The Failure of Torcetrapib -- The Search for the Reason Why

Linda Brookes, MSc


February 14, 2008

In This Article

ILLUMINATE: History and Background

The circumstances that led to the early termination of the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) trial, were well known by the time Philip J. Barter, MD, PhD (Sydney Heart Institute, Australia), chair of the ILLUMINATE steering committee, presented the primary results at the 2007 Scientific Session of the American Heart Association (AHA) in Orlando, Florida.[1] The international phase III, long-term outcomes trial of the cholesteryl ester transfer protein (CETP) inhibitor torcetrapib in patients at high cardiovascular risk was terminated by the sponsor, Pfizer (New York, NY), on December 2, 2006, after interim analysis[2] revealed a statistically significant excess of deaths and cardiovascular events in the group of patients treated with torcetrapib, despite significant improvements in all lipid parameters. Development of torcetrapib was also halted worldwide at that time.

The full report of the ILLUMINATE findings was eagerly awaited because although the trial was not designed to determine the mechanisms of any toxic or beneficial effects of torcetrapib, there was particular interest in whether the data pointed to any potential mechanisms that could account for the increase in events associated with torcetrapib and whether they were directly related to the off-target blood pressure effect of torcetrapib first identified in earlier studies. In brief, Prof. Barter reported that ILLUMINATE patients treated with torcetrapib showed statistically significant changes in serum electrolytes that, together with the rise in blood pressure, suggested activation of the renin-angiotensin-aldosterone system (RAAS) system as a likely effect of the drug. This conclusion was supported by an analysis of data from 1 of 3 phase III imaging studies with torcetrapib and from mechanistic studies of torcetrapib and other CETP inhibitors, all of which were also reported at the 2007 AHA meeting and are discussed below.