Introduction
Most monogenic obesity disorders involve disruptions in the leptin-melanocortin pathway, with melanocortin-4 receptor (MC4R) deficiency being the most common [1]. MC4R deficiency is characterized by early onset obesity and hyperphagia due to impaired satiety regulation [2]. Affected individuals often experience rapid and excessive weight gain in early childhood. This predisposes them, already in adolescence, to a high risk of obesity-related complications, such as type 2 diabetes and hypertension, along with significant psychosocial burden [3]. Therapeutic options remain limited: lifestyle interventions usually have significant but only moderate or short-term effect, and bariatric surgery outcomes are variable [4–6]. Currently, there are several pharmacological treatment options for obesity, both targeted and non-targeted. However, the targeted MC4R-agonist setmelanotide is ineffective in patients with MC4R deficiency and the effects of non-targeted anti-obesity medications, such as the glucagon-like peptide-1 (GLP-1) analogs liraglutide and semaglutide, are mostly described in small observational studies and case series in this patient group [7, 8]. These challenges highlight the urgent need for novel pharmacological approaches to manage hyperphagia and improve weight control and metabolic health in pediatric patients with MC4R deficiency.
Tirzepatide, a dual GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, has recently emerged as an effective therapeutic option for obesity and type 2 diabetes in adults. Tirzepatide improves glucose and insulin homeostasis, stimulates satiety and reduces hunger feelings and food cravings, as GLP-1 and GIP receptors are found in several brain regions involved in appetite regulation [9–11]. Clinical trials with tirzepatide have shown an average body weight reduction of 21% in adults with (severe) obesity, with 50–57% of participants in the 10 mg and 15 mg groups, respectively, achieving weight loss of 20% or more [12, 13]. It could be hypothesized that this medication may be less effective for patients with genetic obesity, as it is not targeted at the defect in the leptin-melanocortin pathway. Nevertheless, a recent study reported similar weight loss responses to tirzepatide in 32 adults carrying MC4R variants compared to non-carriers after 72 weeks of follow-up, suggesting effectiveness of tirzepatide even in the context of MC4R deficiency [14]. However, the effect of tirzepatide on hyperphagia in patients with genetic obesity has not been examined before and effectiveness in pediatric populations is yet unknown, as clinical trials are still ongoing (NCT06075667 and NCT06439277).
In this case report, we describe the use of tirzepatide in an adolescent with MC4R deficiency, focusing on its effects on hyperphagia, body weight, metabolic parameters, and tolerability after 9 months. These observations offer preliminary clinical insights into the potential role of tirzepatide in the management of monogenic obesity in adolescents, a population for whom therapeutic options are currently very limited [15].
Case Presentation
Medical History
A 17-year-old girl was referred to our specialized obesity clinic because of severe early onset obesity and hyperphagia due to melanocortin-4-receptor (MC4R) deficiency. Written informed consent was obtained from the patient for publication of this case report and any accompanying image. This case report was prepared in accordance with the CARE guidelines (see supplementary material for the checklist; for all online suppl. material, see https://doi.org/10.1159/000551729). The patient was born after an uncomplicated pregnancy at full term, with no neonatal feeding issues or signs of hypotonia. From age one, signs of hyperphagia became apparent. She was described as a constantly hungry child who never seemed satisfied, prompting early referral to a dietician. Obesity was present from the age of 3 years. Psychosocially, she also faced challenges early on; bullying at age 4 led to long-term involvement with mental health professionals. Her family history revealed multiple relatives struggling with obesity, including her mother who has undergone a gastric bypass. Genetic testing at age 16 revealed a monoallelic, ACMG class 5 pathogenic variant in MC4R (c.785del p.(Phe262Serfs4)), confirming the diagnosis of MC4R deficiency [16].
The patient had a normal pubertal development with menarche at 12 years, and was post pubertal at the time of referral to our center. She has consistently demonstrated a high level of motivation and discipline throughout puberty, engaging in sports five to six times a week and following extensive dietary and psychological guidance. Nevertheless, she continued to struggle with appetite regulation and weight control, and she presented at our obesity clinic with grade 2 obesity (shown in Fig. 1 and Table 1). Vital signs and laboratory evaluations at intake revealed no obesity-related complications. Despite her maximal efforts in lifestyle modification, the therapeutic response on hunger and body mass index (BMI) remained insufficient. Therefore, treatment with off-label tirzepatide was initiated using a stepwise dose increase, starting at a dose of 2.5 mg weekly. During tirzepatide treatment, the patient switched from Etonogestrel implant to oral contraception. Therefore, we are unfortunately unable to draw any conclusions regarding the effect of the treatment on the menstrual cycle.
