Empagliflozin and Cardiovascular Outcomes: A Systematic Review of Randomized Controlled Trials in Populations With Diabetes and Heart Failure

Abstract

Cardiovascular disease is a principal cause of morbidity and mortality worldwide, disproportionately affecting individuals with type 2 diabetes mellitus (T2DM) and heart failure. Empagliflozin, a sodium-glucose cotransporter 2 inhibitor, has shown promising cardioprotective effects beyond its glucose-lowering properties. This systematic review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, involving a comprehensive literature search of PubMed, Scopus, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) from inception to May 2025. Randomized controlled trials evaluating empagliflozin in adult patients with T2DM or heart failure and reporting cardiovascular outcomes were included. A total of 13 RCTs comprising 21,669 participants were synthesized, encompassing a broad spectrum of populations, including high-risk T2DM, chronic heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF), and post-myocardial infarction cohorts. Empagliflozin was consistently associated with significant reductions in major adverse cardiovascular events, notably a 14-38% reduction in cardiovascular mortality and a 23-35% reduction in heart failure hospitalizations across key trials, such as EMPA-REG OUTCOME, EMPEROR-Reduced, and EMPEROR-Preserved. Smaller mechanistic studies highlighted additional benefits, including improvements in left ventricular function, cardiac remodeling, exercise capacity, and hemodynamic parameters. The safety profile of empagliflozin was favorable, with the main adverse event being an increased incidence of mild genital infections, and no excess in severe adverse or hypoglycemic events. Despite some heterogeneity in trial populations and follow-up, current evidence robustly supports empagliflozin as an effective and safe strategy to reduce cardiovascular risk in patients with T2DM and heart failure. Further research is warranted to explore long-term outcomes and expand indications to broader patient populations.