Separating the Mechanism-Based and Off-Target Actions of Cholesteryl Ester Transfer Protein Inhibitors With
CETP
Gene Polymorphisms
Authors: 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 , Kumari Meena , Kivimaki Mika , Marmot Michael , Asselbergs Folkert W. , van der Harst Pim , Dullaart Robin P.F. , Navis Gerjan , van Veldhuisen Dirk J. , Van Gilst Wiek H. , Thompson John F. , McCaskie Pamela , Palmer Lyle J. , Arca Marcello , Quagliarini Fabiana , Gaudio Carlo , Cambien François , Nicaud Viviane , Poirer Odette , Gudnason Vilmundur , Isaacs Aaron , Witteman Jacqueline C.M. , van Duijn Cornelia M. , Pencina Michael , Vasan Ramachandran S. , D'Agostino Ralph B. , Ordovas Jose , Li Tricia Y. , Kakko Sakari , Kauma Heikki , Savolainen Markku J. , Kesäniemi Y. Antero , Sandhofer Anton , Paulweber Bernhard , Sorli Jose V. , Goto Akimoto , 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. 
Published: December 2009

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.