A MULTI-CENTER RAND, PLACEBO CTRL, DBL BLIND TRIAL - METFORMIN IN OBESE ADOLESCE

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。 摘要 一、假说 这项试验将检验这样一种假设，即在肥胖青少年中，使用缓释二甲双胍(GLucphage XR)治疗，加上生活方式干预，将导致肥胖减少(以体重指数[BMI]衡量)。 二、具体目标 本研究的目的是确定二甲双胍XR治疗肥胖症的安全性和有效性。主要的研究终点是体重指数的变化。将监测药物的毒性和副作用。由于肥胖症是一种与发病率和死亡率相关的疾病，目前还没有被证明有效和持久的治疗方法，二甲双胍XR是一个合理的治疗选择。 三、背景和意义 美国正面临着年轻人中肥胖症的流行。在过去的七年里，根据体重指数(BMI)和30公斤/米的定义，肥胖症的患病率增加了50%[3，4]。对于病态肥胖成年人，定义为体重指数为35公斤/米，死亡率增加152至279%[5]。在退伍军人管理局对25-34岁肥胖男性的研究中，7年来的超额死亡率是13倍[6]。与成年人一样，与儿童和青少年肥胖相关的风险包括高血压和胆固醇水平升高，从而使这些人容易患上心血管疾病。此外，相当数量的肥胖青年胰岛素浓度异常高，从而增加了患2型糖尿病的风险。目前，帮助这些人的选择有限。虽然改变生活方式的尝试(例如，改变饮食和活动水平)在短期内可能会取得一些成功，但从长远来看，保持减肥的尝试往往失败。此外，目前还没有安全的药物可以随着时间的推移安全地显著减轻体重。二甲双胍是一种口服降糖、胰岛素增敏剂，在许多国家用于治疗2型糖尿病已有40多年的历史。1995年3月，它被美国食品和药物管理局批准用于治疗成人2型糖尿病。二甲双胍通过肝脏和外周作用改善胰岛素敏感性，降低胰岛素抵抗。它不会增加胰岛素的分泌[7-11]。此外，二甲双胍减少肝脏葡萄糖的产生并导致体重减轻[12]。与作用相似的现有药物相比，只有二甲双胍具有减肥活性，可能是通过增加一氧化氮的产生和改善胰岛素敏感性[13]。二甲双胍轻微的胃肠道副作用也有可能导致体重减轻。因此，二甲双胍通常是肥胖2型糖尿病患者的首选药物[14]。在一项对非糖尿病肥胖成年人的研究中，二甲双胍治疗导致食物摄入量减少，体重和脂肪减少[15]。二甲双胍通常用于青少年2型糖尿病患者，并有良好的安全记录，即使在儿童不慎给药后也是如此[16]。尽管许多儿科内分泌学家使用二甲双胍治疗肥胖青少年和高胰岛素水平的青少年，但支持这一治疗过程的公开数据有限。出于这个原因，这项研究旨在确定二甲双胍XR是否安全有效地治疗肥胖的非糖尿病青少年。此外，一旦停止使用二甲双胍治疗，关于一个人的体重变化的信息很少。在这项研究中，为期一年的随访阶段将允许确定二甲双胍XR在停用后是否继续有效。相反，将分析在后续阶段收集的数据，以评估一旦停用二甲双胍XR是否会对受试者“S体重”产生有害影响(例如，与对照组受试者相比，在后续阶段，二甲双胍组受试者的体重增加是否会增加)。

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 I. HYPOTHESIS This trial will test the hypothesis that among obese adolescents, treatment with extended-release metformin (Glucophage XR), coupled with a lifestyle intervention, will result in decreased obesity (as measured by Body Mass Index [BMI]) II SPECIFIC AIMS The purpose of this study is to determine the safety and effectiveness of metformin XR in treating obesity. The primary study endpoint is change in BMI. Drug toxicity and side effects will be monitored. Since there is no proven effective and lasting treatment for obesity, a disease that is associated with morbidity and mortality, metformin XR is a reasonable therapeutic option. III. BACKGROUND AND SIGNIFICANCE America is facing an epidemic of obesity among its youth. In the last seven years, there has been a 50% increase in the prevalence of obesity as defined by a Body Mass Index (BMI) > 30 kg/m[3, 4]. For the morbidly obese adult, which is defined as having a BMI > 35 kg/m, mortality is increased by 152 to 279% [5]. In a Veterans Administration study of obese 25-34 year old males, there was a 13-fold excess mortality rate over 7 years [6]. As in adults, risks associated with childhood and adolescent obesity include elevated blood pressure and cholesterol levels, predisposing these individuals to cardiovascular disease. In addition, a significant number of obese youth have abnormally high concentrations of insulin, with an attendant increased risk of developing type 2 diabetes mellitus. Currently, limited options are available to help such individuals. While attempts at lifestyle change (e.g., altering diet and activity level) may have some success in the short term, attempts at maintaining weight loss over the long term often fail. Furthermore, there are no current medications that will safely induce significant weight loss over time. Metformin Metformin is an oral antihyperglycemic, insulin-sensitizing agent that has been used in many countries for treatment of type 2 diabetes for more than 40 years. In March 1995, it was approved by the Food and Drug Administration for the treatment of adult type 2 diabetes. Metformin improves insulin sensitivity and reduces insulin resistance by hepatic and peripheral actions. It does not increase insulin secretion [7-11]. Further, metformin decreases hepatic glucose production and results in weight loss [12]. Compared to available drugs that act similarly, only metformin has weight-lowering activity, perhaps by increasing nitric oxide production and improving insulin sensitivity [13]. It is also possible that the mild gastrointestinal side effects of metformin induce weight loss. Metformin is therefore often the agent of choice in obese, type 2 diabetics [14]. In a study of non-diabetic obese adults, treatment with metformin resulted in decreased food intake, and decreased body weight and fat [15]. Metformin is commonly used in adolescent type 2 diabetics and has a good safety record, even following inadvertent administration to children [16]. Although many pediatric endocrinologists treat obese adolescents and those with high insulin levels with metformin, there are only limited published data to support this therapeutic course. For this reason, this study was designed to determine whether metformin XR is safe and effective in treating obese non-diabetic adolescents. In addition, there is very little information about how one's weight changes once treatment with metformin is discontinued. In this study, the one year Follow-up phase will allow for a determination of whether metformin XR continues to be effective once it is discontinued. Conversely, data collected during the Follow-up phase will be analyzed in order to assess whether there is a deleterious effect on a subject"s weight once metformin XR is discontinued (e.g., whether there will be increased weight gain among the subjects in the Metformin group during the Follow-up phase as compared to the subjects in the Control group).