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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 on a Background of Atorvastatin

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

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

Manuscript received January 17, 2006; revised manuscript received May 24, 2006, accepted June 6, 2006.

^_* Reprint requests and correspondence: Dr. James McKenney, National Clinical Research, 2809 Emerywood Parkway, Suite 140, Richmond, Virginia 23294. (Email: jmckenney{at}ncrinc.net).

OBJECTIVES: This study sought to evaluate the efficacy and safety of torcetrapib in patients with low high-density lipoprotein cholesterol (HDL-C) levels receiving background atorvastatin.

BACKGROUND: Elevating HDL-C levels may reduce the residual cardiovascular risk that is observed in patients treated with statin therapy. Torcetrapib (a cholesteryl ester transfer protein inhibitor) increases HDL-C and decreases low-density lipoprotein cholesterol (LDL-C).

METHODS: This was a multicenter, double-blind, randomized trial. Patients with below-average HDL-C (men <44 mg/dl; women <54 mg/dl) who were eligible for statin therapy according to National Cholesterol Education Program Adult Treatment Panel III guidelines or who had LDL-C >130 mg/dl at screening entered an 8-week run-in period with atorvastatin 20 mg/day before randomization (n = 174) to torcetrapib 10, 30, 60, or 90 mg/day or placebo for 8 weeks. Atorvastatin was continued during treatment with torcetrapib.

RESULTS: After 8 weeks, the percent change from baseline with torcetrapib (least-squares mean difference from placebo) ranged from 8.3% to 40.2% for HDL-C (p 0.0001 for 30-mg and higher doses) and from 0.6% to –18.9% for LDL-C (p < 0.01 for 60-mg and 90-mg doses). Particle size for both HDL and LDL increased with torcetrapib. The incidence of all-causality and treatment-related adverse events was similar across placebo and torcetrapib treatment groups with no evidence of a dose-related response. In some treatment groups, small increases in systolic and diastolic blood pressures were noted.

CONCLUSIONS: In statin-eligible patients, torcetrapib plus background atorvastatin resulted in substantial, dose-dependent increases in HDL-C, accompanied by additional decreases in LDL-C beyond those seen with atorvastatin alone. Torcetrapib plus atorvastatin was generally well tolerated.

Abbreviations and Acronyms   AE = adverse event   apo = apolipoprotein   CETP = cholesteryl ester transfer protein   CVD = cardiovascular disease   DBP = diastolic blood pressure   HDL-C = high-density lipoprotein cholesterol   LDL-C = low-density lipoprotein cholesterol   LS = least-squares   NMR = nuclear magnetic resonance   SBP = systolic blood pressure   ULN = upper limit of normal   VLDL-C = very low-density lipoprotein cholesterol

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