Redefining SGLT2 inhibitors through cytoprotective mechanisms

Sodium-glucose cotransporter-2 (SGLT2) inhibitors have transformed the management of type 2 diabetes by effectively lowering glucose levels through the promotion of glucosuria and natriuresis. Beyond these primary actions, a growing body of experimental and clinical evidence suggests that this drug class exerts a wide range of pleiotropic effects independent of glycemic control. Laboratory studies have shown that SGLT2 inhibitors influence fundamental aspects of cellular metabolism and survival, including the promotion of ketogenesis as an efficient energy source, upregulation of sirtuin 1 that modulates stress resistance and longevity, and attenuation of inflammation and oxidative stress through adenosine monophosphate-activated protein kinase - mechanistic target of rapamycin complex 1 (AMPK - mTORC1) signaling. Collectively, these pathways suggest cytoprotective properties that may underlie the emerging benefits of SGLT2 inhibitors in cardiovascular, renal, and other systemic diseases. This review provides an updated and comprehensive overview of the molecular and cellular mechanisms underlying the extraglycemic actions of SGLT2 inhibitors, links these mechanistic insights to ongoing clinical trials, and underscores their expanding potential for therapeutic repurposing beyond diabetes management.