SGLT2 Inhibitors in Cardiovascular Disease: Mechanisms, Clinical Evidence and Evolving Therapeutic Applications

Abstract

Sodium-glucose cotransporter-2 (SGLT2) inhibitors, originally developed as glucoselowering agents for type 2 diabetes mellitus, have undergone one of the most consequential therapeutic repositionings in modern cardiovascular medicine, transforming from antidiabetic adjuncts into first-line treatments for heart failure and chronic kidney disease irrespective of glycaemic status. The cardiovascular benefits of SGLT2 inhibitors — encompassing reductions in hospitalisation for heart failure, attenuation of adverse ventricular remodelling, slowing of cardiorenal axis deterioration, and a modest but consistent reduction in cardiovascular mortality — operate through a constellation of interacting mechanisms that extend far beyond glucosuric diuresis: haemodynamic unloading, restoration of tubuloglomerular feedback, myocardial metabolic reprogramming towards ketone body oxidation, cardiac sodium-hydrogen exchanger (NHE1) inhibition, NLRP3 inflammasome suppression, and attenuation of both sympathetic overactivation and the renin-angiotensin-aldosterone system. Landmark randomised trials — including EMPAREG OUTCOME, CANVAS, DECLARE-TIMI 58, DAPA-HF, EMPEROR-Reduced, EMPEROR-Preserved, DELIVER, DAPA-CKD, CREDENCE, and SCORED — have collectively established the cardiovascular and renoprotective efficacy of SGLT2 inhibitors across the spectrum of patients with established cardiovascular disease, heart failure with reduced and preserved ejection fraction, and chronic kidney disease, with and without type 2 diabetes. Safety considerations including genital mycotic infections, diabetic ketoacidosis risk, and the canagliflozin-associated lower limb amputation signal require contextualised clinical appraisal. Current international guidelines from the ESC, ACC/AHA, ADA, KDIGO, and others now recommend SGLT2 inhibitors as a cornerstone of management in heart failure, CKD, and cardiometabolic risk reduction. This review comprehensively synthesises the mechanistic basis, landmark trial evidence, guideline positioning, special population considerations, and emerging indications of SGLT2 inhibitors in cardiovascular medicine.