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

 -  Craniopharyngioma at least one year following surgery

 -  Evidence of at least one other endocrinopathy of hypothalamic origin

 -  Stable hormone replacement therapy (with one or more of thyroxine hydrocortisone,
 DDAVP, sex steroids and GH)

 -  Obesity, defined as weight >120% Ideal Body Weight (IBW) or BMI > 27 kg/m2, with
 normal weight for height before tumour diagnosis and weight gain >2SD above mean for
 age for 1 year following tumour treatment (41).

 -  Age 9 -22 years

 -  Minimum of 6 months of standard diet and exercise intervention (run-in period). This
 was chosen to allow a period of prospective measurements to establish individual
 baseline slope of change in BMI SDS prior to initiation of active treatment with
 diazoxide and metformin.

 Exclusion Criteria:

 -  Contraindications for Metformin or Diazoxide use (history or evidence of cardiac,
 renal, or progressive hepatic disease , diabetes or hypoxic conditions)

 -  Pharmacologic doses of glucocorticoids or use of other medications known to affect
 glucose metabolism (e.g. beta-blockers, oral hypoglycemics)

 -  Growth hormone (GH) initiation in the preceding 6 months or planned initiation in the
 next 6 months (to rule out potential confounding effect of GH on weight / body
 composition and glucose metabolism).

 -  Use of other weight loss medications

 -  Inability of the family and/or patient to comply with study protocol

 -  Non English speaking