Sweet relief: exploring mechanisms and therapeutic approaches of sodium-glucose cotransporter-2 inhibitors in cardiovascular-kidney metabolic syndrome

The escalating global burden of chronic multimorbidity has necessitated a fundamental transition from organ-centric treatment models toward integrated, multisystemic management strategies. Central to this evolution is the recognition of the cardiovascular–kidney–liver-metabolic (CKM) syndrome, a clinical framework arising from the profound and bidirectional pathophysiological crosstalk between metabolic dysfunction, chronic kidney disease, and heart failure. Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) have transitioned from simple glucose-lowering drug to a critical pillar of the area of cardiovascular metabolism, demonstrating profound benefits across the cardiovascular, metabolism and renal systems. These therapeutic effects are driven by a complex interplay of hemodynamic and non-hemodynamic mechanisms, including the restoration of tubuloglomerular feedback, optimization of myocardial energetics, and the attenuation of systemic inflammation and oxidative stress. This pharmacological profile aligns precisely with the multi-stage progression of CKM syndrome, offering a cohesive intervention to interrupt the vicious cycle of systemic risk. In this review, we delineated the mechanistic pathways by which SGLT-2i modulate the CKM axis and evaluate the clinical evidence supporting its important role for integrated CKM management, providing a comprehensive perspective on optimizing long-term outcomes through multisystemic targeting.