A new genetic analysis of the SURMOUNT-1 trial data suggests that tirzepatide is an effective treatment for individuals with obesity caused by melanocortin 4 receptor (MC4R) deficiency, the most common monogenic form of the disease.¹ This finding is significant for a patient group in whom lifestyle interventions have previously shown limited success.
Tirzepatide is a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, which has demonstrated substantial weight reduction in people with obesity.²
This study was a genetic analysis of 2,291 participants from the SURMOUNT-1 randomised controlled trial (NCT04184622).¹ The original trial enrolled adults with a body mass index (BMI) of ≥30 kg m−2, or ≥27 kg m−2 with at least one weight-related comorbidity. Researchers conducted genotyping to identify participants carrying pathogenic loss-of-function mutations in the MC4R gene. The clinical characteristics and weight loss trajectory of these carriers were compared with non-carriers over a 72-week period.
Pathogenic MC4R mutations were identified in 1.4% of the cohort (32 of 2,291 participants). At baseline, individuals carrying an MC4R mutation had a significantly higher mean BMI compared with non-carriers (40 kg m−2 versus 38 kg m−2; P = 0.036).
In the treatment arm, the magnitude of weight loss at 72 weeks was comparable between the two groups. MC4R mutation carriers achieved an 18.3% mean weight reduction, while non-carriers achieved a 19.9% reduction. Changes in metabolic parameters were also similar between carriers and non-carriers receiving tirzepatide.
These results indicate that tirzepatide’s efficacy is maintained in people with MC4R deficiency, a condition that is often challenging to manage. The study authors concluded, "tirzepatide is an effective treatment for the most common genetic subtype of obesity, MC4R deficiency."¹ Given the severity of obesity often seen in this population, these findings highlight a promising pharmacological option.
As MC4R deficiency typically presents with severe obesity from childhood, the authors note that trials of tirzepatide and other obesity medications in children and adolescents are needed to build an evidence base for earlier intervention.
This study was funded by Eli Lilly and Company.
References
1. Bhatnagar P, Ahmad NN, Li X, et al. Tirzepatide leads to weight reduction in people with obesity due to MC4R deficiency. Nat Med 2025. https://doi.org/10.1038/s41591-025-03913-2
2. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med 2022;387:205–16. https://doi.org/10.1056/NEJMoa2206038
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