In subjects with low HDL cholesterol levels, CETP inhibition with torcetrapib markedly increased HDL cholesterol levels and also decreased LDL cholesterol levels, both when administered as monotherapy and when administered in combination with a statin.

Objective-Pharmacological inhibition of the cholesteryl ester transfer protein (CETP) in humans increases high-density lipoprotein (HDL) cholesterol (HDL-C) levels; however, its effects on apolipoprotein A-I (apoA-I) containing HDL subspecies, apoA-I turnover, and markers of reverse cholesterol transport are unknown. The present study was designed to address these issues. Methods and Results-Nineteen subjects, 9 of whom were taking 20 mg of atorvastatin for hypercholesterolemia, received placebo for 4 weeks, followed by the CETP inhibitor torcetrapib (120 mg QD) for 4 weeks. In 6 subjects from the nonatorvastatin cohort, the everyday regimen was followed by a 4-week period of torcetrapib (120 mg BID). At the end of each phase, subjects underwent a primed-constant infusion of (5,5,5-2 H 3 )-L-leucine to determine the kinetics of HDL apoA-I. The lipid data in this study have been reported previously. Relative to placebo, 120 mg daily torcetrapib increased the amount of apoA-I in ␣1-migrating HDL in the atorvastatin (136%; PϽ0.001) and nonatorvastatin (153%; PϽ0.01) cohorts, whereas an increase of 382% (PϽ0.01) was observed in the 120 mg twice daily group. HDL apoA-I pool size increased by 8Ϯ15% in the atorvastatin cohort (Pϭ0.16) and by 16Ϯ7% (PϽ0.0001) and 34Ϯ8% (PϽ0.0001) in the nonatorvastatin 120 mg QD and BID cohorts, respectively. These changes were attributable to reductions in HDL apoA-I fractional catabolic rate (FCR), with torcetrapib reducing HDL apoA-I FCR by 7% (Pϭ0.10) in the atorvastatin cohort, by 8% (PϽ0.001) in the nonatorvastatin 120 mg QD cohort, and by 21% (PϽ0.01) in the nonatorvastatin 120 mg BID cohort. Torcetrapib did not affect HDL apoA-I production rate. In addition, torcetrapib did not significantly change serum markers of cholesterol or bile acid synthesis or fecal sterol excretion. Conclusions-These data indicate that partial inhibition of CETP via torcetrapib in patients with low HDL-C: (1) normalizes apoA-I levels within ␣1-migrating HDL, (2) increases plasma concentrations of HDL apoA-I by delaying apoA-I catabolism, and (3) pidemiologic studies have consistently demonstrated that plasma concentrations of high-density lipoprotein (HDL) cholesterol and apolipoprotein A-I (apoA-I) are inversely correlated with the incidence of coronary heart disease (CHD). 1-3 Clinical trial results indicate that even modest increases in HDL cholesterol (HDL-C) concentrations can significantly reduce CHD risk. 4 -5 However, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, or statins, have only modest effects on HDL-C levels, raising them on average by 5% to 10%. 6 Although fibrates and niacin can raise HDL-C levels, the increases in HDL-C are rarely Ͼ25%, and niacin is often not well tolerated.Among the alternative HDL-raising strategies actively being explored is cholesteryl ester transfer protein (CETP) inhibition. 7 CETP is a plasma glycoprotein that facilitates the transfer of cholesteryl esters (CEs) from HDL to apoBcontaining lipoproteins. 8,9 Humans with CETP deficiency attributab...