Pathways of fenofibrate effects on cardiovascular outcomes in ACCORD

描述(申请人提供)：ACCORD试验测试是否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心血管疾病事件，3)在2型糖尿病患者中，辛伐他汀加非诺贝特治疗血脂异常的患者比单独使用辛伐他汀更能减少心血管疾病事件。在ACCORD LIPID中，尽管与单独使用辛伐他汀相比，辛伐他汀加非诺贝特并不能显著减少心血管事件，但预先指定的分析显示，非诺贝特的反应因性别、种族和基线血脂值而异，男性、白人和那些有明显血脂异常的人心血管事件似乎较少。为了更好地了解这种异质性，我们建议识别预测非诺贝特反应的非脂类生物标志物。这些指标包括apoB、apoCIII、apoAI、apoAII、脂蛋白大小和颗粒数、极低密度脂蛋白组成，包括极低密度脂蛋白甘油三酯脂肪酸、纤维蛋白原、C反应蛋白和同型半胱氨酸的脂组图谱。具体地说，我们将1)确定这些生物标记物在ACCORD血脂参与者中预测心血管疾病发生的能力，2)评估非诺贝特对这些生物标记物有利修改的能力，3)确定这些生物标记物在表现出异质性的亚组中预测非诺贝特有利反应的能力。我们将把我们的研究重点放在整个研究队列中的1800人的案例队列上。然而，如上所述，我们还将对非诺贝特治疗心血管疾病的效果似乎存在异质性的三个亚组进行分析：男性与女性，白人与非白人，血脂异常患者与非血脂异常患者。 公共卫生相关性：这项拟议研究的目标是确定有助于预测哪些患者将受益于他汀类药物(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)的血浆生物标志物。这一点特别重要，因为在ACCORD LIPID中，尽管在辛伐他汀中加入非诺贝特的总体效果是温和且不显著的心血管事件的减少，但甘油三酯水平最高和高密度脂蛋白水平最低的受试者亚组可能受益。另一方面，女性和非白人的表现似乎不如男性和白人。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.