Effect of tirzepatide treatment and metformin addition on visual analogue scores (VAS) for Hunger (left-y axis, in blue) and body mass index (BMI) (right y-axis, in orange). Dose escalation of tirzepatide is shown in the green bar.
| Week | VAS hunger score, 0-10 | Weight in kg | Total weight loss since start in % | BMI in kg/m(BMI-SDS)2 | Waist circumference in cm (SDS) |
|---|---|---|---|---|---|
| 0 | 8 | 105.4 | N.A. | 36.99 (3.68) | 125.8 (3.48) |
| 4 | * | 101.7 | −3.5 | 35.69 (3.51) | * |
| 8 | * | 98.9 | −6.2 | 34.71 (3.37) | * |
| 12 | 1–2 | 95.3 | −9.6 | 33.45 (3.19) | * |
| 16 | 4 | 94.1 | −10.7 | 33.03 (3.12) | * |
| 20 | 6–7 | 92.8 | −12.0 | 32.57 (3.04) | * |
| 24 | 7–8 | * | * | * | * |
| 28 | * | 90.8 | −13.9 | 31.27 (2.81) | 122.5 (3.4) |
| 32 | * | * | * | * | * |
| 36 | * | * | * | * | * |
| 37 | 4 | 83.4 | −20.9 | 28.72 (2.3) | * |
| 40 | * | * | * | * | * |
| 41 | 4 | * | * | * | * |
Effects of Tirzepatide on Hunger and BMI
Throughout the treatment, hunger scores and presence of food noise were verbally questioned using a visual analogue score (VAS) grading the most hunger in the past 24 h, with 0 meaning no hunger at all, and 10 being extremely hungry. Before start, the patient scored a VAS hunger score of 8/10 (shown in Fig. 1). After 4 weeks, she experienced a substantial reduction in hyperphagia (not reported using VAS) and a reduction in body weight and BMI. She reported less food noise, absence of hunger feelings and prolonged postprandial satiety. However, in week 1 and 2 this effect was more pronounced than in week 3 and 4. Because of this, the tirzepatide dose was increased to 5.0 mg weekly, resulting in a further BMI decrease, as shown in Figure 1 and Table 1, reaching grade 1 obesity. Due to further fading of the effect on hunger at week 8, a dose escalation to 7.5 mg weekly was initiated. The inhibitory effect on hunger now remained stable throughout week 9 to 12 and at week 12 she graded her hunger with a VAS score of 1-2/10. Because of the good effect on hunger, it was decided to continue the dose of 7.5 mg for another 4 weeks. At week 16, she graded her hunger with a VAS score of 4/10, which further increased to 6-7/10 at week 20. Weight loss was still ongoing, but because of the significant increase in hunger scores, the dose was then increased to 10 mg weekly. Despite the dose increase, hunger scores further increased to 7-8/10 at week 24, resulting in a dose escalation to 12.5 mg weekly. This improved her hunger scores at week 28, albeit only minimally and the patient experienced high burden of the hyperphagia. In all steps of the dose escalation, a positive effect of tirzepatide on body weight and BMI was seen (shown in Fig. 1; Table 1). In consultation with the patient, it was decided to first focus on better hyperphagia management and add metformin 500 mg once daily, before increasing the tirzepatide dose to the maximum dose of 15 mg weekly, as metformin can impact (hypothalamic) appetite regulation and possibly potentiates GLP-1 secretion [17, 18].
After addition of low-dose metformin at week 28, the patient experienced mild gastrointestinal side effects, but they resolved spontaneously within the first weeks. The patient reported improved satiation and demonstrated improved hunger scores, reaching a relatively low VAS hunger score of 4/10 again at week 37. Body weight further decreased with an additional −7%, resulting in a BMI of 28.7 kg/m2 after 9 weeks of combination therapy. Given the patient’s high level of satisfaction with this outcome, it was decided not to further escalate the dose of metformin and/or tirzepatide yet.
