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CLINICAL RESEARCH: PHARMACOTHERAPY OF HDL AND LDL

Efficacy and Safety of Torcetrapib, a Novel Cholesteryl Ester Transfer Protein Inhibitor, in Individuals With Below-Average High-Density Lipoprotein Cholesterol Levels

Michael H. Davidson, MD, FACC^_*,_*, James M. McKenney, PharmD, Charles L. Shear, DrPH and James H. Revkin, MD, FACC

^_* Rush-Presbyterian-St. Luke’s Medical Center, Chicago, Illinois
Virginia Commonwealth University, Richmond, Virginia
Pfizer Global Research and Development, New London, Connecticut

^_* Reprint requests and correspondence: Dr. Michael Davidson, Radiant Research, 515 North State Street, Suite 2700, Chicago, Illinois 60610. (Email: michaeldavidson{at}radiantresearch.com).

OBJECTIVES: This study was designed to evaluate the efficacy and safety of torcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, in subjects with low high-density lipoprotein cholesterol (HDL-C) levels.

BACKGROUND: Evidence suggests HDL-C is atheroprotective. A proven mechanism for increasing the level of HDL-C is the inhibition of CETP.

METHODS: A total of 162 subjects with below-average HDL-C (men <44 mg/dl; women <54 mg/dl) who were not taking lipid-modifying therapy were randomized to double-blind treatment with torcetrapib 10, 30, 60, or 90 mg/day or placebo (30 subjects per group).

RESULTS: The percent change from baseline to Week 8 with torcetrapib (least-squares mean difference from placebo) was dose-dependent and ranged from 9.0% to 54.5% for HDL-C (p 0.0001 for 30 mg and higher doses) and from 3.0% to –16.5% for low-density lipoprotein cholesterol (LDL-C) (p < 0.01 for 90-mg dose). Low-density lipoprotein cholesterol lowering was less in subjects with higher (>150 mg/dl) versus lower levels of baseline triglycerides; at 60 mg, the change in LDL-C was 0.1% versus –22.2% (p < 0.0001), respectively. Particle size for both HDL and LDL increased with torcetrapib. There were no dose-related increases in the frequency of adverse events. Significant blood pressure increases were noted in 2 of 140 subjects.

CONCLUSIONS: Torcetrapib resulted in substantial dose-dependent elevations in HDL-C, accompanied by moderate decreases in LDL-C at the higher doses. Torcetrapib was generally well tolerated.

Abbreviations and Acronyms   AE = adverse event   apo = apolipoprotein   CE = cholesteryl ester   CETP = cholesteryl ester transfer protein   CHD = coronary heart disease   CVD = cardiovascular disease   DBP = diastolic blood pressure   HDL-C = high-density lipoprotein cholesterol   LDL-C = low-density lipoprotein cholesterol   NMR = nuclear magnetic resonance   SBP = systolic blood pressure   VLDL-C = very low-density lipoprotein cholesterol

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