on March 10, 2005
Published online before print March 10, 2005, doi: 10.1161/01.ATV.0000161928.16334.dd
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Submitted on October 1, 2004
Accepted on February 23, 2005
Effects of Cholesteryl Ester Transfer Protein Inhibition on High-Density Lipoprotein Subspecies, Apolipoprotein A-I Metabolism, and Fecal Sterol Excretion
Margaret E. Brousseau *;
From the Lipid Metabolism Laboratory (M.E.B., M.R.D., C.N., B.F.A., E.J.S.), JM-USDA-HNRCA at Tufts University and Tufts-New England Medical Center, Boston, Mass; Department of Medicine and Center for Experimental Therapeutics (J.S.M., M.L.W., D.J.R.), University of Pennsylvania School of Medicine, Philadelphia; Division of Cardiology (F.K.W.), Beth Israel Deaconess Medical Center, Boston, Mass; Department of Medicine (M.R., I.B., B.A.), Center for Metabolism and Endocrinology and Center for Molecular Nutrition, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden; Department of Clinical Biostatistics (J.P.M.), Pfizer, Inc., Groton, Conn; and Department of Clinical Sciences (A.G.D.), Pfizer, Inc., New London, Conn.
* To whom correspondence should be addressed. E-mail: margaret.brousseau{at}tufts.edu.
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 
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 rates (FCRs), with torcetrapib reducing HDL apoA-I FCRs 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 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.
Key words: apolipoprotein A-I • bile acids • cholesteryl ester transfer protein • CETP inhibition • high-density lipoproteins • kinetics
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