Cardioprotective properties of empagliflozin and other SGLT2 inhibitors

Since the publication of the landmark EMPA-REG OUTCOME trial, sodium-glucose cotransporter 2 (SGLT2) inhibitors have redefined the therapeutic landscape of cardiovascular-kidney-metabolic disease. Initially developed as glucose-lowering drugs, empagliflozin and subsequent SGLT2 inhibitors have demonstrated robust benefits in reducing hospitalization for heart failure, slowing the progression of chronic kidney disease and lowering cardiovascular mortality across diverse populations. Although the precise mechanisms underlying these effects are not completely understood, the cardioprotective effects of empagliflozin seem to be mediated by an interconnected network of pleiotropic mechanisms. Empagliflozin modulates haemodynamics, restores endothelial and vascular function, improves mitochondrial bioenergetics through increased mitochondrial activity and substrate flexibility, and attenuates maladaptive cardiac remodelling. In this Review, we synthesize the current mechanistic understanding of SGLT2 inhibitors and highlight key directions for the future of cardiovascular-kidney-metabolic disease management. The next decade of research on SGLT2 inhibitors will be shaped by efforts to close evidence gaps, including in kidney failure and cardio-oncology, as well as the integration of SGLT2 inhibitors with other guideline-directed therapies, optimization of therapeutic sequencing and broad implementation in clinical care.