Novel GLP-1 RAs and SGLT2is improve cardiovascular and limb outcomes in Peripheral Artery Disease

Peripheral artery disease (PAD) is a widespread manifestation of systemic atherosclerosis, significantly increasing risks of major adverse cardiovascular events (MACE) and major adverse limb events (MALE). Despite its prevalence and clinical impact, PAD remains underdiagnosed and undertreated, highlighting critical gaps in current guideline implementation. Existing management strategies often fall short in comprehensively addressing the multifaceted metabolic, lipid, immuno-inflammatory, and thrombotic drivers of the disease, necessitating advanced therapeutic approaches to improve both cardiovascular and limb outcomes.

This review synthesizes advances in the medical management of Peripheral Artery Disease (PAD), focusing on strategies that target the underlying drivers of the disease. It evaluates the efficacy of established and novel pharmacologic interventions, including antithrombotic agents, lipid-lowering therapies, and antidiabetic drugs, in improving cardiovascular and limb outcomes. The review integrates evidence from various studies to propose a phenotype-driven approach for refined risk stratification and individualized, intensive management across the PAD spectrum.

Optimal PAD management requires intensive, multifaceted approaches. Dual pathway antithrombotic therapy, combining low-dose rivaroxaban and aspirin, has emerged as a superior strategy, significantly mitigating both cardiovascular and limb events in patients with high ischemic risk and non-high bleeding risk. For lipid management, statins are first-line therapy, with adjunctive agents like ezetimibe, bempedoic acid, and proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) recommended if LDL-C goals are not met. > Novel antidiabetic agents, specifically glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is), confer substantial cardiovascular and renal benefits independent of glycemic control, with emerging data suggesting that GLP-1 RAs may also reduce limb events. Notably, semaglutide is currently the only anti-obesity pharmacotherapy demonstrated to reduce cardiovascular events in high-risk patients with overweight or obesity without diabetes.