Cholesteryl ester transfer protein inhibition and HDL increase: has the dream ended?

Statins effectively lower plasma low-density lipoprotein cholesterol (LDL-C) levels and reduce the risk of vascular events. However, this benefit might be improved by dealing with other vascular risk factors such as high-density lipoprotein cholesterol (HDL-C). It follows that there has been an interest in drugs that raise plasma HDL-C levels. Among these drugs are the cholesteryl ester transfer protein (CETP) inhibitors. The first CETP inhibitor to be evaluated in an event-based trial was torcetrapib. This drug can considerably elevate serum HDL-C levels (e.g., by 72%). However, a recently published trial (ILLUMINATE) showed that torcetrapib used in combination with atorvastatin was associated with significantly more vascular events and deaths than atorvastatin alone. This finding resulted in the discontinuation of the torcetrapib development programme. The cause(s) of the adverse outcome remain speculative. It has been suggested that a significant rise in systolic blood pressure and possibly the quality of the HDL produced may be relevant. Despite this disappointing outcome it seems to be too early to close the book on CETP inhibitors because two other members of this class are being evaluated. These drugs (JTT-705 and anacetrapib) may be devoid of the adverse effect on systolic blood pressure. Eventually only appropriately designed, event-based trials, will settle the issue of whether CETP inhibitors are clinically useful.