Relationship Between Low-Density Lipoprotein Cholesterol and Lipoprotein(a) Lowering in Response to PCSK9 Inhibition With Evolocumab

Michael Shapiro, Jessica Minnier, Hagai Tavori, Helina Kassahun, Andrea Flower, Ransi Somaratne, Sergio Fazio

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7 Citations (Scopus)

Abstract

Background Beyond their potent LDL (low-density lipoprotein) cholesterol ( LDL -C)-lowering efficacy (50-60%), PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors also reduce Lp(a) (lipoprotein[a]) levels by 25% to 30%, suggesting a 2:1 response ratio. We aimed to characterize the relationship between LDL -C and Lp(a) lowering by evolocumab, a PCSK 9 inhibitor, in a large clinical trial population and to determine the prevalence of concordant/discordant LDL -C and Lp(a) responses to PCSK 9 inhibition. Methods and Results Data were analyzed from 4 randomized, 12-week, multicenter, phase 3 evolocumab trials. Patients with familial hypercholesterolemia, nonfamilial hypercholesterolemia, or statin intolerance participated in the trials. The main measure was the degree of concordance or discordance of LDL -C and Lp(a) in response to PCSK 9 inhibition; concordant response was defined as LDL -C reduction >35% and Lp(a) reduction >10%. The study cohort comprised 895 patients (438 female; median age: 59.0 years [interquartile range: 51-66 years]). Baseline mean level of LDL -C was 133.6 mg/dL (SE: 1.7) and median Lp(a) level was 46.4 mg/dL (interquartile range: 18.4-82.4 mg/dL). A discordant response was observed in 165 (19.7%) patients. With these cutoffs, the prevalence of discordance was higher when considering baseline Lp(a) concentrations >30 mg/dL (26.5%) or >50 mg/dL (28.6%). Conclusions We demonstrate high prevalence of discordance in LDL -C and Lp(a) reduction in response to evolocumab, particularly when considering higher baseline Lp(a) concentrations, indicating the possibility of alternative pathways beyond LDLR ( LDL receptor)-mediated clearance involved in Lp(a) reduction by evolocumab. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifiers: NCT 01763827, NCT 01763866, NCT 01763905, NCT 01763918.

Original languageEnglish (US)
Pages (from-to)e010932
JournalJournal of the American Heart Association
Volume8
Issue number4
DOIs
StatePublished - Feb 19 2019

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Lipoprotein(a)
LDL Lipoproteins
LDL Cholesterol
Clinical Trials
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Hyperlipoproteinemia Type II
LDL Receptors
Hypercholesterolemia
Lipoproteins
AMG 145
Proprotein Convertase 9
Cohort Studies
Population

Keywords

  • lipid‐lowering therapy
  • lipoprotein[a]
  • low‐density lipoprotein cholesterol
  • proprotein convertase subtilisin/kexin type 9

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

@article{1a89ae50321e4734a4f99276a4bae2d0,
title = "Relationship Between Low-Density Lipoprotein Cholesterol and Lipoprotein(a) Lowering in Response to PCSK9 Inhibition With Evolocumab",
abstract = "Background Beyond their potent LDL (low-density lipoprotein) cholesterol ( LDL -C)-lowering efficacy (50-60{\%}), PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors also reduce Lp(a) (lipoprotein[a]) levels by 25{\%} to 30{\%}, suggesting a 2:1 response ratio. We aimed to characterize the relationship between LDL -C and Lp(a) lowering by evolocumab, a PCSK 9 inhibitor, in a large clinical trial population and to determine the prevalence of concordant/discordant LDL -C and Lp(a) responses to PCSK 9 inhibition. Methods and Results Data were analyzed from 4 randomized, 12-week, multicenter, phase 3 evolocumab trials. Patients with familial hypercholesterolemia, nonfamilial hypercholesterolemia, or statin intolerance participated in the trials. The main measure was the degree of concordance or discordance of LDL -C and Lp(a) in response to PCSK 9 inhibition; concordant response was defined as LDL -C reduction >35{\%} and Lp(a) reduction >10{\%}. The study cohort comprised 895 patients (438 female; median age: 59.0 years [interquartile range: 51-66 years]). Baseline mean level of LDL -C was 133.6 mg/dL (SE: 1.7) and median Lp(a) level was 46.4 mg/dL (interquartile range: 18.4-82.4 mg/dL). A discordant response was observed in 165 (19.7{\%}) patients. With these cutoffs, the prevalence of discordance was higher when considering baseline Lp(a) concentrations >30 mg/dL (26.5{\%}) or >50 mg/dL (28.6{\%}). Conclusions We demonstrate high prevalence of discordance in LDL -C and Lp(a) reduction in response to evolocumab, particularly when considering higher baseline Lp(a) concentrations, indicating the possibility of alternative pathways beyond LDLR ( LDL receptor)-mediated clearance involved in Lp(a) reduction by evolocumab. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifiers: NCT 01763827, NCT 01763866, NCT 01763905, NCT 01763918.",
keywords = "lipid‐lowering therapy, lipoprotein[a], low‐density lipoprotein cholesterol, proprotein convertase subtilisin/kexin type 9",
author = "Michael Shapiro and Jessica Minnier and Hagai Tavori and Helina Kassahun and Andrea Flower and Ransi Somaratne and Sergio Fazio",
year = "2019",
month = "2",
day = "19",
doi = "10.1161/JAHA.118.010932",
language = "English (US)",
volume = "8",
pages = "e010932",
journal = "Journal of the American Heart Association",
issn = "2047-9980",
publisher = "Wiley-Blackwell",
number = "4",

