Xiang Mao, Wenhua Liu, Bingqian Hu, Enguo Xu
Background Heart failure (HF) remains a major global health challenge, with high rates of hospitalization and mortality despite advances in therapy. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, originally developed as antidiabetic agents, have demonstrated significant cardiovascular and renal benefits across a wide range of patients. Objective This study aims to evaluate the impact of SGLT2 inhibitors on all-cause mortality, heart failure hospitalization, and secondary outcomes, including NT-proBNP levels, left ventricular (LV) systolic function, and diuretic efficiency in patients with heart failure, irrespective of ejection fraction or diabetes status. Methods A systematic review and a meta-analysis were conducted according to PRISMA 2020 guidelines. Electronic databases (PubMed, Embase, Cochrane CENTRAL, Scopus, and Web of Science) were searched for randomized controlled trials (RCTs) published between January 2017 and November 2025. A total of 15 eligible RCTs encompassing 28,484 participants were included. Data were extracted on clinical and functional outcomes, and pooled estimates were calculated using a DerSimonian–Laird random-effects model. Heterogeneity was assessed using the I ² statistic, and publication bias was evaluated using Egger’s and Begg’s tests. Results SGLT2 inhibitor therapy was associated with a 14% reduction in all-cause mortality (HR = 0.86, 95% CI: 0.79–0.92; p < 0.001) and a 26% reduction in heart failure hospitalization (HR = 0.74, 95% CI: 0.68–0.81; p < 0.001). Heterogeneity was low for mortality ( I ² = 18%) and moderate for hospitalization ( I ² = 39%). SGLT2 inhibitors also significantly decreased the NT-proBNP levels (mean difference −168.4 pg/mL, 95% CI: −245.6 to −91.2; p < 0.001) and improved the LV systolic function (LVEF + 3.8%, 95% CI: +2.4 to +5.2; p < 0.001). Diuretic efficiency improved by an average of 480 mL/day (95% CI: +290 to +640; p = 0.002). The benefits were consistent across subgroups, including patients with HFrEF and HFpEF, with or without diabetes, and across individual SGLT2 inhibitors (empagliflozin, dapagliflozin, and sotagliflozin). No significant publication bias was detected. Conclusions SGLT2 inhibitors significantly reduce the mortality and heart failure hospitalizations while improving the biomarker and cardiac function parameters, independent of diabetes status or heart failure phenotype. The consistency and magnitude of benefit confirm a class effect and support SGLT2 inhibitors as foundational therapy for heart failure across all ejection fraction categories.