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.