Empagliflozin and Right-Sided Heart Failure: A Comprehensive Review of Emerging Evidence and Clinical Perspectives

Right-sided heart failure (RHF) remains a clinically challenging and under-researched condition often managed through extrapolated guidance from left-sided heart failure data. This review explores the therapeutic promise of empagliflozin, a sodium-glucose co-transporter 2 inhibitor, for RHF management. While empagliflozin is currently approved for glycemic control and heart failure with reduced ejection fraction, its potential to improve symptoms, functional capacity, and cardiovascular outcomes in RHF warrants focused investigation. In the absence of RHF-specific randomized controlled trials (RCTs), this review synthesizes insights from preclinical models, subgroup analyses, and surrogate markers drawn from major trials such as EMPEROR-Reduced, EMPEROR-Preserved, and EMPIRE-HF. Empagliflozin's mechanisms are conceptually grouped as hemodynamic, reducing preload, afterload, and venous congestion, and improving right ventricle-pulmonary artery coupling and metabolic, enhancing myocardial energetics, reducing inflammation and fibrosis, and inhibiting the Na⁺/H⁺ exchanger (NHE1). Although RHF patients were not separately stratified in these trials, indirect benefits observed through TAPSE improvement, renal protection, and congestion relief support further exploration. This review emphasizes the need for RHF-specific RCTs, mechanistic studies, and real-world cohorts to validate and expand empagliflozin's therapeutic scope. Overall, empagliflozin emerges as a mechanistically sound and clinically promising candidate for transforming the management of RHF by targeting both cardiac and renal dysfunction.