The first human trial of torcetrapib raises HDL cholesterol by up to 91 percent while producing a lipid profile resembling partial CETP deficiency (Arterioscler Thromb Vasc Biol 2004)

Original title: Raising high-density lipoprotein in humans through inhibition of cholesteryl ester transfer protein: an initial multidose study of torcetrapib

Arterioscler Thromb Vasc Biol · 22 January 2004 · 8

Clark RW, Sutfin TA, Ruggeri RB, Willauer AT, Sugarman ED, Magnus-Aryitey G, Cosgrove PG, Sand TM, Wester RT, Williams JA, Perlman ME, Bamberger MJ

This initial phase 1 multidose study tested whether torcetrapib (CP-529,414) could raise HDL cholesterol in healthy young subjects. Five groups of 8 subjects each received placebo or torcetrapib at 10, 30, 60, or 120 mg once daily, or 120 mg twice daily, for 14 days, and torcetrapib was well tolerated with all treated subjects completing the study. Plasma drug levels correlated with CETP inhibition as expected from in vitro potency, and CETP inhibition increased with dose, raising HDL cholesterol from 16% to 91%. Total plasma cholesterol did not change significantly due to a reduction in non-HDL cholesterol, including 21% to 42% LDL cholesterol lowering at higher doses, while apolipoprotein A-I and E rose 27% and 66% and apoB fell 26% with 120 mg twice daily. These effects of CETP inhibition resembled those seen in partial genetic CETP deficiency, establishing torcetrapib as a basis for further studies in low HDL and dyslipidemia.

Original abstract

Objective: The ability of the potent cholesteryl ester transfer protein (CETP) inhibitor torcetrapib (CP-529,414) to raise high-density lipoprotein cholesterol (HDL-C) levels in healthy young subjects was tested in this initial phase 1 multidose study.

Methods And Results: Five groups of 8 subjects each were randomized to placebo (n=2) or torcetrapib (n=6) at 10, 30, 60, and 120 mg daily and 120 mg twice daily for 14 days. Torcetrapib was well tolerated, with all treated subjects completing the study. The correlation of plasma drug levels with inhibition (EC50=43 nM) was as expected based on in vitro potency (IC50 approximately 50 nM), and increases in CETP mass were consistent with the proposed mechanism of inhibition. CETP inhibition increased with escalating dose, leading to elevations of HDL-C of 16% to 91%. Total plasma cholesterol did not change significantly because of a reduction in nonHDL-C, including a 21% to 42% lowering of low-density lipoprotein cholesterol at the higher doses. Apolipoprotein A-I and E were elevated 27% and 66%, respectively, and apoB was reduced 26% with 120 mg twice daily. Cholesteryl ester content decreased and triglyceride increased in the nonHDL plasma fraction, with contrasting changes occurring in HDL.

Conclusions: These effects of CETP inhibition resemble those observed in partial CETP deficiency. This work serves as a prelude to further studies in subjects with low HDL, or combinations of dyslipidemia, in assessing the role of CETP in atherosclerosis.

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