CLINICAL TRIAL: FENOFIBRATE AND ROSIGLITAZONE IN INSULIN RESISTANT DYSLIPIDEMIC

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 众所周知，胰岛素抵抗(IR)与心血管疾病(CVD)的风险增加有关。大约四分之一的美国人口患有胰岛素抵抗综合征(IRS)。胰岛素抵抗综合征与高甘油三酯(TG)和低高密度脂蛋白胆固醇(HDLC)有关。这种致动脉粥样硬化的脂蛋白模式还包括餐后脂血症，并与心血管疾病风险增加有关。目前尚不清楚与IR相关的心血管疾病风险是否仅仅是相关的脂质和脂蛋白异常的函数，但越来越多的证据表明情况并非如此。除了生活方式干预外，预防胰岛素抵抗患者心血管疾病的治疗选择包括通过激活核激素受体PPAR-α靶向脂质/脂蛋白紊乱的纤维酸化合物，以及最近通过激活相关核激素受体PPAR-伽马直接逆转胰岛素抵抗的噻唑烷二酮类药物。 有趣的是，后一类药物似乎对甘油三酯和高密度脂蛋白浓度没有重大影响，尽管它们降低了胰岛素、葡萄糖和游离脂肪酸，所有这些都有助于肝脏极低密度脂蛋白的产生。然而，之前的研究一直受到限制，因为它们只测量空腹脂肪/脂蛋白，并没有专门针对高甘油三酯和/或低高密度脂蛋白胆固醇的个体。此外，尽管已就促炎细胞因子、C反应蛋白和黏附分子等早期心血管疾病的标志物进行了研究，但关于贝特类药物对这些变量的影响的数据很少。计划中的研究将比较这两类药物对高甘油三酯和低高密度脂蛋白胆固醇的IR患者心血管疾病风险的影响。主要终点将包括空腹和餐后脂类和致动脉粥样硬化的残余脂蛋白，以及心血管疾病的替代标记物，如C反应蛋白、不对称二甲基精氨酸和黏附分子。协变量将包括IR、葡萄糖、胰岛素和游离脂肪酸浓度的变化。 我们假设，虽然贝特对空腹和餐后脂/脂蛋白谱有相对较大的影响，而噻唑二酮对胰岛素和葡萄糖代谢有相对较大的影响，但这两种药物都会减少早期心血管疾病(炎症和内皮功能障碍)的循环标志物。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Insulin resistance (IR) is known to be associated with an increased risk for cardiovascular disease (CVD). Approximately 1/4 of the US population is IR and has the IR syndrome (IRS). IRS is associated with a high plasma triglyceride (TG) and a low high-density lipoprotein cholesterol (HDL-C). This atherogenic lipoprotein pattern also includes postprandial lipemia and is associated with an increased risk for CVD. It is unclear whether the CVD risk associated with IR is merely a function of the associated lipid and lipoprotein abnormalities, but increasing evidence suggests that this is not the case. Treatment options beyond lifestyle interventions to prevent CVD in IR individuals include fibric acid compounds that target the lipid/lipoprotein disturbances via activation of the nuclear hormone receptor PPAR-alpha, and more recently, the thiazolidenedione class of drugs that directly reverse the IR via activation of the related nuclear hormone receptor, PPAR-gamma. Interestingly, the latter class of drugs does not appear to have a major effect on TG and HDL-C concentrations despite the fact that they lower insulin, glucose, and free fatty acids, all of which contribute to hepatic VLDL production. However, prior studies have been limited in that they have measured only fasting lipid/lipoproteins, and they have not specifically targeted individuals with high TG and/or low HDL-C. Furthermore, while the thiazolidenediones have been studied with respect to markers of early CVD such as pro-inflammatory cytokines, C-reactive protein and adhesion molecules, there is little data on the effect of fibrates on these variables. The planned study will compare the effect of these two classes of drugs on CVD risk in IR individuals who have high TG and low HDL-C. Primary endpoints will include fasting and postprandial lipids and atherogenic remnant lipoproteins, along with surrogate markers of CVD such as C-reactive protein, asymmetric dimethylarginine, and adhesion molecules. Covariates will include change in IR, glucose, insulin, and free fatty acid concentrations. We hypothesize that while the fibrate will have a relatively greater effect on the fasting and postprandial lipid/lipoprotein profile, and the thiazolidenedione will have a relatively greater effect on insulin and glucose metabolism, circulating markers of early CVD (inflammation and endothelial dysfunction) will be reduced with both drugs.