Divergent Risks of Endocrine and Nonendocrine Malignancies in GLP-1 Receptor Agonist Users

Objective: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely used for type 2 diabetes mellitus (T2DM). The long-term impact on cancer risk remains uncertain. This study aimed to evaluate the association between GLP-1 RA and the risk of cancer, including site-specific malignancies. Methods: This retrospective cohort study utilized the TriNetX database. Adults with T2DM between 2015 and 2023 were identified. After 1:1 propensity score matching, 144 410 GLP-1 RA users were compared with nonusers. Primary outcomes were all-cause mortality and incident malignant neoplasms. Secondary outcomes included site-specific cancers. Results: GLP-1 RA use was associated with lower all-cause mortality (hazard ratio [HR] 0.693) and a reduced overall incidence of cancer (HR 0.905). Regarding nonendocrine malignancies, significant risk reductions were observed for digestive cancers (HR 0.710) and respiratory cancers (HR 0.691), as well as for other sites including oral, female genital, and central nervous system cancers. In contrast, GLP-1 RA was linked to an increased risk of thyroid gland cancer (HR 1.411). Active-comparator analyses against dipeptidyl peptidase-4 inhibitor and sodium-glucose co-transporter 2 inhibitor yielded broadly consistent findings. Landmark analyses at 3 years showed attenuation of the thyroid cancer signal to nonsignificance, suggesting surveillance bias rather than a true carcinogenic effect. Conclusion: This real-world analysis demonstrates divergent oncologic risks associated with GLP-1 RA use, while the therapy offers potential protective effects against nonendocrine malignancies (particularly digestive and respiratory). The initially elevated thyroid cancer risk was no longer significant at 3 years, suggesting surveillance bias. These findings support the overall oncologic safety of GLP-1 RA in T2DM management, while warranting further long-term studies to confirm these associations.