The different colorectal tumor risk related to GLP-1 receptor agonists and SGLT2 inhibitors use: a network meta-analysis of 68 randomized controlled trials.

BACKGROUND: Recent evidence has raised concerns about potential pro-oncogenic effects associated with glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors, particularly regarding gastrointestinal malignancies. Colorectal tumors, the third most diagnosed cancer globally, already show increased incidence in patients with metabolic disorders who typically require these medications. For example, obese subjects had a significantly higher risk of colorectal tumors than healthy subjects. However, existing evidence on this association remains inconsistent. This network meta-analysis (NMA) evaluated the comparative incidence of colorectal tumors associated with specific GLP-1 receptor agonists and SGLT2 inhibitors. MATERIALS AND METHODS: We conducted a confirmatory NMA focused specifically on colorectal tumor incidence as an adverse effect, following Cochrane methodological recommendations. We performed a frequentist-based NMA of randomized controlled trials (RCTs) evaluating GLP-1 receptor agonists or SGLT2 inhibitors. Our primary outcome was colorectal tumor incidence, with safety profiles assessed by dropout rates as a secondary outcome. RESULTS: This NMA encompassing 68 RCTs with 207 200 participants found that only semaglutide was associated with increased incidence of colorectal tumors compared to controls. A dose-stratified analysis revealed that high-dose injectable semaglutide (2.4 mg/week) was the only regimen associated with increased incidence. Furthermore, when focusing on RCTs of obese subjects, the increased colorectal tumor rate related to semaglutide still existed. Neither other GLP-1 receptor agonists nor any SGLT2 inhibitors demonstrated significant associations with colorectal tumor development. CONCLUSION: Our study provides the first comprehensive NMA addressing the incidence of colorectal tumors related to individual GLP-1 receptor agonists and SGLT2 inhibitors, suggesting a dose-dependent relationship to semaglutide, particularly in its high-dose injectable form (2.4 mg/week). These findings represent a potential risk signal that requires further validation, given the already elevated baseline colorectal tumor risk in the target population, especially in subjects with obesity. Future research should focus on long-term follow-up studies to better characterize the mechanisms and clinical implications of this semaglutide-specific risk signal. WHAT THIS ADDS TO THE EXISTING LITERATURE: This network meta-analysis, based on 68 randomized controlled trials, suggested that only semaglutide, especially in highdose injectable form (2.4 mg/week), was associated with increased incidence of colorectal tumors compared to controls, especially in obese patients. Neither other GLP-1 receptor agonists nor any SGLT2 inhibitors demonstrated significant associations with colorectal tumor development. LEARNING POINTS: Our study provides evidence regarding the increased incidence of colorectal tumors related to semaglutide in a dose dependent way (2.4 mg/week).