To compare all-cause mortality in adults with T2D initiating sodium–glucose cotransporter-2 inhibitors (SGLT2is) versus dipeptidyl peptidase-4 inhibitors (DPP-4is) using a large multinational real-world dataset.

We conducted a retrospective, multinational, active-comparator, new-user cohort study using de-identified electronic health records from TriNetX (2015–2019). Adults aged >18 years with T2D who initiated a SGLT2i or DPP-4i after ≥12 months of continuous therapy were eligible. Propensity score matching (1:1 nearest neighbor) yielded 161,950 patients per group. All-cause mortality over 5 years was evaluated using a Cox proportional-hazards model to estimate hazard ratios and 95% confidence intervals. Kaplan–Meier curves were generated to compare cumulative mortality between groups. Sensitivity analyses and external validation in an independent Hong Kong/Singapore cohort were performed.

Among 449,295 eligible patients, 161,950 initiated a SGLT2i and 161,950 initiated a DPP-4i after matching. Over 5 years, all-cause mortality was markedly lower in the SGLT2i group (9,965 deaths; 6.2%) than in the DPP-4i group (27,330 deaths; 16.9%). Kaplan–Meier estimates showed cumulative mortality rates of 13.16% and 26.05% in the SGLT2i and DPP-4i groups, respectively. SGLT2i use was associated with a significantly reduced mortality risk (Hazard ratios 0.513; 95% confidence intervals 0.502–0.525; P < 0.001). Subgroup analyses revealed consistent reductions in mortality across sex, age categories, and baseline glycemic control levels. External validation confirmed improved survival associated with SGLT2i therapy. Collectively, these findings demonstrate a robust survival advantage of SGLT2is over DPP-4is.

SGLT2is were consistently associated with significantly lower all-cause mortality than DPP-4is. These results underscore their clinical value and support SGLT2is as a preferred therapeutic option for patients with T2D.