PCSK9 inhibition
PCSK9 inhibitors lower Lp(a) by 15-30%, and FOURIER shows most benefit in patients with high baseline Lp(a), a review (Curr Opin Lipidol 2019)
Original title: Proprotein convertase subtilisin/kexin type 9 inhibitors and lipoprotein(a)-mediated risk of atherosclerotic cardiovascular disease: more than meets the eye?
This review by Boffa and Koschinsky examines the relationship between PCSK9 inhibitors (PCSK9i) and Lp(a)-mediated cardiovascular risk. PCSK9i lower Lp(a) by 15-30%, through mechanisms still debated, including effects on Lp(a) clearance via the LDL receptor and on hepatocyte Lp(a)/apo(a) biosynthesis. In the FOURIER cardiovascular outcomes trial, patients with higher baseline Lp(a) derived greater benefit from evolocumab, and those with the lowest combined achieved Lp(a) and LDL cholesterol had the lowest event rate. A meta-analysis of ten phase 3 alirocumab trials reached similar conclusions regarding achieved Lp(a) levels, though an effect independent of LDL cholesterol lowering could not be demonstrated. The authors conclude that while it remains unclear whether PCSK9i specifically lower Lp(a)-attributable risk, patients with elevated Lp(a) may derive incremental benefit from PCSK9i therapy.
Original abstract
Purpose Of Review: Evidence continues to mount for elevated lipoprotein(a) [Lp(a)] as a prevalent, independent, and causal risk factor for atherosclerotic cardiovascular disease. However, the effects of existing lipid-lowering therapies on Lp(a) are comparatively modest and are not specific to Lp(a). Consequently, evidence that Lp(a)-lowering confers a cardiovascular benefit is lacking. Large-scale cardiovascular outcome trials (CVOTs) of inhibitory mAbs targeting proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) may address this issue.
Recent Findings: Although the ability of PCSK9i to lower Lp(a) by 15-30% is now clear, the mechanisms involved continue to be debated, with in-vitro and in-vivo studies showing effects on Lp(a) clearance (through the LDL receptor or other receptors) and Lp(a)/apolipoprotein(a) biosynthesis in hepatocytes. The FOURIER CVOT showed that patients with higher baseline levels of Lp(a) derived greater benefit from evolocumab and those with the lowest combined achieved Lp(a) and LDL-cholesterol (LDL-C) had the lowest event rate. Meta-analysis of ten phase 3 trials of alirocumab came to qualitatively similar conclusions concerning achieved Lp(a) levels, although an effect independent of LDL-C lowering could not be demonstrated.
Summary: Although it is not possible to conclude that PCSK9i specifically lower Lp(a)-attributable risk, patients with elevated Lp(a) could derive incremental benefit from PCSK9i therapy.
Summary written by lp-a.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.