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

Author
item SOFAT, REECHA - University Of Pittsburgh
item HINGORANI, AROON - University Of Pittsburgh
item SMEETH, LIAM - University College London
item HUMPHRIES, STEVE - University College London
item TALMUD, PHILIPPA - University College London
item COOPER, JACKIE - University College London
item SHAH, TINA - University Of Pittsburgh
item SANDHU, MANJINDER - London School Of Hygeine
item RICKETTS, SALLY - London School Of Hygeine
item BOEKHOLDT, S. MATTHIJS - London School Of Hygeine
item WAREHAM, NICHOLAS - University Of Cambridge
item KHAW, KAY TEE - University Of Cambridge
item KUMARI, MEENA - University College London
item KIVIMAKI, MIKA - University College London
item MARMOT, MICHAEL - University College London
item ASSELBERGS, FOLKERT - University Of Cambridge
item VAN DER HARST, PIM - University Of Cambridge
item DULLAART, ROBIN - University Of Cambridge
item NAVIS, GERJAN - University Of Cambridge
item VAN VELDHUISEN, DIRK - University Of Cambridge
item VAN GILST, WIEK - University Of Cambridge
item THOMPSON, JOHN - University Of Groningen
item MCCASKIE, PAMELA - University Of Western Australia
item PALMER, LYLE - University Of Western Australia
item ARCA, MARCELLO - University Of Rome Sapienza
item QUAGLIARINI, FABIANA - University Of Rome Sapienza
item GAUDIO, CARLO - University Of Rome Sapienza
item CAMBIEN, FRANCOIS - Pierre And Marie Curie University
item NICAUD, VIVIANE - Pierre And Marie Curie University
item POIRER, ODETTE - Pierre And Marie Curie University
item GUDNASON, VILMUNDUR - University Of Iceland
item ISAACS, AARON - University Of Iceland
item WITTEMAN, JACQUELINE - University Of Iceland
item VAN DUIJN, CORNELA - University Of Iceland
item PENCINA, MICHAEL - Boston University
item VASAN, RAMACHANDRAN - Boston University
item D'AGOSTINO, RALPH - Boston University
item ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item LI, TRICIA - Boston University
item KAKKO, SAKARI - Harvard School Of Public Health
item KAUMA, HEIKKI - Harvard School Of Public Health
item SAVOLAINEN, MARKKU - Harvard School Of Public Health
item KESANIEMI, Y ANTERO - Harvard School Of Public Health
item SANDHOFER, ANTON - Innsbruck Medical University
item PAULWEBER, BERNHARD - University Of Innsbruck
item SORLI, JOSE - University Of Valencia
item GOTO, AKIMOTO - Aichi Hospital And Research Institute
item YOKOYAMA, SHINJI - Nagoya University
item OKUMURA, KENJI - Nagoya University
item HORNE, BENJAMIN - University Of Utah
item PACKARD, CHRIS - University Of Glasgow
item FREEMAN, DILYS - University Of Glasgow
item FORD, IAN - University Of Glasgow
item SATTAR, NAVEED - University Of Glasgow
item MCCORMACK, VALERIE - World Health Organization (WHO) - France
item LAWLOR, DEBBIE - University Of Bristol
item EBRAHIM, SHAH - London School Of Hygeine
item SMITH, GEORGE - University Of Bristol
item KASTELEIN, JOHN - University Of Amsterdam
item DEANFIELD, JOHN - University College London
item CASAS, JUAN - University College London

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.