Cholesteryl ester transfer protein (CETP) inhibitors raise HDL-cholesterol but torcetrapib, the first-in-class inhibitor tested in a large outcome trial caused 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 hypothesised that common single nucleotide polymorphisms (SNPs) 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 SNPs and torcetrapib treatment on lipid fractions, blood pressure and electrolytes in up to 67,687 individuals from genetic studies and 17,911 from randomised trials. CETP SNPs and torcetrapib treatment reduced CETP activity and had directionally concordant effect on eight lipid and lipoprotein traits (total-, LDL- and HDL-cholesterol, HDL2, HDL3, apolipoproteins A-I, -B, and triglycerides), with the genetic effect on HDL-cholesterol (0.13 mmol/L; 95% CI: 0.11, 0.14) being consistent with that expected of a 10 mg dose of torcetrapib (0.13 mmol/L; 0.10, 0.15). In trials, 60mg torcetrapib elevated systolic and diastolic blood pressure by 4.47mmHg (4.10, 4.84) and 2.08mmHg (1.84, 2.31) respectively. However, the effect of CETP SNPs on systolic 0.16mmHg (−0.28, 0.60) and diastolic blood pressure −0.04mmHg (−0.36, 0.28) was null and significantly different from that expected of 10 mg torcetrapib.
Discordance in the effects of CETP SNPs 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 use in drug development programmes as a new source of randomised evidence for drug target validation in man.
Keywords: genetics, pharmacology, epidemiology