Beyond glucose: SGLT2 inhibitors as foundational therapy in heart failure

Heart failure affects over 64 million people worldwide and remains a leading cause of hospitalization, death, and health care costs. Despite advances with renin angiotensin aldosterone system inhibitors, beta blockers, and mineralocorticoid receptor antagonists, survival gains remain modest, and outcomes in preserved ejection fraction disease have historically been poor. This review examines how sodium glucose cotransporter 2 inhibitors, initially developed as glucose lowering agents, have redefined heart failure therapy. We synthesize mechanistic insights, pivotal trial data, and evolving guidelines to clarify their role as foundational treatment across the ejection fraction spectrum. Evidence was drawn from cardiovascular outcome studies, dedicated heart failure trials, mechanistic investigations, and international guidelines, with focus on physiologic mechanisms, efficacy, and safety. Sodium glucose cotransporter 2 inhibitors provide benefits that extend beyond glucose control. They promote sustained diuresis, improve myocardial energetics, reduce inflammation and fibrosis, and protect renal function. Landmark trials including DAPA HF, EMPEROR Reduced, EMPEROR Preserved, and DELIVER consistently reduced hospitalizations and cardiovascular death across reduced, mildly reduced, and preserved ejection fraction populations, regardless of diabetes status. Benefits emerge early, improve quality of life, and are supported by a favorable safety profile. These findings have rapidly reshaped international guidelines, positioning these drugs alongside renin angiotensin system inhibitors, beta blockers, and mineralocorticoid receptor antagonists as pillars of therapy. Sodium glucose cotransporter 2 inhibitors represent one of the most important therapeutic breakthroughs in cardiovascular medicine, transforming heart failure care from discovery to global standard. The challenge ahead is ensuring equitable access, early adoption, and expanded exploration across cardiometabolic disease.