Alirocumab LDL-C and Lp(a)-lowering effects are discordant in 21.5% of patients, suggesting separate clearance pathways, a pooled analysis of 1,709 patients across 10 ODYSSEY phase 3 trials (Eur J Prev Cardiol 2021)

Original title: Discordant responses of plasma low-density lipoprotein cholesterol and lipoprotein(a) to alirocumab: A pooled analysis from 10 ODYSSEY Phase 3 studies

Eur J Prev Cardiol · 10 April 2020 · 7

Mahmood T, Minnier J, Ito MK, Li QH, Koren A, Kam IW, Fazio S, Shapiro MD

In a post hoc pooled analysis of 10 ODYSSEY phase 3 trials of alirocumab (1,709 patients, 62.4% men, mean age 59.2 years, baseline LDL-C 126.5 mg/dL, baseline median Lp(a) 46.9 mg/dL), the authors examined discordance between LDL-C and Lp(a) response at 24 weeks, defined as LDL-C reduction >35% with Lp(a) reduction <=10%, or the reverse. Discordant response occurred in 21.5% of patients overall (12.6% with strong LDL-C but weak Lp(a) reduction, 8.9% with the reverse pattern), and this discordance was unaffected by baseline Lp(a) or familial hypercholesterolaemia status. The findings suggest alirocumab lowers Lp(a) through pathways other than LDL receptor-mediated clearance, the mechanism thought to drive its LDL-C effect.

Original abstract

Aims: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors consistently reduce low-density lipoprotein cholesterol (LDL-C) by 50-60% and lipoprotein(a) (Lp(a)) by 20-30%, but the mechanism of Lp(a) lowering remains unclear. If Lp(a) is cleared by the LDL receptor, similar to LDL-C, then one would expect PCSK9 inhibition to induce a concordant LDL-C/Lp(a) response in an approximately 2:1 ratio. We aim to determine the prevalence of discordant plasma LDL-C/Lp(a) response to the PCSK9 inhibitor alirocumab.

Methods: This is a post hoc, pooled analysis of 10 randomized controlled trials from the ODYSSEY Phase 3 clinical trial program for alirocumab. Patients enrolled in the trials were high cardiovascular risk and/or with heterozygous familial hypercholesterolemia. The primary end point was prevalence of discordant LDL-C/Lp(a) response to alirocumab at 24 weeks. Discordant response was defined as LDL-C reduction >35% and Lp(a) reduction ≤10%, or LDL-C reduction ≤35% and Lp(a) reduction >10%.

Results: Of the 1709 patients in the pooled study cohort, 62.4% were male, and the mean age was 59.2 (SD: 11.0) years. Baseline mean LDL-C was 126.5 (SD: 46.3) mg/dL and baseline median Lp(a) was 46.9 (interquartile range: 21.8-89.0) mg/dL. Total prevalence of discordant LDL-C/Lp(a) response was 21.5% (12.6% with LDL-C >35% reduction and Lp(a) ≤10% reduction; 8.9% with LDL-C ≤35% reduction and Lp(a) >10% reduction). Baseline Lp(a) and familial hypercholesterolemia status did not affect discordance.

Conclusion: A high prevalence of discordant LDL-C/Lp(a) response was observed with alirocumab, further suggesting that PCSK9 inhibitor therapy with alirocumab reduces plasma Lp(a) through alternative pathways to LDL receptor clearance.

Summary written by lp-a.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.