Medication dosing and adjustments

At 12 months, two patients were receiving 1.7 mg and two patients 2.4 mg of once-weekly semaglutide treatment. By 24 months, one patient remained on 1.7 mg, while three were receiving 2.4 mg weekly. Although all patients initially reached the maximum dose (2.4 mg), one patient was subsequently reduced to 1.7 mg, due to exacerbation of adverse effects (mild GI symptoms). Levothyroxine doses were reduced in all patients, by a mean of 13.9% (range: 100–350 µg weekly) at follow-up (either at 3 or 6 month follow up). Somatropin doses were increased in two patients (from 0.5 to 0.6 mg, and from 0.7 to 0.8 mg, both at the 12-month visit), remained unchanged in one patient, and was reduced by 0.05 mg in one patient (0.3 to 0.25 mg, 6 month follow up). Hydrocortisone doses remained unchanged throughout the observation period.

Qualitative interviews

The qualitative component of this study aimed to gain an in-depth understanding of whether semaglutide influenced the patients’ perceived quality of life. A phenomenological-hermeneutic qualitative research design was employed [29]. Four patients were invited to participate in interviews, and none withdrew. Interviews were conducted via telephone by senior researcher D.M., who was not involved in the participants’ clinical care. A semi-structured interview guide was used to explore patients’ psychological, physical, and social experiences related to weight loss with semaglutide. The guide included open-ended questions designed to elicit detailed, reflective responses while minimising interviewer bias. All interviews were audio-recorded and transcribed verbatim with participants’ consent to ensure data accuracy. The transcripts were analysed using Braun and Clarke’s reflective thematic analysis, employing an inductive approach [30]. The analysis was conducted by J.D., E.G., and D.M. For the sake of anonymity, participants are identified by number in all quoted material.

Statistics

Variables including weight, DXA measurements and TFEQ-R18 scaled score values as well as absolute differences were assumed normally distributed. Blood markers and relative differences were assumed lognormal and transformed accordingly. TFEQ-R18 scaled scores were calculated as (raw score-minimum possible score)/(maximum possible score-minimum possible score ​) × 100. Data were described by means and standard deviations (SD) on the original scale. Differences from baseline to follow-up of lognormal data were back transformed and converted to additive measures by (exp(mean difference) × medianbaseline) - medianbaseline. All comparisons were conducted by paired t-tests. Estimates were reported with 95% confidence intervals (95%CI), and statistical significance was evaluated using an alpha level of 0.05. Data management and statistical calculations were performed in Stata (StataCorp. 2023. Stata Statistical Software: Release 18. College Station, TX: StataCorp LLC).

Eating behaviour

Scaled scores of UE and EE according to the TFEQ-R18 questionnaire continued their decline until the 24th month (? baseline UE: − 27, 95%CI: − 63; 9, p = 0.097; EE: − 44, 95%CI: − 69; − 19, p = 0.011). Cognitive restraint (CR) scores fluctuated around 50, with no significant changes between baseline and 24 months (95%CI: − 30; 42, p = 0.651) (see Fig. 1). The main improvement in eating behavior appeared during the initial months of treatment as previously reported [24].

Fig. 1

Changes in mean scaled scores from the TFEQ-R18 eating behaviour questionnaire, from baseline to 24 months during semaglutide treatment

Body weight and body composition

Body weight and BMI remained reduced at 24 months from baseline (median 16%, 95%CI 8; 34%, p = 0.004; mean − 8.0 kg/m2, 95%CI: − 4.0; − 11.9, p = 0.008). Most participants sustained weight loss with minor fluctuations related to seasonal events, intermittent treatment interruptions, or intercurrent illness. The maximal average weight loss of 17% was achieved within 6 months, as previously documented [24]. Both fat and lean masses were reduced significantly after 24 months of treatment (median 10%, 95%CI: 2; 44%, p = 0.016 and median 19%, 95%CI: 14; 26%, p < 0.001, respectively). DXA scans indicated that the sustained weight loss was primarily from lean mass, as fat mass, although initially reduced, increased again after month 6 (median ratio of lean to fat mass reduction 1.90, 95%CI: 0.5; 7.20, p = 0.223). From month 12 to 24, median weight increased slightly by 3% (95%CI: 1; 14%, p = 0.006) and median fat mass increased by 11% (95%CI: 6; 23% (1–10 kg), p = 0.002). Individual weight gains over this period were 3.0, 2.0, 0.8, and 14.0 kg, with corresponding increases in fat mass of 4.6, 4.2, 3.0, and 10.0 kg, respectively. The BMC (composite of arms, ribs, spine, pelvis and legs) was unchanged from baseline to follow-up at 24 months (mean ? baseline 1 g, 95%CI: − 97; 98, p = 0.983) (see Table 1; Fig. 2).

