What is the potential relationship between Glucagon-like peptide (GLP) agonists and the development of thyroid cancer?

From the Guidelines

A systematic review exploring the relationship between GLP-1 receptor agonists and thyroid cancer is feasible and potentially valuable, as it could help clarify the safety profile of these widely prescribed medications and inform clinical practice regarding monitoring and patient selection. Current evidence suggests a complex relationship between these medications (including semaglutide, liraglutide, dulaglutide, exenatide, and tirzepatide) and thyroid cancer risk. While preclinical rodent studies raised initial concerns, particularly with liraglutide, human clinical data has not demonstrated a clear increased risk 1. The systematic review should examine both randomized controlled trials and observational studies, focusing on specific GLP-1 RAs, duration of exposure, and patient characteristics.

• Key aspects to consider include:
  • The potential biological mechanisms, including GLP-1 receptor expression in thyroid tissue and effects on calcitonin levels
  • Special attention should be given to medullary thyroid carcinoma, which was the focus of early concerns
  • The review should also consider the expanding indications for GLP-1 RAs beyond diabetes to include obesity management, resulting in larger and more diverse patient populations using these medications
  • Recent studies, such as the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial, have found that major adverse cardiovascular events were numerically lower with use of extended-release exenatide compared with placebo, although this difference was not statistically significant 1
  • Another study published in Anaesthesia found that GLP-1 receptor agonists can increase the risk of thyroid C-cell tumors, and are contraindicated in patients with a personal or family history of medullary thyroid carcinoma and in patients with multiple endocrine neoplasia syndrome type 2 1 The review would be particularly relevant given the expanding indications for GLP-1 RAs beyond diabetes to include obesity management, resulting in larger and more diverse patient populations using these medications. This systematic review could help clarify the safety profile of these widely prescribed medications and inform clinical practice regarding monitoring and patient selection, with the most recent and highest quality study being 1.

From the FDA Drug Label

In mice and rats, semaglutide caused a dose-dependent and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure at clinically relevant plasma exposures Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist, have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and GLP-1 receptor agonist use in humans. OZEMPIC is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2 A 104-week carcinogenicity study was conducted in male and female CD-1 mice at doses of 0.03,0.2,1.0, and 3.0 mg/kg/day liraglutide administered by bolus subcutaneous injection yielding systemic exposures 0.2-, 2-, 10- and 45-times the human exposure, respectively, at the MRHD of 1. 8 mg/day based on plasma AUC comparison. A dose-related increase in benign thyroid C-cell adenomas was seen in the 1.0 and the 3.0 mg/kg/day groups with incidences of 13% and 19% in males and 6% and 20% in females, respectively.

Potential for writing a systemic review on GLP-1 agonist and thyroid cancer:

• There is evidence from animal studies that GLP-1 agonists, such as semaglutide and liraglutide, may increase the risk of thyroid C-cell tumors.
• However, the human relevance of these findings is unknown, and clinical studies have not established a causal relationship between GLP-1 receptor agonist use and thyroid cancer.
• A systemic review could investigate the available evidence from clinical trials and postmarketing reports to better understand the potential risk of thyroid cancer associated with GLP-1 agonist use.
• Key considerations for the review would include:
  • The incidence of thyroid C-cell tumors in patients treated with GLP-1 agonists compared to those treated with other antidiabetic medications or placebo.
  • The relationship between GLP-1 agonist dose and duration of treatment and the risk of thyroid C-cell tumors.
  • The potential for confounding variables, such as family history of thyroid cancer or multiple endocrine neoplasia syndrome type 2 (MEN 2), to influence the risk of thyroid C-cell tumors in patients treated with GLP-1 agonists.
  • The clinical implications of the available evidence for the use of GLP-1 agonists in patients with type 2 diabetes mellitus 2, 3.

From the Research

GLP-1 Receptor Agonists and Thyroid Cancer

• The relationship between GLP-1 receptor agonists and thyroid cancer is a topic of ongoing research and debate 4.
• Some studies suggest an increased incidence of differentiated thyroid cancer (DTC) in patients treated with GLP-1 receptor agonists, while others have not confirmed this association 4.
• A black-box warning from the United States Food and Drug Administration (USFDA) recommends against using GLP-1 receptor agonists in patients with a personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2A or 2B (MEN2) 4.

Potential for Systematic Review

• A systematic review of the existing literature on GLP-1 receptor agonists and thyroid cancer could help to clarify the relationship between these two factors 4, 5.
• Such a review could include studies on the incidence of thyroid cancer in patients treated with GLP-1 receptor agonists, as well as studies on the potential mechanisms by which these agents may influence thyroid cancer risk.
• The review could also examine the effectiveness of GLP-1 receptor agonists in reducing the risk of other health outcomes, such as cardiometabolic disorders and infectious illnesses 5.

Key Considerations

• The use of GLP-1 receptor agonists has been associated with a range of benefits and risks, including reduced risk of substance use and psychotic disorders, seizures, and neurocognitive disorders, as well as increased risk of gastrointestinal disorders, hypotension, and syncope 5.
• When considering the potential for a systematic review on GLP-1 receptor agonists and thyroid cancer, it is essential to take into account the complexity of the relationship between these two factors and the need for high-quality evidence to inform clinical practice 4, 5.