Vascular effects of SGLT2 inhibitors: evidence and mechanisms

Abstract

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) were initially developed as glucose-lowering agents for type 2 diabetes mellitus (T2DM). However, robust clinical evidence has demonstrated that their therapeutic benefits extend beyond glycemic control. SGLT2i reduce hospitalization for heart failure (HF), slow the progression of chronic kidney disease (CKD), and provide cardiorenal protection even in individuals without diabetes but with cardiovascular disease. These pleiotropic effects include favorable actions on both macrovascular and microvascular functions, which may contribute to their broad cardiovascular, renal, and metabolic benefits. Although the mechanisms underlying these vascular effects remain incompletely understood, they appear to involve both hemodynamic modulation and direct cellular actions that vary according to disease context and vascular bed. Elucidating these mechanisms is essential to refining therapeutic strategies and guiding optimal patient selection. This short review highlights the multifaceted vascular benefits of SGLT2i, summarizing current clinical and mechanistic insights into their vascular actions, with a particular mention of their role in the context of malignancy. SGLT2i contribute to improved cell viability, proliferation, and angiogenesis by attenuating endothelial cell apoptosis, ferroptosis, and pyroptosis, while also influencing inflammatory and oxidative signaling pathways, and enhancing eNOS phosphorylation and deacetylation. In addition to their endothelial effects, we explore the impact of SGLT2i on vascular smooth muscle cells and perivascular nerves, which can lead to reduced vascular stiffness, calcification, and improved vasodilation. Sex-specific differences in clinical outcomes and mechanisms are also discussed. Finally, we identify key areas for future investigation to better harness the full therapeutic potential of SGLT2i.

Keywords: SGLT2 inhibitors; cardiovascular disease; endothelial cell; kidney disease; vascular smooth muscle cell.