Glucagon-like Peptide-1 Receptor Agonists and Thyroid Cancer: Myth or Reality?
DOI:
https://doi.org/10.58931/cdet.2025.3137Abstract
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).
References
Shah BR, Bajaj HS, Butalia S, Dasgupta K, Eurich DT, Jain R, et al. Pharmacologic glycemic management of type 2 diabetes in adults---2024 update. Can J Diabetes. 2024;48(7):415-424. doi:10.1016/j.jcjd.2024.08.002 DOI: https://doi.org/10.1016/j.jcjd.2024.08.002
Bjerre Knudsen L, Madsen LW, Andersen S, Almholt K, de Boer AS, Drucker DJ, et al. Glucagon-like peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation. Endocrinology. 2010;151(4):1473-1486. doi:10.1210/en.2009-1272 DOI: https://doi.org/10.1210/en.2009-1272
Song Y, Zhou M, Cao Y, Qi J, Geng J, Liu X. Expression of GLP-1 receptor and CD26 in human thyroid C-cells: the association of thyroid C-cell tumorigenesis with incretin-based medicine. Oncol Lett. 2017;13(4):2684-2690. doi:10.3892/ol.2017.5752 DOI: https://doi.org/10.3892/ol.2017.5752
Waser B, Blank A, Karamitopoulou E, Perren A, Reubi JC. Glucagon-like-peptide-1 receptor expression in normal and diseased human thyroid and pancreas. Mod Pathol. 2015;28(3):391-402. doi:10.1038/modpathol.2014.113 DOI: https://doi.org/10.1038/modpathol.2014.113
He L, Zhang S, Zhang X, Liu R, Guan H, Zhang H. Effects of insulin analogs and glucagon-like peptide-1 receptor agonists on proliferation and cellular energy metabolism in papillary thyroid cancer. Onco Targets Ther. 2017;10:5621-5631. doi:10.2147/ott.S150701 DOI: https://doi.org/10.2147/OTT.S150701
Mali G, Ahuja V, Dubey K. Glucagon-like peptide-1 analogues and thyroid cancer: an analysis of cases reported in the European pharmacovigilance database. J Clin Pharm Ther. 2021;46(1):99-105. doi:10.1111/jcpt.13259 DOI: https://doi.org/10.1111/jcpt.13259
Yang Z, Lv Y, Yu M, Mei M, Xiang L, Zhao S, et al. GLP-1 receptor agonist-associated tumor adverse events: a real-world study from 2004 to 2021 based on FAERS. Front Pharmacol. 2022;13:925377. doi:10.3389/fphar.2022.925377 DOI: https://doi.org/10.3389/fphar.2022.925377
Bezin J, Gouverneur A, Pénichon M, Mathieu C, Garrel R, Hillaire-Buys D, et al. GLP-1 receptor agonists and the risk of thyroid cancer. Diabetes Care. 2023;46(2):384-390. doi:10.2337/dc22-1148 DOI: https://doi.org/10.2337/dc22-1148
Dore DD, Seeger JD, Chan KA. Incidence of health insurance claims for thyroid neoplasm and pancreatic malignancy in association with exenatide: signal refinement using active safety surveillance. Ther Adv Drug Saf. 2012;3(4):157-164. doi:10.1177/2042098612446473 DOI: https://doi.org/10.1177/2042098612446473
Liang C, Bertoia ML, Ding Y, Clifford CR, Qiao Q, Gagne JJ, et al. Exenatide use and incidence of pancreatic and thyroid cancer: a retrospective cohort study. Diabetes Obes Metab. 2019;21(4):1037-1042. doi:10.1111/dom.13597 DOI: https://doi.org/10.1111/dom.13597
Funch D, Mortimer K, Ziyadeh NJ, J DS, Zhou L, Ng E, et al. Risk of thyroid cancer associated with use of liraglutide and other antidiabetic drugs in a US commercially insured population. Diabetes Metab Syndr Obes. 2021;14:2619-2629. doi:10.2147/dmso.S305496 DOI: https://doi.org/10.2147/DMSO.S305496
Wang J, Kim CH. Differential risk of cancer associated with glucagon-like peptide-1 receptor agonists: analysis of real-world databases. Endocr Res. 2022;47(1):18-25. doi:10.1080/07435800.2021.1955255 DOI: https://doi.org/10.1080/07435800.2021.1955255
Bea S, Son H, Bae JH, Cho SW, Shin JY, Cho YM. Risk of thyroid cancer associated with glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes: a population-based cohort study. Diabetes Obes Metab. 2024;26(1):108-117. doi:10.1111/dom.15292 DOI: https://doi.org/10.1111/dom.15292
