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

Reecha Sofat; Aroon D. Hingorani; Liam Smeeth; Steve E. Humphries; Philippa J. Talmud; Jackie Cooper; Tina Shah; Manjinder S. Sandhu; Sally L. Ricketts; S. Matthijs Boekholdt; Nicholas Wareham; Kay Tee Khaw; Meena Kumari; Mika Kivimaki; Michael Marmot; Folkert W. Asselbergs; Pim van der Harst; Robin P. F. Dullaart; Gerjan Navis; Dirk J. van Veldhuisen; Wiek H. van Gilst; John F. Thompson; Pamela McCaskie; Lyle J. Palmer; Marcello Arca; Fabiana Quagliarini; Carlo Gaudio; François Cambien; Viviane Nicaud; Odette Poirer; Vilmundur Gudnason; Aaron Isaacs; Jacqueline C. M. Witteman; Cornelia M. van Duijn; Michael Pencina; Ramachandran S. Vasan; Ralph B. D'Agostino; Jose Ordovas; Tricia Y. Li; Sakari Kakko; Heikki Kauma; Markku J. Savolainen; Y. Antero Kesäniemi; Anton Sandhofer; Bernhard Paulweber; Jose V. Sorli; Akimoto Goto; Shinji Yokoyama; Kenji Okumura; Benjamin D. Horne; Chris Packard; Dilys Freeman; Ian Ford; Naveed Sattar; Valerie McCormack; Debbie A. Lawlor; Shah Ebrahim; George Davey Smith; John J. P. Kastelein; John Deanfield; Juan P. Casas

doi:https://doi.org/10.1161/CIRCULATIONAHA.109.865444

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

Reecha Sofat, Aroon D. Hingorani, Liam Smeeth, Steve E. Humphries, Philippa J. Talmud, Jackie Cooper, Tina Shah, Manjinder S. Sandhu, Sally L. Ricketts, S. Matthijs Boekholdt, Nicholas Wareham, Kay Tee Khaw, Meena Kumari, Mika Kivimaki, Michael Marmot, Folkert W. Asselbergs, Pim van der Harst, Robin P. F. Dullaart, Gerjan Navis, Dirk J. van VeldhuisenWiek H. van Gilst, John F. Thompson, Pamela McCaskie, Lyle J. Palmer, Marcello Arca, Fabiana Quagliarini, Carlo Gaudio, François Cambien, Viviane Nicaud, Odette Poirer, Vilmundur Gudnason, Aaron Isaacs, Jacqueline C. M. Witteman, Cornelia M. van Duijn, Michael Pencina, Ramachandran S. Vasan, Ralph B. D'Agostino, Jose Ordovas, Tricia Y. Li, Sakari Kakko, Heikki Kauma, Markku J. Savolainen, Y. Antero Kesäniemi, Anton Sandhofer, Bernhard Paulweber, Jose V. Sorli, Akimoto Goto, Shinji Yokoyama, Kenji Okumura, Benjamin D. Horne, Chris Packard, Dilys Freeman, Ian Ford, Naveed Sattar, Valerie McCormack, Debbie A. Lawlor, Shah Ebrahim, George Davey Smith, John J. P. Kastelein, John Deanfield, Juan P. Casas

Research output: Contribution to journal › Article › Academic › peer-review

77 Citations (Scopus)

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

Original language	English
Pages (from-to)	52-62
Journal	Circulation
Volume	121
Issue number	1
DOIs	https://doi.org/10.1161/CIRCULATIONAHA.109.865444
Publication status	Published - 2010

Access to Document

https://doi.org/10.1161/CIRCULATIONAHA.109.865444

Cite this

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. M., Wareham, N., Khaw, K. T., Kumari, M., Kivimaki, M., Marmot, M., Asselbergs, F. W., van der Harst, P., Dullaart, R. P. F., Navis, G., ... Casas, J. P. (2010). Separating the mechanism-based and off-target actions of cholesteryl ester transfer protein inhibitors with CETP gene polymorphisms. Circulation, 121(1), 52-62. https://doi.org/10.1161/CIRCULATIONAHA.109.865444

@article{bf0ee37decdd45d283eea53b5bc65818,

title = "Separating the mechanism-based and off-target actions of cholesteryl ester transfer protein inhibitors with CETP gene polymorphisms",

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",

author = "Reecha Sofat and Hingorani, {Aroon D.} and Liam Smeeth and Humphries, {Steve E.} and Talmud, {Philippa J.} and Jackie Cooper and Tina Shah and Sandhu, {Manjinder S.} and Ricketts, {Sally L.} and Boekholdt, {S. Matthijs} and Nicholas Wareham and Khaw, {Kay Tee} and Meena Kumari and Mika Kivimaki and Michael Marmot and Asselbergs, {Folkert W.} and {van der Harst}, Pim and Dullaart, {Robin P. F.} and Gerjan Navis and {van Veldhuisen}, {Dirk J.} and {van Gilst}, {Wiek H.} and Thompson, {John F.} and Pamela McCaskie and Palmer, {Lyle J.} and Marcello Arca and Fabiana Quagliarini and Carlo Gaudio and Fran{\c c}ois Cambien and Viviane Nicaud and Odette Poirer and Vilmundur Gudnason and Aaron Isaacs and Witteman, {Jacqueline C. M.} and {van Duijn}, {Cornelia M.} and Michael Pencina and Vasan, {Ramachandran S.} and D'Agostino, {Ralph B.} and Jose Ordovas and Li, {Tricia Y.} and Sakari Kakko and Heikki Kauma and Savolainen, {Markku J.} and Kes{\"a}niemi, {Y. Antero} and Anton Sandhofer and Bernhard Paulweber and Sorli, {Jose V.} and Akimoto Goto and Shinji Yokoyama and Kenji Okumura and Horne, {Benjamin D.} and Chris Packard and Dilys Freeman and Ian Ford and Naveed Sattar and Valerie McCormack and Lawlor, {Debbie A.} and Shah Ebrahim and Smith, {George Davey} and Kastelein, {John J. P.} and John Deanfield and Casas, {Juan P.}",

