Abstract
Purpose
Patients with hypothalamic pathology often develop hypothalamic obesity, causing severe metabolic alterations resulting in increased morbidity and mortality. Treatments for hypothalamic obesity have not proven very effective, although the glucagon-like peptide-1 receptor agonist semaglutide has been shown to have positive effects. We examined semaglutide’s effect on weight loss in a sample of patients with hypothalamic obesity.
Methods
Four female patients with hypothalamic obesity resulting from treatment of craniopharyngiomas were treated with semaglutide for six months. Whole Body Dual-energy x-ray absorptiometry scans were performed, and blood samples drawn at baseline and after six months. Semaglutide dosages were increased monthly along with tracking of body weight and eating behavior (Three Factor Eating Questionnaire, TFEQ-R18).
Results
BMI was reduced in all cases, with an average of 7.9 BMI (range: 6.7 to 10.1) corresponding to a weight loss of 17.0% (range: 11.3–22.4%) or 20.2 kg (range 16.2 kg to 23.4 kg). We found a comparable reduction in total fat mass (17.2%, p = 0.006) and lean mass (16.0%, p = 0.05), whereas bone mass was unchanged (2.6%, p = 0.12). All cases reported an increase in energy levels, improved mobility and physical activity. Unfavorable eating behaviors were reduced after 1 month of treatment (emotional eating − 41 points, p = 0.02, uncontrolled eating − 23 points, p = 0.11). HbA1c and total cholesterol were significantly reduced (p = 0.014 for both).
Conclusion
Semaglutide is a promising and safe treatment option for HO, that improves eating behavior, reduces weight, and improves metabolic markers.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
Hypothalamic obesity (HO) is characterized by abnormal weight gain due to structural damage to the hypothalamus, either caused by a pathological lesion, e.g. a craniopharyngioma (CP), or following surgical or radiological intervention [1]. As a consequence, the neural pathways responsible for the regulation of feeding behavior, satiety and energy expenditure, can be disrupted, thus affecting overall energy balance. This disruption often leads to hyperphagia, insulin and leptin resistance, rapid weight gain and fat accumulation, leading to severe obesity in most patients [2, 3]. HO is associated with considerable metabolic and psychological complications as a consequence to the weight gain with increased risks of cardiovascular morbidity, reduced quality of life and increased mortality [4].
Managing HO presents challenges due to the limited effectiveness of lifestyle and pharmacological interventions [5]. Glucagon-like peptide-1 receptor agonists (GLP1-RA), are efficient drugs when used in the treatment of obesity [6,7,8], and seems to be a promising treatment of HO due to their multifaceted mechanism of action, which extends beyond the affected hypothalamic regions [9]. Results in trials using earlier GLP-1RA such as exenatide have been varying [5, 10,11,12], with relatively low effect as compared to placebo. However, a recent case report demonstrated a marked body weight reduction and improved metabolic parameters using semaglutide [13]. Semaglutide differs from other GLP-1RA in its longer half-life and a more potent effect on weight loss. It activates different areas of the central nervous system compared to liraglutide and it is suggested to cross the blood-brain barrier more effectively, which may enhance its central anorectic effects. These effects include modulation of appetite and satiety centers in the hypothalamus, leading to a reduction in food intake and improved eating behaviors. This is supported by evidence indicating that semaglutide engages neural circuits involved in energy balance and food reward more robustly than liraglutide [14, 15].
Our case series aimed to document the effects of semaglutide treatment in four patients with HO.
Materials and methods
Four female patients with HO were recruited from the outpatient clinic at the department of endocrinology, Aalborg University hospital (Table 1). Inclusion criteria included neuroradiological confirmation of hypothalamic damage (Table 1; Fig. 1) and a continuous increase in body weight post-treatment, despite adhering to a weight loss program.
