The NPC1L1 Gene Exerts a Notable Impact on the Reduction of Low-Density Lipoprotein Cholesterol in Response to Hyzetimibe: A Factorial-Designed Clinical Trial
Background: Hyzetimibe is a novel inhibitor of cholesterol that specifically targets the NPC1L1 gene. Significant inter-individual variability suggests the existence of an abundance of poor responders and non-responders. In addition, the current literature is inconsistent and controversial regarding...
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| Published in | Frontiers in pharmacology Vol. 13; p. 755469 |
|---|---|
| Main Authors | , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Switzerland
Frontiers Media S.A
11.03.2022
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| Online Access | Get full text |
| ISSN | 1663-9812 1663-9812 |
| DOI | 10.3389/fphar.2022.755469 |
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| Abstract | Background:
Hyzetimibe is a novel inhibitor of cholesterol that specifically targets the
NPC1L1
gene. Significant inter-individual variability suggests the existence of an abundance of poor responders and non-responders. In addition, the current literature is inconsistent and controversial regarding the potential impact of the Niemann-Pick C1-Like 1 (NPC1L1) gene on low-density lipoprotein cholesterol (LDL-C) reduction. In light of these concerns, we performed a high-quality clinical trial to investigate the specific characteristics of
NPC1L1
gene variation on LDL-C reduction.
Methods:
This was a multicenter, randomized, double-blind, placebo-controlled, clinical trial with a factorial design. Qualified patients were randomly assigned to one of six treatments: placebo, hyzetimibe (10 or 20 mg), atorvastatin, and atorvastatin plus hyzetimibe (10 or 20 mg). Fasting blood samples were collected and genotyped, and the concentrations of LDL-C and the targeted drug trough were determined to investigate the association between the
NPC1L1
gene expression and the reduction of LDL-C.
Results:
In total, 727 individuals were initially recruited; of these, 444 were eligible to begin the trial. We identified one SNP (g1679C > G) that exerted significantly different impacts on LDL-C levels. As monotherapy, CC carriers experienced significantly higher reductions in the mean LDL-C (−23.99%) than either the GG (−16.45%,
p
< 0.01) or GC (−13.02%,
p
< 0.01) carriers in the hyzetimibe (20 mg) group. In contrast, when co-administered with atorvastatin, GC carriers experienced greater LDL-C reduction than non-GC carriers (-52.23% vs. −45.03%) in the hyzetimibe (20 mg) plus atorvastatin group. Furthermore, the proportions of individuals experiencing a reduction in LDL-C by >50% increased as the dose of hyzetimibe increased from 16.1% to 65.4%.
Conclusion:
The g1679C > G SNP in the
NPC1L1
gene is critical and exerts a differential impact on the response to hyzetimibe treatment. Heterozygotic patients respond with poor efficacy when treated by monotherapy but show good responses in terms of LDL-C reduction when hyzetimibe was co-administered with atorvastatin. To treat hypercholesterolemia in a precise manner with hyzetimibe, it is necessary to identify genotype patients for the g1679C > G SNP. We also highlight the potential necessity for identifying the appropriate subjects to be treated with ezetimibe.
Clinical Trial Registration: [
https://clinicaltrials.gov/
], identifier [CTR20150351] |
|---|---|
| AbstractList | Background:
Hyzetimibe is a novel inhibitor of cholesterol that specifically targets the
NPC1L1
gene. Significant inter-individual variability suggests the existence of an abundance of poor responders and non-responders. In addition, the current literature is inconsistent and controversial regarding the potential impact of the Niemann-Pick C1-Like 1 (NPC1L1) gene on low-density lipoprotein cholesterol (LDL-C) reduction. In light of these concerns, we performed a high-quality clinical trial to investigate the specific characteristics of
NPC1L1
gene variation on LDL-C reduction.
