GLP-1RA based treatment in patients with a PCSK1 mutation has profound effects on body weight - two case reports

Monogenetic obesity involving the POMC and MC4R pathway often result in severe obesity, Case presentation: Two sisters, both in their thirties, with a loss-of-function PCSK1 muta-tion and living with class III obesity (BMI's 42 kg/m2 and 46 kg/m2, respectively) was referred for obesity treatment. None of the women had obesity-related diseases; however, due to severe obesi-ty they were treated with semaglutide and tirzepatide resulting in weight loss between 16%-27% of initial body weight.

Despite a loss-of-function PCSK1 mutation disrupting the POMC pathway, the two cases are suggestive of GLP-1RA efficacy both upstream and downstream POMC, illustrating a need for further investigations of the mechanism of action for GLP-1RA-based therapies.