LIFESTYLE CHANGE AND MEDICATION IN DYSLIPIDEMIC YOUTH WITH OBESITY RELATED IN

与肥胖相关的血脂异常青少年的生活方式改变和药物治疗

• 批准号: 7605884
• 负责人: Siripoom V McKay
• 金额: $ 1.11万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-15 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7605884
• 关键词: Adolescent; Adult; Biliary; Biological Markers; Cardiovascular system; Cessation of life; Child; Childhood; Cholesterol; Clinical Data; Coagulation Process; Computer Retrieval of Information on Scientific Projects Database; Control Groups; Data; Disease regression; Dyslipidemias; Education; Event; Familial Hypercholesterolemia; Fat-Soluble Vitamin; Fatty Acids; Functional disorder; Funding; Grant; Guidelines; Health; High Density Lipoprotein Cholesterol; Hypertriglyceridemia; Incidence; Inflammatory; Institution; Insulin Resistance; Intervention; LDL Cholesterol Lipoproteins; Left; Life Style; Link; Lipids; Low-Density Lipoproteins; Measurement; Measures; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oxidative Stress; Particle Size; Pharmaceutical Preparations; Pharmacologic Substance; Placebo Control; Placebos; Population; Publishing; Randomized; Rate; Research; Research Personnel; Resources; Risk; Safety; Source; Surrogate Markers; Therapeutic; Thick; United States National Institutes of Health; Week; Youth; abstracting; atorvastatin; cardiovascular risk factor; cholesterol absorption; density; diabetic; ezetimibe; improved; inhibitor/antagonist; intima media; particle; prevent

