Background: Early detection of adverse effects of novel therapies and understanding of their mechanisms could improve the safety and efficiency of drug development. We have retrospectively applied large-scale proteomics to blood samples from ILLUMINATE (Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events), a trial of torcetrapib (a cholesterol ester transfer protein inhibitor), that involved 15 067 participants at high cardiovascular risk. ILLUMINATE was terminated at a median of 550 days because of significant absolute increases of 1.2% in cardiovascular events and 0.4% in mortality with torcetrapib. The aims of our analysis were to determine whether a proteomic analysis might reveal biological mechanisms responsible for these harmful effects and whether harmful effects of torcetrapib could have been detected early in the ILLUMINATE trial with proteomics.

Methods: A nested case-control analysis of paired plasma samples at baseline and at 3 months was performed in 249 participants assigned to torcetrapib plus atorvastatin and 223 participants assigned to atorvastatin only. Within each treatment arm, cases with events were matched to controls 1:1. Main outcomes were a survey of 1129 proteins for discovery of biological pathways altered by torcetrapib and a 9-protein risk score validated to predict myocardial infarction, stroke, heart failure, or death.

Results: Plasma concentrations of 200 proteins changed significantly with torcetrapib. Their pathway analysis revealed unexpected and widespread changes in immune and inflammatory functions, as well as changes in endocrine systems, including in aldosterone function and glycemic control. At baseline, 9-protein risk scores were similar in the 2 treatment arms and higher in participants with subsequent events. At 3 months, the absolute 9-protein derived risk increased in the torcetrapib plus atorvastatin arm compared with the atorvastatin-only arm by 1.08% (P=0.0004). Thirty-seven proteins changed in the direction of increased risk of 49 proteins previously associated with cardiovascular and mortality risk.

Conclusions: Heretofore unknown effects of torcetrapib were revealed in immune and inflammatory functions. A protein-based risk score predicted harm from torcetrapib within just 3 months. A protein-based risk assessment embedded within a large proteomic survey may prove to be useful in the evaluation of therapies to prevent harm to patients.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00134264.

背景：尽早发现新疗法的不良反应并了解其机理可以提高药物开发的安全性和效率。我们已对ILLUMINATE（血脂水平管理研究，以了解其对动脉粥样硬化事件的影响）的血样进行回顾性大规模蛋白质组学研究，该试验是torcetrapib（胆固醇酯转移蛋白抑制剂）的一项试验，涉及15,067名心血管疾病高风险参与者。ILLUMINATE终止于中位数550天，因为使用Torcetrapib的心血管事件绝对绝对值显着增加1.2％，死亡率显着增加0.4％。

方法：对249名被分配给torcetrapib加阿托伐他汀的参与者和223名仅被分配给阿托伐他汀的参与者在基线和3个月时对配对血浆样本进行了嵌套病例对照分析。在每个治疗组中，发生事件的病例与对照者1：1匹配。主要结果是对1129种蛋白质进行了调查，以发现被torcetrapib改变的生物学途径，并通过9种蛋白质的风险评分来预测心肌梗塞，中风，心力衰竭或死亡。

结果： torcetrapib血浆中200种蛋白质的浓度发生了显着变化。他们的途径分析揭示了免疫和炎症功能的意外和广泛变化，以及内分泌系统的变化，包括醛固酮功能和血糖控制。基线时，两个治疗组的9个蛋白质风险评分相似，而随后发生事件的参与者的9个蛋白质风险评分更高。在3个月时，与仅使用阿托伐他汀的组相比，torcetrapib联合阿托伐他汀组的绝对9蛋白衍生风险增加了1.08％（P = 0.0004）。37种蛋白质改变了之前与心血管疾病和死亡风险相关的49种蛋白质的风险增加方向。

结论：迄今为止，torcetrapib的未知作用在免疫和炎症功能方面被揭示。基于蛋白质的风险评分仅在3个月内就预测了torcetrapib的危害。嵌入在大型蛋白质组学调查中的基于蛋白质的风险评估可能被证明可用于评估预防对患者造成伤害的疗法。

临床试验注册： URL：https://www.clinicaltrials.gov。唯一标识符：NCT00134264。