From the American College of Cardiology

NEW ORLEANS—The news sent “shock waves” through the industry when torcetrapib (Pfizer), the first drug in a new class of cholesteryl ester transfer protein (CETP) inhibitors specifically targeted to raise low levels of high-density lipoprotein cholesterol (HDL-C), was stopped in its tracks while in clinical phase, despite promising lipid results in 2 clinical trials.

Development of torcetrapib was halted in December, based on reports of an excess cardiovascular (CV) mortality in patients receiving the drug. Nevertheless, Steven Nissen, MD, chairman of the Department of Cardiovascular Medicine at the Cleveland Clinic Foundation in Ohio and lead investigator of ILLUSTRATE (Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atherosclerosis by CETP Inhibition) remains optimistic that raising HDL-C levels is still a promising therapeutic target.

Dr Nissen presented the results of ILLUSRATE at the American College of Cardiology annual meeting, illuminating the study results and suggesting possible explanations for why, despite significantly raising HDL-C and lowering low-density lipoprotein cholesterol (LCL-C) levels, the addition of torcetrapib to atorvastatin did not slow the progression of plaque buildup in coronary arteries. The results were also recently published in the New England Journal of Medicine (2007; 356:1304-1316).

ILLUSTRATE compared atorvastatin alone with atorvastatin and torcetrapib combination therapy in 1188 patients with symptomatic coronary artery disease and >20% stenosis. After baseline intravascular ultrasound (IVUS) examinations, patients were titrated from 10 to 80 mg of atorva-statin for up to 10 weeks, until reaching the LDL-C target of 100 ± 15 mg/dL. They were then randomized to add 60 mg torcetrapib daily or placebo for 2 years, and then IVUS was repeated. The groups were well matched for cholesterol levels and all other relevant variables. Similar numbers of patients dropped out of each group.

At 24 months, no changes were seen in the atorvastatin-only group. But the group receiving torcetrapib on top of statin therapy showed significant decreases in LDL-C and increases in HDL-C (Table). Maximal HDL-C levels were reached by 6 to 9 months; at 24 months, HDL-C levels were actually higher than the LDL-C levels, for a ratio of 0.93, “a ratio never before achieved in any major clinical trial,” said Dr Nissen.

However, the percent change in coronary atheroma volume was nearly identical in the 2 groups: 0.19% with atorvastatin alone and 0.12% with torcetrapib plus atorvastatin.

“Thus, for the primary efficacy parameter, torcetrapib, despite a 61% increase in HDL-C and a 20% relative decrease in LDL-C, did not slow progression of coronary atherosclerosis,” he said.

In contrast, mixed results were seen for the secondary end points, with a significant difference in normalized atheroma volumes but no change in 10- mm subsegments of the most diseased segments. “The observed progression rate in the torcetrapib treatment group was substantially higher than would be expected for an achieved LDL of 70 mg/dL,” Dr Nissen emphasized.

“In nearly all prespecified subgroups there’s no significant heterogeneity in the effects of torcetrapib,” including by gender, age, smoking status, HDL-C or LDL-C level, or presence or absence of diabetes or the metabolic syndrome, he noted. However, results favored atorvastatin monotherapy if baseline percent atheroma volumes were less than the median and favored adding torcetrapib if baseline volumes were above the median.

Of most significance was the finding that torcetrapib raised systolic blood pressure (BP), with a time-averaged increase of 4.6 mm Hg. The incidence of hypertension was 23.7% with torcetrapib versus 10.6% with monotherapy.

The question remains whether torcetrapib itself is responsible for the negative findings or if CETP inhibition itself is the problem. Dr Nissen offered some possible explanations:
• Inhibiting CETP with torcetrapib may generate HDL particles that do not function normally in reverse cholesterol transport

• BP increases in the torcetrapib group may have counterbalanced any beneficial effects of the lipid changes on atherosclerosis progression

• The BP changes may reflect a more general toxic effect that prevents beneficial effects and increases adverse clinical outcomes.

Because many patients continue to have CV events despite meaningful reductions in LDL-C, raising HDL-C levels remains a significant therapeutic goal. The increased BP that was seen with torcetrapib for now appears a major contributor to its inability to slow the progression of atherosclerosis, despite the extremely positive benefits to the lipid profile.

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