Glucagon-like Peptide-1 Receptor Agonists and Thyroid Cancer: Myth or Reality?

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are being used increasingly for the management of type 2 diabetes mellitus (T2DM) or obesity because of their association with robust glucose lowering, weight loss, and cardiorenal benefits. The association between GLP-1RA treatments and thyroid cancer has been a topic of discussion since their early development with the understanding that GLP-1 receptors are present on rodent thyroid parafollicular cells (C-cells), and that GLP-1RAs can cause an increase in calcitonin, and both C-cell hyperplasia and medullary thyroid carcinoma (MTC). This data from rodent studies has led to GLP-1RAs being contraindicated in patients with a personal or family history of MTC or with multiple endocrine neoplasia syndrome type 2. Despite this contraindication, the human relevance of GLP-1RA induced MTC in rodents has not been proven. Normal or hyperplastic C-cells in humans may not express the GLP-1 receptor, and studies of human MTCs have shown variable expression of the GLP-1 receptor. Studies have shown conflicting evidence regarding the expression of the GLP-1 receptor in human papillary thyroid cancer (PTC) cell lines: however, GLP-1RAs did not have significant effects on the proliferation of PTC cells. Because of the data that potentially links GLP-1RAs to an increased risk of thyroid cancer, clinical studies in humans are important in addressing this issue. I will review the relevant data from human studies that have analyzed the potential link between GLP-1RA treatment and thyroid cancer, including pharmacovigilance and observational studies as well as randomized controlled trials (RCTs).