SGLT2 Inhibitors in Heart Failure: A Meta-Analysis of Randomized Trials and Observational Studies

Background: Heart failure (HF) remains a leading cause of morbidity and mortality worldwide. Sodium–glucose cotransporter-2 (SGLT2) inhibitors have demonstrated cardiovascular benefits in HF beyond glucose lowering, yet uncertainties remain regarding consistency across the ejection fraction spectrum, individual agents, and real-world populations. We conducted a comprehensive meta-analysis of randomized controlled trials (RCTs) and observational studies to evaluate the efficacy and safety of SGLT2 inhibitors across HF phenotypes.Methods: MEDLINE, Embase, the Cochrane Library, and ClinicalTrials.gov were systematically searched from inception through November 2025 for RCTs and observational cohort studies evaluating empagliflozin, dapagliflozin, canagliflozin, ertugliflozin, or sotagliflozin in HF patients. Studies compared SGLT2 inhibitors with placebo or standard care. To account for differing bias structures, RCTs and observational studies were analyzed separately using random-effects models. The primary outcome was the composite of cardiovascular (CV) death or hospitalization for heart failure (HHF). Secondary outcomes included HHF alone, CV death, all-cause mortality, and safety endpoints. Heterogeneity was assessed using the I² statistic, publication bias with funnel plots and Egger’s test, and reporting followed PRISMA guidelines.Results: Seventeen RCTs, including 20,749 patients and 21 observational studies comprising more than 300,000 patients, were analyzed, spanning HFrEF, HFmrEF, and HFpEF populations. In pooled RCT analyses, SGLT2 inhibitors reduced CV death or HHF by approximately 25% compared with placebo (hazard ratio [HR] 0.73, 95% CI 0.68–0.78), corresponding to absolute risk reductions of 4–5% over a median follow-up of ~1.5 years. This benefit was largely driven by a ~30% reduction in HHF, while CV death declined by ~15–18%. All-cause mortality was reduced by ~17% (HR ~0.83). Treatment effects were consistent across agents, diabetes status, renal function, age, sex, and body mass index, and across the full ejection fraction spectrum. In HFpEF, CV death or HHF was reduced by ~17%, with a ~25% reduction in HHF alone, while numerically greater effects were observed in HFrEF. Observational data supported these findings, showing substantial reductions in HHF and all-cause mortality. Heterogeneity for primary RCT outcomes was low (I² <25%). SGLT2 inhibitors were well tolerated, with no excess risk of serious adverse events or major safety concerns.Conclusions: SGLT2 inhibitors provide consistent and clinically meaningful benefits in HF, significantly reducing HF hospitalizations and improving survival across HF phenotypes, with a favorable safety profile.