Energy balance in hypothalamic obesity in response to treatment with a once-weekly GLP-1 receptor agonist

Abstract

Background/Objectives: Hypothalamic obesity (HO) frequently occurs following suprasellar tumors from a combination of decreased energy expenditure and increased energy intake. Glucagon-like peptide-1 receptor agonist (GLP1RA) therapy is associated with increased satiety and energy expenditure. We hypothesized GLP1RA therapy in patients with HO would cause both lower energy intake and increased energy expenditure. Subjects/Methods: Forty-two patients aged 10–26 years (median 16 years) with HO with suprasellar tumors were randomized to GLP1RA (exenatide extended release once-weekly, ExQW, n=23) or placebo (n=19). Thirty seven (81%) patients completed the 36-week double-blind placebo-controlled trial. Total energy expenditure (TEE) was measured with doubly labeled water, physical activity was assessed with actigraphy, and intake was estimated with ad libitum buffet meal. Results are presented as adjusted mean between-group difference. Results: As compared with treatment with placebo, treatment with ExQW was associated with decreased energy intake during a buffet meal (−1 800 kJ (−430 kcal), 95% CI −3 184 to −418 kJ, p= 0.02). There were no significant differences in physical activity between groups. ExQW (vs. placebo) treatment was associated with a decrease in TEE (−695 kJ/day (−166 kcal/day), 95% CI −1 130 to −264 kJ/day, p< 0.01, adjusted for baseline TEE). The treatment effect was still significant after further adjustment for change in body composition (−372 kJ/day (−89 kcal/day), 95% CI −699 to −42 kJ/day, p= 0.04) or change in leptin (−695 kJ/day (−166 kcal/day), 95% CI −1 130 to −264 kJ/day, p< 0.01). This decrease in TEE occurred despite an increase in lean mass and fat mass (1.7 vs. 1.3 kg lean mass, p= 0.88 and 1.5 vs. 4.6 kg fat mass, p= 0.04, ExQW vs. placebo). Conclusions: Treatment with a GLP1RA was associated with a decrease in food intake but also a decrease in TEE that was disproportionate to change in body composition.

Evaluating eating behaviour, energy homeostasis and obesity in childhood onset craniopharyngioma: A feasibility study

“…Preliminary evidence was found for greater food approach behaviours, including hyperphagic behaviours of greater severity (26), in patients with craniopharyngioma compared to sex, pubertal stage and age matched controls. Shoemaker and colleagues (17) also found similar levels of hyperphagia and variability in scores across patients using the Hyperphagia questionnaire, with high levels of enjoyment of food, like the current study. Together, these findings suggests that young people with craniopharyngioma experience enjoyment from their food, but in some cases, this heightened food responsivity could lead to problematic behaviours, such as stealing food or anger outbursts if access to food is removed.…”

“…Analysis of the preliminary data was conducted to inform a larger, multi-centre trial to assess interventions designed to improve eating behaviour in young people with hypothalamic obesity. To the authors’ knowledge, only one study has conducted an ad libitum meal to measure dietary intake in craniopharyngioma patients (17). However, in the current small, feasibility study, only a weak relationship between total energy intake and BMISDS was found in patients with craniopharyngioma, suggesting that it is difficult to assess whether the amount of food consumed is a primary driver of obesity for these patients using an acute measure from a standard meal alone.…”

“…This point highlights the inconsistencies of research into eating behaviour and the development of obesity within this patient group, both in terms of study design and findings to date, and provides the impetus to design larger, multi-centre trials with appropriate control groups within international networks of collaborators to further this field. The MRI and OGTT measures were also well tolerated, and while challenging to collect complete datasets, should be considered for future research designed to investigate the neural and physiological mechanisms underlying the development of obesity, and could be applied to further understand mechanisms of action of new drug therapies, such as GLP1 agonists, in this patient group (17). Full characterization of the patients is important in any future trial to ascertain whether behavioural and pharmacological interventions are differentially effective based on key factors, such as hypothalamic damage, development of obesity post-surgery and endocrine abnormalities.…”

“…The extent of hypothalamic damage across patient groups (24) or methodological limitations could explain the discrepancy between these findings, including the number of patients willing and able to accurately complete self-reported dietary intake diaries (21). Alternative measures that could be employed to assess eating behaviour are the ad libitum meal, which has only been used by one research group with craniopharyngioma patients to date (17, 25), and validated psychological questionnaires that have been specifically designed to measure different eating behaviour traits (e.g. Hyperphagia (26); Child Eating Behaviour Questionnaire (27)).…”

Liraglutide for Weight Management in Children and Adolescents With Prader–Willi Syndrome and Obesity

“…A study of 10- to 26-year-olds with hypothalamic obesity with suprasellar tumors reported that exenatide treatment was associated with a decrease in energy intake during an ad libitum buffet meal and a decrease in total energy expenditure that was disproportionate to change in body composition ( 24 ).…”