PCSK9 inhibition
Lp(a) reduction from PCSK9 inhibition does not independently lower cardiovascular events, a pooled analysis of 10 phase 3 alirocumab trials in 4983 patients (Atherosclerosis 2019)
Original title: Lipoprotein(a) reductions from PCSK9 inhibition and major adverse cardiovascular events: Pooled analysis of alirocumab phase 3 trials
This post-hoc pooled analysis of 10 phase 3 ODYSSEY trials examined whether Lp(a) reductions with alirocumab (n=4983 patients with cardiovascular disease or risk factors and hypercholesterolaemia) were associated with fewer major adverse cardiovascular events (MACE), independent of LDL cholesterol changes. Median baseline Lp(a) was 23.5 mg/dL; alirocumab reduced Lp(a) by a median 25.6% versus 2.5% with placebo, and by 21.4% versus 0.0% with ezetimibe. Over 6699 patient-years, 104 patients experienced MACE. A 12% relative risk reduction in MACE per 25% Lp(a) reduction (P=0.0254) was no longer significant after adjusting for LDL-C changes (hazard ratio per 25% reduction 0.89, 95% CI 0.79-1.01, P=0.0780), though the association remained significant among patients with baseline Lp(a) at or above 50 mg/dL. The findings suggest Lp(a) reduction from PCSK9 inhibition is not independently associated with fewer cardiovascular events in this population, and that greater Lp(a) reductions or higher baseline Lp(a) may be needed to show a benefit.
Original abstract
Background And Aims: Elevated lipoprotein(a) [Lp(a)] levels are considered a causal factor for cardiovascular disease. In phase 3 ODYSSEY trials, alirocumab reduced levels of low-density lipoprotein cholesterol (LDL-C) and Lp(a), with concomitant reductions in the risk of major adverse cardiovascular events (MACE). We assessed whether lower on-study and greater percentage reductions in Lp(a) are associated with a lower risk of MACE.
Methods: Post-hoc analysis of data pooled from 10 phase 3 ODYSSEY trials comparing alirocumab with control (placebo or ezetimibe) in patients (n = 4983) with cardiovascular disease and/or risk factors, and hypercholesterolemia despite statin/other lipid-lowering therapies.
Results: Median (Q1, Q3) baseline Lp(a) levels were 23.5 (8.0, 67.0) mg/dL. Median Lp(a) changes from baseline with alirocumab were -25.6% vs. -2.5% with placebo (absolute reductions 6.8 vs. 0.5 mg/dL) in placebo-controlled trials, and -21.4% vs. 0.0% with ezetimibe (4.5 vs. 0.0 mg/dL) in ezetimibe-controlled trials. During follow-up (6699 patient-years), 104 patients experienced MACE. A 12% relative risk reduction in MACE per 25% reduction in Lp(a) (p=0.0254) was no longer significant after adjustment for LDL-C changes: hazard ratio per 25% reduction: 0.89 (95% confidence interval, 0.79-1.01; p=0.0780). In subgroup analysis, the association between Lp(a) reduction and MACE remained significant in a fully adjusted model among participants with baseline Lp(a) ≥50 mg/dL (p-interaction vs. Lp(a) < 50 mg/dL: 0.0549).
Conclusions: In this population, Lp(a) reductions were not significantly associated with MACE independently of LDL-C reductions. Reducing the risk of MACE by targeting Lp(a) may require greater reductions in Lp(a) with more potent therapies and/or higher initial Lp(a) levels.
Summary written by lp-a.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.