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United States Department of Agriculture

Agricultural Research Service

Research Project: NUTRITION, OBESITY, CARDIOVASCULAR HEALTH AND GENOMICS Title: Separating the mechanism-based and off-target actions of cholesteryl ester transfer protein inhibitors with CETP gene polymorphisms

Authors
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: October 20, 2009
Publication Date: January 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: 10/30/2014
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