Abstract
Lipoprotein(a) [Lp(a)] is a genetically determined, cholesterol-rich particle increasingly recognized as a key player in atherosclerotic cardiovascular disease. This narrative review synthesizes contemporary evidence establishing Lp(a) as a causal, independent, and clinically significant risk factor for peripheral artery disease (PAD). Epidemiologic and large-scale genetic studies, including Mendelian randomization, confirm that elevated Lp(a) levels are associated with increased incidence of PAD, major adverse limb events (MALE), abdominal aortic aneurysm, and disease progression. Mechanistically, Lp(a) promotes lower-limb atherosclerosis through proatherogenic, prothrombotic, proinflammatory, and procalcific pathways, contributing to complex lesion morphology and poor revascularization outcomes. Clinically, higher Lp(a) levels are linked to symptomatic disease severity, polyvascular involvement, and worse prognosis, including amputation and mortality, even among patients receiving guideline-directed therapy. While conventional lipid-lowering agents have minimal effects on Lp(a), emerging RNA-targeted therapies capable of reducing Lp(a) by >80% offer promising prospects for directly modifying this risk factor. Current clinical guidance supports a one-time measurement of Lp(a) in PAD patients to identify those with residual risk, who may benefit from intensified conventional management and consideration for novel therapies or clinical trials. This review summarizes the robust evidence linking Lp(a) to PAD, highlights implications for risk stratification and management, and delineates future research directions aimed at translating potent Lp(a) lowering into improved limb-specific outcomes.