MON-715 - Marked Weight Loss And Diabetes Remission With Tirzepatide In Monogenic MC4R Pathway Obesity

Background: Pathogenic variants in the melanocortin-4 receptor (MC4R) pathway can cause hyperphagia and early-onset severe obesity. Setmelanotide, an MC4R agonist, is approved for obesity due to select MC4R pathway mutations; however, adverse effects and adherence challenges may limit its effectiveness. The role of incretin-based therapies in monogenic MC4R pathway obesity remains less well defined. We present a case of a patient with monogenic MC4R pathway obesity who achieved significant weight loss and diabetes remission with incretin-based therapy after limited response to setmelanotide.

Clinical

Case: A 20-year-old male with lifelong severe obesity (235 kg, BMI 78.52 kg/m2 ), prediabetes (hemoglobin A1c [HbA1c] 5.7%), migraines, attention deficit hyperactivity disorder), anxiety, depression, hearing loss, developmental disorder, and asthma transitioned to adult endocrine care after pediatric endocrine follow-up. He had been near the 90th percentile for weight throughout childhood, with accelerated weight gain beginning at age 11. Genetic testing revealed a monoallelic MC4R mutation and a heterozygous Nuclear Receptor Coactivator 1 (NCOA1/SRC-1) variant with uncertain pathogenic interpretation. At age 18, he enrolled in a placebo-controlled pharmaceutical drug trial of setmelanotide and remained on therapy for approximately one year. Treatment adherence was inconsistent due to perceived side effects, including skin hyperpigmentation and spontaneous penile erections. Despite therapy, his weight remained unchanged and he subsequently developed type 2 diabetes mellitus (HbA1c 6.5%).
Given the patient’s class III obesity and new-onset diabetes, setmelanotide was discontinued and tirzepatide, a dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, was initiated. Over 14 months, he achieved a total weight loss of 54 kg, with substantial improvement in functional status. Glycemic control improved rapidly, with HbA1c decreasing to 5.5% within five months, and further to 5.1%, consistent with diabetes remission. Gastrointestinal adverse effects occurred at higher doses but were mitigated with dose reduction, allowing sustained therapy.

Conclusion: This case demonstrates that incretin-based therapy can produce substantial weight loss and diabetes remission in patients with monogenic MC4R pathway obesity who have limited tolerability or response to MC4R agonist therapy. While targeted melanocortin pathway treatment remains important in those individuals, GLP-1–based medications should be considered when obesity-related comorbidities are present and adherence to MC4R agonists is challenging. Individualized, patient-centered treatment selection is critical in the management of genetically mediated obesity.

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