Lipoprotein(a) reductions from PCSK9 inhibition and major adverse cardiovascular events: Pooled analysis of alirocumab phase 3 trials.
Aged
Antibodies, Monoclonal, Humanized
/ adverse effects
Anticholesteremic Agents
/ adverse effects
Biomarkers
/ blood
Cardiovascular Diseases
/ blood
Cholesterol, LDL
/ blood
Clinical Trials, Phase III as Topic
Down-Regulation
Dyslipidemias
/ blood
Female
Humans
Lipoprotein(a)
/ blood
Male
Middle Aged
PCSK9 Inhibitors
Proprotein Convertase 9
/ metabolism
Randomized Controlled Trials as Topic
Risk Assessment
Risk Factors
Serine Proteinase Inhibitors
/ adverse effects
Time Factors
Treatment Outcome
Alirocumab
Cardiovascular risk
Cholesterol-lowering drugs
Low-density lipoprotein cholesterol
PCSK9
lipoprotein(a)
Journal
Atherosclerosis
ISSN: 1879-1484
Titre abrégé: Atherosclerosis
Pays: Ireland
ID NLM: 0242543
Informations de publication
Date de publication:
09 2019
09 2019
Historique:
received:
28
09
2018
revised:
24
05
2019
accepted:
06
06
2019
pubmed:
30
6
2019
medline:
29
7
2020
entrez:
30
6
2019
Statut:
ppublish
Résumé
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. 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. 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). 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.
Sections du résumé
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.
Identifiants
pubmed: 31253441
pii: S0021-9150(19)31353-X
doi: 10.1016/j.atherosclerosis.2019.06.896
pii:
doi:
Substances chimiques
Antibodies, Monoclonal, Humanized
0
Anticholesteremic Agents
0
Biomarkers
0
Cholesterol, LDL
0
LPA protein, human
0
Lipoprotein(a)
0
PCSK9 Inhibitors
0
Serine Proteinase Inhibitors
0
PCSK9 protein, human
EC 3.4.21.-
Proprotein Convertase 9
EC 3.4.21.-
alirocumab
PP0SHH6V16
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
194-202Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.