The EU’s drug watchdog, the EMA has raised concerns regarding the link between a raised thyroid cancer signal and semaglutide, the main active pharmaceutical ingredient (API) found in the popular drugs used for weight loss, Ozempic and Wegovy.
A spokesman for NovoNordisk, the company that makes the Ozempic and Wegovy said that a causal association between semaglutide and thyroid cancer has not been demonstrated in large scale clinical trials and post marketing surveillance.
Both the EMA and the FDA, the US drug watchdog, mention on Wegovy’s patient safety label that semaglutide causes thyroid tumours in rodents but its effects in human is unknown. Hence, as a consequence, the FDA advises against taking Wegovy in those with either a personal or family history of thyroid cancer.
Although, the GLP-1 agonists like semaglutide carry a black box warning for patients with a personal or family history of multiple endocrine neoplasm or medullary thyroid carcinoma, the findings the increased growth or hyperplasia of the thyroid c cells found in rodent studies have not been borne out in human studies.
GLP-1 Agonists
Thyroid specialists have been looking closely at the GLP-1 agonists, such as semaglutide, that were originally used to treat type II diabetes but have since become the most popular weight loss drug in history. Drugs such as semaglutide bind to the GLP-1 receptor and initiate a cascade effect, leading to the increased production of insulin, whilst at the same time preventing the release of glucagon and preventing the production of hepatic (liver) glucose production (Goldenberg RM, Steen O 2019).
It was found that these classes of drugs were extremely effective at reducing high blood sugar levels, or hyperglycemia, in type II diabetic patients. The GLP-1 receptors themselves, to which the drug binds to are located on the pancreatic β-cells, arterial smooth muscle cells in the kidneys and lungs and also in glands in the duodenum called Brunner’s glands (PykeC et al 2014).
GLP-1 Rodent Studies Concerns
The reason these classes of drug are of special interest to the thyroid specialist are due to the findings in the initial mouse studies performed prior to the clinical trials. These early mouse trials found that C cells underwent growth or hyperplasia, increased risk of the incidence of thyroidal C (thyroid C cells are those cells in the thyroid gland that are responsible for secreting calcitonin) cell adenoma and carcinoma and raised calcitonin levels after the administration of one dose of semaglutide in male and female rats (McGovern 2016). Researchers found that in male rats, the calcitonin levels, the hormone produced by the thyroid gland that helps reduce calcium levels in the blood, remained elevated for 6 weeks after treatment. However, these findings were not found when the above studies were carried out in monkeys (McGovern 2016).
Obviously, the above results are a cause for concern, but researchers found that the variation between rodent and primate studies was due to the fact that the rodent thyroidal C cells expressed the GLP-1 receptors (Rasol 2013), while this and other studies have demonstrated that the GLP-1 receptors are not expressed on primate and human C cells in the thyroid glands (Waser et al 2015).
Semaglutide Human Clinical Trials
When the human clinical trials for semaglutide were performed there was no evidence of elevated calcitonin levels, C cell hyperplasia or increased risk of medullary carcinoma. However, concerns still remained leading to the cautionary advice issued by the FDA warning clinicians not to prescribe semaglutide to patients with a personal or family history of medullary thyroid carcinoma or patients with multiple endocrine neoplasia 2.
A more recent systematic review and meta-analysis using data from 37 studies having 46,719 patients found pancreatic and thyroid cancer incidence was not increased with semaglutide similarly all neoplasm (an abnormal growth of tissue that can be benign (noncancerous) or malignant (cancerous) were not increased with semaglutide use (Nagendra L et al 2023).
Summary
There has been no proven link between thyroid cancer and semaglutide although anyone with either a personal or family history of thyroid cancer should avoid taking semaglutide.
References:
Goldenberg RM, Steen O. Semaglutide: Review and place in therapy for adults with type 2 diabetes. Can J Diabetes. 2019 Mar;43(2):136-145.
McGovern TJ. Tertiary pharmacology/toxicology review application number 209637Orig1s000: Ozempic (semaglutide). 2016 Dec.
Nagendra, L., Harish, B.G., Sharma, M. and Dutta, D., 2023. Semaglutide and cancer: A systematic review and meta-analysis. Diabetes & Metabolic Syndrome: Clinical Research & Reviews, p.102834.
Pyke C, Heller RS, Kirk RK, Ørskov C, Reedtz-Runge S, Kaastrup P, Hvelplund A, Bardram L, Calatayud D, Knudsen LB. GLP-1 receptor localization in monkey and human tissue: novel distribution revealed with extensively validated monoclonal antibody. Endocrinology. 2014
Rosol TJ. On-target effects of GLP-1 receptor agonists on thyroid C-cells in rats and mice. Toxicol Pathol. 2013 Feb;41(2):303-9.
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 Mar;28(3):391-402.
Written by Mr. Shazlee Ashan
BSc Pharmacy, MSc Endocrinology, PgDip Infectious Diseases, Ipresc
