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

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.

Fig. 1. Baseline BMI distribution and tirzepatide-induced weight loss in MC4R mutation carriers versus noncarriers.

a, The distribution of BMI at baseline for MC4R mutation carriers and noncarriers. b, Least-squares mean estimands of the percentage change in body weight from baseline to week 72, with error bars representing 95% confidence intervals (CI). Genetic effects on change in body weight were assessed using aggregated data on carriers of 14 MC4R LoF mutations (beta coefficient −0.88, SEM 3.2); statistical significance was assessed using a REGENIE collapsed burden test incorporating the treatment interaction effect (unadjusted two-sided P value 0.79). c, Time course effect on body weight change. Least-squares mean estimands were generated for each time point based on a three-way interaction among MC4R carrier status, pooled treatment and visit. Blue and gray bars represent tirzepatide treatment and placebo arms, respectively, with error bars representing 95% CI.