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.

Figure 1 a-c

Relationship between torcetrapib dose and HDL cholesterol and HDL2 and HDL3 sub-fractions. P values refer to the results of a meta- regression and N refers to the total number of individuals in the three dose-ranging studies contributing to this analysis

Figure 2

Effect of CETP genotype on HDL Cholesterol in individuals of European ancestry. The B1B1 genotype is used as the reference group

Figure 3

Figure 3a The effect of torcetrapib and CETP gene variants on six lipid traits evaluated in both genetic studies and randomised trials Figure 3b Observed effects of the CETP gene and expected effects of a 5 and 10 mg dose of torcetrapib dose on HDL- cholesterol

Figure 4

Effect of CETP genotype on (a) systolic and (b) diastolic blood pressure in populations of European descent. Weighted mean difference is given, with the B1B1 genotype used as the reference genotype.

Figure 5 a-d

Observed effect of the CETP gene and expected effects of a 5 and 10 mg dose of torcetrapib on (a) systolic and (b) diastolic blood pressure, and (c) serum potassium and (d) sodium levels.