Pathways of fenofibrate effects on cardiovascular outcomes in ACCORD

描述（申请人提供）：雅阁试验测试了1）强化葡萄糖控制是否比标准葡萄糖控制更能减少心血管疾病（CVD）事件，2）强化血压控制是否比标准血压控制更能减少CVD事件，3）辛伐他汀联合非诺贝特治疗血脂异常较单用辛伐他汀更能减少2型糖尿病患者的心血管事件（雅阁Lipid）。在雅阁Lipid研究中，尽管辛伐他汀联合非诺贝特与辛伐他汀单药相比未显著降低CVD事件，但预先规定的分析显示，不同性别、人种和基线血脂值的非诺贝特应答存在异质性，男性、白人和显著血脂异常患者的CVD事件似乎较少。为了更好地了解这种异质性，我们建议确定非诺贝特反应的非脂质生物标志物预测。这些包括apoB、apoCIII、apoAI、apoAII、脂蛋白大小和颗粒数、VLDL组成，包括VLDL TG脂肪酸、纤维蛋白原、CRP和同型半胱氨酸的脂质组学分析。具体而言，我们将1）确定这些生物标志物预测雅阁Lipid参与者子队列中CVD发生的能力，2）评估非诺贝特有利地改变这些生物标志物的能力，3）确定这些生物标志物预测非诺贝特在表现出异质性的亚组中的有利反应的能力。我们将把研究重点放在整个研究队列的1800人的病例队列上。然而，如前所述，我们还将对三个亚组进行分析，其中非诺贝特治疗对CVD的影响似乎存在异质性：男性vs.女性，白人vs.非白人，血脂异常vs.非血脂异常。 公共卫生相关性：本研究的目的是确定血浆生物标志物，这些生物标志物可用于预测哪些患者将对他汀类药物（如本研究中使用的辛伐他汀）和贝特类药物（如本研究中使用的非诺贝特）的联合治疗产生有益反应。这一点尤其重要，因为在雅阁Lipid中，虽然辛伐他汀加用非诺贝特的总体效果是心血管事件适度且无显著性降低，但甘油三酯水平最高和HDL胆固醇水平最低的受试者亚组可能受益。另一方面，妇女和非白人的表现似乎不如男子和白人。我们的结果应该有助于我们理解这些不同的结果。

DESCRIPTION (provided by applicant): The ACCORD trial tested whether 1) intensive glucose ontrol reduces cardiovascular disease (CVD) events more than standard glucose control, 2) intensive blood pressure control reduces CVD events more than standard blood pressure control, 3) treatment of dyslipidemia with simvastatin plus fenofibrate reduce CVD events more than treatment with simvastatin alone in people with type 2 diabetes mellitus (ACCORD Lipid). In ACCORD Lipid, although simvastatin plus fenofibrate did not significantly reduce CVD events compared to simvastatin alone, pre- specified analyses demonstrated heterogeneity in response to fenofibrate by gender, race, and baseline lipid values with men, whites, and those with significant dyslipidemia appearing to have fewer CVD events. To better understand this heterogeneity, we propose to identify non-lipid biomarkers predictive of fenofibrate response. These include apoB, apoCIII, apoAI, apoAII, lipoprotein size and particle number, VLDL composition, including lipidomic profiling of VLDL TG fatty acids, fibrinogen, CRP, and homocysteine. Specifically we will 1) determine the ability of these biomarkers to predict the occurrence of CVD in a sub-cohort of ACCORD Lipid participants 2) assess the ability of fenofibrate to favorably modify these biomarkers and 3) determine the ability of these biomarkers to predict favorable responses to fenofibrate in the subgroups that demonstrated heterogeneity. We will focus our study on a case-cohort of 1800 individuals from the entire study cohort. However, as noted, we will also conduct analyses on three subgroups in which there appeared to be heterogeneity regarding the effects of fenofibrate treatment on CVD: men vs. women, Whites vs non-whites, and dyslipidemics vs non-dyslipidemics. PUBLIC HEALTH RELEVANCE: This goal of the proposed study is to identify plasma biomarkers hat will be useful in predicting which patients will respond beneficially to the combination of a statin (such as simvastatin used in this study) and a fibrate (such as fenofibrate used in this study). This is particularly important because in ACCORD Lipid, although the overall effect of adding fenofibrate to simvastatin was a modest and non-significant reduction in cardiovascular events, a subgroup of subjects with the highest triglyceride and lowest HDL cholesterol levels may have benefited. On the other hand, women and non-whites did not appear to do as well as men and whites. Our results should help us understand these different results.