Why GLP-1 Drug Labels Carry a Thyroid Tumor Warning, and What Human Studies Show

The first thing printed on the U.S. prescribing information for Ozempic, and for other long-acting GLP-1 drugs, is a boxed warning about thyroid C-cell tumors. It is the most serious type of warning the FDA requires, which can make it alarming to read. The story behind it is mostly a story about rodents, and about how hard it is to rule a rare cancer in or out in people.

According to the Ozempic label, two-year studies in mice and rats found a statistically significant increase in thyroid C-cell adenomas, with C-cell carcinomas also increased, at exposures the label describes as clinically relevant. The label states that it is unknown whether semaglutide causes these tumors, including medullary thyroid carcinoma (MTC), in humans, because the human relevance of the rodent findings has not been determined. It also notes postmarketing reports of MTC in patients treated with liraglutide, while saying those reports are insufficient to establish or exclude a causal link.

C-cells are the thyroid cells that make the hormone calcitonin. A 2010 study in Endocrinology, led by Novo Nordisk scientists, reported that rodent C-cells carry GLP-1 receptors and that GLP-1 receptor agonists stimulated calcitonin release and later C-cell proliferation in rats and, to a lesser extent, mice. Human and monkey C-cells showed low receptor expression, and 20 months of liraglutide at more than 60 times human exposure did not produce C-cell hyperplasia in monkeys. The authors still wrote that the long-term consequences of sustained GLP-1 receptor activation in the human thyroid remain unknown.

The observational evidence is mixed. A 2023 French nested case-control study in Diabetes Care reported that one to three years of GLP-1 drug use was associated with a higher risk of all thyroid cancer (adjusted hazard ratio 1.58) and of medullary thyroid cancer (1.78); commentators raised the possibility of confounding by obesity and of more thyroid testing in treated patients. A 2024 BMJ cohort study across Denmark, Norway and Sweden, comparing about 145,000 GLP-1 drug users with DPP-4 inhibitor users over a mean 3.9 years, found no association with thyroid cancer overall (hazard ratio 0.93), though the authors noted a small increase could not be excluded.

After reviewing these and other studies, the European Medicines Agency's safety committee concluded in October 2023 that the available evidence does not support a causal association, and asked manufacturers to keep monitoring.

The warning matters most for a specific group: the label contraindicates these drugs for people with a personal or family history of MTC or with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2), so family history is worth raising with a prescriber before starting. The label also lists symptoms to report, such as a neck lump, trouble swallowing, shortness of breath or persistent hoarseness, and says routine calcitonin or ultrasound screening is of uncertain value. For everyone else, current evidence is reassuring but not final.