Hypothalamic Obesity Following Craniopharyngioma Surgery: A Pilot Trial of Combined Metformin and Diazoxide Therapy

To study the effect of combined diazoxide-metformin therapy on body weight in youth with hypothalamic obesity following treatment for craniopharyngioma. A secondary objective is to evaluate changes in insulin resistance (IR), beta-cell function, features of the metabolic syndrome, muscle metabolism and intramyocellular lipid. Hypothesis: Treatment with diazoxide and metformin will result in weight loss or slowed weight gain and improved metabolic profile, compared to pretreatment levels.

46 children under the age of 22 years have been treated surgically for craniopharyngioma tumor and are currently followed at the Hospital for Sick Children, Toronto. Approximately 50% are obese (BMI ≥ 95th percentile for age and gender assessed from the updated Centre for Disease Control growth charts), all of whom have panhypopituitarism requiring hormone replacement therapy. These children are assessed regularly in Endocrine Clinic and also are invited to attend a comprehensive care clinic for evaluation by an endocrinologist (Principal Investigator), neurosurgical clinical nurse practitioner, dietitian, exercise physiologist, psychologist and social worker to provide multi-disciplinary dietary and exercise consultation and psychological counseling for weight related concerns. This clinic will provide the infrastructure for recruitment and follow-up of study patients. Recruitment of eight subjects for this pilot study will occur over 6 months from patients attending the comprehensive clinic. This number was chosen as it is equivalent to the number chosen in the pilot study of octreotide by Lustig which showed beneficial changes in body mass index with treatment. This study evaluates a novel combination therapy in children with hypothalamic obesity at very high risk for complications. Evaluation of insulin resistance and metabolic changes on therapy will allow a better understanding of how insulin secretion relates to weight gain in this population. Successful therapy in a pilot setting will provide necessary data for a larger randomized trial in individuals with hypothalamic obesity including children with craniopharyngioma and others with damage to the hypothalamus secondary to other tumors, surgery or cranial irradiation.