The continuing complexities of high-density lipoprotein metabolism in drug discovery and development.

The termination of the Phase III clinical trial of Pfizer's CETP inhibitor torcetrapib, Investigation of lipid level management to understand its impact in atherosclerotic events (ILLUMINATE), due to excess mortality in the treatment group raised many questions for those involved in the discovery and development of drugs targeting high-density lipoprotein and of atherosclerosis in general. Although the reasons for the failure of torcetrapib are still not known, some of the consequences for the wider field are already apparent. Several imaging studies with torcetrapib showed no change in the various measures of lesion size, which gave some confidence in the interpretation of such studies. Although the case for raising high-density lipoprotein is strong and widely accepted, there will be a much closer interrogation of drugs targeting new mechanisms that will result in longer development times. In the meantime, existing drugs which modify high-density lipoprotein are being revisited, particularly niacin. This editorial commentary briefly discusses these and related issues from the perspective of 6 months following the termination of ILLUMINATE.