CONTEXT: Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretins secreted from enteroendocrine cells post-prandially in part to regulate glucose homeostasis. Dysregulation of these hormones is evident in T2DM.

Two new drug classes, exenatide (GLP-1 mimetic) and sitagliptin (dipeptidyl peptidase [DPP] 4 inhibitor) have been approved by regulatory agencies for treating T2DM. Liraglutide (GLP-1 mimetic) and vildagliptin (DPP 4 inhibitor) are expected to arrive on the market soon.

EVIDENCE ACQUISITION: The background of incretin-based therapy and selected clinical trials of these four drugs are reviewed. A MEDLINE search was conducted for published articles using the key words incretin, GIP, GLP-1, exendin-4, exenatide, DPP 4, liraglutide, sitagliptin, and vildagliptin.

EVIDENCE SYNTHESIS: Exenatide and liraglutide are injection-based. Three-year follow-up data on exenatide showed a sustained weight loss and HbA_1c reduction of 1%. Nausea and vomiting are common. Results from phase 3 studies are pending on liraglutide. Sitagliptin and vildagliptin are orally active. In 26-week studies, sitagliptin educes HbA_1c by 0.6–0.8% as monotherapy, by 1.8% as initial combination therapy with metformin, and by 0.7% as add-on therapy to metformin. Vildaglitpin monotherapy lowered HbA_1c by 1.0–1.4% after 24 weeks. Their major side effects are urinary tract and nasopharyngeal infections and headaches. Exenatide and liraglutide cause weight loss while sitagliptin and vildagliptin do not.

CONCLUSION: The availability of GLP-1 mimetics and DPP 4 inhibitors has increased our armamentarium for treating T2DM. Unresolved issues such as the effects of GLP-1 mimetics and DPP 4 inhibitors on cell mass, the mechanism by which GLP-1 mimetics lowers glucagon levels, and exactly how DPP 4 inhibitors lead to a decline in plasma glucose levels without an increase in insulin secretion, need further research.