All-cause and cause-specific mortality assessment in patients receiving sodium glucose co-transporter-2 inhibitors

BACKGROUND: Sodium glucose co-transporter-2 inhibitors (SGLT2i) impact on cardiovascular and renal events are well-documented; however, the effects on all-cause and cause-specific mortality have remained inconsistent across available trials. We aim to evaluate the relationship between SGLT2i and all-cause, and cause specific mortality in patients with diabetes mellitus, heart failure, or chronic kidney disease. METHODS: A systematic literature search on electronic databases for relevant randomized controlled trials (RCTs) from inception until September 10, 2025 was performed. Risk ratios (RRs) with corresponding 95% confidence intervals (CIs) were calculated using a random-effects model. RESULTS: A total of 18 RCTs including 95,913 patients were analyzed. SGLT2 inhibitors did not significantly reduce overall all-cause mortality compared with control (RR: 0.92 [95% CI, 0.80-1.05]), although a significant reduction was observed in older (>65 years) adults (RR: 0.93 [95% CI, 0.87-0.98]). Non-cardiovascular mortality was neutral overall (RR: 0.94 [95% CI, 0.86-1.02]) but was reduced in younger (<65 years) participants (RR: 0.87 [95% CI, 0.78-0.96]). SGLT2i use was associated with significant reductions in cardiovascular mortality (RR: 0.86 [95% CI, 0.81-0.92]) and renal mortality (RR: 0.31 [95% CI, 0.11-0.90]), with consistent effects across age and follow-up subgroups for cardiovascular mortality. CONCLUSION: SGLT2i significantly reduce cardiovascular and renal mortality across patients with diabetes mellitus, heart failure, and chronic kidney disease, cementing their role as cornerstone cardiorenal therapy. Notably, subgroup analyses further suggest potential all-cause mortality benefit in older adults and non-cardiovascular mortality benefit in younger patients. These findings, though exploratory, carry meaningful implications for personalizing SGLT2i therapy across the lifespan.