Peripheral artery disease: advances in medical therapy

Peripheral artery disease (PAD) is a prevalent manifestation of systemic atherosclerosis, associated with elevated risks of major adverse cardiovascular events (MACE) and major adverse limb events (MALE). Despite its clinical significance, PAD remains underdiagnosed and undertreated, reflecting substantial gaps in guideline implementation. This review highlights advances in the medical management of PAD, focusing on strategies targeting the metabolic, lipid, immuno-inflammatory, and thrombotic drivers of disease to improve cardiovascular and limb outcomes. Optimal management requires intensive, multifaceted approaches that integrate lifestyle modification (including smoking cessation, a healthy diet, and physical activity), risk factor control, and pharmacologic interventions. Dual pathway antithrombotic therapy with low-dose rivaroxaban and aspirin has emerged as a superior strategy to mitigate both cardiovascular and limb events in patients with high ischaemic risk and non-high bleeding risk. Statins are the first-line lipid-lowering therapy for all patients with PAD, and if low-density lipoprotein cholesterol (LDL-C) goals are not achieved with maximally tolerated doses, adjunctive agents-such as ezetimibe, bempedoic acid, and proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i)-should be added. Novel antidiabetic agents, particularly glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is), confer cardiovascular and renal benefits independent of glycaemic control, with emerging data suggesting that GLP-1 RAs may also reduce limb events. To date, semaglutide remains the only anti-obesity pharmacotherapy that has been demonstrated to reduce cardiovascular events in high-risk patients with overweight or obesity in the absence of diabetes. We propose a phenotype-driven approach to enable refined risk stratification across the PAD spectrum, supporting individualized and, when needed, more intensive management.