Objective:

To evaluate overall and site-specific cancer outcomes among adults with T2DM using GLP-1RAs and to assess the biological mechanisms influencing tumor development.

Approach:

• Study Design: Systematic review and meta-analysis conducted following PRISMA 2020 guidelines.
• Search Strategy: Comprehensive search conducted on PubMed, Scopus, and Web of Science for studies from 2015 to June 8, 2026.
• Data Analysis: Pooled hazard ratios (HRs) calculated using the Generic Inverse Variance method under a random-effects model.

Key Findings:

• Significant reduction in overall cancer risk among GLP-1RAs users (HR = 0.86, 95% CI: 0.74–0.99; p = 0.04).
• Pooled analysis showed significant reductions in specific cancers: pancreatic, colorectal, endometrial, ovarian, hepatocellular, esophageal, and gastric.
• No significant associations found for thyroid, breast, kidney, or prostate cancers.
• Limited mechanistic evidence primarily indirect, with few studies on pathways related to inflammation, proliferation, apoptosis, and metabolism.

Interpretation:

GLP-1RAs are not associated with increased cancer risk and may be linked to reduced risk for certain cancer types, but findings are based on observational evidence and exhibit substantial heterogeneity.

Limitations:

• Substantial heterogeneity in study designs and populations may affect the robustness of conclusions.
• Limited mechanistic validation of findings.
• Reliance on observational studies may limit the ability to draw definitive conclusions.

Conclusion:

Further investigation is needed to clarify mechanisms and confirm findings regarding the association of GLP-1RAs with cancer risk in T2DM patients.