Effect of SGLT2 inhibitors on heart failure outcomes in patients with and without diabetes: A systematic review and meta‑analysis of randomized controlled trials

Heart failure (HF) is a debilitating condition with high morbidity and mortality rates worldwide. Sodium‑glucose cotransporter 2 inhibitors (SGLT2i) exhibit cardiovascular (CV) and renal protective effects beyond glucose lowering, and may serve a role in managing HF across numerous patient populations, including non‑diabetics. Therefore, the present systematic review and meta‑analysis aimed to evaluate the efficacy of SGLT2i in reducing HF hospitalizations, CV mortality and adverse events in patients with and without type 2 diabetes mellitus. Following the Preferred Reporting Items for Systematic Reviews and Meta‑Analyses 2020 guidelines, comprehensive literature searches were conducted across PubMed, Scopus, Web of Science and Cochrane Central databases up to May 2025. Randomized controlled trials (RCTs; phases II‑IV) enrolling adults with HF, irrespective of ejection fraction or diabetes status, comparing SGLT2i with placebo or standard‑of‑care were included in the present study. Outcomes analyzed encompassed HF hospitalizations, CV and all‑cause mortality, adverse events and patient‑reported quality of life measures. Meta‑analysis was performed with RevMan 5.4 using a random‑effects model. Data from 28 RCTs, including numerous high‑quality trials, consistently demonstrated that SGLT2i significantly reduced the risk of first and total hospitalization for HF by 24% [odds ratio (OR)=0.76; 95% CI: 0.64‑0.91; P=0.002; I²=0%] and 33% (OR=0.67; 95% CI: 0.63‑0.72; P<0.00001; I²=33%), respectively. In addition, the use of SGLT2i decreased all‑cause and CV‑associated mortality by 28% (OR=0.72; 95% CI: 0.61‑0.86; P=0.0002; I²=88%) and 24% (OR=0.76; 95% CI: 0.70‑0.83; P<0.00001; I²=57%), respectively. Furthermore, adverse events occurred in 22% (OR=0.78; 95% CI: 0.59‑1.02; P=0.07; I²=97%), regardless of the diabetic status of the patients. Publication bias was significant (P<0.05) in studies addressing total hospitalization, while studies evaluating all‑cause mortality, CV‑associated mortality and adverse events did not exhibit significant publication bias (P≥0.05). The majority of studies were found to have a low risk of bias, with only a small number of studies exhibiting a high risk of bias. Low‑to‑high certainty of evidence was observed. Overall, SGLT2i were indicated to be effective in reducing hospitalization for HF and improving survival in a broad spectrum of patients, including those without diabetes. The multifactorial mechanisms of SGLT2i are likely to contribute to these benefits, supporting their emerging role in HF management.