LIFESTYLE CHANGE AND MEDICATION IN DYSLIPIDEMIC YOUTH WITH OBESITY RELATED IN

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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.