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Cholesteryl ester transfer protein (CETP) as a drug target for cardiovascular disease.
- Source :
-
Nature communications [Nat Commun] 2021 Sep 24; Vol. 12 (1), pp. 5640. Date of Electronic Publication: 2021 Sep 24. - Publication Year :
- 2021
-
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.<br /> (© 2021. The Author(s).)
- Subjects :
- Amides therapeutic use
Benzodiazepines therapeutic use
Cardiovascular Diseases metabolism
Cholesterol Ester Transfer Proteins genetics
Cholesterol Ester Transfer Proteins metabolism
Coronary Disease metabolism
Esters therapeutic use
Humans
Mendelian Randomization Analysis
Oxazolidinones therapeutic use
Quinolines therapeutic use
Sulfhydryl Compounds therapeutic use
Anticholesteremic Agents therapeutic use
Cardiovascular Diseases prevention & control
Cholesterol Ester Transfer Proteins antagonists & inhibitors
Coronary Disease prevention & control
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 12
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 34561430
- Full Text :
- https://doi.org/10.1038/s41467-021-25703-3