Table 1 Changes in body composition from baseline to 24 months during semaglutide treatment. BMC = bone mineral contentFig. 2

Changes in body composition measured by dual-energy X-ray absorptiometry (DXA) from baseline to 24 months during semaglutide treatment

Qualitative assessments

During analysis of the interviews after 24 months of semaglutide treatment, five main themes emerged; (1) Hunger and thoughts about food, (2) mobility and musculoskeletal pain, (3) social life, (4) work life and (5) side effects to semaglutide treatment. These themes highlight the participants’ experiences with weight loss after semaglutide treatment and its impact on different aspects of their daily lives.

Hunger and thoughts about food

Participants reported a significant and lasting reduction in persistent hunger, describing how they no longer felt an overwhelming drive to consume food, starting already shortly after treatment initiation. For some, this change allowed them to regulate portion sizes more effectively and develop a more natural sense of satiety:

“I no longer have that endless hunger - I was never full before, but now I am.” (1).

“I have to say, it’s gotten easier to hold back at mealtimes. Before, I wouldn’t think twice about going for a second helping, but now I find it easier to wait 20–30 minutes after my first plate to see if I’m still hungry.” (2).

These findings suggest that semaglutide plays a role in suppressing the feeling of excessive hunger, allowing for more controlled eating behaviours in these individuals with hypothalamic obesity.

Mobility and pain

Several participants reported experiencing improved mobility and reduced musculoskeletal pain, attributing these changes to their weight loss. Everyday activities, such as bending down or going on walks, became easier:

“Also, for example, when I’m tidying up at the kindergarten, it’s easier for me to bend down and pick up the markers from the floor.” (3).

“I can tell my knees don’t hurt anymore, unlike before. That’s probably because I was carrying more weight back then.” (4).

Additionally, some participants noted that they could engage in outdoor activities with greater ease and enjoyment:

“I really enjoy getting out into nature now, whether I’m walking or cycling.” (4).

Other changes included increased endurance and a noticeable improvement in breathing:

“I don’t get out of breath as easily.” (1)

“Just being able to breathe - I can actually fill my lungs completely now.” (2).

Overall, participants described feeling physically stronger, less fatigued, and more capable of completing daily tasks with greater efficiency.

Social life

Weight loss and improved well-being had a positive impact on participants’ social lives. Several expressed newfound confidence in public settings and an increased willingness to engage in social interactions:

“Well, I’m glowing - and it’s done wonders for my confidence. It’s made it so much easier to go out and meet new people, whereas before, I tended to hold back a bit.” (4).

Some participants also mentioned that they were no longer isolating themselves at home:

“I was brave enough to go to the folk high school as well.” (3).

“…before, I used to hide away within my own four walls, but now I go out, meet other people, and gain new experiences. My social network has grown, and that has had a positive impact on my confidence.” (4).

This increase in self-confidence also led to a greater interest in personal appearance and clothing choices:

I also feel braver about going into stores I wouldn’t have visited before - browsing clothes, trying things on, and even asking for the staff’s opinion. Like, ‘What do you think?’.” (4).

“I’m so proud that I can just go to the supermarket now and buy clothes. I actually did it… I bought a blouse just before Christmas…” (3).

Work life

Participants reported positive changes in their work life, particularly in terms of increased energy levels and productivity:

“Before, I used to feel tired after cleaning - and at work too. But now it takes half the time because it’s so much easier to get through. I can really feel my energy blooming. I’m not exhausted after a workday like I used to be. Before, I was completely drained and couldn’t do anything at home after working six or eight hours.” (4).

For some, weight loss also led to a greater willingness to seek new job opportunities:

“I’m not working full-time right now. At the moment, I’m working as a part-time substitute, but I’m looking for a permanent position. I feel more confident going to interviews and presenting myself as I am now.” (4).

These findings suggest that changes in hunger and weight loss not only improved participants’ physical health, but also enhanced their professional self-esteem and career aspirations.

Side effects

Local irritation in the area of the injection site and hair loss was reported by one patient each, but gastrointestinal symptoms were the most common side effect:

“I have really, really hard stools - it’s very painful.” (4).

“It’s like my digestion just stops, as if the food won’t go do down my food pipe properly” (4).

“When I eat fatty food, I have to go to the toilet shortly after.” (2).

“I felt unwell when I ate fatty foods - it almost always made me vomit and gave me a headache - but it’s completely fine now.” (1).