Separating the Mechanism-Based and Off-Target Actions of Cholesteryl Ester Transfer Protein Inhibitors With
CETP
Gene Polymorphisms
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Published:2010-01-05
Issue:1
Volume:121
Page:52-62
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ISSN:0009-7322
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Container-title:Circulation
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language:en
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Short-container-title:Circulation
Author:
Sofat Reecha1, Hingorani Aroon D.1, Smeeth Liam1, Humphries Steve E.1, Talmud Philippa J.1, Cooper Jackie1, Shah Tina1, Sandhu Manjinder S.1, Ricketts Sally L.1, Boekholdt S. Matthijs1, Wareham Nicholas1, Khaw Kay Tee1, Kumari Meena1, Kivimaki Mika1, Marmot Michael1, Asselbergs Folkert W.1, van der Harst Pim1, Dullaart Robin P.F.1, Navis Gerjan1, van Veldhuisen Dirk J.1, Van Gilst Wiek H.1, Thompson John F.1, McCaskie Pamela1, Palmer Lyle J.1, Arca Marcello1, Quagliarini Fabiana1, Gaudio Carlo1, Cambien François1, Nicaud Viviane1, Poirer Odette1, Gudnason Vilmundur1, Isaacs Aaron1, Witteman Jacqueline C.M.1, van Duijn Cornelia M.1, Pencina Michael1, Vasan Ramachandran S.1, D'Agostino Ralph B.1, Ordovas Jose1, Li Tricia Y.1, Kakko Sakari1, Kauma Heikki1, Savolainen Markku J.1, Kesäniemi Y. Antero1, Sandhofer Anton1, Paulweber Bernhard1, Sorli Jose V.1, Goto Akimoto1, Yokoyama Shinji1, Okumura Kenji1, Horne Benjamin D.1, Packard Chris1, Freeman Dilys1, Ford Ian1, Sattar Naveed1, McCormack Valerie1, Lawlor Debbie A.1, Ebrahim Shah1, Smith George Davey1, Kastelein John J.P.1, Deanfield John1, Casas Juan P.1
Affiliation:
1. 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....
Abstract
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.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Physiology (medical),Cardiology and Cardiovascular Medicine
Cited by
93 articles.
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