Pathways of fenofibrate effects on cardiovascular outcomes in ACCORD

描述（由申请人提供）：ACCORD试验测试了1)强化血糖控制比标准血糖控制更能减少心血管疾病（CVD）事件，2)强化血压控制比标准血压控制更能减少CVD事件，3)在2型糖尿病患者中，用辛伐他汀加非诺贝特治疗比单独用辛伐他汀治疗更能减少CVD事件（ACCORD脂质）。在ACCORD脂质研究中，尽管辛伐他汀加非诺贝特与单独使用辛伐他汀相比并没有显著降低心血管事件，但预先指定的分析表明，非诺贝特对性别、种族和基线脂质值的反应存在异质性，男性、白人和那些有明显血脂异常的人似乎心血管事件较少。为了更好地理解这种异质性，我们建议鉴定非诺贝特反应的非脂质生物标志物。这些包括载脂蛋白ob、载脂蛋白ii、载脂蛋白ai、载脂蛋白aii、脂蛋白大小和颗粒数量、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。具体来说，我们将1)确定这些生物标志物在ACCORD脂质参与者亚队列中预测CVD发生的能力；2)评估非诺贝特对这些生物标志物有利修饰的能力；3)确定这些生物标志物在显示异质性的亚组中预测非诺贝特有利反应的能力。我们将研究的重点放在来自整个研究队列的1800人的病例队列上。然而，如上所述，我们还将对三个亚组进行分析，其中非诺贝特治疗CVD的效果似乎存在异质性：男性与女性，白人与非白人，血脂异常与非血脂异常。

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.