year = "2010",

doi = "https://doi.org/10.1161/CIRCULATIONAHA.109.865444",

language = "English",

volume = "121",

pages = "52--62",

journal = "Circulation",

issn = "0009-7322",

publisher = "Lippincott Williams and Wilkins Ltd.",

number = "1",

}

Sofat, R, Hingorani, AD, Smeeth, L, Humphries, SE, Talmud, PJ, Cooper, J, Shah, T, Sandhu, MS, Ricketts, SL, Boekholdt, SM, Wareham, N, Khaw, KT, Kumari, M, Kivimaki, M, Marmot, M, Asselbergs, FW, van der Harst, P, Dullaart, RPF, Navis, G, van Veldhuisen, DJ, van Gilst, WH, Thompson, JF, McCaskie, P, Palmer, LJ, Arca, M, Quagliarini, F, Gaudio, C, Cambien, F, Nicaud, V, Poirer, O, Gudnason, V, Isaacs, A, Witteman, JCM, van Duijn, CM, Pencina, M, Vasan, RS, D'Agostino, RB, Ordovas, J, Li, TY, Kakko, S, Kauma, H, Savolainen, MJ, Kesäniemi, YA, Sandhofer, A, Paulweber, B, Sorli, JV, Goto, A, Yokoyama, S, Okumura, K, Horne, BD, Packard, C, Freeman, D, Ford, I, Sattar, N, McCormack, V, Lawlor, DA, Ebrahim, S, Smith, GD, Kastelein, JJP, Deanfield, J & Casas, JP 2010, 'Separating the mechanism-based and off-target actions of cholesteryl ester transfer protein inhibitors with CETP gene polymorphisms', Circulation, vol. 121, no. 1, pp. 52-62. https://doi.org/10.1161/CIRCULATIONAHA.109.865444

TY - JOUR

T1 - Separating the mechanism-based and off-target actions of cholesteryl ester transfer protein inhibitors with CETP gene polymorphisms

AU - Sofat, Reecha

AU - Hingorani, Aroon D.

AU - Smeeth, Liam

AU - Humphries, Steve E.

AU - Talmud, Philippa J.

AU - Cooper, Jackie

AU - Shah, Tina

AU - Sandhu, Manjinder S.

AU - Ricketts, Sally L.

AU - Boekholdt, S. Matthijs

AU - Wareham, Nicholas

AU - Khaw, Kay Tee

AU - Kumari, Meena

AU - Kivimaki, Mika

AU - Marmot, Michael

AU - Asselbergs, Folkert W.

AU - van der Harst, Pim

AU - Dullaart, Robin P. F.

AU - Navis, Gerjan

AU - van Veldhuisen, Dirk J.

AU - van Gilst, Wiek H.

AU - Thompson, John F.

AU - McCaskie, Pamela

AU - Palmer, Lyle J.

AU - Arca, Marcello

AU - Quagliarini, Fabiana

AU - Gaudio, Carlo

AU - Cambien, François

AU - Nicaud, Viviane

AU - Poirer, Odette

AU - Gudnason, Vilmundur

AU - Isaacs, Aaron

AU - Witteman, Jacqueline C. M.

AU - van Duijn, Cornelia M.

AU - Pencina, Michael

AU - Vasan, Ramachandran S.

AU - D'Agostino, Ralph B.

AU - Ordovas, Jose

AU - Li, Tricia Y.

AU - Kakko, Sakari

AU - Kauma, Heikki

AU - Savolainen, Markku J.

AU - Kesäniemi, Y. Antero

AU - Sandhofer, Anton

AU - Paulweber, Bernhard

AU - Sorli, Jose V.

AU - Goto, Akimoto

AU - Yokoyama, Shinji

AU - Okumura, Kenji

AU - Horne, Benjamin D.

AU - Packard, Chris

AU - Freeman, Dilys

AU - Ford, Ian

AU - Sattar, Naveed

AU - McCormack, Valerie

AU - Lawlor, Debbie A.

AU - Ebrahim, Shah

AU - Smith, George Davey

AU - Kastelein, John J. P.

AU - Deanfield, John

AU - Casas, Juan P.

PY - 2010

Y1 - 2010

N2 - 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

AB - 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

U2 - https://doi.org/10.1161/CIRCULATIONAHA.109.865444

DO - https://doi.org/10.1161/CIRCULATIONAHA.109.865444

M3 - Article

C2 - 20026784

SN - 0009-7322

VL - 121

SP - 52

EP - 62

JO - Circulation

JF - Circulation

IS - 1

ER -