Current understanding of sodium-glucose transporter 2 inhibitors in cardiovascular-kidney-metabolic syndrome

Cardiovascular-kidney-metabolic (CKM) syndrome is a recently defined clinical entity that encompasses cardiovascular disease (CVD), chronic kidney disease (CKD) and metabolic disorders. It has emerged as a growing public health concern that adversely affects the quality of life and imposes a substantial burden on human health. Sodium-glucose cotransporter 2 inhibitor (SGLT-2i) is a novel class of oral hypoglycemic agent with novel insulin-independent mechanism. In the last decade, published studies highlight its substantial effects on renal and cardiovascular outcomes. SGLT-2i is recommended for patients with stages 2-4 CKM syndrome, particularly those with CKD or diabetes to delay disease progression, and improve long-term clinical outcomes. This review comprehensively summarizes the current clinical evidence and elucidates the underlying mechanisms of SGLT-2i in CKM syndrome. Glycosuria and natriuresis, the primary effects of SGLT2 inhibition, play a pivotal role in improving glycemic control, reducing body weight, and lowering blood pressure. These initial effects trigger a cascade of downstream mechanisms: hemodynamic optimization via interstitial fluid reduction, enhanced cardiac efficiency through ketogenesis, and attenuation of inflammation and oxidative stress. Additional systemic benefits include increased fatty acid utilization, reduced hyperuricemia and stimulated erythropoiesis, thereby generating a network of interrelated therapeutic benefits in CKM syndrome. The pleiotropic effects of SGLT-2i position it as a highly promising therapeutic strategy for CKM syndrome. A deeper understanding of underlying mechanisms will better inform the application of SGLT-2i for this newly defined condition and guide optimal treatment strategies.