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. ABSTRACT HYPOTHESIS Primary Hypothesis: When compared with TLC plus placebo control group: 1. Insulin resistant children given atorvastatin plus TLC will show a decrease in LDL-C concentration of 30 %. 2. Insulin resistant children given atorvastatin plus ezetimibe plus TLC will show a LDL-C concentration decrease of 40-45%. Secondary Hypothesis: 1. Insulin resistant children given atorvastatin plus TLC for 6 weeks will show an increase in LDL-C particle size of 5% when compared to placebo plus TLC 2. Insulin resistant children given TLC plus placebos will show a decrease in LDL-cholesterol by 5%. SPECIFIC AIMS To measure LDL-C concentration, LDL particle size, and CVD biomarkers (including inflammatory, oxidative stress, and abnormal coagulation markers) in two groups of insulin resistant children (type 2 diabetes mellitus and obese insulin resistant without type 2 diabetes). These measurements will be taken before and after randomization to the following 3 groups 1. TLC plus 2 placebos 2. TLC plus atorvastatin 3. TLC plus atorvastatin plus ezetimibe III. BACKGROUND AND SIGNIFICANCE Background: Insulin resistance is linked to many major health problems, whose incidences are rising in the pediatric population , . Adult studies have shown dyslipidemia, endothelial dysfunction, and increased cardiovascular (CV) risk are associated with diabetes mellitus type 2 and obesity related insulin resistance . Adult diabetic dyslipidemia and the dyslipidemia associated with insulin resistance manifests as elevated triglycerides, low high density cholesterol (HDL-C), and only mildly elevated low density lipoproteins (LDL-C). The lipid profile is being characterized in the same way in insulin resistant children. , Low density lipoprotein cholesterol (LDL-C) has been recognized as a surrogate marker for cardiovascular (CV) risk in adults . Lowering LDL-C with statin therapy has been shown in adult studies to decrease the rate of CV thromboembolic events . Adults with obesity related insulin resistance and type 2 diabetes the LDL-C particle is small small and dense. This small dense quality may partially explain why diabetics have an increased risk of CVD when their LDL-C concentration is relatively normal . Many studies on the effect of statins on LDL-C concentration and particle size in adults have been published , . There is little data on the use of statins in the pediatric population. Atorvastatin has only been given to children with heterozygous familial hypercholesterolemia to lower LDL-cholesterol in 2 large studies , . One study has shown regression in the intima-media thickness of the carotid arteryxv. The safety profile has been equal to placebo for children with familial hypercholesterolemia in these studies. Ezetimibe is a new selective dietary and biliary cholesterol absorption inhibitor . Adults taking statins alone that have not been able to lower their LDL-C to levels recommended by the revised National Cholesterol Education Panel III, have now been able to lower their LDL-C concentration within NCEP III guidelines with the addition of Ezetimibe . Ezetimibe has not been shown to prevent fat soluble vitamins or fatty acids from being absorbed enterically. Ezetimibe has a similar safety profile, when added to statin therapy, to the safety profile of monotherapy with a statinxix. The LDL-cholesterol in children with familial hypercholesterolemia is very elevatedxv. The natural progression to premature CV death if this population is left untreated is known . NCEP criteria for children and adolescents allow practitioners to identify children with familial hypercholesterolemia that need pharmaceutical intervention to improve their lipid profiles and decrease their risk of progressive CVD . The NCEP and ADA criteria for children may be allowing the undertreatment of a subset of the dyslipidemic insulin resistant pediatric population due to lack of sufficient data to support treatment guidelines at lower LDL-C concentrationsxxi . Although children with obesity related insulin resistance have LDL-C concentrations that are not as elevated as children with heterozygous familial hypercholesterolemia, their LDL-C may be more atherogenic. Obesity related insulin resistant children and children with type 2 diabetes mellitus may have small dense LDL-C. Treatment to lower total LDL-C concentration and increase LDL particle size may be needed. There is no clinical data of the effect of atorvastatin, ezetimibe, or therapeutic lifestyle change (TLC) on the lipid profile of insulin resistant children. We hypothesize treating insulin resistant children with atorvastatin, ezetimibe, and TLC may decrease the LDL-C concentration, and increase the LDL-C particle size.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 摘要 假设 主要假设： 与TLC+安慰剂对照组相比： 1. 接受阿托伐他汀联合TLC治疗的胰岛素抵抗儿童将显示LDL-C浓度降低30%。 2. 接受阿托伐他汀+依折麦布+TLC治疗的胰岛素抵抗儿童将显示LDL-C浓度降低40- 45%。 次要假设： 1. 与安慰剂+TLC相比，接受阿托伐他汀+TLC治疗6周的胰岛素抵抗儿童的LDL-C颗粒大小增加5% 2. 接受TLC加安慰剂治疗的胰岛素抵抗儿童的LDL-胆固醇降低5%。 具体目标 测量两组胰岛素抵抗儿童（2型糖尿病和肥胖胰岛素抵抗不伴2型糖尿病）的LDL-C浓度、LDL颗粒大小和CVD生物标志物（包括炎症、氧化应激和异常凝血标志物）。 这些测量将在随机分配至以下3组之前和之后进行 1. TLC +2种安慰剂 2. TLC+阿托伐他汀 3. TLC+阿托伐他汀+依折麦布 三. 背景和意义背景： 胰岛素抵抗与许多主要的健康问题有关，这些问题在儿科人群中的发病率正在上升。 成人研究表明，血脂异常、内皮功能障碍和心血管（CV）风险增加与2型糖尿病和肥胖相关的胰岛素抵抗相关。 成人糖尿病血脂异常和与胰岛素抵抗相关的血脂异常表现为甘油三酯升高、高密度胆固醇（HDL-C）降低和低密度脂蛋白（LDL-C）仅轻度升高。 在胰岛素抵抗儿童中，脂质谱的特征也是相同的。, 低密度脂蛋白胆固醇（LDL-C）已被公认为成人心血管（CV）风险的替代标志物。成人研究显示，他汀类药物治疗降低LDL-C可降低CV血栓栓塞事件的发生率。 肥胖相关的胰岛素抵抗和2型糖尿病成人LDL-C颗粒小而致密。 这种小而密的质量可能部分解释了为什么当糖尿病患者的LDL-C浓度相对正常时，他们患CVD的风险会增加。 已经发表了许多关于他汀类药物对成人LDL-C浓度和颗粒大小影响的研究。 关于他汀类药物在儿科人群中的使用数据很少。 在2项大型研究中，阿托伐他汀仅用于杂合子家族性高胆固醇血症儿童，以降低LDL胆固醇。 一项研究显示颈动脉内膜中层厚度的消退xv。 在这些研究中，家族性高胆固醇血症儿童的安全性特征与安慰剂相同。 依折麦布是一种新型的选择性膳食和胆汁胆固醇吸收抑制剂。 单独服用他汀类药物的成年人无法将其LDL-C降低至修订后的国家胆固醇教育小组III推荐的水平，现在可以在添加依折麦布的情况下将其LDL-C浓度降低至NCEP III指南范围内。 依折麦布尚未显示可阻止脂溶性维生素或脂肪酸的肠吸收。 依折麦布与他汀类药物联合治疗的安全性特征与他汀类药物单药治疗的安全性特征相似。 家族性高胆固醇血症儿童的LDL-胆固醇水平非常高xv。如果该人群不接受治疗，则会自然进展为CV过早死亡。 NCEP儿童和青少年标准允许从业人员识别需要药物干预以改善其血脂谱并降低其进行性CVD风险的家族性高胆固醇血症儿童。 由于缺乏足够的数据支持较低LDL-C浓度下的治疗指南，NCEP和ADA儿童标准可能允许血脂异常胰岛素抵抗儿科人群的一个子集治疗不足xxi。 尽管肥胖相关胰岛素抵抗儿童的LDL-C浓度不像杂合子家族性高胆固醇血症儿童那样升高，但他们的LDL-C可能更易致动脉粥样硬化。 肥胖相关的胰岛素抵抗儿童和2型糖尿病儿童可能具有小而密的LDL-C。 可能需要治疗以降低总LDL-C浓度并增加LDL颗粒大小。 尚无阿托伐他汀、依折麦布或治疗性生活方式改变（TLC）对胰岛素抵抗儿童血脂谱影响的临床数据。 我们假设用阿托伐他汀、依折麦布和TLC治疗胰岛素抵抗儿童可能会降低LDL-C浓度，并增加LDL-C颗粒大小。