Separating the Mechanism-Based and Off-Target Actions of Cholesteryl Ester Transfer Protein Inhibitors With CETP Gene Polymorphisms
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Background— Cholesteryl ester transfer protein (CETP) inhibitors raise high-density lipoprotein (HDL) cholesterol, but torcetrapib, the first-in-class inhibitor tested in a large outcome trial, caused an unexpected blood pressure elevation and increased cardiovascular events. Whether the hypertensive effect resulted from CETP inhibition or an off-target action of torcetrapib has been debated. We hypothesized that common single-nucleotide polymorphisms in the CETP gene could help distinguish mechanism-based from off-target actions of CETP inhibitors to inform on the validity of CETP as a therapeutic target. Methods and Results— We compared the effect of CETP single-nucleotide polymorphisms and torcetrapib treatment on lipid fractions, blood pressure, and electrolytes in up to 67 687 individuals from genetic studies and 17 911 from randomized trials. CETP single-nucleotide polymorphisms and torcetrapib treatment reduced CETP activity and had a directionally concordant effect on 8 lipid and lipoprotein traits (total, low-density lipoprotein, and HDL cholesterol; HDL2; HDL3; apolipoproteins A-I and B; and triglycerides), with the genetic effect on HDL cholesterol (0.13 mmol/L, 95% confidence interval [CI] 0.11 to 0.14 mmol/L) being consistent with that expected of a 10-mg dose of torcetrapib (0.13 mmol/L, 95% CI 0.10 to 0.15). In trials, 60 mg of torcetrapib elevated systolic and diastolic blood pressure by 4.47 mm Hg (95% CI 4.10 to 4.84 mm Hg) and 2.08 mm Hg (95% CI 1.84 to 2.31 mm Hg), respectively. However, the effect of CETP single-nucleotide polymorphisms on systolic blood pressure (0.16 mm Hg, 95% CI −0.28 to 0.60 mm Hg) and diastolic blood pressure (−0.04 mm Hg, 95% CI −0.36 to 0.28 mm Hg) was null and significantly different from that expected of 10 mg of torcetrapib. Conclusions— Discordance in the effects of CETP single-nucleotide polymorphisms and torcetrapib treatment on blood pressure despite the concordant effects on lipids indicates the hypertensive action of torcetrapib is unlikely to be due to CETP inhibition or shared by chemically dissimilar CETP inhibitors. Genetic studies could find a place in drug-development programs as a new source of randomized evidence for drug-target validation in humans.
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Individuals at higher genetic predisposition to obesity smoke more, which could represent an attempt to self-administer smoking for its nicotinic effects on appetite suppression and weight loss.
“individuals at higher genetic predisposition to obesity who smoke more 87,88 , which could represent an attempt to self-administer smoking for its nicotinic effects on appetite suppression and weight loss 89 .”
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- Authors
- Sofat, R., Hingorani, A. D., Smeeth, L., Humphries, S. E., Talmud, P. J., Cooper, J., Shah, T., Sandhu, M. S., Ricketts, S. L., Boekholdt, S. M., Wareham, N., Khaw, K. T., Kumari, M., Kivimaki, M., Marmot, M., Asselbergs, F. W., van der Harst, P., Dullaart, R. P. F., Navis, G., van Veldhuisen, D. J., Van Gilst, W. H., Thompson, J. F., McCaskie, P., Palmer, L. J., Arca, M., Quagliarini, F., Gaudio, C., Cambien, F., Nicaud, V., Poirer, O., Gudnason, V., Isaacs, A., Witteman, J. C. M., van Duijn, C. M., Pencina, M., Vasan, R. S., D'Agostino, R. B., Ordovas, J., Li, T. Y., Kakko, S., Kauma, H., Savolainen, M. J., Kesäniemi, Y. A., Sandhofer, A., Paulweber, B., Sorli, J. V., Goto, A., Yokoyama, S., Okumura, K., Horne, B. D., Packard, C., Freeman, D., Ford, I., Sattar, N., McCormack, V., Lawlor, D. A., Ebrahim, S., Smith, G. D., Kastelein, J. J. P., Deanfield, J., & Casas, J. P.
