SGLT2 Inhibitors in the Modern Cardiology Era: Mechanisms, Outcomes, and Clinical Applications

Sodium-glucose cotransporter-2 (SGLT2) inhibitors were initially developed as antihyperglycemic agents for type 2 diabetes mellitus but have become foundational therapies in cardiovascular and cardiorenal medicine. Randomized trials and meta-analyses show their most consistent benefits are reducing heart failure hospitalization and slowing chronic kidney disease progression, including in patients without diabetes. In contrast, their effects on major adverse cardiovascular events, myocardial infarction, stroke, arrhythmias, and postmyocardial infarction outcomes remain more variable and incompletely defined. Mechanistically, SGLT2 inhibitors act through natriuresis, osmotic diuresis, plasma-volume redistribution, improved renal hemodynamics, reduced ventricular loading, attenuation of inflammation and fibrosis, and possible improvements in myocardial energetics and vascular biology. In heart failure, they are now central to guideline-directed medical therapy across reduced, mildly reduced, and preserved ejection fraction phenotypes, with increasing support for early in-hospital initiation in selected patients. In chronic kidney disease, they link renal protection with meaningful cardiovascular benefit, particularly for heart failure outcomes. This review summarizes their pharmacology, mechanisms, cardiovascular evidence, safety, implementation challenges, and future directions in precision cardiorenal therapy.