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

作者：Pallav Bhatnagar, Nadia N. Ahmad, Xuan Li, Matthew P. Coghlan, Lee M. Kaplan, I. Sadaf Farooqi · 发表于：Nature Medicine · 年份：2025 · DOI：10.1038/s41591-025-03913-2 · 被引用次数：16 · 研究领域：Regulation of Appetite and Obesity、Biochemical Analysis and Sensing Techniques、Diabetes Treatment and Management

Abstract 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.