Comparative Safety of SGLT2 Versus DPP4 Inhibitors in Patients with Type 2 Diabetes: A Meta-Analysis of Randomized Controlled Trials.

Type 2 diabetes mellitus (T2DM) necessitates long-term pharmacological management, with drug safety now a pivotal factor in therapy selection. Sodium‒glucose cotransporter 2 inhibitors (SGLT2is) and dipeptidyl peptidase 4 inhibitors (DPP4is) are widely prescribed oral antidiabetic agents; however, their comparative safety profiles remain under debate. A systematic search of PubMed, Embase, the Cochrane Library, and Web of Science was performed up to June 2, 2025. Forty-two randomized controlled trials (RCTs) that compared SGLT2is with DPP4is in adults with T2DM were included. Pooled risk ratios (RRs) with 95% confidence intervals (CIs) were calculated using Review Manager (RevMan) 5.3. Heterogeneity was assessed with I2, and publication bias with funnel plots and Egger's test. SGLT2is were associated with a higher overall risk of total adverse events (AEs) (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 (UTIs) (RR 1.45, 95% CI 1.25-1.70), with no difference in upper respiratory tract infections (URTIs) (RR 0.78, 95% CI 0.61-1.02). For organ injury, a non-significant trend toward renal injury was noted (RR 1.83, 95% CI 0.92-3.67), with no difference in liver injury (RR 0.64, 95% CI 0.28-1.46) or fracture (RR 0.83, 95% CI 0.25-2.70). Severe outcomes-including hypoglycemia (RR 1.07, 95% CI 0.88-1.29), mortality (RR 1.48, 95% CI 0.59-3.71), diabetic ketoacidosis (DKA) (RR 2.99, 95% CI 0.31-28.45), and major adverse cardiovascular events (MACEs) (RR 1.21, 95% CI 0.35-4.19)-did not differ. Hypersensitivity risk was also comparable (RR 1.25, 95% CI 0.65-2.42). SGLT2is have an overall favorable safety profile but increase the risks of genitourinary infections and transient renal impairment. Risk stratification and monitoring are essential for high-risk individuals, for whom DPP4is may be safer. These findings provide robust RCT-based evidence to inform individualized treatment and guideline updates. This systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement. The protocol was prospectively registered with the International Prospective Register of Systematic Reviews (PROSPERO; registration number CRD420251115623).