Publication: Cholesteryl ester transfer protein (CETP) as a drug target for cardiovascular disease
Issued Date
2021-12-01
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ISSN
20411723
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2-s2.0-85115675591
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Mahidol University
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SCOPUS
Bibliographic Citation
Nature Communications. Vol.12, No.1 (2021)
Suggested Citation
Amand F. Schmidt, Nicholas B. Hunt, Maria Gordillo-Marañón, Pimphen Charoen, Fotios Drenos, Mika Kivimaki, Deborah A. Lawlor, Claudia Giambartolomei, Olia Papacosta, Nishi Chaturvedi, Joshua C. Bis, Christopher J. O’Donnell, Goya Wannamethee, Andrew Wong, Jackie F. Price, Alun D. Hughes, Tom R. Gaunt, Nora Franceschini, Dennis O. Mook-Kanamori, Magdalena Zwierzyna, Reecha Sofat, Aroon D. Hingorani, Chris Finan Cholesteryl ester transfer protein (CETP) as a drug target for cardiovascular disease. Nature Communications. Vol.12, No.1 (2021). doi:10.1038/s41467-021-25703-3 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/75919
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Title
Cholesteryl ester transfer protein (CETP) as a drug target for cardiovascular disease
Author(s)
Amand F. Schmidt
Nicholas B. Hunt
Maria Gordillo-Marañón
Pimphen Charoen
Fotios Drenos
Mika Kivimaki
Deborah A. Lawlor
Claudia Giambartolomei
Olia Papacosta
Nishi Chaturvedi
Joshua C. Bis
Christopher J. O’Donnell
Goya Wannamethee
Andrew Wong
Jackie F. Price
Alun D. Hughes
Tom R. Gaunt
Nora Franceschini
Dennis O. Mook-Kanamori
Magdalena Zwierzyna
Reecha Sofat
Aroon D. Hingorani
Chris Finan
Nicholas B. Hunt
Maria Gordillo-Marañón
Pimphen Charoen
Fotios Drenos
Mika Kivimaki
Deborah A. Lawlor
Claudia Giambartolomei
Olia Papacosta
Nishi Chaturvedi
Joshua C. Bis
Christopher J. O’Donnell
Goya Wannamethee
Andrew Wong
Jackie F. Price
Alun D. Hughes
Tom R. Gaunt
Nora Franceschini
Dennis O. Mook-Kanamori
Magdalena Zwierzyna
Reecha Sofat
Aroon D. Hingorani
Chris Finan
Other Contributor(s)
Faculty of Tropical Medicine, Mahidol University
Bristol Medical School
NIHR Bristol Biomedical Research Centre
Edinburgh Medical School
VA Boston Healthcare System
Istituto Italiano di Tecnologia
British Heart Foundation
Utrechts Instituut voor Farmaceutische Wetenschappen
University Medical Center Utrecht
University of Washington School of Medicine
The University of North Carolina at Chapel Hill
University College London
University of Bristol
Brunel University London
Medical Research Council
Leids Universitair Medisch Centrum
Mahidol University
Harvard Medical School
Health Data Research UK
Bristol Medical School
NIHR Bristol Biomedical Research Centre
Edinburgh Medical School
VA Boston Healthcare System
Istituto Italiano di Tecnologia
British Heart Foundation
Utrechts Instituut voor Farmaceutische Wetenschappen
University Medical Center Utrecht
University of Washington School of Medicine
The University of North Carolina at Chapel Hill
University College London
University of Bristol
Brunel University London
Medical Research Council
Leids Universitair Medisch Centrum
Mahidol University
Harvard Medical School
Health Data Research UK
Abstract
Development of cholesteryl ester transfer protein (CETP) inhibitors for coronary heart disease (CHD) has yet to deliver licensed medicines. To distinguish compound from drug target failure, we compared evidence from clinical trials and drug target Mendelian randomization of CETP protein concentration, comparing this to Mendelian randomization of proprotein convertase subtilisin/kexin type 9 (PCSK9). We show that previous failures of CETP inhibitors are likely compound related, as illustrated by significant degrees of between-compound heterogeneity in effects on lipids, blood pressure, and clinical outcomes observed in trials. On-target CETP inhibition, assessed through Mendelian randomization, is expected to reduce the risk of CHD, heart failure, diabetes, and chronic kidney disease, while increasing the risk of age-related macular degeneration. In contrast, lower PCSK9 concentration is anticipated to decrease the risk of CHD, heart failure, atrial fibrillation, chronic kidney disease, multiple sclerosis, and stroke, while potentially increasing the risk of Alzheimer’s disease and asthma. Due to distinct effects on lipoprotein metabolite profiles, joint inhibition of CETP and PCSK9 may provide added benefit. In conclusion, we provide genetic evidence that CETP is an effective target for CHD prevention but with a potential on-target adverse effect on age-related macular degeneration.