GLP-1 Receptor Agonists in Diabetic Lower Extremity Peripheral Artery Disease: From Mechanisms to Clinical Practice

Diabetic lower extremity peripheral artery disease (PAD) is a complex and multifactorial complication of diabetes mellitus, characterized by extensive distal disease burden, accelerated progression, and a markedly elevated risk of major adverse limb events. Despite considerable advances in endovascular and surgical revascularization, limb salvage rates in this population remain suboptimal, largely due to the limited efficacy of current pharmacological options in improving microvascular perfusion, accelerating wound healing, or preventing re-occlusion. In recent years, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as a transformative therapeutic class, demonstrating cardiovascular protective effects beyond glycemic control. Large-scale real-world studies have generated encouraging signals regarding their potential to reduce amputation risk and promote wound healing. However, the current evidence base remains limited, and the precise molecular mechanisms by which GLP-1 RAs may protect the diabetic lower extremity require further elucidation. This review systematically examines the epidemiology and pathophysiology of diabetic lower extremity PAD, elucidates the molecular mechanisms of GLP-1 RA-mediated vascular protection, critically evaluates clinical and real-world evidence, and discusses key challenges and future directions for optimizing therapeutic outcomes in this high risk population.