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