GLP-1 receptor agonist therapy and risk of small intestinal neoplasms: Real-world evidence from a global network.

Abstract

e16499 Background: As indications for GLP-1 RAs expand, their long-term oncologic safety remains a key concern. Supraphysiologic GLP-1 receptor stimulation has raised concerns for tumorigenesis in receptor-expressing tissues, including the gastrointestinal tract. While the safety of GLP-1 RAs in thyroid and pancreatic malignancies has been evaluated, their impact on small intestinal neoplasms remains poorly understood despite a rising incidence of these cancers. Emerging real-world data suggest potential anti-inflammatory and metabolic benefits of GLP-1 RAs with reduced colorectal cancer risk; however, it is unclear whether such effects extend to the small intestine, which harbors a high density of GLP-1- secreting L cells. We examined the association between GLP-1 RA therapy and the incidence of small intestinal malignancies compared with other standard therapies. Methods: We conducted a retrospective cohort study using the TriNetX Global Collaborative Network including adults (18–80 years) with DM or overweight/obesity. Patients prescribed a GLP-1 RA within 1 year of diagnosis were compared with those receiving other standard therapies, excluding individuals with pre-existing GI or hereditary cancer risk conditions. 1:1 PSM was performed for demographics, BMI, HbA1c and lifestyle factors. Primary and secondary small intestinal neoplasm outcomes were assessed at 3, 5 and 10 years with ARR and 95% CIs calculated. Results: At 3 years, GLP-1 RA use was associated with a lower absolute risk of malignant small intestinal neoplasms compared with non-GLP-1 therapy (1.4% vs 3.8%; ARR 2.4%, 95% CI 2.0–2.8; p< 0.0001). Similar risk reductions persisted at 5 years (ARR 2.6%, 95% CI 2.2%–3.0%) and 10 years (ARR 3.2%, 95% CI 2.7%–3.6%; both p< 0.0001). Lower absolute risks were also observed for benign neoplasms and carcinoid tumors across all time points. No consistent differences were observed for small intestinal lymphoma or GIST at earlier follow-up, though modest risk reductions for lymphoma emerged at 10 years. Conclusions: Despite theoretical concerns regarding incretin-based therapies and gastrointestinal tumorigenesis, our study found no evidence of increased risk for small intestinal malignancies among GLP-1 RA users. Instead, lower absolute risk was observed compared to controls concurring oncologic safety. Given limitations of retrospective analyses mechanistic and prospective studies are needed to further study the drivers of this observed inverse association. OUTCOMES at 10 years GLP1 Receptor agonist (%) No GLP1 therapy (%) ARR(95% CI) P VALUE Malignant neoplasms of the small intestine 0.021 0.053 3.2 (2.7 – 3.6) <0.0001 Benign neoplasms of the small intestine 0.051 0.0066 1.6 (1 - 2.1) <0.0001 Lymphoma of small intestine 0.014 0.018 0.4 (0.1 – 0.7) 0.0126 Carcinoid tumor of the small intestine 0.011 0.020 0.9 (0.6 – 1.2) <0.0001 GIST Small intestine 0.005 0.006 0.1 (0.1 – 0.3) 0.6920