Why GLP-1 Drugs Cause Thyroid Tumors in Rats but Probably Not in Humans | Research

The takeaway

GLP-1 receptor agonists cause thyroid C-cell growth and calcitonin release in rodents, but primate and human thyroid cells lack the receptor expression needed for this effect, suggesting the rodent finding may not apply to people.

>60x human dose, no thyroid effect in primates
Monkeys given liraglutide at more than 60 times the human exposure level for 20 months showed no C-cell hyperplasia, in stark contrast to rodents

What the researchers found

GLP-1 receptor agonists including liraglutide caused thyroid C-cell hyperplasia and calcitonin release in rodents through a GLP-1 receptor-mediated mechanism. However, this effect appears species-specific: human and monkey thyroid C-cells had low GLP-1 receptor expression, GLP-1 agonists did not activate calcitonin release in primate cells, and 20 months of liraglutide treatment at >60x human exposure did not cause C-cell hyperplasia in monkeys. In human patients treated with liraglutide for 2 years, calcitonin levels remained at the lower end of normal with no meaningful increase above clinically relevant thresholds.

Why it matters

This is the key study that explained why GLP-1 drugs carry a thyroid cancer warning on their labels — rodent studies showed thyroid tumors — while providing the first strong evidence that this risk may not translate to humans. It delineated a species-specific difference in GLP-1 receptor biology that has been central to the safety debate around every GLP-1 RA since.

The numbers in context

>60x human exposure in monkeys for 20 months · No C-cell hyperplasia in primates · Human calcitonin remained in lower normal range · 2-year human exposure data · Cutoff: 20 pg/ml calcitonin

How the study worked

Multi-species study: GLP-1 receptor localization via immunohistochemistry in rodent, monkey, and human thyroid tissue. Calcitonin release and gene expression measured in rodent C-cells. Adenylate cyclase activation tested in primate cells. 20-month liraglutide treatment in cynomolgus monkeys at >60x human exposure. 2-year calcitonin monitoring data from human clinical trials.

Who was studied

Sprague-Dawley rats, mice (including GLP-1R knockout), cynomolgus monkeys, human thyroid tissue, and type 2 diabetes patients from clinical trials

What this study cannot tell us

The human data comes from clinical trial calcitonin monitoring, not direct thyroid tissue examination. Long-term consequences of sustained GLP-1 receptor activation in human thyroid remain unknown. The 2-year human follow-up may not be sufficient to detect very slow-growing thyroid cancers. Monkey study used one GLP-1 RA (liraglutide) and may not generalize to all agents.

How to read the evidence

This is a rigorous multi-species preclinical study combining rodent, primate, and human tissue data with clinical trial biomarker monitoring. Published in a top endocrinology journal by researchers from Novo Nordisk and leading academic collaborators. The evidence is moderate overall — strong for mechanism but the human safety question requires longer follow-up.

When this study was published

Published in 2010, this study was conducted during liraglutide's regulatory review. Its core finding — that the rodent thyroid signal is species-specific — has been reinforced by over a decade of subsequent human safety data, though the FDA boxed warning remains on all GLP-1 RA labels.

The bigger picture

This study has been one of the most cited papers in GLP-1 RA safety discussions. The thyroid cancer signal in rodents delayed drug approvals and required prominent label warnings. By demonstrating species-specific GLP-1 receptor expression in the thyroid, this work provided the mechanistic basis for cautious optimism that the rodent signal wouldn't translate to humans — a conclusion supported by subsequent years of pharmacovigilance data from millions of patients.

Questions still open

After 15+ years of GLP-1 RA use in millions of patients, has the human epidemiological data definitively resolved the thyroid cancer question?
Do different GLP-1 receptor agonists vary in their potential to affect human thyroid C-cells, even at the low receptor expression levels found?
Could very long-term GLP-1 RA use (decades) produce thyroid effects that 2-year clinical trials cannot detect?

Common questions

Should I worry about thyroid cancer if I'm taking a GLP-1 drug like semaglutide or liraglutide?

The thyroid cancer warning on GLP-1 drugs comes from rodent studies where these drugs caused thyroid C-cell tumors. However, this study showed that human thyroid cells have very few GLP-1 receptors compared to rodents, and the effect does not appear to occur in primates. Over a decade of real-world use has not shown a clear increase in thyroid cancer in humans. Still, people with a personal or family history of medullary thyroid carcinoma should not use these drugs.

What are thyroid C-cells and what do they have to do with GLP-1 drugs?

C-cells are specialized cells in your thyroid gland that produce calcitonin, a hormone involved in calcium regulation. In rodents, these cells have many GLP-1 receptors, so GLP-1 drugs overstimulate them, causing abnormal growth. In humans, C-cells have far fewer GLP-1 receptors, which is why the drugs don't appear to have the same effect on human thyroids.

Read the original research

Glucagon-like Peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation.

Endocrinology, 151(4), 1473-86

View on PubMed ↗Publisher’s paper ↗

Citation

Bjerre Knudsen, Lotte; Madsen, Lars Wichmann; Andersen, Søren; Almholt, Kasper; de Boer, Anne S; Drucker, Daniel J; Gotfredsen, Carsten; Egerod, Frederikke Lihme; Hegelund, Anne Charlotte; Jacobsen, Helene; Jacobsen, Søren Dyring; Moses, Alan C; Mølck, Anne-Marie; Nielsen, Henriette S; Nowak, Jette; Solberg, Helene; Thi, Tu D L; Zdravkovic, Milan; Moerch, Ulrik. (2010). Glucagon-like Peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation.. Endocrinology, 151(4), 1473-86. https://doi.org/10.1210/en.2009-1272