In this systematic review and meta-analysis published in the Diabetes Therapy, investigators evaluated comparative safety profiles of sodium–glucose cotransporter 2 inhibitors (SGLT2is) and dipeptidyl peptidase-4 inhibitors (DPP4is) in adults with type 2 diabetes mellitus. Forty-two randomized controlled trials identified through searches of PubMed, Embase, the Cochrane Library, and Web of Science up to June 2, 2025 were included. Pooled risk ratios (RRs) with 95% confidence intervals (CIs) were calculated.

SGLT2is were associated with a higher overall risk of total adverse events (RR 1.05; 95% CI 1.01–1.08). Infection-related risks included increased genital infections (RR 5.31; 95% CI 3.93–7.18) and urinary tract infections (RR 1.45; 95% CI 1.25–1.70), with no difference in upper respiratory tract infections (RR 0.78; 95% CI 0.61–1.02). A non-significant trend toward renal injury was observed (RR 1.83; 95% CI 0.92–3.67), while liver injury (RR 0.64; 95% CI 0.28–1.46) and fracture (RR 0.83; 95% CI 0.25–2.70) did not differ. No differences were observed for hypoglycemia (RR 1.07; 95% CI 0.88–1.29), mortality (RR 1.48; 95% CI 0.59–3.71), diabetic ketoacidosis (RR 2.99; 95% CI 0.31–28.45), major adverse cardiovascular events (RR 1.21; 95% CI 0.35–4.19), or hypersensitivity (RR 1.25; 95% CI 0.65–2.42).

Limitations include predominantly short follow-up durations (24–52 weeks), limited representation of high-risk populations, heterogeneity in drug types and dosages, and limited data for rare adverse events.

Overall, SGLT2is were associated with increased genitourinary infections compared with DPP4is, with no differences observed for several severe outcomes. Larger and longer-term trials are needed to further evaluate safety in high-risk populations.