A systematic review including 29 studies on incretin-based drug therapy for type 2 diabetes, with a total of 12 996 subjects was abstracted in DARE. The drugs studied were either glucagonlike peptide 1 (GLP-1) analogues (exenatide 7 studies, n=2 781; liraglutide 2 studies, n=403) or dipeptidyl peptidase 4 (DPP4) inhibitors (sitagliptin 8 studies, n=4 937; vildagliptin 12 studies, n=4 875). GLP-1 analogues were mostly studied as add-ons to existing oral hypoglycemic therapy and compared with a double-blind injectable placebo, metformin, or subcutaneous insulin. DPP4 inhibitors were given as monotherapy or as add-on therapy to oral hypoglycemic agents or insulin and compared with placebo or with a hypoglycemic agent. Only 3 of the 29 studies had durations of longer than 30 weeks.
Incretins lowered hemoglobin A1c compared with placebo (weighted mean difference –0.97%, 95% CI –1.13% to –0.81%, for GLP-1 analogues and –0.74%, 95% CI –0.85% to –0.62% for DPP4 inhibitors) and were noninferior to other hypoglycemic agents. GLP-1 analogues resulted in weight loss (1.4 kg and 4.8 kg vs placebo and insulin, respectively) while DPP4 inhibitors were weight neutral. In the few available trials, incretin-based medications were found to be noninferior compared with non–incretin-based pharmacologic therapies, with the exception of metformin being superior to vildagliptin. Adverse effects included gastrointestinal side effects, nausea and vomiting with GLP-1 analogues and an increased risk of infections and headache with DPP4 inhibitors. Long-term efficacy and safety could not be evaluated.
A systematic review evaluated the association between DPP-4 inhibitor and GLP-1 receptor agonist use and major adverse cardiac events (MACE). 11 pooled analyses, 17 meta-analyses, and 8 RCTs were included. Over the short term (up to 4 years), patients with T2DM exposed to a DPP-4 inhibitor or GLP-1 receptor agonist were not at increased risk for MACE (or its component endpoints) compared with those who received comparator agents. Two meta-analyses showed a significant reduction in the incidence of MACE associated with DPP-4 inhibitor therapy as a drug class, but this beneficial effect was not observed in other meta-analyses that included large RCT cardiovascular outcome studies. In 4 RCTs that evaluated alogliptin, saxagliptin, sitagliptin, or lixisenatide, there was no overall increased risk for MACE relative to placebo in T2DM patients at high risk for cardiovascular events events or with established disease, although there was an increased rate of hospitalization for heart failure associated with saxagliptin. A fifth RCT showed that liraglutide reduced MACE risk by 13% versus placebo.