Cureus. 2026 Feb;18(2):
e104397
Sodium-glucose cotransporter 2 (SGLT2) inhibitors have become foundational therapies in the management of heart failure, extending beyond their original indication as glucose-lowering agents. Experimental and clinical evidence indicates that their cardioprotective effects are largely independent of glycemic control and are mediated through integrated hemodynamic, metabolic, and anti-inflammatory mechanisms. At the myocardial level, SGLT2 inhibitors promote a shift in substrate utilization toward fatty acids and ketone bodies, improving mitochondrial efficiency and cellular energy balance. These effects are accompanied by reductions in oxidative stress, inflammation, and maladaptive remodeling, as well as favorable vascular and cardiorenal interactions. Large randomized controlled trials have consistently demonstrated significant reductions in heart failure hospitalization across patients with and without diabetes. DAPA-HF and EMPEROR-Reduced established efficacy in heart failure with reduced ejection fraction, while EMPEROR-Preserved and DELIVER extended these benefits to patients with mildly reduced and preserved ejection fractions. Although reductions in cardiovascular mortality are most robust in reduced ejection fraction, improvements in morbidity and health-related quality of life have been observed across phenotypes. With a generally favorable safety profile in nondiabetic populations and strong Class I guideline recommendations in heart failure with reduced ejection fraction, SGLT2 inhibitors are now recognized as one of the four core pillars of guideline-directed medical therapy. Their widespread implementation represents a major advance in disease-modifying treatment, though optimization of real-world uptake remains an ongoing clinical priority.
Keywords: clinical outcomes; guideline-directed therapy; heart failure; ketone bodies; myocardial energy metabolism; sglt2 inhibitors