OBJECTIVE: To assess the efficacy and safety of omarigliptin and trelagliptin, novel dipeptidyl peptidase-4 inhibitors administered once-weekly (DPP-4i QW).METHODS: We systematically searched for placebo- and active-controlled randomized trials in adults with type 2 diabetes mellitus.RESULTS: Fifteen primary studies with 5709 participants were included. DPP-4i QW were more effective than placebo in reducing hemoglobin A (HbA) (Weighted Mean Difference (WMD) -0.63%; 95% CI -0.80, -0.46; I = 84%) and had a similar glucose-lowering effect with daily DPP-4i (WMD 0.01%; -0.08, 0.11%; I = 34%). Omarigliptin was less effective compared with oral antidiabetic agents, other than daily DPP-4i, (WMD 0.24%; 0.10, 0.38; I = 12%). Omarigliptin did not affect body weight (WMD versus placebo 0.60 kg; 0.25, 0.96; I = 0%). Risk for any hypoglycemia was similar between DPP-4i QW and placebo (Odds Ratio 1.32; 0.78, 2.22; I = 0%). Incidence of other adverse events did not differ between DPP-4i QW and control.CONCLUSIONS: DPP-4i QW were superior to placebo and similar to daily DPP-4i in terms of glycemic control, and were not associated with any specific adverse events. There is limited comparative effectiveness evidence against other agents, while their effect on hard clinical safety outcomes is unknown.