In this observational study of real-world evidence, we observed a significant and clinically relevant effect of semaglutide on weight loss in a group of patients with HO due to brain tumors affecting the hypothalamic region. Semaglutide also demonstrated efficacy in weight management in patients previously treated with liraglutide. To our knowledge, this is the largest published real-world data-set on the efficacy of semaglutide on HO.

The only RCT to date exploring GLP-1 analogues for HO was a 36-week study conducted in 2021 including 35 participants completing the study. In this trial patients were randomly assigned to once-weekly exenatide or placebo. The study failed to demonstrate a significant change in BMI between the two treatment arms but found a significant reduction in body fat mass and waist/height ratio in the treated group compared to placebo [18]. Another, much smaller and non-controlled intervention with exenatide found similar results [19]. We believe that the discrepancies in weight loss results between our study and the two studies using exenatide might be explained by the choice of drug. Second-generation GLP-1 analogues, such as semaglutide, relative to first-generation analogues like exenatide or liraglutide, have previously shown enhanced efficacy compared to other GLP-1 analogues [24,25,26]. The underlying mechanisms distinguishing the effects of different GLP-1 analogues remain controversial. Studies have shown that semaglutide (and liraglutide) in contrast to exendin-4 do not cross the blood-brain barrier (BBB) [27, 28]. However, as the hypothalamus and hindbrain lack BBB, semaglutide might act directly on these structures. Semaglutide has an enhanced binding affinity and stability compared to first-generation GLP-1 analogues due to an amino acid replacement (preventing dipeptidyl peptidase 4 degradation) and a C18 fatty diacid addition [23]. These modifications not only increase the plasma half-life, enabling weekly dosing, but may also enhance the pharmacodynamic properties of the drug, possibly accounting for some of the differences in reported effects between GLP-1 analogues.

Six case reports focusing on either a single individual or very few individuals with HO found results similar to our study with substantial weight reduction accompanying treatment with GLP-1 analogues. Most of these studies used liraglutide, but also exendin-4, dulaglutide, exenatide and semaglutide were used [13,14,15,16,17, 20].

Pharmacological treatments for acquired HO, besides GLP-1 receptor agonists, have previously been investigated, of which the most promising include treatment with methionine aminopeptidase inhibitors [29], dextroamphetamine [30, 31] and Tesomet (tesofensine combined with metoprolol) [32]. Of these, the largest study with the longest follow-up was the randomized controlled trial of Tesomet treatment versus placebo in 21 patients with acquired HO over 24 weeks showing a mean weight loss of 6.3% with mild, although significant, side-effects such as headache, sleep-disturbances and dry mouth [32]. Other approaches to treat HO have been limited by the lack of effect or serious side-effects [33,34,35,36].

From larger RCTs on semaglutide in patients with Type 2 diabetes as well as in people with obesity without Type 2 diabetes there is substantial evidence demonstrating the robust effects on body weight reduction [9, 37,38,39,40]. In studies of common obesity, semaglutide has shown larger effect sizes than we found in our data while the reported weight loss in subjects with Type 2 Diabetes has been slightly lower [9, 37,38,39,40]. We do not have an exact explanation of these differences. However, we are not surprised to find effect sizes within the previously reported range as our patient group was quite heterogenous regarding degree of obesity, dosage of semaglutide and presence of diabetes making a direct comparison with RCTs on common obesity or Type 2 Diabetes difficult. It is noteworthy that those patients who withdraw from treatment due to gastro-intestinal side effects or the cost of the medication (only partly covered by subsidy) all rapidly re-gained weight (data not shown), underlining the importance of continuous treatment for sustained weight management as previously reported [41].

The effect of semaglutide on body weight regulation is known to be partly mediated by regulation of the hypothalamic appetite center. However, in patients with HO arising from brain tumors or surgical or irradiation damage, it is unlikely that the GLP-1 receptors in hypothalamus remain completely intact. We speculate that residual response in the arcuate nucleus might still be present, particularly under supra-physiological dosages of GLP-1 RA. One case report from 2020 showing effect of high-dose liraglutide after failed response to gastric bypass in a patient with craniopharyngioma supports this suggestion [14].

Another explanation of the treatment response could be due to extra-hypothalamic effects of the GLP-1 analogues. A previous study found a significant association between the extent of hypothalamic damage as visualized by Magnetic Resonance Imaging and the response to GLP-1 analogue treatment (BMI and body fat). This association is hypothesized to reflect increased extra-hypothalamic effects in the presence of more extensive hypothalamic damage [42]. Some of these effects are thought to be related to areas in the brain stem and vagus nerve. Other extrahypothalamic effects of GLP-1 have been identified in the orbitofrontal cortex, the striatum, the area postrema and the insula [43, 44]. Finally, the well-established local effect of GLP-1 in the intestinal tract may also contribute to weight loss in acquired HO.

Despite the fact that many substitution therapies are considered weight dependent, we did not find any specific pattern in dosage changes of the substitution therapy during the observation time reflecting the many different factors affecting the hormone levels in a real-life setting.

The strengths of this study are the relatively large number of participants, the relatively long follow-up time and the real-life setting demonstrating the feasibility of the clinical implementation of the treatment. However, due to the retrospective real-life data design, several limitations also apply. The primary limitation of our study was the absence of a placebo control group. However, we found a much greater weight loss on semaglutide than reported in the before-mentioned RCT investigating exenatide [7], even without further weight loss support or dietician counselling. Thus, we find it unlikely that the massive weight loss in our patients is solely attributed to a placebo effect or confounding. We did not have systematical data on (changes in) hyperphagia nor the presence of nausea and other side-effects which is an important limitation to the study compared to most RCTs. Only two patients (8%) stopped the treatment due to intolerable side effects which is comparable to previous findings [40]. The median dosage of semaglutide of 1.6 mg in our data was lower than in most weight loss trials, but we do not have evidence of side-effects as the main cause of not achieving the maximum dosage. Furthermore, we did not have measures of the quality of the weight loss regarding changes in waist circumference and/or body composition which are important in terms of metabolic health. Finally, the patient group was rather heterogenous in terms of degree of obesity and duration of the disease, reflecting the real-life setting. We did not have data to assess whether obesity occurred primarily before or after surgery of the patient and/or whether early intervention with semaglutide would have made any difference to the weight loss response. We tried to address this question by adding a co-variate of disease duration before start of semaglutide to the model, but did not find any significant difference. To further address such questions, we believe, there is a need for large (multi-center) RCTs, however, the rarity of HO, make such RCTs difficult and time costly.

In conclusion, treatment with semaglutide in a daily clinical setting demonstrated good feasibility and efficacy in patients with HO who historically have been challenging to treat for significant weight gain. Thus, the study highlights the potential of semaglutide as a viable treatment option for managing the profound weight issues in this patient group. The field of medical treatment for obesity is entering an exciting new era (e.g. development of dual and tri-agonists treatments). This advancement holds significant promise for patients with obesity including patients suffering from HO.