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Evidence from a Randomized Trial That Simvastatin, but Not Ezetimibe, Upregulates Circulating PCSK9 Levels

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted inhibitor of the low-density lipoprotein (LDL) receptor and an important regulator of LDL metabolism. Elevated PCSK9 levels have been associated with cardiovascular risk. The purpose of this study was to investigate how...

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Autores principales: Berthold, Heiner K., Seidah, Nabil G., Benjannet, Suzanne, Gouni-Berthold, Ioanna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3609731/
https://www.ncbi.nlm.nih.gov/pubmed/23544125
http://dx.doi.org/10.1371/journal.pone.0060095
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author Berthold, Heiner K.
Seidah, Nabil G.
Benjannet, Suzanne
Gouni-Berthold, Ioanna
author_facet Berthold, Heiner K.
Seidah, Nabil G.
Benjannet, Suzanne
Gouni-Berthold, Ioanna
author_sort Berthold, Heiner K.
collection PubMed
description BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted inhibitor of the low-density lipoprotein (LDL) receptor and an important regulator of LDL metabolism. Elevated PCSK9 levels have been associated with cardiovascular risk. The purpose of this study was to investigate how ezetimibe and simvastatin, alone and in combination, affect PCSK9 circulating concentrations. METHODS: A single center, randomized, open-label parallel 3-group study in healthy men (mean age 32±9 years, body mass index 25.7±3.2 kg/m(2)) was performed. Each group of 24 subjects was treated for 14 days with either simvastatin 40 mg/d, ezetimibe 10 mg/d, or with both drugs. Multivariate analysis was used to investigate parameters influencing the change in PCSK9 concentrations under treatment. RESULTS: The baseline plasma PCSK9 concentrations in the total cohort were 52±20 ng/mL with no statistically significant differences between the groups. They were increased by 68±85% by simvastatin (P = 0.0014), by 10±38% by ezetimibe (P = 0.51) and by 67±91% by simvastatin plus ezetimibe (P = 0.0013). The increase in PCSK9 was inversely correlated with baseline PCSK9 concentrations (Spearman’s R = –0.47, P<0.0001) and with the percent change in LDL cholesterol concentrations (Spearman’s R = –0.30, P<0.01). In multivariate analyses, only baseline PCSK9 concentrations (β = –1.68, t = –4.04, P<0.0001), percent change in LDL cholesterol from baseline (β = 1.94, t = 2.52, P = 0.014), and treatment with simvastatin (P = 0.016), but not ezetimibe (P = 0.42), significantly influenced changes in PCSK9 levels. Parameters without effect on PCSK9 concentration changes were age, body mass index, body composition, thyroid function, kidney function, glucose metabolism parameters, adipokines, markers of cholesterol synthesis and absorption, and molecular markers of cholesterol metabolism. CONCLUSIONS: Ezetimibe does not increase circulating PCSK9 concentrations while simvastatin does. When added to simvastatin, ezetimibe does not cause an incremental increase in PCSK9 concentrations. Changes in PCSK9 concentrations are tightly regulated and mainly influenced by baseline PCSK9 levels and changes in LDL cholesterol. TRIAL REGISTRATION: ClinicalTrials.gov NCT00317993
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spelling pubmed-36097312013-03-29 Evidence from a Randomized Trial That Simvastatin, but Not Ezetimibe, Upregulates Circulating PCSK9 Levels Berthold, Heiner K. Seidah, Nabil G. Benjannet, Suzanne Gouni-Berthold, Ioanna PLoS One Research Article BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted inhibitor of the low-density lipoprotein (LDL) receptor and an important regulator of LDL metabolism. Elevated PCSK9 levels have been associated with cardiovascular risk. The purpose of this study was to investigate how ezetimibe and simvastatin, alone and in combination, affect PCSK9 circulating concentrations. METHODS: A single center, randomized, open-label parallel 3-group study in healthy men (mean age 32±9 years, body mass index 25.7±3.2 kg/m(2)) was performed. Each group of 24 subjects was treated for 14 days with either simvastatin 40 mg/d, ezetimibe 10 mg/d, or with both drugs. Multivariate analysis was used to investigate parameters influencing the change in PCSK9 concentrations under treatment. RESULTS: The baseline plasma PCSK9 concentrations in the total cohort were 52±20 ng/mL with no statistically significant differences between the groups. They were increased by 68±85% by simvastatin (P = 0.0014), by 10±38% by ezetimibe (P = 0.51) and by 67±91% by simvastatin plus ezetimibe (P = 0.0013). The increase in PCSK9 was inversely correlated with baseline PCSK9 concentrations (Spearman’s R = –0.47, P<0.0001) and with the percent change in LDL cholesterol concentrations (Spearman’s R = –0.30, P<0.01). In multivariate analyses, only baseline PCSK9 concentrations (β = –1.68, t = –4.04, P<0.0001), percent change in LDL cholesterol from baseline (β = 1.94, t = 2.52, P = 0.014), and treatment with simvastatin (P = 0.016), but not ezetimibe (P = 0.42), significantly influenced changes in PCSK9 levels. Parameters without effect on PCSK9 concentration changes were age, body mass index, body composition, thyroid function, kidney function, glucose metabolism parameters, adipokines, markers of cholesterol synthesis and absorption, and molecular markers of cholesterol metabolism. CONCLUSIONS: Ezetimibe does not increase circulating PCSK9 concentrations while simvastatin does. When added to simvastatin, ezetimibe does not cause an incremental increase in PCSK9 concentrations. Changes in PCSK9 concentrations are tightly regulated and mainly influenced by baseline PCSK9 levels and changes in LDL cholesterol. TRIAL REGISTRATION: ClinicalTrials.gov NCT00317993 Public Library of Science 2013-03-27 /pmc/articles/PMC3609731/ /pubmed/23544125 http://dx.doi.org/10.1371/journal.pone.0060095 Text en © 2013 Berthold et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Berthold, Heiner K.
Seidah, Nabil G.
Benjannet, Suzanne
Gouni-Berthold, Ioanna
Evidence from a Randomized Trial That Simvastatin, but Not Ezetimibe, Upregulates Circulating PCSK9 Levels
title Evidence from a Randomized Trial That Simvastatin, but Not Ezetimibe, Upregulates Circulating PCSK9 Levels
title_full Evidence from a Randomized Trial That Simvastatin, but Not Ezetimibe, Upregulates Circulating PCSK9 Levels
title_fullStr Evidence from a Randomized Trial That Simvastatin, but Not Ezetimibe, Upregulates Circulating PCSK9 Levels
title_full_unstemmed Evidence from a Randomized Trial That Simvastatin, but Not Ezetimibe, Upregulates Circulating PCSK9 Levels
title_short Evidence from a Randomized Trial That Simvastatin, but Not Ezetimibe, Upregulates Circulating PCSK9 Levels
title_sort evidence from a randomized trial that simvastatin, but not ezetimibe, upregulates circulating pcsk9 levels
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3609731/
https://www.ncbi.nlm.nih.gov/pubmed/23544125
http://dx.doi.org/10.1371/journal.pone.0060095
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