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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 中心，不一定是研究者的机构。 抽象的 假设 主要假设： 与 TLC 加安慰剂对照组相比： 1. 胰岛素抵抗儿童服用阿托伐他汀加TLC后，LDL-C浓度会降低30%。 2. 胰岛素抵抗儿童服用阿托伐他汀加依折麦布加 TLC 后，LDL-C 浓度会降低 40-45%。 次要假设： 1. 与安慰剂加 TLC 相比，胰岛素抵抗儿童服用阿托伐他汀加 TLC 6 周后，LDL-C 颗粒大小将增加 5% 2. 胰岛素抵抗儿童接受 TLC 加安慰剂后，LDL 胆固醇会降低 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但无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为以下 3 组之前和之后进行 1. TLC加2个安慰剂 2. TLC加阿托伐他汀 3. TLC加阿托伐他汀加依折麦布 三． 背景和意义 背景： 胰岛素抵抗与许多重大健康问题有关，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有关。 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）低、低密度脂蛋白（LDL-C）仅轻度升高。 胰岛素抵抗儿童的血脂谱也以同样的方式进行表征。 , 低密度脂蛋白胆固醇 (LDL-C) 已被认为是成人心血管 (CV) 风险的替代标志物。成人研究表明，用他汀类药物治疗降低 LDL-C 可以降低 CV 血栓栓塞事件的发生率。 患有肥胖症相关胰岛素抵抗和2型糖尿病的成年人中，LDL-C颗粒小而致密。 这种小而密的性质可能部分解释了为什么糖尿病患者在 LDL-C 浓度相对正常时患 CVD 的风险会增加。 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已发表。 关于儿科人群使用他汀类药物的数据很少。 在两项大型研究中，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低密度脂蛋白胆固醇。 一项研究表明颈动脉内膜中层厚度有所退化xv。 在这些研究中，对于患有家族性高胆固醇血症的儿童，其安全性与安慰剂相同。 依折麦布是一种新型选择性饮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 LDL-C 降低至修订后的国家胆固醇教育小组 III 推荐的水平，现在通过添加依泽替米贝，能够降低 NCEP III 指南中的 LDL-C 浓度。 尚未证明依折麦布可以阻止脂溶性维生素或脂肪酸被肠道吸收。 当依折麦布添加到他汀类药物治疗中时，其安全性与他汀类药物单一疗法的安全性相似。 患有家族性高胆固醇血症的儿童的低密度脂蛋白胆固醇非常升高xv。如果该人群不及时治疗，自然进展为心血管疾病过早死亡是已知的。 儿童和青少年的 NCEP 标准允许从业人员识别患有家族性高胆固醇血症的儿童，这些儿童需要药物干预来改善其血脂状况并降低进展性 CVD 的风险。 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 儿童标准可能允许对一部分血脂异常胰岛素抵抗儿童群体进行治疗不足。 尽管与肥胖相关的胰岛素抵抗儿童的 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 可能更容易导致动脉粥样硬化。 肥胖相关的胰岛素抵抗儿童和患有 2 型糖尿病的儿童可能存在小密度 LDL-C。 可能需要进行治疗以降低总 LDL-C 浓度并增加 LDL 颗粒大小。 目前尚无阿托伐他汀、依折麦布或生活方式改变治疗 (TLC) 对胰岛素抵抗儿童血脂影响的临床数据。 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 粒径。