Effects of Exenatide on Overweight Adolescents With Prader-Willi Syndrome

Effects of Exenatide on Obesity and Appetite in Overweight Patients With Prader-Willi Syndrome

Prader-Willi Syndrome (PWS) is one of the most common genetic causes of obesity. Obesity is a major source of morbidity and mortality in this population. It can lead to sleep apnea, cor pulmonale, diabetes mellitus, and atherosclerosis. PWS has distinct characteristics that set it apart from other forms of obesity including insatiable appetite and food-seeking behavior which can be disruptive to home and school activities, and can cause severe social and psychological turmoil within families. PWS is also associated with unique hormonal abnormalities, most notably hyperghrelinemia. Ghrelin is a gut hormone produced in the stomach that stimulates food intake during a fast. It is hypothesized that the extremely high ghrelin levels in patients with PWS may cause or contribute to their insatiable appetite. Exenatide, a medication used in the treatment of type 2 diabetes mellitus in adults, appears to suppress ghrelin levels and cause weight loss. It was designed to mimic glucagon-like peptide 1 (GLP-1), an incretin hormone that stimulates insulin secretion and delays gastric emptying, among other effects. In the present study, the investigators will investigate the effects of a 6 month trial of exenatide in overweight adolescents with PWS. The investigators will quantify the changes in weight and body composition, as well as subjective measures of appetite, and concentrations of appetite-associated hormones. The investigators hypothesize that exenatide will improve weight, body composition, appetite, and plasma ghrelin levels during the treatment period.

BACKGROUND:

Prader-Willi syndrome (PWS) is associated with hyperphagia and hyperghrelinemia with major morbidity because of obesity without effective medical treatment targeting hyperphagia. Exenatide (Byetta [synthetic Exendin-4]; AstraZeneca, Wilmington DE) is a GLP-1 receptor agonist which reduces appetite and weight and may be an effective treatment in PWS.

OBJECTIVE: The objective of this study is to determine the effect of a 6-month trial of exenatide on appetite, weight and gut hormones in youth with PWS.

Inclusion Criteria:

• Diagnosis of Prader Willi Syndrome confirmed by genetic testing (DNA methylation or FISH)
• Ages 13-20 years
• body mass index (BMI) > 85th percentile for age and gender

Exclusion Criteria:

• Is currently using or has previously used a glucagon-like peptide-1 (GLP-1) agonist
• History of pancreatitis, or renal failure
• History of familial pancreatitis
• Amylase, or lipase levels > 2.5 times the upper limit of normal any time in the previous 2 years
• Creatinine clearance < 30 mL/min
• Other syndromic diagnoses
• gastrointestinal (GI) or renal illness in the 1 month prior to entering study
• Inability to take study drug
• Pregnancy
• Initiation of growth hormone (GH), estrogen, or testosterone or change > 25% of dose/kg/day during the 6 months prior to starting study
• Non-English speaking