Cholesteryl Ester Transfer Protein (CETP) as a Drug Target for Cardiovascular Disease

Amand F Schmidt; Debbie A Lawlor; Tom R Gaunt

doi:10.1038/s41467-021-25703-3

Cholesteryl Ester Transfer Protein (CETP) as a Drug Target for Cardiovascular Disease

Amand F Schmidt^*, Debbie A Lawlor, Tom R Gaunt

^*Corresponding author for this work

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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. 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
Number of pages	10
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-25703-3
Publication status	Published - 24 Sept 2021

Bibliographical note

Funding Information:
A.F.S. has received Servier funding for unrelated work. M.Z. conducted this research as an employee of BenevolentAI. Since completing the work M.Z. is now a full-time employee of GlaxoSmithKline. Since completing the work C.J.O. is now a full-time employee of Novartis Institutes for Biomedical Research. D.A.L. has received support from Roche Diagnostics and Medtronic Ltd. for research unrelated to this paper. T.R.G. receives funding from GlaxoSmithKline and Biogen.

Funding Information:
This research has been conducted using the UK Biobank Resource under Application Number 12113. The authors are grateful to UK Biobank participants. We gratefully acknowledge the support of UCLEB and CHARGE. Funding and role of funding sources: A.F.S. is supported by BHF grant PG/18/5033837 and the UCL BHF Research Accelerator AA/18/6/34223. C.F. and A.F.S. received additional support from the National Institute for Health Research University College London Hospitals Biomedical Research Centre. M.G.M. is supported by a BHF Fellowship FS/17/70/33482. A.D.H. is an NIHR Senior Investigator. This work was supported by the UKRI/NIHR Strategic Priorities Award in Multimorbidity Research (MR/V033867/1). This work was additionally supported by a grant [R01 LM010098] from the National Institutes of Health (USA). We further acknowledge support from the Rosetrees and Stoneygate Trust. The UCLEB Consortium is supported by a British Heart Foundation Program Grant (RG/10/12/ 28456). T.R.G. receives support from the UK Medical Research Council (MC_UU_00011/4). D.O.M.K. is supported by the Dutch Science Organization (ZonMW-VENI Grant 916.14.023). A D.H. receives support from the UK Medical Research (MC_UU_12019/1). M.K. is supported by the Wellcome Trust (221854/Z/20/ Z), the UK Medical Research Council (MR/S011676/1, MR/R024227/1), National Institute on Aging (NIH), US (R01AG062553), and the Academy of Finland (311492). D.A.L. is supported by a Bristol BHF Accelerator Award (AA/18/7/34219) and BHF Chair (CH/F/20/90003) and works in a unit that receives support from the University of Bristol and the UK Medical Research Council (MC_UU_00011/6). D.A.L. is a National Institute of Health Research Senior Investigator (NF-0616-10102). N.F. is supported by the National Institutes of Health (R01-MD012765, R01-DK117445, R21-HL140385). P.C. is supported by the Thailand Research Fund (MRG6280088. UK Biobank was established by the Wellcome Trust medical charity, Medical Research Council, Department of Health, Scottish Government, and the Northwest Regional Development Agency. It has also had funding from the Welsh Assembly Government and the British Heart Foundation. Infrastructure for the CHARGE Consortium is supported in part by the National Heart, Lung, and Blood Institute grant R01HL105756. The preliminary meta-analysis of RCT data were presented at BPS 2018 by NH. The preprint version of this paper has been deposited on medrxiv: https://doi.org/10.1101/2020.09.07.20189571.

Publisher Copyright:
© 2021, The Author(s).

