OBJECTIVE: To review the pharmacology, pharmacokinetics, safety, and efficacy of sitagliptin, a dipeptidyl peptidase IV (DPP-IV) inhibitor in the management of type 2 diabetes mellitus. DATA SOURCES: A MEDLINE search (1966-February 2006) was conducted for English-language articles using the terms dipeptidyl peptidase IV inhibitor, incretin, MK-0431, and sitagliptin. Abstracts from the American Diabetes Association annual meetings in 2004 and 2005 were included as sources of data. STUDY SELECTION AND DATA EXTRACTION: Articles pertaining to the pharmacology of sitagliptin, its pharmacokinetics, safety and efficacy were reviewed. DATA SYNTHESIS: Sitagliptin is a potent, competitive, reversible inhibitor of the DPP-IV enzyme. It is eliminated renally, with a terminal half-life of 11.8-14.4 hours. In Phase 11 clinical trials, sitagliptin was found to be superior to placebo for the treatment of type 2 diabetes mellitus. Results of a small trial comparing sitagliptin with glipizide indicate that both treatments are comparable. The efficacy of sitagliptin has also been demonstrated when used as adjunctive therapy with metformin. Few adverse effects have been reported. Weight gain and hypoglycemia have not been seen with sitagliptin therapy. CONCLUSIONS: Based on its unique mechanism of action, sitagliptin will provide practitioners with an additional tool in the treatment of diabetes. Review of the literature to date implies sitagliptin may be effective as monotherapy in type 2 diabetes. In addition, existing evidence supports the use of sitagliptin as adjunct therapy to sulfonylureas and metformin. Another advantage of sitagliptin use is that it appears to be free from the adverse effects of weight gain and hypoglycemia that are associated with currently available treatments.