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. 2021 Jul 23;28(8):816-822. doi: 10.1177/2047487320915803. Epub 2020 Apr 10.

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.

Trial registration: ClinicalTrials.gov NCT01709513 NCT01644175 NCT01644188 NCT01623115 NCT01709500 NCT01617655 NCT01507831 NCT01644474 NCT01730040 NCT01730053.

Keywords: Lipoprotein(a); PCSK9 inhibition; alirocumab; low-density lipoprotein cholesterol.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal, Humanized* / therapeutic use
  • Anticholesteremic Agents* / therapeutic use
  • Cholesterol, LDL / blood*
  • Clinical Trials, Phase III as Topic
  • Humans
  • Lipoprotein(a) / blood*
  • Male
  • Middle Aged
  • PCSK9 Inhibitors / therapeutic use*
  • Proprotein Convertase 9
  • Randomized Controlled Trials as Topic
  • Treatment Outcome

Substances

  • Antibodies, Monoclonal, Humanized
  • Anticholesteremic Agents
  • Cholesterol, LDL
  • Lipoprotein(a)
  • PCSK9 Inhibitors
  • PCSK9 protein, human
  • Proprotein Convertase 9
  • alirocumab

Associated data

  • ClinicalTrials.gov/NCT01709513
  • ClinicalTrials.gov/NCT01644175
  • ClinicalTrials.gov/NCT01644188
  • ClinicalTrials.gov/NCT01623115
  • ClinicalTrials.gov/NCT01709500
  • ClinicalTrials.gov/NCT01617655
  • ClinicalTrials.gov/NCT01507831
  • ClinicalTrials.gov/NCT01644474
  • ClinicalTrials.gov/NCT01730040
  • ClinicalTrials.gov/NCT01730053