SomaLogic, Inc., Boulder, CO (S.A.W., R.K.D., R.O., S.J.W.).
Department of Medicine (A.C.M., P.G.).
Circulation. 2018 Mar 6;137(10):999-1010. doi: 10.1161/CIRCULATIONAHA.117.028213. Epub 2017 Oct 3.
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.
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.
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% (=0.0004). Thirty-seven proteins changed in the direction of increased risk of 49 proteins previously associated with cardiovascular and mortality risk.
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.
URL: https://www.clinicaltrials.gov. Unique identifier: NCT00134264.
早期发现新型疗法的不良反应，并了解其机制，可以提高药物开发的安全性和效率。我们对 ILLUMINATE（研究脂质水平管理以了解其对动脉粥样硬化事件的影响）试验中的大量血液样本进行了回顾性大规模蛋白质组学分析，该试验涉及 15067 名心血管高危参与者，使用了 torcetrapib（胆固醇酯转移蛋白抑制剂）。由于 torcetrapib 使心血管事件的绝对风险增加了 1.2%，死亡率增加了 0.4%，ILLUMINATE 在中位随访 550 天的时候终止。我们分析的目的是确定蛋白质组学分析是否可以揭示导致这些有害影响的生物学机制，以及是否可以通过蛋白质组学在 ILLUMINATE 试验早期检测到 torcetrapib 的有害影响。
在 249 名接受 torcetrapib 加阿托伐他汀治疗和 223 名仅接受阿托伐他汀治疗的参与者的配对基线和 3 个月的血浆样本中进行了嵌套病例对照分析。在每个治疗组中，将发生事件的病例与对照组 1:1 匹配。主要终点是对 1129 种蛋白质进行调查，以发现 torcetrapib 改变的生物学途径，并验证 9 种蛋白质风险评分预测心肌梗死、卒中和心力衰竭或死亡的能力。
血浆中 200 种蛋白质的浓度发生了显著变化。它们的通路分析显示，免疫和炎症功能出现了意想不到的广泛变化，以及包括醛固酮功能和血糖控制在内的内分泌系统的变化。在基线时，2 种治疗组的 9 种蛋白质风险评分相似，随后发生事件的参与者评分较高。在 3 个月时，torcetrapib 加阿托伐他汀组与阿托伐他汀组相比，9 种蛋白质衍生的绝对风险增加了 1.08%（=0.0004）。在以前与心血管和死亡率风险相关的 49 种蛋白质中，有 37 种蛋白质朝着增加风险的方向变化。
torcetrapib 以前未知的作用在免疫和炎症功能中被揭示出来。基于蛋白质的风险评分在仅仅 3 个月内预测了 torcetrapib 的危害。嵌入大型蛋白质组学调查中的基于蛋白质的风险评估可能在评估预防患者伤害的治疗方法方面证明是有用的。
