006) was conducted, using exenatide as the search term. The manufacturer's prescribing information was also used. STUDY SELECTION AND DATA EXTRACTION:English-language articles were selected and data were extracted with a focus on clinical outcomes associated with the treatment of patients with type 2 diabetes. DATA SYNTHESIS:Exenatide exerts a glucoregulatory effect by various mechanisms including secretion of glucose-dependent insulin, suppression of inappropriately high glucagon levels in patients with type 2 diabetes, delayed gastric emptying, and reduction of food intake. In placebo-controlled clinical studies, plasma exenatide concentrations appeared to exhibit dose-proportional kinetics, reaching peak plasma levels between 2 and 3 hours after a single subcutaneous injection. Exenatide's elimination half-life ranged from 3.3 to 4.0 hours, and the time to reach maximum concentration was about 2 hours. Interactions between exenatide and agents such as digoxin and lisinopril were not considered significant. In Phase III trials, exenatide demonstrated significant reduction of hemoglobin A1c levels from baseline and compared with placebo after 30 weeks of treatment in patients unable to achieve optimal glycemic control with metformin, a sulfonylurea, or oral combination therapy (0.4-0.9%). Patients' weight decreased with exenatide (0.9-2.8 kg), but adverse gastrointestinal (GI) events were common. Exenatide combined with thiazolidonediones, D-phenylalanine derivatives, meglitinides, or alpha glucosidase inhibitors has not been studied. CONCLUSIONS:Clinical trials have demonstrated that exenatide improves glycemic control when added to sulfonylureas and metformin, and it may be an alternative to insulin glargine in patients requiring additional therapy. Hypoglycemia has been encountered in clinical trials of exenatide, especially upon initiation of therapy with sulfonylureas (not with metformin); close patient monitoring is therefore recommended. Further studies should assess the impact of exenatide on clinical outcomes such as micro- and macrovascular disease.