Methods:
This was a multicenter, randomized, double-blind, placebo-controlled, clinical trial with a factorial design. Qualified patients were randomly assigned to one of six treatments: placebo, hyzetimibe (10 or 20 mg), atorvastatin, and atorvastatin plus hyzetimibe (10 or 20 mg). Fasting blood samples were collected and genotyped, and the concentrations of LDL-C and the targeted drug trough were determined to investigate the association between the
NPC1L1
gene expression and the reduction of LDL-C.
Results:
In total, 727 individuals were initially recruited; of these, 444 were eligible to begin the trial. We identified one SNP (g1679C > G) that exerted significantly different impacts on LDL-C levels. As monotherapy, CC carriers experienced significantly higher reductions in the mean LDL-C (−23.99%) than either the GG (−16.45%,
p
< 0.01) or GC (−13.02%,
p
< 0.01) carriers in the hyzetimibe (20 mg) group. In contrast, when co-administered with atorvastatin, GC carriers experienced greater LDL-C reduction than non-GC carriers (-52.23% vs. −45.03%) in the hyzetimibe (20 mg) plus atorvastatin group. Furthermore, the proportions of individuals experiencing a reduction in LDL-C by >50% increased as the dose of hyzetimibe increased from 16.1% to 65.4%.
Conclusion:
The g1679C > G SNP in the
NPC1L1
gene is critical and exerts a differential impact on the response to hyzetimibe treatment. Heterozygotic patients respond with poor efficacy when treated by monotherapy but show good responses in terms of LDL-C reduction when hyzetimibe was co-administered with atorvastatin. To treat hypercholesterolemia in a precise manner with hyzetimibe, it is necessary to identify genotype patients for the g1679C > G SNP. We also highlight the potential necessity for identifying the appropriate subjects to be treated with ezetimibe.
Clinical Trial Registration: [
https://clinicaltrials.gov/
], identifier [CTR20150351] Background: Hyzetimibe is a novel inhibitor of cholesterol that specifically targets the NPC1L1 gene. Significant inter-individual variability suggests the existence of an abundance of poor responders and non-responders. In addition, the current literature is inconsistent and controversial regarding the potential impact of the Niemann-Pick C1-Like 1 (NPC1L1) gene on low-density lipoprotein cholesterol (LDL-C) reduction. In light of these concerns, we performed a high-quality clinical trial to investigate the specific characteristics of NPC1L1 gene variation on LDL-C reduction. Methods: This was a multicenter, randomized, double-blind, placebo-controlled, clinical trial with a factorial design. Qualified patients were randomly assigned to one of six treatments: placebo, hyzetimibe (10 or 20 mg), atorvastatin, and atorvastatin plus hyzetimibe (10 or 20 mg). Fasting blood samples were collected and genotyped, and the concentrations of LDL-C and the targeted drug trough were determined to investigate the association between the NPC1L1 gene expression and the reduction of LDL-C. Results: In total, 727 individuals were initially recruited; of these, 444 were eligible to begin the trial. We identified one SNP (g1679C > G) that exerted significantly different impacts on LDL-C levels. As monotherapy, CC carriers experienced significantly higher reductions in the mean LDL-C (-23.99%) than either the GG (-16.45%, p < 0.01) or GC (-13.02%, p < 0.01) carriers in the hyzetimibe (20 mg) group. In contrast, when co-administered with atorvastatin, GC carriers experienced greater LDL-C reduction than non-GC carriers (-52.23% vs. -45.03%) in the hyzetimibe (20 mg) plus atorvastatin group. Furthermore, the proportions of individuals experiencing a reduction in LDL-C by >50% increased as the dose of hyzetimibe increased from 16.1% to 65.4%. Conclusion: The g1679C > G SNP in the NPC1L1 gene is critical and exerts a differential impact on the response to hyzetimibe treatment. Heterozygotic patients respond with poor efficacy when treated by monotherapy but show good responses in terms of LDL-C reduction