The withdrawal of torcetrapib from drug development: implications for the future of drugs that alter HDL metabolism

In December 2006, Pfizer withdrew torcetrapib, a cholesterol ester transferase protein (CETP) that elevates plasma HDL levels, from further development following an excess in mortality in the active treatment arm of the study. Although torcetrapib successfully elevated HDL levels, significant increases in blood pressure were observed in three surrogate outcome studies that were conducted over the approximate same time period. Two of these studies examined carotid intima-medial thickness and one examined coronary artery atheroma load and none of the studies found a significant benefit in favour of torcetrapib therapy. It is likely that the torcetrapib-induced increase in blood pressure contributed to the apparent adverse effect of the drug on mortality and further studies are needed to determine why this occurred and whether it is a class effect of CETP inhibitors. In addition, further research is needed to determine whether the manner which CETP alters vascular biology and, in particular, the effect that it has on vascular inflammation associated with denuded endothelium. Despite disappointing results so far, CETP inhibitors should not be abandoned as much remains to be learnt from them and they may yet prove to be a valuable class of lipid-modifying drug.