PCSK9 Inhibition with alirocumab increases the catabolism of lipoprotein(a) particles in statin-treated patients with elevated lipoprotein(a).

Abstract

BACKGROUND:

Lipoprotein(a) (Lp(a)) is a low-density lipoprotein (LDL) particle containing apolipoprotein(a) (apo(a)) covalently linked to apolipoprotein B-100 (apoB). Statin-treated patients with elevated Lp(a) have an increased risk of atherosclerotic cardiovascular disease (ASCVD). Recent trials show that proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition decreases Lp(a) and cardiovascular events, particularly in high risk patients with elevated Lp(a). We investigated the kinetic mechanism whereby alirocumab, a PCSK9 inhibitor, lowers Lp(a) in statin-treated patients with high Lp(a) and ASCVD.

METHODS:

The effects of 12-week alirocumab treatment (150 mg every 2 weeks) on apo(a) kinetics were studied in 21 patients with elevated Lp(a) concentration (>0.5 g/L). Apo(a) fractional catabolic rate (FCR) and production rate (PR) were determined using intravenous D3-leucine administration, mass spectrometry and compartmental modelling. All patients were on long-term statin treatment.

RESULTS:

Alirocumab significantly decreased plasma concentrations of total cholesterol (-39%), LDL-cholesterol (-67%), apoB (-56%), apo(a) (-25%) and Lp(a) (-22%) (P< 0.001 for all). Alirocumab also significantly lowered plasma apo(a) pool size (-26%, P <0.001) and increased the FCR of apo(a) (+28%, P< 0.001), but did not alter apo(a) PR, which remained significantly higher relative to a reference group of patients on statins with normal Lp(a) (P< 0.001).

CONCLUSIONS:

In statin-treated patients, alirocumab lowers elevated plasma Lp(a) concentrations by accelerating the catabolism of Lp(a) particles. This may be consequent on marked upregulation of hepatic receptors (principally for LDL) and/or reduced competition between Lp(a) and LDL particles for these receptors; the mechanism could contribute to the benefit of PCSK9 inhibition with alirocumab on cardiovascular outcomes.

• Authors: Gerald F Watts, Dick C Chan, Jing Pang, Louis Ma, Qidi Ying, Shashi Aggarwal, Santica M Marcovina, P Hugh R Barrett
• Journal: Metabolism: clinical and experimental (Metabolism) Vol. 107 Pg. 154221 (06 2020) ISSN: 1532-8600 [Electronic] United States
• PMID: 32240727 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Antibodies, Monoclonal, Humanized
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Hypolipidemic Agents
• Lipoprotein(a)
• PCSK9 Inhibitors
• Cholesterol
• Apoprotein(a)
• PCSK9 protein, human
• alirocumab

Topics

• Adolescent
• Adult
• Aged
• Antibodies, Monoclonal, Humanized (pharmacology, therapeutic use)
• Apoprotein(a) (blood)
• Cholesterol (blood)
• Coronary Artery Disease (drug therapy)
• Female
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (therapeutic use)
• Hyperlipidemias (blood, drug therapy)
• Hypolipidemic Agents (pharmacology, therapeutic use)
• Lipoprotein(a) (metabolism)
• Male
• Middle Aged
• PCSK9 Inhibitors
• Young Adult