The trouble with torcetrapib： Imaging studies shed little light on why HDL-raising drug failed

　　Three new imaging studies have shown that torcetrapib， a novel HDL-raising drug that was recently shown to increase the risk of death and cardiovascular events， failed to halt the progression of atherosclerosis as measured by intravascular ultrasound (IVUS) and carotid intima-media thickness (IMT) .

　　Presenting the results of two carotid IMT studies， known as Rating Atherosclerotic Disease Change by Imaging with a New Cholesteryl-Ester-Transfer ProteinInhibitor (RADIANCE) 1 and 2， at the American College of Cardiology 2007 Scientific Sessions， Dr John Kastelein (Academic Medical Center， Amsterdam， the Netherlands)， told the press that something “strange” is going on with the novel cholesteryl-ester-transfer-protein (CETP) inhibitor. In all three studies， there were dramatic increases in HDL cholesterol and significant reductions in LDL cholesterol， but this improvement in lipid parameters was offset by significant increases in blood pressure.

　　“When you focus on the primary end point， there is a striking resemblance to all three imaging trials that actually showed no benefit whatsoever with this drug，” said Kastelein.

　　With an increased risk of cardiovascular events terminating the large torcetrapib morbidity and mortality trial， the neutral imaging studies are good news to investigators who still believe the drug class might eventually come to fruition as an agent to raise HDL-cholesterol levels and combat cardiovascular disease.

　　“We believe the failure doesn‘t necessarily rule out the possibility that another drug in the class， one that is completely clean， with no blood-pressure effects and no other evidence of toxicity， could possibly work，” said Dr Steven Nissen (Cleveland Clinic， OH)， lead author of the IVUS study， a trial known as the Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atherosclerosis by CETP Inhibition and HDL Elevation (ILLUSTRATE). “We think that the bar to jump over now has gotten a lot higher， and it’s going to be very challenging to move forward， [but] I think we should go forward.”

　　ILLUSTRATE and RADIANCE 1 are published online March 26， 2007 in the New England Journal of Medicine， along with an accompanying editorial by Dr Alan Tall (Columbia University， New York)