CETP inhibitor torcetrapib

CETP inhibitor torcetrapib

Why CETP inhibitor torcetrapib failed to slow atherosclerosis progression and increased mortality?

Torcetrapib was the first cholesteryl ester transfer protein (CETP) inhibitor to be used in clinical trials. Even though it raised the HDL cholesterol levels and reduced LDL cholesterol levels, it failed to produce regression of atherosclerosis and increased all cause mortality. Two potential reasons have been suggested for the lack of benefit of torcetrapib. One hypothesis is that the HDL particles produced by CETP inhibition do not participate in reverse cholesterol transport. Another possibility is that torcetrapib has some toxicity that counterbalances the beneficial effects of increasing HDL cholesterol by CETP inhibition.

A substudy of the ILLUSTRATE (Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atherosclerosis by CETP Inhibition and HDL Elevation) by Stephen J Nicholls, E Murat Tuzcu, Danielle M Brennan, Jean-Claude Tardif and Steven E Nissen [1] sought to find out the reason by a subgroup analysis. They found that majority of the torcetrapib treated patients showed no regression of atherosclerosis as assessed by intravascular ultrasound. Regression was seen only with the highest levels of HDL cholesterol. Serum sodium levels were elevated and serum potassium lowered on torcetrapib treatment, indicating and aldosterone like effect. This may explain the substantially increased blood pressure in the torcetrapib treatment group.

In fact the ILLUMINATE trial [2] was stopped prematurely because of an increased risk of death and cardiovascular events in patients receiving torcetrapib. That study had shown a 72.1% rise in HDL cholesterol and 24.9% reduction in LDL cholesterol as well as 5.4 mm Hg increase in systolic blood pressure at 12 months. There was a decrease in serum potassium, and increases in serum sodium, bicarbonate, and aldosterone levels in the study. Further development of the drug (torcetrapib) was stopped following the study results. It is thought that other CETP inhibitors without this off target toxicity may produce regression of atherosclerosis. Even though the blood pressure was elevated in ILLUMINATE trial, stroke rate which is generally considered a sensitive indicator of the adverse clinical effect of rise in blood pressure, was not documented. So it is possible that torcetrapib has some unknown toxicity which deters its beneficial effect on regression of atherosclerosis by raising HDL levels.

References

1. Stephen J Nicholls, E Murat Tuzcu, Danielle M Brennan, Jean-Claude Tardif, Steven E Nissen. Cholesteryl ester transfer protein inhibition, high-density lipoprotein raising, and progression of coronary atherosclerosis: insights from ILLUSTRATE (Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atherosclerosis by CETP Inhibition and HDL Elevation). Circulation. 2008 Dec 9;118(24):2506-14.
2. Philip J Barter, Mark Caulfield, Mats Eriksson, Scott M Grundy, John J P Kastelein, Michel Komajda, Jose Lopez-Sendon, Lori Mosca, Jean-Claude Tardif, David D Waters, Charles L Shear, James H Revkin, Kevin A Buhr, Marian R Fisher, Alan R Tall, Bryan Brewer, ILLUMINATE Investigators. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. 2007 Nov 22;357(21):2109-22.