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.
  
  
  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.
authors.affiliation: Centre for Clinical Pharmacology, Department of Medicine, University College London, London, United Kingdom.
authors.forename: Reecha
authors.initials: R
authors.lastname: Sofat
authors.forename: Aroon D
authors.initials: AD
authors.lastname: Hingorani
authors.forename: Liam
authors.initials: L
authors.lastname: Smeeth
authors.forename: Steve E
authors.initials: SE
authors.lastname: Humphries
authors.forename: Philippa J
authors.initials: PJ
authors.lastname: Talmud
authors.forename: Jackie
authors.initials: J
authors.lastname: Cooper
authors.forename: Tina
authors.initials: T
authors.lastname: Shah
authors.forename: Manjinder S
authors.initials: MS
authors.lastname: Sandhu
authors.forename: Sally L
authors.initials: SL
authors.lastname: Ricketts
authors.forename: S Matthijs
authors.initials: SM
authors.lastname: Boekholdt
authors.forename: Nicholas
authors.initials: N
authors.lastname: Wareham
authors.forename: Kay Tee
authors.initials: KT
authors.lastname: Khaw
authors.forename: Meena
authors.initials: M
authors.lastname: Kumari
authors.forename: Mika
authors.initials: M
authors.lastname: Kivimaki
authors.forename: Michael
authors.initials: M
authors.lastname: Marmot
authors.forename: Folkert W
authors.initials: FW
authors.lastname: Asselbergs
authors.forename: Pim
authors.initials: P
authors.lastname: van der Harst
authors.forename: Robin P F
authors.initials: RP
authors.lastname: Dullaart
authors.forename: Gerjan
authors.initials: G
authors.lastname: Navis
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: van Veldhuisen
authors.forename: Wiek H
authors.initials: WH
authors.lastname: Van Gilst
authors.forename: John F
authors.initials: JF
authors.lastname: Thompson
authors.forename: Pamela
authors.initials: P
authors.lastname: McCaskie
authors.forename: Lyle J
authors.initials: LJ
authors.lastname: Palmer
authors.forename: Marcello
authors.initials: M
authors.lastname: Arca
authors.forename: Fabiana
authors.initials: F
authors.lastname: Quagliarini
authors.forename: Carlo
authors.initials: C
authors.lastname: Gaudio
authors.forename: François
authors.initials: F
authors.lastname: Cambien
authors.forename: Viviane
authors.initials: V
authors.lastname: Nicaud
authors.forename: Odette
authors.initials: O
authors.lastname: Poirer
authors.forename: Vilmundur
authors.initials: V
authors.lastname: Gudnason
authors.forename: Aaron
authors.initials: A
authors.lastname: Isaacs
authors.forename: Jacqueline C M
authors.initials: JC
authors.lastname: Witteman
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.forename: Michael
authors.initials: M
authors.lastname: Pencina
authors.forename: Ramachandran S
authors.initials: RS
authors.lastname: Vasan
authors.forename: Ralph B
authors.initials: RB
authors.lastname: D'Agostino
authors.forename: Jose
authors.initials: J
authors.lastname: Ordovas
authors.forename: Tricia Y
authors.initials: TY
authors.lastname: Li
authors.forename: Sakari
authors.initials: S
authors.lastname: Kakko
authors.forename: Heikki
authors.initials: H
authors.lastname: Kauma
authors.forename: Markku J
authors.initials: MJ
authors.lastname: Savolainen
authors.forename: Y Antero
authors.initials: YA
authors.lastname: Kesäniemi
authors.forename: Anton
authors.initials: A
authors.lastname: Sandhofer
authors.forename: Bernhard
authors.initials: B
authors.lastname: Paulweber
authors.forename: Jose V
authors.initials: JV
authors.lastname: Sorli
authors.forename: Akimoto
authors.initials: A
authors.lastname: Goto
authors.forename: Shinji
authors.initials: S
authors.lastname: Yokoyama
authors.forename: Kenji
authors.initials: K
authors.lastname: Okumura
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Horne
authors.forename: Chris
authors.initials: C
authors.lastname: Packard
authors.forename: Dilys
authors.initials: D
authors.lastname: Freeman
authors.forename: Ian
authors.initials: I
authors.lastname: Ford
authors.forename: Naveed
authors.initials: N
authors.lastname: Sattar
authors.forename: Valerie
authors.initials: V
authors.lastname: McCormack
authors.forename: Debbie A
authors.initials: DA
authors.lastname: Lawlor
authors.forename: Shah
authors.initials: S
authors.lastname: Ebrahim
authors.forename: George Davey
authors.initials: GD
authors.lastname: Smith
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
authors.forename: John
authors.initials: J
authors.lastname: Deanfield
authors.forename: Juan P
authors.initials: JP
authors.lastname: Casas
mesh_terms: D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D015415:Biomarkers; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors* / Q000097:blood / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004573:Electrolytes / Q000097:blood; D005838:Genotype; D006801:Humans; D006937:Hypercholesterolemia / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics; D006973:Hypertension / Q000139:chemically induced / Q000453:epidemiology / Q000235:genetics; D008075:Lipoproteins, HDL / Q000097:blood; D020641:Polymorphism, Single Nucleotide; D011804:Quinolines / Q000008:administration & dosage / Q000009:adverse effects*; D016032:Randomized Controlled Trials as Topic / Q000706:statistics & numerical data; D012307:Risk Factors; D044465:White People / Q000706:statistics & numerical data
chemical_list: D000924:Anticholesteremic Agents; D015415:Biomarkers; C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D004573:Electrolytes; D008075:Lipoproteins, HDL; D011804:Quinolines; C483909:torcetrapib