SGLT2 Inhibitors as Endothelial Protectors: Mechanisms of Vascular Restoration in Type 2 Diabetes

Endothelial dysfunction is a fundamental catalyst of atherosclerosis and cardiovascular mortality in type 2 diabetes mellitus (T2DM). While sodium-glucose co-transporter 2 inhibitors (SGLT2is) provide robust cardioprotection, whether these benefits stem from direct vasculature effects or from secondary systemic hemodynamics remains an active translational frontier. At the cellular level, preclinical data suggests that SGLT2is may modulate homeostatic pathways by suppressing NADPH oxidase-mediated oxidative stress, attenuating NF-κB/NLRP3-driven inflammatory cascades, and preserving endothelial nitric oxide synthase (eNOS) activity. In clinical cohorts, these molecular actions correlate with heterogeneous changes in flow-mediated dilation (FMD) and reductions in arterial stiffness. However, translating these cellular findings to macrovascular outcomes is highly confounded by concurrent volume contraction, blood pressure lowering and metabolic shifts.