From bench to bedside: A systematic review of empagliflozin's cardioprotective mechanisms and clinical outcomes in heart failure

Empagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, has demonstrated robust benefits in heart failure (HF), but existing reviews often examine either molecular mechanisms or clinical outcomes in isolation. This systematic review integrates evidence from both preclinical and clinical studies to provide a unified evaluation of empagliflozin’s cardioprotective role. Following PRISMA 2020 guidelines and a PROSPERO-registered protocol (CRD420251186611), major biomedical databases were searched for mechanistic, translational, and clinical studies of empagliflozin in HF. Thirty four studies met inclusion criteria. Preclinical studies consistently showed that empagliflozin attenuates inflammation, oxidative stress, mitochondrial dysfunction, and myocardial fibrosis. In clinical studies, empagliflozin significantly improved natriuretic peptide levels, ventricular loading conditions, and structural remodeling, with reductions in left ventricular (LV) volumes and fibrosis markers. Across major trials (EMPEROR-Reduced, EMPEROR-Preserved, EMPA-REG OUTCOME, EMPA-AHF-RESPONSE, EMPULSE), empagliflozin reduced the risk of cardiovascular death or HF hospitalization by 24-35%, lowered total HF events, improved diuretic efficiency, slowed renal function decline, and enhanced quality of life (Kansas City Cardiomyopathy Questionnaire (KCCQ) scores ) . Integrating mechanistic and clinical evidence provides a cohesive understanding of empagliflozin’s therapeutic potential and supports its widespread adoption in HF management.