Sodium-Glucose Cotransporter 2 Inhibitors in Heart Failure with Preserved Ejection Fraction: A Systematic Review and Meta-Analysis with Trial Sequential Analysis

1ObjectiveTo assess the effects of SGLT2 inhibitors on cardiovascular outcomes in HFpEF/HFmrEF. DesignSystematic review, random-effects meta-analysis using Hartung-Knapp, and trial sequential analysis (TSA). Data sourcesMEDLINE, Embase, and CENTRAL; searches updated through August 13, 2025. Eligibility criteriaParallel-group randomized trials enrolling adults with LVEF 40% (HFmrEF 40-49%; HFpEF 50%). Main outcome measuresTime-to-event composite of cardiovascular death or first heart failure hospitalization (primary); Kansas City Cardiomyopathy Questionnaire (KCCQ-TSS), components, and safety (secondary). ResultsTwo dedicated HFpEF trials (n=12,251) reported the primary outcome. The pooled hazard ratio was 0.80 (95% CI 0.73-0.87; I2=0%; 2 0; 95% prediction interval 0.67-0.96). TSA crossed efficacy boundaries and exceeded the diversity-adjusted required information size, indicating conclusive evidence for the composite. Effects were consistent in patients with and without diabetes and across EF 40-49% vs 50% (no significant interactions). KCCQ improved (+2.3 points, 95% CI 1.0-3.6; responders 5 pts: 42% vs 38%). Safety showed more genital mycotic infections, with no increase in serious adverse events or acute kidney injury. ConclusionsSGLT2 inhibitors robustly reduce cardiovascular death/heart failure hospitalization and improve health status in HFpEF/HFmrEF, supporting their role as foundational therapy, irrespective of diabetes status; effects on mortality alone remain imprecise. RegistrationPROSPERO CRD420251167908. Data and code: https://doi.org/10.5281/zenodo.18409428 PROSPEROCRD420251167908 Data availabilityhttps://doi.org/10.5281/zenodo.18409428