TorcetrapibLandmark
Mendelian randomization shows the hypertensive effect of torcetrapib is not caused by CETP inhibition (Circulation 2010)
Original title: Separating the mechanism-based and off-target actions of cholesteryl ester transfer protein inhibitors with CETP gene polymorphisms
Researchers compared the effects of common CETP single-nucleotide polymorphisms with torcetrapib treatment on lipids, blood pressure, and electrolytes, using up to 67 687 individuals from genetic studies and 17 911 from randomized trials, to test whether the hypertensive effect of torcetrapib in ILLUMINATE reflected CETP inhibition or an off-target action. CETP variants and torcetrapib both reduced CETP activity and had concordant effects on eight lipid traits, with the genetic effect on HDL cholesterol (0.13 mmol/L) matching that expected from a 10-mg torcetrapib dose (0.13 mmol/L). However, while 60 mg of torcetrapib raised systolic and diastolic blood pressure by 4.47 and 2.08 mmHg in trials, CETP variants had a null effect on systolic (0.16 mmHg) and diastolic (-0.04 mmHg) blood pressure. The authors conclude the hypertensive action of torcetrapib is unlikely due to CETP inhibition, demonstrating a role for human genetic studies in drug-target validation.
Original 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.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.