Throughout the outpatient treatment process, there had been a continuous focus on weight loss, including physical activity and diet, albeit with varying degrees of effectiveness. During the initial consultation patients received a dietary counseling session that focused on a balanced calorie-restricted diet. Adherence was routinely assessed at each monthly visit, where semaglutide dose was increased according to general guidelines, body weight recorded and eating behavior assessed via The Three Factor Eating Questionnaire, revised 18-item version (TFEQ). Body composition was assessed by whole body Dual-energy X-ray Absorptiometry-scan (DXA) before initiating treatment and after six months. Biochemical markers including alanine transamine (ALAT), glycated hemoglobin (HbA1c), triglycerides (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL) and total cholesterol were measured fasting before treatment and after 6 months (Table 4). Written informed consent for publication of their clinical details and/or clinical images was obtained from the patients and data were managed in anonymized form.
The three factor eating questionnaire
TFEQ has been validated for use in many populations [16,17,18,19,20] and assesses 3 subtypes of eating behavior; Cognitive restraint (CR), uncontrolled eating (UE) and emotional eating (EE). Generally, higher CR-scores have been associated with a healthier eating behavior, as opposed to high scores of UE and EE [17].
Statistics
Data were presented as mean ± standard deviation (SD) or range, Student’s paired t-tests were used to compare changes in DXA estimates. A monthly pairwise comparison of the TFEQ questionnaire score (0-100 point scaled scores) was performed using repeated paired t-tests. A p-value < 0.05 was considered statistically significant.
Results
Population demographics
All four patients had hypothalamic and pituitary damage due to previous treatment for a craniopharyngioma, including both surgery and radiotherapy (Table 1; Fig. 1). Ages ranged from 22 to 69 years with previous follow-up of 16–49 years, where continuous increases in bodyweight was observed. One patient had class II obesity (36.0 kg/m2) and 3 patients had class III obesity (45.2–55.5 kg/m2). In all cases, onset of obesity occurred after the diagnosis of hypothalamic lesions and subsequent surgical or radiotherapy treatments. None of our included patients received treatment for, or had previously undiagnosed diabetes mellitus.
All participants initiated semaglutide therapy with 0.25 mg once weekly and dosages were increased to their maximally tolerated dose (1.7 or 2.4 mg weekly, Fig. 2). We observed only transient adverse effects including nausea and constipation.
Body weight
Continuous weight loss was observed in all cases. At baseline, the average weight was 126.0 kg (78.8–172.0 kg), which decreased to 105.8 kg (62.6–148.6 kg) after 6 months of treatment corresponding to a 17.0% (11.3–22.4%) reduction. In terms of BMI (kg/m2), this represented a mean reduction of 7.9 (6.7–10.1) from 48.0 (35.0-55.5) at baseline to 40.1 (28.6–48.9) (Fig. 2).
Body composition
Overall body fat and lean mass decreased by 17.2% (p = 0.006, range: -12.8;-27.8%) and 16.0% (p = 0.05, range: -11.3;-22.4%), respectively (Table 2). Significant body fat reductions were observed in both the trunk (16.4%, p = 0.02, range: -9.8;-26.5%), and the extremities (upper 21.8%, p = 0.006, range: -17.6;-25.4%; lower 17.1%, p = 0.005, range: -12.3;-30.9%). Lean mass was reduced in the trunk (15.0%, p = 0.025, range: -10.3;-19.6%), upper extremities (13.3%, p = 0.131, range: +1.3;-22.8%) and lower extremities (19.8%, p = 0.096, range: -14.3;-26.3%). Bone mineral density did not change (p = 0.12, Table 2).
Eating behavior
The scaled scores of EE decreased from 47.2 to 5.6% (p = 0.02) and for UE from 33.3 to 10.2% (p = 0.11) after one month of semaglutide treatment (Table 3; Fig. 3). Both EE and UE scores remained very low during the remainder of follow-up (Fig. 3A and B). The mean CR scores did not significantly change, although intra-personal fluctuation was observed (Fig. 3C).
