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

Nat Commun. 2021 Sep 24;12(1):5640. doi: 10.1038/s41467-021-25703-3.

Authors

Amand F Schmidt^{1

2

3}, Nicholas B Hunt⁴, Maria Gordillo-Marañón^{5

6}, Pimphen Charoen^{5

7

8}, Fotios Drenos^{5

9}, Mika Kivimaki¹⁰, Deborah A Lawlor^{11

12

13}, Claudia Giambartolomei¹⁴, Olia Papacosta¹⁵, Nishi Chaturvedi^{5

16}, Joshua C Bis¹⁷, Christopher J O'Donnell^{18

19}, Goya Wannamethee¹⁵, Andrew Wong¹⁶, Jackie F Price²⁰, Alun D Hughes^{5

6

16}, Tom R Gaunt^{11

12

13}, Nora Franceschini²¹, Dennis O Mook-Kanamori²², Magdalena Zwierzyna^{5

6}, Reecha Sofat²³, Aroon D Hingorani^#^{5

6

24}, Chris Finan^#^{5

6

25

24}

Affiliations

¹ Institute of Cardiovascular Science, Faculty of Population Health, University College London, London, UK. amand.schmidt@ucl.ac.uk.
² UCL British Heart Foundation Research Accelerator, London, UK. amand.schmidt@ucl.ac.uk.
³ Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands. amand.schmidt@ucl.ac.uk.
⁴ Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands.
⁵ Institute of Cardiovascular Science, Faculty of Population Health, University College London, London, UK.
⁶ UCL British Heart Foundation Research Accelerator, London, UK.
⁷ Department of Tropical Hygiene, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
⁸ Integrative Computational BioScience (ICBS) Center, Mahidol University, Bangkok, Thailand.
⁹ Department of Life Sciences, College of Health, Medicine, and Life Sciences, Brunel University London, Uxbridge, UK.
¹⁰ Department of Epidemiology and Public Health, University College London, London, UK.
¹¹ MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.
¹² Population Health, Bristol Medical School, University of Bristol, Bristol, UK.
¹³ Bristol NIHR Bristol Biomedical Research Centre, University Hospitals Bristol National Health Service Foundation Trust and University of Bristol, Bristol, UK.
¹⁴ Istituto Italiano di Tecnologia, Central RNA Lab, Genova, Italy.
¹⁵ Primary Care and Population Health, University College London, London, UK.
¹⁶ MRC Unit for Lifelong Health and Ageing at UCL, London, UK.
¹⁷ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
¹⁸ Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
¹⁹ Department of Medicine, VA Boston Healthcare System, Boston, MA, USA.
²⁰ Usher Institute, University of Edinburgh, Edinburgh, UK.
²¹ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.
²² Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
²³ Institute of Health Informatics, University College London, London, UK.
²⁴ Health Data Research UK, London, UK.
²⁵ Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands.

^# Contributed equally.

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.

Publication types

Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Systematic Review

MeSH terms

Amides / therapeutic use
Anticholesteremic Agents / therapeutic use*
Benzodiazepines / therapeutic use
Cardiovascular Diseases / metabolism
Cardiovascular Diseases / prevention & control*
Cholesterol Ester Transfer Proteins / antagonists & inhibitors*
Cholesterol Ester Transfer Proteins / genetics
Cholesterol Ester Transfer Proteins / metabolism
Coronary Disease / metabolism
Coronary Disease / prevention & control*
Esters / therapeutic use
Humans
Mendelian Randomization Analysis
Oxazolidinones / therapeutic use
Quinolines / therapeutic use
Sulfhydryl Compounds / therapeutic use

Substances

Amides
Anticholesteremic Agents
CETP protein, human
Cholesterol Ester Transfer Proteins
Esters
Oxazolidinones
Quinolines
Sulfhydryl Compounds
Benzodiazepines
dalcetrapib
torcetrapib
evacetrapib
anacetrapib

Abstract

Publication types

MeSH terms

Substances

Grants and funding