Effects of cholesteryl ester transfer protein inhibition on high-density lipoprotein subspecies, apolipoprotein A-I metabolism, and fecal sterol excretion

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-H-2(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 alpha 1-migrating HDL in the atorvastatin ( 136%; P < 0.001) and nonatorvastatin (153%; P < 0.01) cohorts, whereas an increase of 382% ( P < 0.01) was observed in the 120 mg twice daily group. HDL apoA-I pool size increased by 8 +/- 15% in the atorvastatin cohort ( P = 0.16) and by 16 +/- 7% ( P < 0.0001) and 34 +/- 8% ( P < 0.0001) 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% ( P = 0.10) in the atorvastatin cohort, by 8% ( P < 0.001) in the nonatorvastatin 120 mg QD cohort, and by 21% ( P < 0.01) 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 alpha 1-migrating HDL, ( 2) increases plasma concentrations of HDL apoA-I by delaying apoA-I catabolism, and ( 3) does not significantly influence fecal sterol excretion.