Pasternak B, Wintzell V, Hviid A, Eliasson B, Gudbjörnsdottir S, Jonasson C, et al. Glucagon-like peptide 1 receptor agonist use and risk of thyroid cancer: Scandinavian cohort study. BMJ. 2024;385:e078225. doi:10.1136/bmj-2023-078225 DOI: https://doi.org/10.1136/bmj-2023-078225
Baxter SM, Lund LC, Andersen JH, Brix TH, Hegedüs L, Hsieh MH, Su CT, Cheng MC, Chang ZC, Lai EC, Hussain S, Chu C, Gomes T, Antoniou T, Eskander A, Bouck Z, Tadrous M, Bea S, Choi EY, Shin JY, Modig K, Talbäck M, Ljung R, Gulseth HL, Karlstad Ø, Hicks B, Pottegård A. Glucagon-Like Peptide 1 Receptor Agonists and Risk of Thyroid Cancer: An International Multisite Cohort Study. Thyroid. 2025 Jan;35(1):69-78. doi: 10.1089/thy.2024.0387. DOI: https://doi.org/10.1089/thy.2024.0387
Goldenberg RM, Jain AB. Comment on Bezin et al. GLP-1 receptor agonists and the risk of thyroid cancer. Diabetes Care 2023;46:384-390. Diabetes Care. 2023;46(5):e117. doi:10.2337/dc22-2300 DOI: https://doi.org/10.2337/dc22-2300
Silverii GA, Monami M, Gallo M, Ragni A, Prattichizzo F, Renzelli V, et al. Glucagon-like peptide-1 receptor agonists and risk of thyroid cancer: a systematic review and meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2024;26(3):891-900. doi:10.1111/dom.15382 DOI: https://doi.org/10.1111/dom.15382
Hegedüs L, Sherman SI, Tuttle RM, von Scholten BJ, Rasmussen S, Karsbøl JD, et al. No evidence of increase in calcitonin concentrations or development of c-cell malignancy in response to liraglutide for up to 5 years in the LEADER trial. Diabetes Care. 2018;41(3):620-622. doi:10.2337/dc17-1956 DOI: https://doi.org/10.2337/dc17-1956
Bethel MA, Patel RA, Thompson VP, Merrill P, Reed SD, Li Y, et al. Changes in serum calcitonin concentrations, incidence of medullary thyroid carcinoma, and impact of routine calcitonin concentration monitoring in the EXenatide Study of Cardiovascular Event Lowering (EXSCEL). Diabetes Care. 2019;42(6):1075-1080. doi:10.2337/dc18-2028 DOI: https://doi.org/10.2337/dc18-2028
Holman RR, Bethel MA, Mentz RJ, Thompson VP, Lokhnygina Y, Buse JB, et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2017;377(13):1228-1239. doi:10.1056/NEJMoa1612917 DOI: https://doi.org/10.1056/NEJMoa1612917
Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311-322. doi:10.1056/NEJMoa1603827 DOI: https://doi.org/10.1056/NEJMoa1603827
Husain M, Birkenfeld AL, Donsmark M, Dungan K, Eliaschewitz FG, Franco DR, et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2019;381(9):841-851. doi:10.1056/NEJMoa1901118 DOI: https://doi.org/10.1056/NEJMoa1901118
Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. 2019;394(10193):121-130. doi:10.1016/s0140-6736(19)31149-3 DOI: https://doi.org/10.1016/S0140-6736(19)31149-3
Davies MJ, Bergenstal R, Bode B, Kushner RF, Lewin A, Skjøth TV, et al. Efficacy of Liraglutide for weight loss among patients with type 2 diabetes: the SCALE diabetes randomized clinical trial. Jama. 2015;314(7):687-699. doi:10.1001/jama.2015.9676 DOI: https://doi.org/10.1001/jama.2015.9676
Lincoff AM, Brown-Frandsen K, Colhoun HM, Deanfield J, Emerson SS, Esbjerg S, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med. 2023;389(24):2221-2232. doi:10.1056/NEJMoa2307563 DOI: https://doi.org/10.1056/NEJMoa2307563
Tao Z, Deng X, Guo B, Ding Z, Fan Y. Subgroup analysis of steadily increased trends in medullary thyroid carcinoma incidence and mortality in the USA, 2000-2020: a population-based retrospective cohort study. Endocr Relat Cancer. 2024;31(5). doi:10.1530/erc-23-0319 DOI: https://doi.org/10.1530/ERC-23-0319
European Medicines Agency. Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 23-26 October 2023 [Internet]. [Accessed December 30, 2024]. Available from: https://www.ema.europa.eu/en/news/meeting-highlights-pharmacovigilance-risk-assessment-committee-prac-23-26-october-2023.
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