This NMA, the first to assess colorectal tumor risk across GLP-1 agonists and SGLT2 inhibitors, suggested that semaglutide, particularly the high-dose injectable formulation (2.4 mg/week) in individuals with obesity – may be associated with a dose–dependent increase in colorectal tumor incidence. Here, SLC5A2 is linked to obesity due to melanocortin 4 receptor deficiency.