Efficacy and Safety of SGLT2 Inhibitors and Sotagliflozin in Heart Failure: A Systematic Review and Meta-Analysis of 59 Randomized Controlled Trials.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors have become a cornerstone of heart failure (HF) therapy, yet the totality of randomized evidence - including smaller trials beyond the landmark cardiovascular (CV) outcome studies - has not been comprehensively synthesized. We searched PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform (ICTRP) from inception to March 2026 for randomized controlled trials (RCTs) comparing any SGLT2 inhibitor or the dual sodium-glucose cotransporter-1/2 (SGLT1/SGLT2) inhibitor sotagliflozin with placebo or standard care in adults with HF. Random-effects Mantel-Haenszel risk ratios (RRs) with Hartung-Knapp-Sidik-Jonkman (HKSJ) confidence intervals (CIs) were used. Certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. The protocol was prospectively registered with the International Prospective Register of Systematic Reviews (PROSPERO; CRD420251167908). Of 6,239 records identified, 114 studies met inclusion criteria and 59 RCTs (29,692 participants) were included in the quantitative synthesis. SGLT2 inhibitors reduced all-cause mortality (ACM; RR 0.90, 95% CI 0.83-0.98; p = 0.016; 26 trials; low certainty), although trim-and-fill adjustment for publication bias attenuated the finding (adjusted RR 0.92, 95% CI 0.84-1.00). HF hospitalization (HFH) was reduced (RR 0.74, 95% CI 0.69-0.79; 15 trials; moderate certainty), as were CV death (RR 0.86, 95% CI 0.76-0.98; seven trials; moderate certainty), the composite of CV death and HFH (RR 0.80, 95% CI 0.75-0.85; eight trials; high certainty), and serious adverse events (RR 0.94, 95% CI 0.90-0.99; 20 trials; high certainty). Genital infections were significantly increased (RR 3.75, 95% CI 1.72-8.19); no significant increases were observed for diabetic ketoacidosis (DKA), acute kidney injury (AKI), urinary tract infection (UTI), or hypotension. Subgroup analyses showed a greater ACM benefit in HF with reduced ejection fraction (HFrEF) than in HF with preserved ejection fraction (HFpEF) (interaction p = 0.039). Results were directionally consistent across 13 sensitivity scenarios and five alternative statistical models. SGLT2 inhibitors reduce HFH, CV death, the composite endpoint, and serious adverse events with moderate-to-high certainty; the all-cause mortality reduction is of low certainty and sensitive to publication bias.