Torcetrapib raises apolipoprotein A-I in alpha1-migrating HDL by up to 382 percent at twice-daily dosing, without changing fecal sterol excretion (Arterioscler Thromb Vasc Biol 2005)

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

Arterioscler Thromb Vasc Biol · 10 March 2005 · 6

Brousseau ME, Diffenderfer MR, Millar JS, Nartsupha C, Asztalos BF, Welty FK, Wolfe ML, Rudling M, Björkhem I, Angelin B, Mancuso JP, Digenio AG et al.

This study examined how CETP inhibition affects apolipoprotein A-I (apoA-I)-containing HDL subspecies, apoA-I turnover, and reverse cholesterol transport markers. Nineteen subjects, 9 on atorvastatin, received placebo for 4 weeks then torcetrapib 120 mg once daily for 4 weeks, with 6 non-atorvastatin subjects continuing to 120 mg twice daily; isotope tracer infusion measured HDL apoA-I kinetics after each phase. Relative to placebo, torcetrapib raised apoA-I in alpha1-migrating HDL by 136% (atorvastatin cohort) and 153% (non-atorvastatin once-daily), and by 382% at twice-daily dosing (all p < 0.01). HDL apoA-I pool size rose 8% (atorvastatin, not significant), 16%, and 34% (both p < 0.0001) across the same groups, driven by reduced apoA-I fractional catabolic rate rather than changed production. Torcetrapib did not significantly affect markers of cholesterol or bile acid synthesis or fecal sterol excretion, showing that partial CETP inhibition normalizes alpha1-HDL apoA-I and raises HDL apoA-I mainly by delaying its catabolism.

Original 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.

Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.