}

TY - JOUR

T1 - Relationship Between Low-Density Lipoprotein Cholesterol and Lipoprotein(a) Lowering in Response to PCSK9 Inhibition With Evolocumab

AU - Shapiro, Michael

AU - Minnier, Jessica

AU - Tavori, Hagai

AU - Kassahun, Helina

AU - Flower, Andrea

AU - Somaratne, Ransi

AU - Fazio, Sergio

PY - 2019/2/19

Y1 - 2019/2/19

N2 - Background Beyond their potent LDL (low-density lipoprotein) cholesterol ( LDL -C)-lowering efficacy (50-60%), PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors also reduce Lp(a) (lipoprotein[a]) levels by 25% to 30%, suggesting a 2:1 response ratio. We aimed to characterize the relationship between LDL -C and Lp(a) lowering by evolocumab, a PCSK 9 inhibitor, in a large clinical trial population and to determine the prevalence of concordant/discordant LDL -C and Lp(a) responses to PCSK 9 inhibition. Methods and Results Data were analyzed from 4 randomized, 12-week, multicenter, phase 3 evolocumab trials. Patients with familial hypercholesterolemia, nonfamilial hypercholesterolemia, or statin intolerance participated in the trials. The main measure was the degree of concordance or discordance of LDL -C and Lp(a) in response to PCSK 9 inhibition; concordant response was defined as LDL -C reduction >35% and Lp(a) reduction >10%. The study cohort comprised 895 patients (438 female; median age: 59.0 years [interquartile range: 51-66 years]). Baseline mean level of LDL -C was 133.6 mg/dL (SE: 1.7) and median Lp(a) level was 46.4 mg/dL (interquartile range: 18.4-82.4 mg/dL). A discordant response was observed in 165 (19.7%) patients. With these cutoffs, the prevalence of discordance was higher when considering baseline Lp(a) concentrations >30 mg/dL (26.5%) or >50 mg/dL (28.6%). Conclusions We demonstrate high prevalence of discordance in LDL -C and Lp(a) reduction in response to evolocumab, particularly when considering higher baseline Lp(a) concentrations, indicating the possibility of alternative pathways beyond LDLR ( LDL receptor)-mediated clearance involved in Lp(a) reduction by evolocumab. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifiers: NCT 01763827, NCT 01763866, NCT 01763905, NCT 01763918.

AB - Background Beyond their potent LDL (low-density lipoprotein) cholesterol ( LDL -C)-lowering efficacy (50-60%), PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors also reduce Lp(a) (lipoprotein[a]) levels by 25% to 30%, suggesting a 2:1 response ratio. We aimed to characterize the relationship between LDL -C and Lp(a) lowering by evolocumab, a PCSK 9 inhibitor, in a large clinical trial population and to determine the prevalence of concordant/discordant LDL -C and Lp(a) responses to PCSK 9 inhibition. Methods and Results Data were analyzed from 4 randomized, 12-week, multicenter, phase 3 evolocumab trials. Patients with familial hypercholesterolemia, nonfamilial hypercholesterolemia, or statin intolerance participated in the trials. The main measure was the degree of concordance or discordance of LDL -C and Lp(a) in response to PCSK 9 inhibition; concordant response was defined as LDL -C reduction >35% and Lp(a) reduction >10%. The study cohort comprised 895 patients (438 female; median age: 59.0 years [interquartile range: 51-66 years]). Baseline mean level of LDL -C was 133.6 mg/dL (SE: 1.7) and median Lp(a) level was 46.4 mg/dL (interquartile range: 18.4-82.4 mg/dL). A discordant response was observed in 165 (19.7%) patients. With these cutoffs, the prevalence of discordance was higher when considering baseline Lp(a) concentrations >30 mg/dL (26.5%) or >50 mg/dL (28.6%). Conclusions We demonstrate high prevalence of discordance in LDL -C and Lp(a) reduction in response to evolocumab, particularly when considering higher baseline Lp(a) concentrations, indicating the possibility of alternative pathways beyond LDLR ( LDL receptor)-mediated clearance involved in Lp(a) reduction by evolocumab. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifiers: NCT 01763827, NCT 01763866, NCT 01763905, NCT 01763918.

KW - lipid‐lowering therapy

KW - lipoprotein[a]

KW - low‐density lipoprotein cholesterol

KW - proprotein convertase subtilisin/kexin type 9

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U2 - 10.1161/JAHA.118.010932

DO - 10.1161/JAHA.118.010932

M3 - Article

VL - 8

SP - e010932

JO - Journal of the American Heart Association

JF - Journal of the American Heart Association

SN - 2047-9980

IS - 4

ER -