Biomarkers
After 6 months of treatment, HbA1c, total cholesterol and HDL had decreased, whereas TG, LDL and ALAT remained unchanged (Table 4).
Discussion
In our cohort, semaglutide proved to be an effective and safe treatment for HO in craniopharyngioma. We observed positive changes in eating behavior, a considerable weight reduction and improvements in glucose and lipid metabolism.
The effect of exenatide and liraglutide in HO have been examined in several studies, including a recent double-blinded trial of 40 patients, without consistent weight reductions [5, 10, 11, 21, 22]. Semaglutide seems to have a more potent effect on weight loss [13]. All of our patients experienced substantial weight losses in the range of 7 to 10 BMI, in line with the only previous case report to use semaglutide in a patient with HO [13]. We found significant improvements in HbA1c, TG and total cholesterol, which is consistent with findings in persons with non-hypothalamic obesity treated with semaglutide [24]. This has not been clearly demonstrated in studies on earlier GLP1-RA in HO [10, 11], including a systematic review where HbA1c was not or only slightly improved and cholesterol unchanged [21].
Fat loss was evenly distributed, whereas lean mass was only significantly reduced in the trunk and not the extremities. This could be ascribed to the low number of participants, although a relative preservation of lean mass has been reported in obese patients treated with semaglutide, with large reductions in body fat mass [7, 23]. The relative reduction in body mass is in line with our observations of reductions in lean mass of 11–22% and in fat mass of 13–28%. The clinical significance of this, is yet to be studied. Nevertheless, all patients in our cohort reported increased vigor and energy levels, without perceived strength losses. Physical activity was not tracked during the study, but patients reported feeling less limited by their weight and increased activity levels as a consequence of this.
Eating behavior in HO is affected by neuroendocrine dysfunctions due to hypothalamic damage, leading to changes including impaired sensitivity to key hormones, which play critical roles in hunger and satiety signaling [3, 25]. Patients with HO are known to exhibit a higher cognitive restraint as compared to patients with non-hypothalamic obesity, but a comparable uncontrolled eating and hunger score [26]. This is in line with our findings, where major and lasting decreases in EE (88%) were observed after one month of treatment. The same trend was observed for UE, although not statistically significant. These sub-categories refer to eating behaviors that are largely unaffected by physiological hunger cues. The patients reported changes in food choices, including increases in vegetable consumption and reduced cravings of sweets and high-calorie processed foods. All patients reported decreased food focus. Comparable effects of other GLP-1RA on eating behavior in HO have previously been reported and include a reduction in hyperphagia, an increased post-prandial satiety, and an overall decreased food focus [5, 11, 27,28,29,30,31].
Data availability
Datasets generated during and/or analyzed during the current study are not publicly available, but are available from the corresponding author on reasonable request.
References
Müller HL, Tauber M, Lawson EA et al (2022) Hypothalamic syndrome. Nat Rev Dis Primers 8(1):24
Roth CL (2011) Hypothalamic obesity in patients with craniopharyngioma: profound changes of several weight regulatory circuits. Front Endocrinol 2:49
Müller HL (2020) Management of hypothalamic obesity. Endocrinol Metab Clin North Am 49(3):533–552
Karavitaki N, Cudlip S, Adams CBT, Wass JAH, Craniopharyngiomas (2006) Endocr Rev 27(4):371–397
