Harnessing the Power of Proteomics to Assess Drug Safety and Guide Clinical Trials
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Assessing drug safety and efficacy is costly, and many promising candidates can present unwanted side effects. Can new developments in proteomic biomarkers help provide timely monitoring of efficacy and protect participant safety? In this issue of Circulation, Williams et al1 tackled this question with a retrospective study on whether patients treated with torcetrapib in the ILLUMINATE trial (Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events) showed signs of increased cardiovascular risks early on.
The ILLUMINATE trial enrolled >15 000 patients at high coronary heart disease risk between August 2004 and December 2005. The patients were randomized into 2 groups receiving treatment with torcetrapib plus atorvastatin versus treatment with atorvastatin alone. Torcetrapib is a small-molecule inhibitor of cholesteryl ester transfer protein (CETP), a plasma enzyme that transfers lipids between low-density lipoprotein and high-density lipoprotein (HDL). CETP inhibition is known mechanistically to increase plasma good cholesterol HDL and decrease bad cholesterol low-density lipoprotein, 2 factors known to be correlated with a lower and higher incidence of coronary heart diseases in humans, respectively. Hence, torcetrapib looked like a poster child of rational drug design and a blockbuster in the making. Yet the ILLUMINATE trial was terminated abruptly in December 2006 after a median follow-up of 550 days because of unwanted side effects and an increase in cardiovascular events in torcetrapib-treated individuals.
With the benefit of hindsight, it seems credible now that although HDL is associated with lower coronary heart disease risk, it may not causally reduce it. Since ILLUMINATE, Mendelian randomization analyses have noted that single-nucleotide polymorphisms associated with higher HDLs do not necessarily reduce myocardial infarction risks.2 Moreover, individuals with certain rare mutations …