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<p>The magnitude of weight reduction in the SURMOUNT-1 trial of the dual GLP-1 and GIP receptor agonist tirzepatide suggests that this treatment may be particularly effective in addressing the treatment needs of people with severe obesity (body mass index &gt;40 kg m<sup>−2</sup>), some of whom may carry rare penetrant genetic variants. Here we investigated the clinical response of men and women in the SURMOUNT-1 trial who carried pathogenic mutations in the melanocortin 4 receptor (<i>MC4R</i>) gene, the most common genetic cause of obesity. We found that 32 of 2,291 people (1.4%) for whom data were available carried pathogenic <i>MC4R</i> mutations. At baseline, <i>MC4R</i> mutation carriers exhibited a higher body mass index compared with noncarriers (40 kg m<sup>−2</sup> versus 38 kg m<sup>−2</sup>; <i>P</i> = 0.036). In the treatment arm, the weight loss trajectory over 72 weeks was comparable in both groups: 18.3% weight reduction in <i>MC4R</i> mutation carriers versus 19.9% in noncarriers. We conclude that tirzepatide is an effective treatment for the most common genetic subtype of obesity, MC4R deficiency.</p>

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Tirzepatide leads to weight reduction in people with obesity due to MC4R deficiency

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月26日

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  • Pallav Bhatnagar,
  • Nadia N. Ahmad,
  • Xuan Li,
  • Matthew Coghlan,
  • Lee M. Kaplan,
  • I. Sadaf Farooqi

摘要

The magnitude of weight reduction in the SURMOUNT-1 trial of the dual GLP-1 and GIP receptor agonist tirzepatide suggests that this treatment may be particularly effective in addressing the treatment needs of people with severe obesity (body mass index >40 kg m−2), some of whom may carry rare penetrant genetic variants. Here we investigated the clinical response of men and women in the SURMOUNT-1 trial who carried pathogenic mutations in the melanocortin 4 receptor (MC4R) gene, the most common genetic cause of obesity. We found that 32 of 2,291 people (1.4%) for whom data were available carried pathogenic MC4R mutations. At baseline, MC4R mutation carriers exhibited a higher body mass index compared with noncarriers (40 kg m−2 versus 38 kg m−2; P = 0.036). In the treatment arm, the weight loss trajectory over 72 weeks was comparable in both groups: 18.3% weight reduction in MC4R mutation carriers versus 19.9% in noncarriers. We conclude that tirzepatide is an effective treatment for the most common genetic subtype of obesity, MC4R deficiency.