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

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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 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).