when hyzetimibe was co-administered with atorvastatin. To treat hypercholesterolemia in a precise manner with hyzetimibe, it is necessary to identify genotype patients for the g1679C > G SNP. We also highlight the potential necessity for identifying the appropriate subjects to be treated with ezetimibe. Clinical Trial Registration: [https://clinicaltrials.gov/], identifier [CTR20150351].Background: Hyzetimibe is a novel inhibitor of cholesterol that specifically targets the NPC1L1 gene. Significant inter-individual variability suggests the existence of an abundance of poor responders and non-responders. In addition, the current literature is inconsistent and controversial regarding the potential impact of the Niemann-Pick C1-Like 1 (NPC1L1) gene on low-density lipoprotein cholesterol (LDL-C) reduction. In light of these concerns, we performed a high-quality clinical trial to investigate the specific characteristics of NPC1L1 gene variation on LDL-C reduction. Methods: This was a multicenter, randomized, double-blind, placebo-controlled, clinical trial with a factorial design. Qualified patients were randomly assigned to one of six treatments: placebo, hyzetimibe (10 or 20 mg), atorvastatin, and atorvastatin plus hyzetimibe (10 or 20 mg). Fasting blood samples were collected and genotyped, and the concentrations of LDL-C and the targeted drug trough were determined to investigate the association between the NPC1L1 gene expression and the reduction of LDL-C. Results: In total, 727 individuals were initially recruited; of these, 444 were eligible to begin the trial. We identified one SNP (g1679C > G) that exerted significantly different impacts on LDL-C levels. As monotherapy, CC carriers experienced significantly higher reductions in the mean LDL-C (-23.99%) than either the GG (-16.45%, p < 0.01) or GC (-13.02%, p < 0.01) carriers in the hyzetimibe (20 mg) group. In contrast, when co-administered with atorvastatin, GC carriers experienced greater LDL-C reduction than non-GC carriers (-52.23% vs. -45.03%) in the hyzetimibe (20 mg) plus atorvastatin group. Furthermore, the proportions of individuals experiencing a reduction in LDL-C by >50% increased as the dose of hyzetimibe increased from 16.1% to 65.4%. Conclusion: The g1679C > G SNP in the NPC1L1 gene is critical and exerts a differential impact on the response to hyzetimibe treatment. Heterozygotic patients respond with poor efficacy when treated by monotherapy but show good responses in terms of LDL-C reduction when hyzetimibe was co-administered with atorvastatin. To treat hypercholesterolemia in a precise manner with hyzetimibe, it is necessary to identify genotype patients for the g1679C > G SNP. We also highlight the potential necessity for identifying the appropriate subjects to be treated with ezetimibe. Clinical Trial Registration: [https://clinicaltrials.gov/], identifier [CTR20150351]. Hyzetimibe is a novel inhibitor of cholesterol that specifically targets the gene. Significant inter-individual variability suggests the existence of an abundance of poor responders and non-responders. In addition, the current literature is inconsistent and controversial regarding the potential impact of the Niemann-Pick C1-Like 1 (NPC1L1) gene on low-density lipoprotein cholesterol (LDL-C) reduction. In light of these concerns, we performed a high-quality clinical trial to investigate the specific characteristics of gene variation on LDL-C reduction. This was a multicenter, randomized, double-blind, placebo-controlled, clinical trial with a factorial design. Qualified patients were randomly assigned to one of six treatments: placebo, hyzetimibe (10 or 20 mg), atorvastatin, and atorvastatin plus hyzetimibe (10 or 20 mg). Fasting blood samples were collected and genotyped, and the concentrations of LDL-C and the targeted drug trough were determined to investigate the association between the gene expression and the reduction of LDL-C. In total, 727 individuals were initially recruited; of these, 444 were eligible to begin the