Effects on Eating Behavior
The patient completed the Dutch Eating Behavior Questionnaire for Children (DEBQ-C) at 0 and 24 weeks [19]. The scores for restricted eating and external eating remained stable (very high and under average, respectively), but emotional eating increased from above average to high. The high burden of the increased hunger scores and hyperphagia between weeks 20-24 could be the explanation for the increase in emotional eating behavior. Food preference and food intake were discussed verbally with the patient. Immediately after the initiation of tirzepatide treatment, portion sizes were drastically reduced. However, as hunger scores increased, portion sizes slightly increased again too. Despite this, the patient still notices a big difference compared to before tirzepatide, with food intake being more controlled and smaller meals spread throughout the day. No changes in food preference were reported.
Effects on Laboratory Results
Vital signs and fasting laboratory evaluations before start of tirzepatide treatment (week −4) revealed no obesity-related complications. Laboratory testing was repeated at week 28. After 28 weeks, fasting glucose levels were stable (4.6 and 4.5 mmol/L, respectively) as were insulin levels (96 and 37 pmol/L, respectively). Notably, HbA1c decreased from 34 to 26 mmol/mol. Triglycerides decreased from 0.85 to 0.39 mmol/L, while LDL-C and HDL-C remained equal. No changes were seen in AST, ALT and GGT. Leptin decreased from 65.6 to 36.5 μg/L.
Effects on Quality of Life
Two validated questionnaires on quality of life were completed by the patient at 0 and 24 weeks: the Pediatric Quality of Life Inventory (PedsQL) and the Impact of Weight on Quality of Life-kids (IWQOL) [20, 21]. After 24 weeks, the patient improved on all domains of the PedsQL: physical functioning (90 > 93%), emotional functioning (65 > 85%), social functioning (30 > 55%), functioning at school (50 > 65%). Total PedsQL score improved from 63% to 77%. In contrast, the IWQOL total score remained stable at 54.6%, with improvement or no change in the domains “my environment” and “my family” (46 > 63% and stable at 100%, respectively), but worsening of the domains “physical discomfort” and “my body” (79 > 66% and 14 > 11%, respectively).
Adverse Effects
The patient experienced no issues with adherence to the therapy. Tirzepatide was well tolerated, with no serious adverse effects reported to date. Mild gastrointestinal side effects (e.g., nausea) at the beginning of the tirzepatide treatment resolved spontaneously and no dose adjustments were necessary for adverse events. Metformin addition was also well tolerated, with transient nausea and diarrhea occurring shortly after initiation of the treatment.
Discussion
In this case report, we demonstrate the effectiveness of tirzepatide in a 17-year-old adolescent with MC4R deficiency, following gradual titration to a maximum dose of 12.5 mg tirzepatide once weekly. Our patient did experience clinically meaningful weight loss, already on lower doses of tirzepatide, with a reduction of −13.9% body weight at 28 weeks. Initially, a positive effect on hunger and satiety was observed in this patient; however, this effect was not lasting throughout 28 weeks of follow-up. Because of this, metformin was added to the tirzepatide treatment in a low dose, resulting in an improvement in hunger and satiety and an additional reduction of −7% body weight from week 28 to 37. Total body weight reduction at week 37 was −20.9%. To date, no data are available on the efficacy of tirzepatide in pediatric or adolescent populations, highlighting the clinical relevance of this observation.
Hyperphagia is a core clinical feature of MC4R deficiency and is associated with significant distress and burden [15]. Lifestyle interventions can improve weight and metabolic complications, but do not effectively improve hyperphagia in these patients. In addition to evaluating weight, we analyzed hunger and satiety in this case report. Our patient reported a reduction in appetite and hunger along with improved satiety shortly after the initiation of tirzepatide. This finding is consistent with the hypothesized mechanisms of GLP-1 and GIP receptor agonists in appetite regulation and energy intake [10]. An alternative explanation for the observed effect on appetite may lie in the potential ability of GLP-analogs to reduce hypothalamic micro inflammation, which has shown to play an important role in the onset and progression of metabolic diseases, including obesity [22]. However, both hypotheses do not explain why hunger scores in our patient rapidly increased again after 12 weeks of treatment, despite continued effectiveness on weight loss and BMI. Tirzepatide is not specifically targeted at the defect in the leptin-melanocortin pathway, which might explain the hyperphagia breaking through the different doses of tirzepatide. Cohort studies and longer-term studies including measurements of hunger scores and eating behavior are necessary to further evaluate the effect of tirzepatide in patients with genetic obesity and hyperphagia.
