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The different colorectal tumor risk related to GLP-1 receptor agonists and SGLT2 inhibitors use: a network
Chao-Ming Hung1,2, Bing-Yan Zeng3,4, Chih-Wei Hsu5
1Division of General Surgery, Department of Surgery, E-Da Cancer Hospital, I-Shou University, Kaohsiung, Taiwan.
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).
Insights
High-dose semaglutide (2.4 mg/week) may increase colorectal tumor risk, particularly in obese patients. This finding from a network meta-analysis requires further validation for glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose co-transporter 2 (SGLT2) inhibitors.
Area of Science:
- Pharmacovigilance and Oncology
- Metabolic Disease Therapeutics
Background:
- Concerns exist regarding potential pro-oncogenic effects of GLP-1 receptor agonists and SGLT2 inhibitors.
- Colorectal tumors are globally prevalent, with higher incidence in patients with metabolic disorders often treated with these drugs.
- Existing evidence on the association between these medications and colorectal tumors is inconsistent.
Purpose of the Study:
- To conduct a network meta-analysis (NMA) evaluating the comparative incidence of colorectal tumors associated with specific GLP-1 receptor agonists and SGLT2 inhibitors.
- To assess potential safety concerns, specifically colorectal tumor incidence, as an adverse effect of these drug classes.
Main Methods:
- A frequentist-based network meta-analysis (NMA) of randomized controlled trials (RCTs) was performed, adhering to Cochrane methodological recommendations.
- The primary outcome was colorectal tumor incidence.
- Dropout rates were analyzed as a secondary outcome to assess safety profiles.
Main Results:
- The NMA included 68 RCTs with 207,200 participants.
- Only semaglutide was associated with an increased incidence of colorectal tumors compared to controls.
- High-dose injectable semaglutide (2.4 mg/week) was the sole regimen linked to increased incidence, observed even in RCTs involving obese subjects. Other GLP-1 receptor agonists and SGLT2 inhibitors showed no significant associations.
Conclusions:
- This comprehensive NMA suggests a dose-dependent relationship between semaglutide, particularly its high-dose injectable form, and colorectal tumor incidence.
- The findings signal a potential risk requiring further validation, especially given the elevated baseline colorectal tumor risk in the target population, including obese individuals.
- Future research should prioritize long-term follow-up studies to elucidate the mechanisms and clinical implications of this semaglutide-specific risk.
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