Cardiovascular Mechanisms and Clinical Implications of SGLT2 Inhibitors in Heart Failure: A Narrative Review
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This narrative review aims to synthesize contemporary evidence on the cardiorenal mechanisms, clinical efficacy, safety, and practical implementation of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in heart failure (HF). A focused narrative literature search was conducted using PubMed/MEDLINE and major international professional society guideline repositories, primarily covering publications from January 2019 to September 1, 2026. Priority was given to randomized controlled trials, prespecified trial analyses, meta-analyses, human mechanistic studies, and contemporary international clinical practice guidelines. Major randomized controlled trials consistently demonstrated the cardiovascular and renal benefits of SGLT2 inhibition across the HF spectrum, although the magnitude and certainty of renal benefits varied across populations and outcomes. The DAPA-HF and EMPEROR-Reduced trials established reductions in worsening HF events and HF hospitalizations among patients with heart failure with reduced ejection fraction (HFrEF), whereas the EMPEROR-Preserved and DELIVER trials extended these benefits to patients with heart failure with mildly reduced ejection fraction (HFmrEF) and heart failure with preserved ejection fraction (HFpEF). The EMPULSE trial supported the initiation of empagliflozin following clinical stabilization during hospitalization for acute HF, while dedicated renal outcome trials demonstrated clinically meaningful kidney protection. Mechanistically, SGLT2 inhibition reduces sodium and glucose reabsorption in the renal proximal tubule, restores tubuloglomerular feedback, lowers intraglomerular pressure, and promotes modest natriuresis and osmotic diuresis. Additional mechanisms involving erythropoiesis, metabolic regulation, mitochondrial function, and anti-inflammatory and antifibrotic effects may contribute to cardiovascular protection, although several pathways remain supported primarily by preclinical and translational evidence rather than definitive human studies. Important safety considerations include genital mycotic infections, volume depletion, and the rare but clinically significant risk of euglycemic diabetic ketoacidosis.
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