The −13.9% reduction of body weight in our patient after 28 weeks of tirzepatide treatment, measured in a real-world setting, is comparable to the weight changes observed in 25 adult MC4R variant carriers and 1,698 non-carriers in the SURMOUNT-1 trial, who achieved a pooled reduction in body weight between −10 and −15% after 6 months of treatment with 5, 10 or 15 mg of tirzepatide [12]. Interestingly enough, with addition of low-dose metformin due to hunger scores which were not longer well controlled, body weight kept reducing until follow-up at 37 weeks. Also in the tirzepatide-only-phase with slightly increasing hunger scores, she kept losing weight. This might be a consequence of the GIP component of tirzepatide, directly influencing adipocytes and lipolysis, which likely works normally despite the MC4R mutation [23]. Future studies should include body composition measurements and more extensive biochemical analysis (i.e., free fatty acid levels) to further explore these hypotheses, as these data were unfortunately unavailable for this patient.
The effects of tirzepatide treatment in this patient should also be compared to the GLP-1 analogs liraglutide and semaglutide. Liraglutide successfully reduced BMI-SDS by −0.22 after 56 weeks in adolescents with common obesity compared to placebo [24]. In adolescents with common obesity, semaglutide led to BMI reductions of −16% after 68 weeks of treatment [25]. As noted by Welling et al. [7], GLP-1 analogs are the most studied non-targeted anti-obesity agents in patients with genetic obesity. However, most research has been conducted in adults, with studies in adolescents being largely limited to case reports and case series. In an RCT by Iepsen et al. [26], liraglutide demonstrated −6% weight loss after 16 weeks in 14 adults with MC4R deficiency, showing a similar response to controls without MC4R deficiency. In our patient, after 16 weeks of tirzepatide treatment, −10.7% weight loss was achieved. A recent case series by Salama et al. [27] involving two adolescents with MC4R deficiency, showed an 8% absolute BMI reduction after 6 months of semaglutide treatment in one patient, and a 26% absolute BMI reduction after 16 months of semaglutide treatment in another. Another case report reported weight loss of −5.7% and −11% in an adolescent with MC4R deficiency, respectively, 3 and 12 months after treatment with semaglutide [28]. After 3 months of tirzepatide treatment, our patient had lost nearly −10% body weight, which increased to −13.9% at 7 months, showing a seemingly greater effect compared to liraglutide and semaglutide, although this should be interpreted with caution.
Tirzepatide was generally well tolerated in our patient, with only mild gastrointestinal side effects that resolved spontaneously. No serious adverse events were observed, consistent with safety profiles reported in adult trials. However, ongoing monitoring remains essential, especially given the potential for long-term metabolic or gastrointestinal effects in adolescents.
An overall improvement in quality of life was observed in this patient, particularly in the social and emotional domains. However, obesity-related quality of life worsened in the areas of physical discomfort and body image. This highlights that, despite significant weight loss, attention must be given to the mental consequences of having obesity and hyperphagia at a young age, particularly in relation to self-image.
Conclusion
These observations suggest that tirzepatide may be an effective therapeutic option for weight management in adolescents with (severe) obesity due to MC4R deficiency. In contrast to substantial BMI reduction, hyperphagia showed only short-term improvements, which were not maintained during the follow-up period in this case and necessitated intensification of the treatment through co-treatment with low-dose metformin. Cohort studies with extended follow-up are needed to assess the long-term effectiveness on hyperphagia and BMI as well as adverse events of tirzepatide in the pediatric population with common obesity and in patients with leptin-melanocortin pathway defects.
Acknowledgments
We would like to thank the patient for granting her consent to this case report and for sharing her experiences.
Statement of Ethics
The study was approved by the medical Ethics Committee of Erasmus MC (MEC-2012-257) and written informed consent was obtained from the patient for publication of the details of her medical case and any accompanying images. As the patient is older than 16 years, national regulations do not require parental consent.
Conflict of Interest Statement
The institution of the authors has received funding for clinical trial research from Rhythm Pharmaceuticals, Inc. The current study is not linked to this. MB and EvR receive personal royalties from Ambo Anthos for the lay book Fat: the Secret Organ. The other authors declare no conflicts of interest.
Funding Sources
This study was not supported by any sponsor or funder.
Author Contributions
Evd.W. and M.B. conceptualized and drafted the initial manuscript and critically reviewed and revised the manuscript. Ev.R. and Evd.A. contributed substantially to the interpretation of the data and critically reviewed and revised the manuscript. All authors approved the final manuscript as submitted.