Effects of PCSK9 inhibitors on vascular function, lipid profile, and cardiovascular outcomes in patients with peripheral artery disease: A systematic review and meta-analysis

Background: Peripheral artery disease (PAD) reflects systemic atherosclerosis driven by dyslipidemia, particularly elevated LDL-C. Despite first-line statin therapy, many patients fail to reach lipid targets or are intolerant, necessitating alternatives. We conducted a meta-analysis to assess proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in PAD. Methods: A systematic search in PubMed, Embase, Cochrane Library, Web of Science, and Scopus was done up to August 2025. Studies evaluated effects on surrogate vascular markers [ankle-brachial index (ABI), flow-mediated dilation (FMD), carotid intima-media thickness (IMT), lipid profile] and clinical outcomes [major adverse cardiovascular events (MACE), revascularization, amputation, myocardial infarction (MI), and mortality]. Results: Six studies, assessing 6059 patients were included. PCSK9 inhibitors significantly reduced carotid IMT, LDL-C, total cholesterol, and triglycerides compared with placebo. Based on the available studies, no significant effects were observed on ABI, FMD, or HDL. Clinically, PCSK9 inhibitors lowered the risk of MACE (RR = 0.76, 95% CI [0.60-0.97]), major amputation (RR = 0.38, 95% CI [0.15-0.95]), and MI (RR = 0.63, 95% CI [0.5, 0.79]). Revascularization rates and all-cause mortality were not significant. Conclusion: PCSK9 inhibitors may provide lipid-lowering and vascular benefits in patients with PAD, reducing cardiovascular and limb events. While their impact on hemodynamic parameters and mortality remains uncertain, these findings support PCSK9 inhibitors may be effective adjunctive therapy in high-risk PAD populations. These findings support PCSK9 inhibitors may be an effective adjunctive therapy for atherosclerotic risk reduction in high-risk PAD populations. Prospective trials dedicated to limb-specific outcomes are now warranted.