Separating the mechanism-based and off-target actions of cholesteryl ester transfer protein inhibitors with CETP gene polymorphisms.
Sofat R., Hingorani AD., Smeeth L., Humphries SE., Talmud PJ., Cooper J., Shah T., Sandhu MS., Ricketts SL., Boekholdt SM., Wareham N., Khaw KT., Kumari M., Kivimaki M., Marmot M., Asselbergs FW., van der Harst P., Dullaart RPF., Navis G., van Veldhuisen DJ., Van Gilst WH., Thompson JF., McCaskie P., Palmer LJ., Arca M., Quagliarini F., Gaudio C., Cambien F., Nicaud V., Poirer O., Gudnason V., Isaacs A., Witteman JCM., van Duijn CM., Pencina M., Vasan RS., D'Agostino RB., Ordovas J., Li TY., Kakko S., Kauma H., Savolainen MJ., Kesäniemi YA., Sandhofer A., Paulweber B., Sorli JV., Goto A., Yokoyama S., Okumura K., Horne BD., Packard C., Freeman D., Ford I., Sattar N., McCormack V., Lawlor DA., Ebrahim S., Smith GD., Kastelein JJP., Deanfield J., Casas JP.
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.