De-risking the clinical development of cholesteryl ester transfer protein inhibitors: how much is good enough?

Abstract

This editorial refers to ‘Torcetrapib impairs endothelial function in hypertension’†, by B. Simic et al. , on page 1615 Modification of HDL cholesterol (HDL-C) metabolism is the next frontier in cardiovascular drug development, and modulation of cholesteryl ester transfer protein (CETP) is an important addition to our armentarium in this field. Clinical trials have shown that CETP inhibitors substantially improve blood lipid profiles by raising plasma levels of HDL-C while simultaneously lowering LDL-C over and above what can be achieved with statin therapy.1–3 The Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) trial was the first phase III trial testing the efficacy of the CETP inhibitor torcetrapib (Pfizer, New York, NY, USA) in reducing the risk of cardiovascular events. ILLUMINATE had to be halted in late 2006 after an interim analysis by the Data Safety and Monitoring Board had indicated a statistically significant increase in total mortality in the torcetrapib arm.4 Almost simultaneously, the entire clinical development programme of torcetrapib was stopped. This unexpected finding has called into question the validity of CETP as a potential therapeutic target, but it has also challenged the concept of raising HDL-C levels to reduce cardiovascular disease risk. Despite suffering from this unprecedented set back, CETP is still considered by many to be a viable therapeutic target, and other CETP inhibitors are being developed by a robust number of pharmaceutical companies. Following the publication of ILLUMINATE, analyses of the imaging trials with torcetrapib, in vitro and in vivo experiments, genetic epidemiology studies, and phase II studies with other CETP inhibitors have been used to clarify whether torcetrapib's unexpected detrimental effects were an off-target side effect of the compound itself, or a phenomenon …