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United States Department of Agriculture

Agricultural Research Service

Research Project: NUTRITION, OBESITY, CARDIOVASCULAR HEALTH AND GENOMICS

Location: Boston, Massachusetts

Title: Separating the mechanism-based and off-target actions of cholesteryl ester transfer protein inhibitors with CETP gene polymorphisms)

Author
item Sofat, Reecha
item Hingorani, Aroon
item Smeeth, Liam
item Humphries, Steve
item Talmud, Philippa
item Cooper, Jackie
item Shah, Tina
item Sandhu, Manjinder
item Ricketts, Sally
item Boekholdt, S. matthijs
item Wareham, Nicholas
item Khaw, Kay tee
item Kumari, Meena
item Kivimaki, Mika
item Marmot, Michael
item Asselbergs, Folkert
item Van der harst, Pim
item Dullaart, Robin
item Navis, Gerjan
item Van veldhuisen, Dirk
item Van gilst, Wiek
item Thompson, John
item Mccaskie, Pamela
item Palmer, Lyle
item Arca, Marcello
item Quagliarini, Fabiana
item Gaudio, Carlo
item Cambien, Francois
item Nicaud, Viviane
item Poirer, Odette
item Gudnason, Vilmundur
item Isaacs, Aaron
item Witteman, Jacqueline
item Van duijn, Cornela
item Pencina, Michael
item Vasan, Ramachandran
item D'agostino, Ralph
item Ordovas, Jose
item Li, Tricia
item Kakko, Sakari
item Kauma, Heikki
item Savolainen, Markku
item Kesaniemi, Y antero
item Sandhofer, Anton
item Paulweber, Bernhard
item Sorli, Jose
item Goto, Akimoto
item Yokoyama, Shinji
item Okumura, Kenji
item Horne, Benjamin
item Packard, Chris
item Freeman, Dilys
item Ford, Ian
item Sattar, Naveed
item Mccormack, Valerie
item Lawlor, Debbie
item Ebrahim, Shah
item Smith, George
item Kastelein, John
item Deanfield, John
item Casas, Juan

Submitted to: Circulation
Publication Type: Peer reviewed journal
Publication Acceptance Date: 10/20/2009
Publication Date: 1/5/2010
Citation: 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., Wareham, N., Khaw, K., Kumari, M., Kivimaki, M., Marmot, M., Asselbergs, F.W., Van Der Harst, P., Dullaart, R.P., 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., Van Duijn, C.M., Pencina, M., Vasan, R.S., D'Agostino, R.B., Ordovas, J.M., Li, T.Y., Kakko, S., Kauma, H., Savolainen, M.J., Kesaniemi, Y., 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., Deanfield, J., Casas, J.P. 2010. Separating the mechanism-based and off-target actions of cholesteryl ester transfer protein inhibitors with CETP gene polymorphisms. Circulation. 11(1):52-62.

Interpretive Summary: Cholesteryl ester transfer protein (CETP) is a key factor in human lipoprotein metabolism shuttling lipids between different blood lipoproteins. There is an inverse correlation between CETP levels or activity and high-density lipoprotein (HDL) cholesterol, the protective lipoprotein fraction. Therefore, inhibition of CETP has been considered as an alternative to raise HDL levels and decrease Cardiovascular Disease Risk., 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 investigated whether 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. For this purpose, we compared the effect of CETP polymorphisms and torcetrapib treatment on lipid fractions, blood pressure, and electrolytes in about 68,000 individuals from genetic studies and about 18,000 from randomized trials. CETP single-nucleotide polymorphisms and torcetrapib treatment reduced CETP activity and had a directionally concordant effect on blood lipids. However, the effect of CETP polymorphisms on systolic and diastolic blood pressure was null and significantly different from that expected of 10 mg of torcetrapib. Therefore, discordance in the effects of CETP 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. These results supports the notion that genetic studies could find a place in drug-development programs as a new source of randomized evidence for drug-target validation in humans.

Technical 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.

Last Modified: 8/24/2016
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