Gatta-Cherifi B, Mohammedi K, Cariou T et al (2024) Impact of exenatide on weight loss and eating behaviour in adults with craniopharyngioma-related obesity: the CRANIOEXE randomized placebo-controlled trial. Eur J Endocrinol Published Online March 7. https://doi.org/10.1093/ejendo/lvae024
Silver HJ, Olson D, Mayfield D et al (2023) Effect of the glucagon-like peptide-1 receptor agonist liraglutide, compared to caloric restriction, on appetite, dietary intake, body fat distribution and cardiometabolic biomarkers: a randomized trial in adults with obesity and prediabetes. Diabetes Obes Metab 25(8):2340–2350
Wilding JPH, Batterham RL, Calanna S et al (2021) Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med 384(11):989–1002
Drucker DJ (2022) GLP-1 physiology informs the pharmacotherapy of obesity. Mol Metab 57:101351
Perez FA, Elfers C, Yanovski JA, Shoemaker AH, Abuzzahab MJ, Roth CL (2021) MRI measures of hypothalamic injury are associated with glucagon-like peptide-1 receptor agonist treatment response in people with hypothalamic obesity. Diabetes Obes Metab 23(7):1532–1541
Roth CL, Perez FA, Whitlock KB et al (2021) A phase 3 randomized clinical trial using a once-weekly glucagon-like peptide-1 receptor agonist in adolescents and young adults with hypothalamic obesity. Diabetes Obes Metab 23(2):363–373
Zoicas F, Droste M, Mayr B, Buchfelder M, Schöfl C (2013) GLP-1 analogues as a new treatment option for hypothalamic obesity in adults: report of nine cases. Eur J Endocrinol 168(5):699–706
Roth CL, McCormack SE (2024) Acquired hypothalamic obesity: a clinical overview and update. Diabetes Obes Metab 26(Suppl 2):34–45
Sciacovelli C, Moschione G, Garelli S, Pagotto U (2023) Semaglutide for treating obesity Induced by Craniopharyngioma Resection: a successful case study. JCEM Case Rep 1(4):luad074
Müller TD, Blüher M, Tschöp MH, DiMarchi RD (2022) Anti-obesity drug discovery: advances and challenges. Nat Rev Drug Discov 21(3):201–223
Gabery S, Salinas CG, Paulsen SJ et al (2020) Semaglutide lowers body weight in rodents via distributed neural pathways. JCI Insight 5(6). https://doi.org/10.1172/jci.insight.133429
Karlsson J, Persson LO, Sjöström L, Sullivan M (2000) Psychometric properties and factor structure of the three-factor eating questionnaire (TFEQ) in obese men and women. Results from the Swedish obese subjects (SOS) study. Int J Obes Relat Metab Disord 24(12):1715–1725
de Lauzon B, Romon M, Deschamps V et al (2004) The three-factor eating Questionnaire-R18 is able to distinguish among different eating patterns in a general population. J Nutr 134(9):2372–2380
Cappelleri JC, Bushmakin AG, Gerber RA et al (2009) Psychometric analysis of the three-factor eating Questionnaire-R21: results from a large diverse sample of obese and non-obese participants. Int J Obes 33(6):611–620
Mostafavi SA, Akhondzadeh S, Mohammadi MR et al (2017) The reliability and validity of the Persian Version of three-factor eating Questionnaire-R18 (TFEQ-R18) in overweight and obese females. Iran J Psychiatry 12(2):100–108
Anglé S, Engblom J, Eriksson T et al (2009) Three factor eating questionnaire-R18 as a measure of cognitive restraint, uncontrolled eating and emotional eating in a sample of young Finnish females. Int J Behav Nutr Phys Act 6:41
Ng VWW, Gerard G, Koh JJK, Loke KY, Lee YS, Ng NBH (2024) The role of glucagon-like peptide 1 receptor agonists for weight control in individuals with acquired hypothalamic obesity-A systematic review. Clin Obes Published Online January 25:e12642
Lomenick JP, Buchowski MS, Shoemaker AH (2016) A 52-week pilot study of the effects of exenatide on body weight in patients with hypothalamic obesity. Obesity 24(6):1222–1225
Bikou A, Dermiki-Gkana F, Penteris M, Constantinides TK, Kontogiorgis C (2024) A systematic review of the effect of semaglutide on lean mass: insights from clinical trials. Expert Opin Pharmacother. Published Online April 18:1–9
