Pathways of fenofibrate effects on cardiovascular outcomes in ACCORD

ACCORD 中非诺贝特对心血管结局的影响途径

基本信息

批准号：
8339945
负责人：
HENRY N GINSBERG
金额：
$ 75.53万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8339945
关键词：
Accounting Affect Age Apolipoproteins B Biological Markers C-reactive protein Cardiovascular Diseases Cardiovascular system Cohort Studies Combined Modality Therapy Diabetes Mellitus Dyslipidemias Ensure Event Fatty Acids Fenofibrate Fibrates Fibrinogen Gender Glucose Goals Heterogeneity High Density Lipoprotein Cholesterol Homocysteine Homocystine Hypertriglyceridemia Individual Intervention Lipids Lipoproteins Matched Group Measurement Measures Mediating Myocardial Infarction Non-Insulin-Dependent Diabetes Mellitus Outcome Participant Particle Size Pathway interactions Patients Placebos Plasma Population Race Randomized Rest Role Simvastatin Specific qualifier value Stroke Study Subject Subgroup Testing Very low density lipoprotein Woman arm blood glucose regulation blood pressure regulation case control cohort high risk interest meetings men non-diabetic novel response trend

项目摘要

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.

描述（由申请人提供）：ACCORD 试验测试了是否 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 CVD 事件，3) 治疗对于 2 型糖尿病患者，辛伐他汀联合非诺贝特治疗血脂异常比单独使用辛伐他汀治疗更能减少 CVD 事件 (ACCORD Lipid)。在 ACCORD Lipid 中，虽然与单用辛伐他汀相比，辛伐他汀加非诺贝特并未显着减少 CVD 事件，但预先指定的分析表明，性别、种族和基线血脂值对非诺贝特的反应存在异质性，其中男性、白人和患有严重血脂异常的人似乎CVD 事件较少。为了更好地理解这种异质性，我们建议鉴定预测非诺贝特反应的非脂质生物标志物。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。具体来说，我们将 1) 确定这些生物标志物预测 ACCORD Lipid 参与者子队列中 CVD 发生的能力 2) 评估非诺贝特有利地修改这些生物标志物的能力，以及 3) 确定这些生物标志物预测有利的能力亚组中对非诺贝特的反应表现出异质性。我们的研究重点是整个研究队列中 1800 名个体的病例队列。然而，如前所述，我们还将对非诺贝特治疗对 CVD 的影响似乎存在异质性的三个亚组进行分析：男性与女性、白人与非白人以及血脂异常者与非血脂异常者。公共健康相关性：拟议研究的目标是确定血浆生物标志物，这将有助于预测哪些患者将对他汀类药物（例如本研究中使用的辛伐他汀）和贝特类药物（例如用于本研究的非诺贝特）的组合产生有益的反应。这项研究）。这一点尤其重要，因为在 ACCORD Lipid 中，尽管在辛伐他汀中添加非诺贝特的总体效果是适度且非显着地减少了心血管事件，但甘油三酯最高和 HDL 胆固醇水平最低的受试者亚组可能受益。另一方面，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。