trial. We identified one SNP (g1679C > G) that exerted significantly different impacts on LDL-C levels. As monotherapy, CC carriers experienced significantly higher reductions in the mean LDL-C (-23.99%) than either the GG (-16.45%, < 0.01) or GC (-13.02%, < 0.01) carriers in the hyzetimibe (20 mg) group. In contrast, when co-administered with atorvastatin, GC carriers experienced greater LDL-C reduction than non-GC carriers (-52.23% vs. -45.03%) in the hyzetimibe (20 mg) plus atorvastatin group. Furthermore, the proportions of individuals experiencing a reduction in LDL-C by >50% increased as the dose of hyzetimibe increased from 16.1% to 65.4%. The g1679C > G SNP in the gene is critical and exerts a differential impact on the response to hyzetimibe treatment. Heterozygotic patients respond with poor efficacy when treated by monotherapy but show good responses in terms of LDL-C reduction when hyzetimibe was co-administered with atorvastatin. To treat hypercholesterolemia in a precise manner with hyzetimibe, it is necessary to identify genotype patients for the g1679C > G SNP. We also highlight the potential necessity for identifying the appropriate subjects to be treated with ezetimibe. Clinical Trial Registration: [https://clinicaltrials.gov/], identifier [CTR20150351]. Background: Hyzetimibe is a novel inhibitor of cholesterol that specifically targets the NPC1L1 gene. Significant inter-individual variability suggests the existence of an abundance of poor responders and non-responders. In addition, the current literature is inconsistent and controversial regarding the potential impact of the Niemann-Pick C1-Like 1 (NPC1L1) gene on low-density lipoprotein cholesterol (LDL-C) reduction. In light of these concerns, we performed a high-quality clinical trial to investigate the specific characteristics of NPC1L1 gene variation on LDL-C reduction.Methods: This was a multicenter, randomized, double-blind, placebo-controlled, clinical trial with a factorial design. Qualified patients were randomly assigned to one of six treatments: placebo, hyzetimibe (10 or 20 mg), atorvastatin, and atorvastatin plus hyzetimibe (10 or 20 mg). Fasting blood samples were collected and genotyped, and the concentrations of LDL-C and the targeted drug trough were determined to investigate the association between the NPC1L1 gene expression and the reduction of LDL-C.Results: In total, 727 individuals were initially recruited; of these, 444 were eligible to begin the trial. We identified one SNP (g1679C > G) that exerted significantly different impacts on LDL-C levels. As monotherapy, CC carriers experienced significantly higher reductions in the mean LDL-C (−23.99%) than either the GG (−16.45%, p < 0.01) or GC (−13.02%, p < 0.01) carriers in the hyzetimibe (20 mg) group. In contrast, when co-administered with atorvastatin, GC carriers experienced greater LDL-C reduction than non-GC carriers (-52.23% vs. −45.03%) in the hyzetimibe (20 mg) plus atorvastatin group. Furthermore, the proportions of individuals experiencing a reduction in LDL-C by >50% increased as the dose of hyzetimibe increased from 16.1% to 65.4%.Conclusion: The g1679C > G SNP in the NPC1L1 gene is critical and exerts a differential impact on the response to hyzetimibe treatment. Heterozygotic patients respond with poor efficacy when treated by monotherapy but show good responses in terms of LDL-C reduction when hyzetimibe was co-administered with atorvastatin. To treat hypercholesterolemia in a precise manner with hyzetimibe, it is necessary to identify genotype patients for the g1679C > G SNP. We also highlight the potential necessity for identifying the appropriate subjects to be treated with ezetimibe.Clinical Trial Registration: [https://clinicaltrials.gov/], identifier [CTR20150351] |
| Author | Yang, Liyun Qi, Xiao Ouyang, Dongsheng Cui, Yimin Zhao, Hongbin Liao, Jianwei Zhou, Luping |
