Cholesteryl ester transfer protein (CETP) as a drug target for cardiovascular disease

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

doi:10.1038/s41467-021-25703-3

Cholesteryl ester transfer protein (CETP) as a drug target for cardiovascular disease

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

^*Corresponding author for this work

University College London
British Heart Foundation
University Medical Center Utrecht
Utrecht University
Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand
Mahidol University
Brunel University London
University of Bristol
Population Health Sciences, Bristol, United Kingdom
NIHR Bristol Biomedical Research Centre, Bristol, UK
Italian Institute of Technology
Medical Research Council
University of Washington
Harvard University
Department of Veterans Affairs
University of Edinburgh
University of North Carolina at Chapel Hill
Leiden University Medical Center
Health Data Research UK

Research output: Contribution to journal › Article › Academic › peer-review

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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.

Original language	English
Article number	5640
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-25703-3
Publication status	Published - 1 Dec 2021
Externally published	Yes

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SDG 3 Good Health and Well-being

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10.1038/s41467-021-25703-3

Cholesteryl-ester-transfer-protein-cetp-as-a-drug-target-for-cardiovascular-disease.pdfFinal published version, 1.28 MBLicence: CC BY

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Schmidt, A. F., Hunt, N. B., Gordillo-Marañón, M., Charoen, P., Drenos, F., Kivimaki, M., Lawlor, D. A., Giambartolomei, C., Papacosta, O., Chaturvedi, N., Bis, J. C., O’Donnell, C. J., Wannamethee, G., Wong, A., Price, J. F., Hughes, A. D., Gaunt, T. R., Franceschini, N., Mook-Kanamori, D. O., ... Finan, C. (2021). Cholesteryl ester transfer protein (CETP) as a drug target for cardiovascular disease. Nature communications, 12(1), Article 5640. https://doi.org/10.1038/s41467-021-25703-3

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title = "Cholesteryl ester transfer protein (CETP) as a drug target for cardiovascular disease",

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{\textquoteright}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.",

author = "Schmidt, \{Amand F.\} and Hunt, \{Nicholas B.\} and Maria Gordillo-Mara{\~n}{\'o}n and Pimphen Charoen and Fotios Drenos and Mika Kivimaki and Lawlor, \{Deborah A.\} and Claudia Giambartolomei and Olia Papacosta and Nishi Chaturvedi and Bis, \{Joshua C.\} and O{\textquoteright}Donnell, \{Christopher J.\} and Goya Wannamethee and Andrew Wong and Price, \{Jackie F.\} and Hughes, \{Alun D.\} and Gaunt, \{Tom R.\} and Nora Franceschini and Mook-Kanamori, \{Dennis O.\} and Magdalena Zwierzyna and Reecha Sofat and Hingorani, \{Aroon D.\} and Chris Finan",

year = "2021",

month = dec,

day = "1",

doi = "10.1038/s41467-021-25703-3",

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Schmidt, AF, Hunt, NB, Gordillo-Marañón, M, Charoen, P, Drenos, F, Kivimaki, M, Lawlor, DA, Giambartolomei, C, Papacosta, O, Chaturvedi, N, Bis, JC, O’Donnell, CJ, Wannamethee, G, Wong, A, Price, JF, Hughes, AD, Gaunt, TR, Franceschini, N, Mook-Kanamori, DO, Zwierzyna, M, Sofat, R, Hingorani, AD & Finan, C 2021, 'Cholesteryl ester transfer protein (CETP) as a drug target for cardiovascular disease', Nature communications, vol. 12, no. 1, 5640. https://doi.org/10.1038/s41467-021-25703-3

TY - JOUR

T1 - Cholesteryl ester transfer protein (CETP) as a drug target for cardiovascular disease

AU - Schmidt, Amand F.

AU - Hunt, Nicholas B.

AU - Gordillo-Marañón, Maria

AU - Charoen, Pimphen

AU - Drenos, Fotios

AU - Kivimaki, Mika

AU - Lawlor, Deborah A.

AU - Giambartolomei, Claudia

AU - Papacosta, Olia

AU - Chaturvedi, Nishi

AU - Bis, Joshua C.

AU - O’Donnell, Christopher J.

AU - Wannamethee, Goya

AU - Wong, Andrew

AU - Price, Jackie F.

AU - Hughes, Alun D.

AU - Gaunt, Tom R.

AU - Franceschini, Nora

AU - Mook-Kanamori, Dennis O.

AU - Zwierzyna, Magdalena

AU - Sofat, Reecha

AU - Hingorani, Aroon D.

AU - Finan, Chris

PY - 2021/12/1

Y1 - 2021/12/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85115675591

UR - https://www.ncbi.nlm.nih.gov/pubmed/34561430

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DO - 10.1038/s41467-021-25703-3

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C2 - 34561430

SN - 2041-1723

VL - 12

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 5640

ER -

Cholesteryl ester transfer protein (CETP) as a drug target for cardiovascular disease

Abstract

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