Separating the mechanism-based and off-target actions of cholesteryl ester transfer protein inhibitors with CETP gene polymorphisms.
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.
Sofat
Reecha
R
Centre for Clinical Pharmacology, Department of Medicine, University College London, London, United Kingdom.
Hingorani
Aroon D
AD
Smeeth
Liam
L
Humphries
Steve E
SE
Talmud
Philippa J
PJ
Cooper
Jackie
J
Shah
Tina
T
Sandhu
Manjinder S
MS
Ricketts
Sally L
SL
Boekholdt
S Matthijs
SM
Wareham
Nicholas
N
Khaw
Kay Tee
KT
Kumari
Meena
M
Kivimaki
Mika
M
Marmot
Michael
M
Asselbergs
Folkert W
FW
van der Harst
Pim
P
Dullaart
Robin P F
RP
Navis
Gerjan
G
van Veldhuisen
Dirk J
DJ
Van Gilst
Wiek H
WH
Thompson
John F
JF
McCaskie
Pamela
P
Palmer
Lyle J
LJ
Arca
Marcello
M
Quagliarini
Fabiana
F
Gaudio
Carlo
C
Cambien
François
F
Nicaud
Viviane
V
Poirer
Odette
O
Gudnason
Vilmundur
V
Isaacs
Aaron
A
Witteman
Jacqueline C M
JC
van Duijn
Cornelia M
CM
Pencina
Michael
M
Vasan
Ramachandran S
RS
D'Agostino
Ralph B
RB
Ordovas
Jose
J
Li
Tricia Y
TY
Kakko
Sakari
S
Kauma
Heikki
H
Savolainen
Markku J
MJ
Kesäniemi
Y Antero
YA
Sandhofer
Anton
A
Paulweber
Bernhard
B
Sorli
Jose V
JV
Goto
Akimoto
A
Yokoyama
Shinji
S
Okumura
Kenji
K
Horne
Benjamin D
BD
Packard
Chris
C
Freeman
Dilys
D
Ford
Ian
I
Sattar
Naveed
N
McCormack
Valerie
V
Lawlor
Debbie A
DA
Ebrahim
Shah
S
Smith
George Davey
GD
Kastelein
John J P
JJ
Deanfield
John
J
Casas
Juan P
JP
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
D000924:Anticholesteremic Agents; D015415:Biomarkers; C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D004573:Electrolytes; D008075:Lipoproteins, HDL; D011804:Quinolines; C483909:torcetrapib