GRAVITY: GLP-1 analogues in craniopharyngioma

Craniopharyngioma is a rare tumour in the hypothalamic-pituitary region, which is associated with increased mortality (with an average 20-year survival rate of 62%), comorbidities and impaired quality of life of patients. It has an incidence of 0,5-2,5 cases per 1 million population per year globally, has its peak incidence at ages 5-15 and 45-60 years, and is mainly treated with neurosurgery and radiotherapy. Due to its localization, these patients suffer from hypothalamic/pituitary dysfunction, which is important for weight homeostasis, and obesity rates in these patients are found in up to 75%. Obesity is an important risk factor for obstructive sleep apnea syndrome (OSAS) which occurred in 46% in a study in patients with craniopharyngioma, diabetes mellitus type II (T2DM), and the metabolic syndrome, which occurred in 45-51% and in turn doubles risk on cardiovascular disease and increases mortality. For T2DM, a standardized incidence ratio was found of 4.4 (95% confidence interval 2.8-6.8) in our craniopharyngioma study population. Weight gain in patients with craniopharyngioma occurs mostly in the first year after treatment. This is a big issue in patients with craniopharyngioma, as they are at risk of cardiovascular disease and are impaired in their mobility and quality of life.
Until now, no proper treatment has been found for hypothalamic obesity: lifestyle changes are essentially useless (6). Bariatric surgery in the form of Roux-en-Y gastric bypass, as a last resort, seems effective in small studies in up to two years of follow-up, but is an invasive intervention, and questions on safety issues for the medication are raised. Reliable, less invasive options to treat obesity in patients with craniopharyngioma, are basically not available at this point, but highly desirable in patients with this rare disease. Key to the effectiveness of bariatric surgery in the general obese population, is a decrease in appetite, which is caused by changes in gut hormones like glucagon-like peptide-1 (GLP-1). GLP-1 activates POMC neurons: these are neurons of the first order that regulate neurons of the second order, who have their influence on satiety, feeding, the sympathetic nervous system and the pituitary. GLP-1 analogues have been introduced in patients with diabetes mellitus, and studies have proved the efficacy of weight loss by GLP-1 analogues such as liraglutide in the obese non-craniopharyngioma population. As bariatric surgery appears to be an effective treatment in patients with craniopharyngioma and hypothalamic obesity, this suggests that the gut-hypothalamic feedback still effective. Therefore GLP-1 analogues could be effective as well. Our aim is to find an option to prevent obesity in patients diagnosed with craniopharyngioma. This may increase their quality of life, and decrease comorbidities (such as OSAS, the metabolic syndrome and T2DM) and mortality. We hypothesize that GLP-1 analogues be used to lower the prevalence of obesity in patients with craniopharyngioma if implemented early after first treatment. Our objective is to investigate whether GLP-1 analogue semaglutide is effective on treating obesity in patients with craniopharyngioma aged 16 years or older. Therefore, we will perform a randomized controlled trial with one year of semaglutide versus placebo. Both groups will receive lifestyle advices through general care and will be followed-up two years after stopping the study medication.

We hypothesize (hypothalamic) obesity can be treated with GLP-1 analogues in patients with craniopharyngioma.

Endpoints wil be determined at end of treatment (after 56 weeks). Follow-up will be continued until 107 weeks and endpoints will be determined again.

Semaglutide once weekly in increasing dosis, versus placebo, for ~1year.