Safety Profile of SGLT-2 Inhibitors in Older Adults: A Systematic Review and Network Meta-Analysis

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are widely used in older adults for diabetes, heart failure, and kidney disease. This is the first network meta-analysis focusing on the effects of SGLT2i in older adults. METHODS: Databases were searched for randomized clinical trials comparing SGLT2i against non-SGLT2i controls or other SGLT2i in relevant populations. Key safety outcomes included acute renal failure (ARF), genital infections, volume depletion, mortality, and serious adverse events (SAEs). Pooled odds ratios (OR) with 95% confidence intervals (CI) were generated using random-effects models for direct and mixed treatment comparisons. RESULTS: From 97 included trials in the meta-analysis, SGLT2i versus non-SGLT2i were associated with reduced risks of ARF (OR 0.86, 95% CI 0.79-0.94), mortality (OR 0.84, 0.75-0.93), and SAEs (OR 0.84, 0.78-0.89), but increased risks of genital infections (OR 3.32, 2.68-4.12) and volume depletion (OR 1.18, 1.09-1.27). The risk of genital infections was observed more frequently with higher doses (high-dose OR 4.73 vs. low-dose OR 2.90) and escalated sharply with age (≥75 years OR 9.29, 3.13-27.6). The mortality benefit was strongest in adults ≥75 years (OR 0.58, 0.38-0.88). Intra-class analysis revealed distinct safety profiles; for instance, empagliflozin reduced the ARF risk, while sotagliflozin increased the volume depletion risk. Bootstrap and trial sequential analyses confirmed the results' robustness. Grading of Recommendations Assessment, Development, and Evaluation assessment indicated moderate certainty of evidence. CONCLUSIONS: In older adults, SGLT2i maintain a favorable benefit-risk profile, with significant reductions in mortality and SAEs, though risks of genital infections and volume depletion require vigilance. The risk of genital infections exhibits a strong dose-response relationship and increases markedly in the oldest adults, while the mortality benefit appears to be most pronounced in those aged 75 years and older. This study provides actionable insights for personalized therapy in geriatric care.