| AuthorAffiliation | 1 Department of Clinical Pharmacology , Xiangya Hospital , Central South University , Changsha , China 4 Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples , Changsha , China 2 Institute of Clinical Pharmacology , Central South University , Changsha , China 3 Zhejiang Hisun Pharmaceutical Co. Ltd , Taizhou , China 5 Peking University First Hospital , Beijing , China |
| AuthorAffiliation_xml | – name: 2 Institute of Clinical Pharmacology , Central South University , Changsha , China – name: 1 Department of Clinical Pharmacology , Xiangya Hospital , Central South University , Changsha , China – name: 3 Zhejiang Hisun Pharmaceutical Co. Ltd , Taizhou , China – name: 4 Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples , Changsha , China – name: 5 Peking University First Hospital , Beijing , China |
| Author_xml | – sequence: 1 givenname: Jianwei surname: Liao fullname: Liao, Jianwei – sequence: 2 givenname: Liyun surname: Yang fullname: Yang, Liyun – sequence: 3 givenname: Luping surname: Zhou fullname: Zhou, Luping – sequence: 4 givenname: Hongbin surname: Zhao fullname: Zhao, Hongbin – sequence: 5 givenname: Xiao surname: Qi fullname: Qi, Xiao – sequence: 6 givenname: Yimin surname: Cui fullname: Cui, Yimin – sequence: 7 givenname: Dongsheng surname: Ouyang fullname: Ouyang, Dongsheng |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/35359877$$D View this record in MEDLINE/PubMed |
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| CitedBy_id | crossref_primary_10_1007_s10528_023_10649_6 crossref_primary_10_3390_jcm12010363 crossref_primary_10_1038_s41598_024_71120_z crossref_primary_10_1186_s12863_023_01155_0 crossref_primary_10_3389_fphar_2023_1081980 |
| Cites_doi | 10.1136/bmj.326.7404.1423 10.1016/s0002-9149(02)02798-4 10.1152/ajpgi.00061.2008 10.1016/s0735-1097(02)02610-4 10.1016/j.ygeno.2005.08.007 10.1002/jcph.310 10.1111/jcpt.12176 10.1016/S0140-6736(12)60367-5 10.3389/fphar.2021.665372 10.1161/01.CIR.0000068312.21969.C8 10.1194/jlr.M011080 10.1093/eurheartj/eht055 10.1016/S0140-6736(20)32233-9 10.1016/j.jacc.2018.11.002 10.1056/NEJMoa1405386 10.1161/CIRCULATIONAHA.118.039415 10.1016/j.atherosclerosis.2006.10.036 10.1161/CIRCULATIONAHA.117.030950 10.1016/S0140-6736(20)32332-1 10.1016/s0195-668x(02)00807-2 10.1056/NEJMoa1410489 10.1126/science.1093131 10.1016/j.ijcme.2016.11.002 10.1016/j.atherosclerosis.2015.12.032 |
| ContentType | Journal Article |
| Copyright | Copyright © 2022 Liao, Yang, Zhou, Zhao, Qi, Cui and Ouyang. Copyright © 2022 Liao, Yang, Zhou, Zhao, Qi, Cui and Ouyang. 2022 Liao, Yang, Zhou, Zhao, Qi, Cui and Ouyang |
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| Keywords | hyzetimibe factorial design precise treatment SNP ezetimibe NPC1L1 gene |
| Language | English |
| License | Copyright © 2022 Liao, Yang, Zhou, Zhao, Qi, Cui and Ouyang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 This article was submitted to Pharmacogenetics and Pharmacogenomics, a section of the journal Frontiers in Pharmacology Edited by: Wanqing Liu, Wayne State University, United States Reviewed by: Luis A. Salazar, University of La Frontera, Chile Salvador F. Alino, University of Valencia, Spain |
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| Snippet | Background:
Hyzetimibe is a novel inhibitor of cholesterol that specifically targets the
NPC1L1
gene. Significant inter-individual variability suggests the... Hyzetimibe is a novel inhibitor of cholesterol that specifically targets the gene. Significant inter-individual variability suggests the existence of an... Background: Hyzetimibe is a novel inhibitor of cholesterol that specifically targets the NPC1L1 gene. Significant inter-individual variability suggests the... |
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| SubjectTerms | ezetimibe factorial design hyzetimibe NPC1L1 gene Pharmacology precise treatment SNP |
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| Title | The NPC1L1 Gene Exerts a Notable Impact on the Reduction of Low-Density Lipoprotein Cholesterol in Response to Hyzetimibe: A Factorial-Designed Clinical Trial |
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