Tirzepatide and metformin effects on hunger and BMI in an adolescent with hyperphagia and severe obesity due to MC4R Deficiency: a case report.

INTRODUCTION: Tirzepatide, a dual GLP-1/GIP receptor agonist, is recently approved for the treatment of type 2 diabetes and obesity in adults. Melanocortin-4-receptor (MC4R) deficiency is the most common monogenic cause of obesity and presents with hyperphagia and early onset obesity. While tirzepatide seems to be effective in inducing weight loss in adults with MC4R deficiency, its effects on hyperphagia and weight loss in pediatric patients are unexplored. CASE PRESENTATION: A 17-year-old girl was admitted to our specialized obesity clinic because of hyperphagia and severe early-onset obesity due to MC4R deficiency. She had an extensive history of lifestyle interventions and psychological support and maintained a high level of physical activity. Despite these efforts, she presented with a BMI of 37 kg/m2 (3.68 SDS) and a substantial psychosocial burden. Vital signs and laboratory evaluations revealed no obesity-related complications. Tirzepatide was initiated at a dose of 2.5 mg weekly and slowly titrated to a maximum dose of 12.5 mg weekly. She initially experienced a substantial reduction in hyperphagia and reported less food noise, a reduction in hunger feelings and prolonged postprandial satiety. However, after 12 weeks hunger scores started to increase again, approaching pre-treatment levels at 28 weeks of follow-up. Metformin was added at 28 weeks in an attempt to better manage of hyperphagia, resulting in a reduction in hyperphagia. Despite these increasing hunger feelings from week 12 to 28, substantial weight loss was achieved, and the patient lost -13.9% of her initial body weight at 28 weeks. After addition of metformin, the patient lost an additional -7% of her weight. Total body weight reduction at week 37 was -20.9%. Tirzepatide was well tolerated, with no adverse effects reported at 41 weeks of follow-up. CONCLUSION: This case report suggests that tirzepatide is effective in reducing body weight in adolescents with MC4R deficiency. However, the question remains what the effect is on hunger and satiety in the long run and at a higher dose. Cohort studies are needed to assess long-term safety and effectiveness of tirzepatide in the pediatric population and in managing hyperphagia.