Research Groups and Themes

ICEP

Keywords

Drug target validation
Mendelian randomization
CETP
PCSK9
drug therapy
cardiovascular disease

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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8074 (C18281/A29019) ICEP2 - Programme Award: Towards improved casual evidence and enhanced prediction of cancer risk and survival
Martin, R. M. (Principal Investigator)
1/10/20 → 30/09/25
Project: Research
8073 MRC IEU - Programme 6
Lawlor, D. A. (Principal Investigator)
1/04/18 → 31/03/23
Project: Research

Cite this

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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. 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. ",

keywords = "Drug target validation, Mendelian randomization, CETP, PCSK9, drug therapy, cardiovascular disease",

author = "Schmidt, {Amand F} and Lawlor, {Debbie A} and Gaunt, {Tom R}",

note = "Funding Information: A.F.S. has received Servier funding for unrelated work. M.Z. conducted this research as an employee of BenevolentAI. Since completing the work M.Z. is now a full-time employee of GlaxoSmithKline. Since completing the work C.J.O. is now a full-time employee of Novartis Institutes for Biomedical Research. D.A.L. has received support from Roche Diagnostics and Medtronic Ltd. for research unrelated to this paper. T.R.G. receives funding from GlaxoSmithKline and Biogen. Funding Information: This research has been conducted using the UK Biobank Resource under Application Number 12113. The authors are grateful to UK Biobank participants. We gratefully acknowledge the support of UCLEB and CHARGE. Funding and role of funding sources: A.F.S. is supported by BHF grant PG/18/5033837 and the UCL BHF Research Accelerator AA/18/6/34223. C.F. and A.F.S. received additional support from the National Institute for Health Research University College London Hospitals Biomedical Research Centre. M.G.M. is supported by a BHF Fellowship FS/17/70/33482. A.D.H. is an NIHR Senior Investigator. This work was supported by the UKRI/NIHR Strategic Priorities Award in Multimorbidity Research (MR/V033867/1). This work was additionally supported by a grant [R01 LM010098] from the National Institutes of Health (USA). We further acknowledge support from the Rosetrees and Stoneygate Trust. The UCLEB Consortium is supported by a British Heart Foundation Program Grant (RG/10/12/ 28456). T.R.G. receives support from the UK Medical Research Council (MC_UU_00011/4). D.O.M.K. is supported by the Dutch Science Organization (ZonMW-VENI Grant 916.14.023). A D.H. receives support from the UK Medical Research (MC_UU_12019/1). M.K. is supported by the Wellcome Trust (221854/Z/20/ Z), the UK Medical Research Council (MR/S011676/1, MR/R024227/1), National Institute on Aging (NIH), US (R01AG062553), and the Academy of Finland (311492). D.A.L. is supported by a Bristol BHF Accelerator Award (AA/18/7/34219) and BHF Chair (CH/F/20/90003) and works in a unit that receives support from the University of Bristol and the UK Medical Research Council (MC_UU_00011/6). D.A.L. is a National Institute of Health Research Senior Investigator (NF-0616-10102). N.F. is supported by the National Institutes of Health (R01-MD012765, R01-DK117445, R21-HL140385). P.C. is supported by the Thailand Research Fund (MRG6280088. UK Biobank was established by the Wellcome Trust medical charity, Medical Research Council, Department of Health, Scottish Government, and the Northwest Regional Development Agency. It has also had funding from the Welsh Assembly Government and the British Heart Foundation. Infrastructure for the CHARGE Consortium is supported in part by the National Heart, Lung, and Blood Institute grant R01HL105756. The preliminary meta-analysis of RCT data were presented at BPS 2018 by NH. The preprint version of this paper has been deposited on medrxiv: https://doi.org/10.1101/2020.09.07.20189571. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

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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. 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.

KW - Drug target validation

KW - Mendelian randomization

KW - CETP

KW - PCSK9

KW - drug therapy

KW - cardiovascular disease

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DO - 10.1038/s41467-021-25703-3

M3 - Article (Academic Journal)

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

Bibliographical note

Research Groups and Themes

Keywords

UN SDGs

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Projects

8074 (C18281/A29019) ICEP2 - Programme Award: Towards improved casual evidence and enhanced prediction of cancer risk and survival

8073 MRC IEU - Programme 6

Cite this