- Affiliations
- London School of Hygiene & Tropical Medicine (GB)
- From the Centre for Clinical Pharmacology, Department of Medicine (R.S., A.D.H., T.S.), Department of Epidemiology and Public Health (A.D.H., M. Kumari, M. Kivimaki, M.M., J.P.C.), and Centre for Cardiovascular Genetics (S.E.H., P.J.T., J.C.), University College London, London, United Kingdom; Department of Epidemiology and Population Health (L.S., V.M., S.E., J.P.C.), London School of Hygiene and Tropical Medicine, London, United Kingdom; Department of Public Health and Primary Care (M.S.S., S.L.R....
- University of London (GB)
- ORCID
- Sofat, Reecha
- Hingorani, Aroon D.
- Smeeth, Liam
- Humphries, Steve E.
- Talmud, Philippa J.
- Cooper, Jackie
- Shah, Tina
- Sandhu, Manjinder S.
- Ricketts, Sally L.
- Boekholdt, S. Matthijs
- Wareham, Nicholas
- Khaw, Kay Tee
- Marmot, Michael
- Asselbergs, Folkert W.
- Dullaart, Robin P.F.
- Thompson, John F.
- Palmer, Lyle J.
- Arca, Marcello
- Quagliarini, Fabiana
- Gaudio, Carlo
- Gudnason, Vilmundur
- Isaacs, Aaron
- Pencina, Michael
- Vasan, Ramachandran S.
- Kakko, Sakari
- Savolainen, Markku J.
- Paulweber, Bernhard
- Yokoyama, Shinji
- Okumura, Kenji
- Horne, Benjamin D.
- Packard, Chris
- Freeman, Dilys
- Ford, Ian
- Sattar, Naveed
- McCormack, Valerie
- Lawlor, Debbie A.
- Ebrahim, Shah
- Smith, George Davey
- Kastelein, John J.P.
- Deanfield, John
- Casas, Juan P.
- Venue
- Circulation
- Published
- 2010-01-05
- Volume
- 121
- Issue
- 1
- Pages
- 52-62
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- PMC
- PMC2811869
- OpenAlex
- W2101396854
- Cited by
- 104
- References
- 61
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 1 · 2023: 3 · 2022: 2 · 2021: 5 · 2020: 1 · 2019: 4 · 2018: 3 · 2017: 6 · 2016: 13 · 2015: 12 · 2014: 5 · 2013: 7 · 2012: 13
- FWCI
- 11.81
- Type
- journal article
- Language
- en
- Update notices
- correction (2010-02-23)
- Open access
- bronze
- doi.org
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion)
- PubMed Central (acceptedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion)
- Explore Bristol Research (submittedVersion)
- Bristol Research (University of Bristol) (submittedVersion)
- Repository of Digital Objects for Teaching Research and Culture (University of Valencia) (submittedVersion, cc-by-nc)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Funders
- Wellcome Trust (082178)
- National Institute for Health and Care Research
- British Heart Foundation (PG/08/094/26019, RG/08/008/25291, PG/04/110/17827, FS/05/125/19379, FS05/125, FS/07/011, FS/07/011/22085, RG/07/008/23674)
- Agency for Healthcare Research and Quality (HS06516)
- National Institute on Aging (AG1764406S1, AG 13196, R37AG013196, R01AG013196)
- National Heart, Lung, and Blood Institute (HL36310, R01HL036310)
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Paraoxonase enzyme and polymorphisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- cholesteryl ester transfer protein, CETP inhibitors, torcetrapib, off-target effects, single nucleotide polymorphisms, elevated blood pressure, HDL cholesterol, lipoproteins, apolipoprotein A-I, apolipoprotein B, triglycerides, cardiovascular risk, genetic association, hypertriglyceridemia
- MeSH terms
- Anticholesteremic Agents, Blood Pressure, Dose-Response Relationship, Drug, Electrolytes, Genotype, Humans, Hypercholesterolemia, Hypertension, Lipoproteins, HDL, Quinolines, Risk Factors, Biomarkers, Randomized Controlled Trials as Topic, Polymorphism, Single Nucleotide, White People, Cholesterol Ester Transfer Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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