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

Author

Listed:
  • Amand F. Schmidt

    (University College London
    UCL British Heart Foundation Research Accelerator
    University Medical Center Utrecht)

  • Nicholas B. Hunt

    (Utrecht University)

  • Maria Gordillo-Marañón

    (University College London
    UCL British Heart Foundation Research Accelerator)

  • Pimphen Charoen

    (University College London
    Mahidol University
    Mahidol University)

  • Fotios Drenos

    (University College London
    Brunel University London)

  • Mika Kivimaki

    (University College London)

  • Deborah A. Lawlor

    (MRC Integrative Epidemiology Unit at the University of Bristol
    University of Bristol
    University Hospitals Bristol National Health Service Foundation Trust and University of Bristol)

  • Claudia Giambartolomei

    (Istituto Italiano di Tecnologia, Central RNA Lab)

  • Olia Papacosta

    (University College London)

  • Nishi Chaturvedi

    (University College London
    MRC Unit for Lifelong Health and Ageing at UCL)

  • Joshua C. Bis

    (University of Washington)

  • Christopher J. O’Donnell

    (Brigham and Women’s Hospital, Harvard Medical School
    VA Boston Healthcare System)

  • 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
    UCL British Heart Foundation Research Accelerator
    MRC Unit for Lifelong Health and Ageing at UCL)

  • Tom R. Gaunt

    (MRC Integrative Epidemiology Unit at the University of Bristol
    University of Bristol
    University Hospitals Bristol National Health Service Foundation Trust and University of Bristol)

  • Nora Franceschini

    (University of North Carolina)

  • Dennis O. Mook-Kanamori

    (Leiden University Medical Center)

  • Magdalena Zwierzyna

    (University College London
    UCL British Heart Foundation Research Accelerator)

  • Reecha Sofat

    (University College London)

  • Aroon D. Hingorani

    (University College London
    UCL British Heart Foundation Research Accelerator
    Health Data Research UK)

  • Chris Finan

    (University College London
    UCL British Heart Foundation Research Accelerator
    University Medical Center Utrecht
    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.

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, 2021. "Cholesteryl ester transfer protein (CETP) as a drug target for cardiovascular disease," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25703-3
    DOI: 10.1038/s41467-021-25703-3
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    Cited by:

    1. Shufen Zheng & Philip S. Tsao & Cuiping Pan, 2024. "Abdominal aortic aneurysm and cardiometabolic traits share strong genetic susceptibility to lipid metabolism and inflammation," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    2. Diana Dunca & Sandesh Chopade & María Gordillo-Marañón & Aroon D. Hingorani & Karoline Kuchenbaecker & Chris Finan & Amand F. Schmidt, 2024. "Comparing the effects of CETP in East Asian and European ancestries: a Mendelian randomization study," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    3. Ashish Patel & Dipender Gill & Paul Newcombe & Stephen Burgess, 2023. "Conditional inference in cis‐Mendelian randomization using weak genetic factors," Biometrics, The International Biometric Society, vol. 79(4), pages 3458-3471, December.

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