Sodium-glucose cotransporter 2 (SGLT2) inhibitors across the cardiovascular-kidney-metabolic continuum: mechanistic and clinical perspectives on heart failure with preserved ejection fraction prevention

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have evolved from glucose-lowering agents into foundational therapies across the cardiovascular-kidney-metabolic (CKM) continuum. Large cardiovascular and renal outcome trials have consistently demonstrated reductions in heart failure (HF) hospitalization among patients both with and without diabetes and across the full spectrum of left ventricular ejection fraction, thereby transforming the management of established HF. Increasing attention has focused on whether SGLT2 inhibition may also influence upstream mechanisms implicated in the pathophysiology of HF with preserved ejection fraction (HFpEF) and potentially modify the trajectory toward its clinical onset. HFpEF arises from complex interactions among metabolic dysfunction, renal impairment, systemic inflammation, endothelial dysfunction, ventricular-arterial stiffening, and progressive atrial and ventricular remodeling within the CKM axis. SGLT2 inhibitors may influence several of these pathways through natriuresis and osmotic diuresis, improvement in ventricular loading conditions, attenuation of neurohormonal activation, enhancement of myocardial energetics, and anti-inflammatory and antifibrotic effects. Emerging mechanistic and imaging studies further suggest favorable effects on left atrial remodeling, diastolic reserve, pulmonary vascular load, and right ventricular–pulmonary arterial coupling. Although randomized trials specifically designed to evaluate primary prevention of HFpEF are lacking, consistent reductions in HF events across high-risk CKM populations support a potential disease-modifying role. This review integrates mechanistic and clinical evidence to examine how SGLT2 inhibition may alter the trajectory toward HFpEF and highlights priorities for future research.