Beyond maximally tolerated statins: PCSK9 inhibitors as a critical adjunct for cardiovascular risk reduction in peripheral artery disease—a systematic review and meta-analysis

BACKGROUND: The role of PCSK9 inhibitors in PAD remains uncertain, despite their established benefits in atherosclerotic cardiovascular disease. This meta-analysis aimed to evaluate their effects on cardiovascular, functional, limb, and survival outcomes in PAD. METHODS: We systematically searched PubMed, Scopus, and ClinicalTrials.gov through August 2025 for RCTs and cohort studies comparing PCSK9 inhibitors with placebo or standard therapy in PAD. Primary outcomes were MACE and major amputation. Data were analyzed using fixed- or random-effects models depending on heterogeneity. RESULTS: Six studies (five RCTs, one cohort) involving 4,563 patients were included. PCSK9 inhibitors significantly reduced MACE (HR 0.77; 95% CI: 0.65 to 0.92) and lowered LDL-C levels (MD -55.76 mg/dL; 95% CI: -63.19 to -48.34). Positive but non-significant trends were observed for major amputation (HR 0.35; 95% CI: 0.11 to 1.07), all-cause mortality (HR 0.58; 95% CI: 0.26 to 1.30), and walking performance (SMD 2.38; 95% CI: -1.97 to 6.73). Safety endpoints could not be pooled because of inconsistent reporting across studies; however, the available evidence suggested a generally favorable safety profile, with no clear excess in serious adverse events and low discontinuation rates. Subgroup analysis showed no significant difference between Alirocumab and Evolocumab for MACE, all-cause mortality, or LDL-C reduction. CONCLUSIONS: .