Researchers at Cleveland Clinic reported that the drug Torcetrapib, despite raising high density lipoprotein cholesterol ( HDL ) by more than 60%, did not slow the progression of plaque buildup in the coronary arteries as measured using an ultrasound probe.

Steven Nissen, chairman of Cardiovascular Medicine at Cleveland Clinic and lead investigator of this clinical trial, will present the study on Monday, March 26 at 8:30 a.m. at the American College of Cardiology's (ACC) 56th Annual Scientific Session. Dr. Nissen is also President of the ACC. The study will be simultaneously published in the New England Journal of Medicine. All development of Torcetrapib was terminated on Dec. 2, 2006 after the safety board monitoring a separate large clinical outcomes trial reported that Torcetrapib increased the risk of death and other adverse cardiovascular outcomes.

" We found that the Torcetrapib / Atorvastatin combination markedly increased HDL cholesterol levels and lowered LDL cholesterol in patients. Unfortunately this drug also substantially raised blood pressure and failed to slow the buildup of plaque," Steven Nissen, chairman of Cardiovascular Medicine at Cleveland Clinic and lead investigator of the clinical trial, said. " It is yet to be determined of this failure represents a problem unique to Torcetrapib or predicts a lack of efficacy for the entire class of similar drugs. These findings further demonstrate the great difficulty in developing therapies to disrupt the atherosclerotic disease process."

The development of drugs to raise HDL has been a key research priority because, despite lowering LDL cholesterol with statin drugs, many patients continue to experience heart attacks, stroke or sudden cardiac death.

A total of 1,188 coronary artery disease patients were enrolled in the " Investigation of Lipid Level management using coronary UltraSound To assess Reduction of Atherosclerosis by CETP Inhibition and HDL Elevation" ( ILLUSTRATE ) trial. All patients had a clinical indication for cardiac catheterization, had a baseline intravascular ultrasound ( IVUS ) and received 10-80 mg of Atorvastatin ( Lipitor ) adjusted during a two- to 10-week period until LDL levels reached national guidelines.

Patients were then randomized to receive either 60 mg of Torcetrapib or a matching placebo for two years. At the end of the treatment period, a second IVUS was performed, examining the same coronary arteries. Researchers measured the change in plaque volume in the artery, comparing the baseline to the follow-up ultrasound. They also measured patients' blood cholesterol levels and biomarkers of inflammation at several points during the trial.

Patients in the Torcetrapib / Atorvastatin group experienced a 61 percent relative increase in HDL cholesterol levels and a 20 percent relative decrease in LDL levels, as compared with patients in the Atorvastatin-only group. Despite those results, there was no statistical difference between the two groups in plaque volume changes. Plaque volume increased by 0.19 percent in the Atorvastatin-only patients and 0.12 percent in the combination group, p = 0.72. Torectrapib was also associated with a substantial increase in blood pressure, averaging 4.6 mm.

IVUS is a technique in which a tiny ultrasound probe is inserted into the coronary arteries, providing a precise and reproducible method for determining the change in plaque, or atheroma, burden during treatment.

Source: Cleveland Clinic, 2007


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