Article, see p 999

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 …

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评估药物的安全性和功效是昂贵的，许多有前途的候选人可能会出现不良的副作用。蛋白质组生物标志物的新发展能否帮助及时监控疗效并保护参与者安全？在本期《循环》中，Williams等人^1进行了一项回顾性研究，通过对ILLUMINATE试验中使用Torcetrapib治疗的患者（研究血脂水平管理以了解其对动脉粥样硬化事件的影响）是否显示出早期心血管风险增加的迹象进行了回顾性研究。

在2004年8月至2005年12月之间，ILLUMINATE试验招募了15000多例具有高冠心病风险的患者。将患者随机分为两组，分别接受Torcetrapib联合阿托伐他汀治疗与单独使用阿托伐他汀治疗。Torcetrapib是胆固醇酯转移蛋白（CETP）的小分子抑制剂，胆固醇转移酶是一种血浆酶，可在低密度脂蛋白和高密度脂蛋白（HDL）之间转移脂质。从机制上讲，CETP抑制作用可增加血浆中的好胆固醇HDL并降低坏胆固醇的低密度脂蛋白，这两个因素分别已知与人类冠心病的发生率较低和较高相关。因此，torcetrapib看起来像是合理药物设计的代言人，并且在制作过程中轰动一时。

借助事后观察，现在看来尽管HDL与降低冠心病的风险有关，但似乎并没有因果关系降低它的可信度。自从ILLUMINATE以来，孟德尔随机分析已指出，与较高的HDL相关的单核苷酸多态性并不一定降低心肌梗塞的风险。²此外，具有某些罕见突变的人……