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

• 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
• 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

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）：协定试验测试了1）强化葡萄糖是否比标准葡萄糖控制更能减少心血管疾病（CVD）事件（CVD）事件，2）强化血压控制比标准血压更能降低CVD事件，而不是标准血压控制，3）与单独的Fenofibrate用Simbibrate相比，与单独的Fenofibrate相比，与imibibibrate MistiT的治疗相比，MISTATINT的治疗更多（Accord脂质）。根据脂质的脂质，尽管与单独的辛伐他汀相比，辛伐他汀加非诺佛特型并未显着降低CVD事件，但预定的分析表明，通过性别，种族和基线脂质值与男性，白人以及与患有明显的患病障碍的性别较大的患者相比，响应于性别，种族和基线脂质值的异质性均与CVD较少的事件相比。为了更好地理解这种异质性，我们建议鉴定非脂质生物标志物可预测非诺贝特反应。其中包括APOB，APOCIII，ApoAI，Apoaii，脂蛋白的大小和颗粒数，VLDL组成，包括VLDL TG脂肪酸的脂肪组分析，纤维蛋白原，CRP和同型半胱氨酸。具体而言，我们将1）确定这些生物标志物预测Accord脂质参与者中CVD的发生的能力2）评估Fenobibrate有利地修改这些生物标志物的能力，并确定这些生物标志物的能力，确定这些生物标志物可以预测在亚组中预测表现出呈现肾小体的纤维群的有利反应的能力。我们将把研究重点放在整个研究队列中的1800个个人的病例中。但是，如前所述，我们还将对三个亚组进行分析，在三个亚组中，对于非诺诺式治疗对CVD的影响似乎存在异质性：男性与女性，白人与非白人和非脂肪症相对于非脱脂病。 公共卫生相关性：拟议的研究的目标是识别等离子生物标志物帽子将有助于预测哪些患者将对他汀类药物的组合（例如本研究中使用的辛伐他汀）和纤维化（例如本研究中使用的fenofibrate）有益地反应。这一点尤其重要，因为脂质虽然将拟诺核化的总体效果添加到辛伐他汀的总体效果是心血管事件的适度且不显着的降低，但甘油三酸酯和最低HDL胆固醇水平的受试者亚组的亚组可能受益。另一方面，女性和非白人似乎并不像男人和白人那样做。我们的结果应该有助于我们了解这些不同的结果。