Bergmann NC, Davies MJ, Lingvay I, Knop FK (2023) Semaglutide for the treatment of overweight and obesity: a review. Diabetes Obes Metab 25(1):18–35
Kim JH, Choi JH (2013) Pathophysiology and clinical characteristics of hypothalamic obesity in children and adolescents. Ann Pediatr Endocrinol Metab 18(4):161–167
Holmer H, Pozarek G, Wirfält E et al (2010) Reduced energy expenditure and impaired feeding-related signals but not high energy intake reinforces hypothalamic obesity in adults with childhood onset craniopharyngioma. J Clin Endocrinol Metab 95(12):5395–5402
James BL, Loken E, Roe LS, Rolls BJ (2017) The weight-related eating questionnaire offers a concise alternative to the three-factor eating questionnaire for measuring eating behaviours related to weight loss. Appetite 116:108–114
Leon AD, Roemmich J, Casperson S (2019) Responses on the three factor eating Questionnaire Restraint and Disinhibition scales Change after a Controlled Energy-Restricted Diet (P21-002-19). Curr Developments Nutr 3(Suppl 1). https://doi.org/10.1093/cdn/nzz041.P21-002-19
van Schaik J, Begijn DGA, van Iersel L et al (2020) Experiences with Glucagon-Like Peptide-1 receptor agonist in children with acquired hypothalamic obesity. Obes Facts 13(4):361–370
Ando T, Haraguchi A, Matsunaga T et al (2014) Liraglutide as a potentially useful agent for regulating appetite in diabetic patients with hypothalamic hyperphagia and obesity. Intern Med 53(16):1791–1795
Botero Suarez CS, Broutin D, Yau H (2023) FRI064 the role of GLP-1 receptor agonists in the treatment of Pituitary and Hypothalamic Tumor Induced obesity. J Endocr Soc 7(Supplement1). https://doi.org/10.1210/jendso/bvad114.074
Acknowledgements
We would like to thank the laboratory technicians at the research unit at Steno Diabetes Center North Denmark and the department of endocrinology, Aalborg University hospital, Aalborg, for invaluable help in performing the analyses.
Funding
This research/project was conducted without any external funding.
Open access funding provided by Aalborg University Hospital
Author information
Authors and Affiliations
Contributions
Conceptualization: J.D., P.V., E.H.N., J.S.K., H.L.M.; Methodology: J.D., P.V., E.H.N., J.S.K., H.L.M.; Formal analysis and investigation: L.B.L., E.G., J.D., K.S.E.; Writing - original draft preparation: E.G., L.BL., J.D; Writing - review and editing: E.G., L.B.L., J.D., P.V., E.H.N., J.S.K., K.S.E., H.L.M.; Funding acquisition: None; Resources: J.D., H.L.M., E.H.N.; Supervision: J.D., P.V., E.H.N., J.S.K.
Corresponding author
Ethics declarations
Informed consent
Informed consent was obtained from all individual participants in the study.
Competing interests
E.G., L.B.L., E.H.N., J.S.K. and K.S.E. have no competing interests to declare that are relevant to the content of this article. P.V. is head of research at the Steno Diabetes Center North Denmark, funded by an unrestricted grant by the Novo Nordisk Foundation. H.L.M. has received reimbursement of participation fees for scientific meetings and continuing medical education events from the following companies: Ferring, Pfizer, Sandoz/Hexal, Novo Nordisk, IPSEN, Rhythm Pharmaceuticals, and Merck Serono. He has also received reimbursement of travel expenses from Merck Serono, Rhythm Pharmaceuticals, and IPSEN and a lecture honoraria from Pfizer. J.D. has received unrestricted research grants from IPSEN and Pfizer.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Gjersdal, E., Larsen, L.B., Ettrup, K.S. et al. Semaglutide as a promising treatment for hypothalamic obesity: a six-month case series on four females with craniopharyngioma. Pituitary (2024). https://doi.org/10.1007/s11102-024-01426-8
Accepted:
Published:
DOI: https://doi.org/10.1007/s11102-024-01426-8