Implication of Perivascular Adipose Tissue as a Potential Therapeutic Target for the Vascular Defensive Actions of Incretin-Based Therapies and SGLT2 Inhibitors

Cardiovascular disease is a predominant cause of illness in individuals with type 2 diabetes mellitus and obesity. Although glucose reduction has traditionally been the principal therapeutic target for treating hyperglycemia, recent cardiovascular outcome trials have revealed that incretin-based therapies and sodium-glucose cotransporter-2 (SGLT2) inhibitors provide significant cardiovascular benefits beyond merely lowering blood glucose levels. The precise mechanisms underlying the multifaceted vascular effects of these therapies are not fully understood. Perivascular adipose tissue (PVAT) has been identified as an active player in regulating vascular tone and inflammation. Under physiological conditions, PVAT exhibits anticontractile and vasoprotective effects; however, under metabolic and cardiovascular pathological conditions, PVAT undergoes inflammatory and oxidative remodeling, which can lead to endothelial dysfunction, increased arterial stiffness, and hypertension. Recent experimental and translational studies suggest that incretin-based therapies and SGLT2 inhibitors may help improve the homeostasis of PVAT, consequently enhancing vascular function and regulating blood pressure. Despite these developments, the potential role of PVAT as a target for metabolic therapies has not been thoroughly reviewed. This review aims to address this critical knowledge gap and proposes PVAT and its signaling as novel therapeutic targets through which incretin-based treatments and SGLT2 inhibitors could provide vascular protection, thereby redefining cardiometabolic pharmacotherapy.