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  • Title: Effects of cholesteryl ester transfer protein inhibition on high-density lipoprotein subspecies, apolipoprotein A-I metabolism, and fecal sterol excretion.
    Author: Brousseau ME, Diffenderfer MR, Millar JS, Nartsupha C, Asztalos BF, Welty FK, Wolfe ML, Rudling M, Björkhem I, Angelin B, Mancuso JP, Digenio AG, Rader DJ, Schaefer EJ.
    Journal: Arterioscler Thromb Vasc Biol; 2005 May; 25(5):1057-64. PubMed ID: 15761191.
    Abstract:
    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 (5,5,5-2H3)-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 alpha1-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 alpha1-migrating HDL, (2) increases plasma concentrations of HDL apoA-I by delaying apoA-I catabolism, and (3) does not significantly influence fecal sterol excretion.
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