Can we determine the mechanism behind cancer risk reduction with glucagon-like peptide-1 receptor agonists (GLP-1RAs)?

10535 Background: Growing evidence suggests that GLP-1RAs may reduce cancer risk in patients with type 2 diabetes (T2D). Most studies have focused on obesity-related cancers (ORCs), with weight loss proposed as a key mechanism. Additional potential mechanisms include the anti-inflammatory effects of GLP-1RAs on various pathways. We evaluated the impact of GLP-1RAs on weight loss and ORC incidence, as well as their effects on lung cancer, which is considered a non-ORC. Methods: We utilized the TriNetX database to analyze patients with T2D prescribed a single GLP-1RA from 2010 to 2021. Patients with prior cancer diagnoses were excluded. Semaglutide, dulaglutide, and liraglutide were individually compared to exenatide due to their greater weight loss potential. Propensity score matching (1:1) was used to adjust for demographics, comorbidities, HbA1c, BMI, and medications. Patients were followed for 3 and 5 years, and Cox proportional hazards analyses assessed the risk of 13 ORCs and lung cancer. Results: We identified 726,846 patients prescribed GLP-1RAs and conducted multiple comparisons, which were well-matched across analyses. Among the agents, semaglutide demonstrated the greatest weight-loss effect, while exenatide had the least. However, the differences in weight loss did not translate to significant changes in the risk of ORCs. The hazard ratios for semaglutide were 1.11 (95% CI: 0.95–1.29) at 3 years and 1.08 (95% CI: 0.95–1.24) at 5 years. For liraglutide, the hazard ratios were 1.02 (95% CI: 0.88–1.19) at 3 years and 1.05 (95% CI: 0.93–1.20) at 5 years. Dulaglutide had hazard ratios of 1.03 (95% CI: 0.89–1.20) at 3 years and 1.01 (95% CI: 0.89–1.14) at 5 years. None of these differences were statistically significant compared to exenatide. Similarly, no significant differences were observed in the risk for lung cancer. For semaglutide, the hazard ratios were 0.88 (95% CI: 0.59–1.30) at 3 years and 0.88 (95% CI: 0.62–1.25) at 5 years. Liraglutide had hazard ratios of 0.91 (95% CI: 0.62–1.34) at 3 years and 0.90 (95% CI: 0.65–1.24) at 5 years, and dulaglutide had hazard ratios of 1.02 (95% CI: 0.71–1.49) at 3 years and 1.10 (95% CI: 0.81–1.49) at 5 years. These findings indicate no significant differences in cancer risks, whether for obesity-related cancers or non-ORC, lung cancer, among the four GLP-1RAs. Conclusions: All four GLP-1RAs demonstrated similar cancer risks for obesity-related cancers despite differences in weight loss among the agents. Similarly, no differences were observed in the risk of non-obesity-related cancer, specifically lung cancer. This suggests that weight loss does not clearly explain a link between GLP-1RAs and reduced cancer risk, as the results were consistent for both obesity-related and non-obesity-related cancers.