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 and Chris Finan
Additional contact information
Amand F. Schmidt: University College London
Nicholas B. Hunt: Utrecht University
Maria Gordillo-Marañón: University College London
Pimphen Charoen: University College London
Fotios Drenos: University College London
Mika Kivimaki: University College London
Deborah A. Lawlor: MRC Integrative Epidemiology Unit at the University of Bristol
Claudia Giambartolomei: Istituto Italiano di Tecnologia, Central RNA Lab
Olia Papacosta: University College London
Nishi Chaturvedi: University College London
Joshua C. Bis: University of Washington
Christopher J. O’Donnell: Brigham and Women’s Hospital, Harvard Medical School
Goya Wannamethee: University College London
Andrew Wong: MRC Unit for Lifelong Health and Ageing at UCL
Jackie F. Price: University of Edinburgh
Alun D. Hughes: University College London
Tom R. Gaunt: MRC Integrative Epidemiology Unit at the University of Bristol
Nora Franceschini: University of North Carolina
Dennis O. Mook-Kanamori: Leiden University Medical Center
Magdalena Zwierzyna: University College London
Reecha Sofat: University College London
Aroon D. Hingorani: University College London
Chris Finan: University College London

Nature Communications, 2021, vol. 12, issue 1, 1-10

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-25703-3

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