PCSK9 Inhibitors in Peripheral Arterial Disease: A Systematic Review

Dyslipidaemia is a key modifiable risk factor for peripheral arterial disease (PAD), and statin therapy for lipid-lowering is well established in its management. Proprotein convertase subtilisin/kexin type-9 (PCSK9) inhibitors lower lipids and cardiovascular risk; however, their impact on limb-based outcomes in PAD remains uncertain.

A systematic review was conducted in accordance with Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Studies evaluating PCSK9 inhibitor therapy in patients with PAD were eligible for inclusion.

Four studies met the inclusion criteria and were included in the review, comprising three randomized controlled trials (RCTs) and 1 prospective case series, with a total of 3,770 patients. The majority of included participants were derived from a large multicenter RCT, FOURIER, which contributed 3,642 patients from its PAD subgroup. In the FOURIER PAD subgroup, Evolocumab significantly reduced major adverse limb events (MALEs) compared with placebo in patients receiving background statin therapy (Hazard Ratio 0.58; 95% Confidence Interval 0.38-0.88). Smaller studies in patients with PAD and chronic limb-threatening ischemia reported improvements in amputation-free survival, wound healing, walking performance, and markers of endothelial function and atherosclerotic burden.

PCSK9 inhibitors appear to provide limb-related benefits in patients with PAD, without ill-effects. These benefits include decrease in MALEs and improvements in functional and physiological parameters, and may extend beyond lipid lowering alone. However, current evidence is limited, heterogeneous, and exploratory. Dedicated, adequately powered randomized trials focusing on clearly defined limb outcomes are needed to clarify the role of PCSK9 inhibitors in PAD management.