Sunday, December 17, 2006
Cholesterol: the good, the bad, and the stopped trials
# The Lancet, Vol 368, page 2034
One of the most promising new approaches in cardiovascular medicine hit the buffers on Dec 2 when Pfizer announced the stopping of its phase III clinical trial development of torcetrapib. Only days previously, the company had announced its hope to have the drug licensed next year in the USA. Torcetrapib was the lead compound in a new class of inhibitors of cholesterol ester transfer protein (CETP). Inhibition of this enzyme increases concentrations of HDL-cholesterol. The hope was that the combination of a statin (to reduce simultaneously concentrations of LDL-cholesterol) with a CETP inhibitor would further decrease the risk of atherothrombotic´cardiovascular events. Observational studies and randomised trials (with a fibrate or nicotinic acid) have shown that HDL-cholesterol concentrations are inversely associated with cardiovascular risk.
The company’s announcement followed routine scrutiny by the data and safety monitoring board for the ILLUMINATE study. This trial was a large international randomised study of torcetrapib plus atorvastatin versus atorvastatin alone in 15 000 patients with or at risk of coronary heart disease. There had been 82 deaths in the torcetrapib plus atorvastatin group, compared with 51 deaths in the group taking atorvastatin.
Why the Pfizer combination caused excess deaths is not known. A hint comes from a recent study of torcetrapib with atorvastatin, in which systolic blood pressure was slightly higher in the patients taking the combination than in those taking the single agent. Another view is that somehow HDL-cholesterol becomes dysfunctional after CETP inhibition.
The big question is whether the excess deaths observed in ILLUMINATE indicate a class eff ect for CETP inhibitors. Two other companies are studying CETP inhibitors in clinical trials, but data are not yet available. It would be intriguing to know whether and how patients in these studies are being informed about the demise of torcetrapib.
www.thelancet.com Vol 368 December 9, 2006
