Abstract / Summary
Sodium-glucose cotransporter 2 (SGLT2) inhibitors were initially developed as glucose-lowering agents for type 2 diabetes and have rapidly emerged as foundational therapies in cardiovascular medicine. Large, randomized trials have demonstrated strong reductions in heart failure hospitalization and cardiovascular death across the full spectrum of left ventricular ejection fraction, irrespective of diabetes status, with additional benefits in patients with chronic kidney disease and after acute heart failure decompensation. Beyond heart failure, accumulating evidence suggests potential therapeutic effects in myocardial infarction, atrial fibrillation, cerebrovascular disease, heart valve diseases, and pulmonary hypertension, although the level of evidence remains heterogeneous across these conditions. The mechanisms underlying these broad benefits remain incompletely understood. While SGLT2 was long considered to be predominantly expressed in renal proximal tubules, recent data indicate low, heterogeneous, and inducible expression in extra-renal tissues, including endothelial cells, monocytes, hepatocytes, epicardial adipose-derived preadipocytes, vascular tissue, cardiomyocytes, and diseased cardiovascular tissues. In the cardiovascular system, SGLT2 expression appears dynamic rather than constitutive, with induction driven by numeous stimuli such as oxidative stress, metabolic stress, angiotensin II, thrombin and factor Xa, sympathic nervous system stress, inflammatory cytokines, low-grade inflammation disease-associated plasma, and pro-remodeling signals. Once induced, SGLT2 may contribute to endothelial dysfunction not only through increased intracellular glucose uptake but also as a local amplifier within a feed-forward circuit involving NADPH oxidases and the renin-angiotensin system, disrupting the eNOS-NO/ROS balance and driving NF-κB-mediated inflammation, cellular senescence, pro-thrombotic activation, vascular remodeling, fibrosis, and calcification. These processes may contribute to a stress-induced cycle that amplifies oxidative and inflammatory injury, alongside the well-established renal and systemic actions of SGLT2 inhibitors. This review summarizes current evidence on the distribution, regulation, and cardiovascular consequences of SGLT2 expression, and integrates these mechanistic insights with clinical data. Understanding the inducible cardiovascular biology of SGLT2 may help explain the pleiotropic benefits of SGLT2 inhibitors and guide future applications. SGLT2 inhibitors reduce heart failure events beyond glycemic control. Their cardiovascular benefits are not fully explained by renal actions. Extra-renal SGLT2 expression remains debated and poorly characterized. Is SGLT2 an inducible mediator of endothelial dysfunction in cardiovascular disease? Cardiovascular SGLT2 appears low at baseline but inducible by pathological stress. Induced SGLT2 may amplify oxidative stress, inflammation, and senescence. This pathway may also promote thrombosis, fibrosis, and vascular calcification. This framework may guide biomarker studies and broader cardiovascular use of SGLT2 inhibitors.