Cardiovascular (CV) disease, chronic kidney disease, obesity, and diabetes mellitus have reached epidemic proportions over the past few decades. Accumulating evidence highlights the strong interconnection between these conditions, leading to the definition of a broader disease entity known as cardio-renal-metabolic (CRM) syndrome. This newly recognized clinical entity presents important challenges in identifying the optimal treatment strategy within a holistic, patient-centered framework. In line with this, sodium glucose cotransporter 2 inhibitors (SGLT2is), owing to their multifaceted pharmacological effects, have been suggested as possible treatment options in the management of CRM. SGLT2is exert their antihyperglycemic effects by impeding the renal reabsorption of sodium and glucose, causing glycosuria and natriuresis. Research has confirmed that their unique beneficial effects extend beyond glycemic control, reducing CV death and hospitalizations in patients with heart failure, and the incidence of kidney failure in dedicated kidney outcome studies—regardless of diabetes status. Furthermore, these agents contribute to weight loss and blood pressure reduction. Their benefits appear to stem from a combination of factors, which include reduced oxidative stress, lower levels of inflammation, regulated neurohormonal activation, improved endothelial function, and enhanced metabolic efficiency. This review aims to provide a comprehensive analysis of the pathophysiological mechanisms underlying the effects of SGLT2is in CRM syndrome, synthesize evidence from landmark clinical trials, evaluate current experimental and diagnostic approaches, and provide the emerging role of SGLT2is in the treatment of this new clinical entity.
