What are the current recommendations for Glucagon-like peptide-1 (GLP-1) agonists and their association with thyroid disease?

From the Guidelines

The current recommendation for GLP-1 agonists in relation to the thyroid is to exercise caution, particularly in patients with personal or family history of medullary thyroid carcinoma (MTC) or Multiple Endocrine Neoplasia syndrome type 2 (MEN2), as stated in the most recent guideline from 2024 1.

Key Considerations

• GLP-1 agonists such as semaglutide, liraglutide, dulaglutide, and tirzepatide are contraindicated in patients with a personal or family history of MTC or MEN2, as indicated in the 2018 expert consensus decision pathway 1.
• Before initiating these medications, clinicians should screen patients for these conditions, and no routine thyroid monitoring is required for patients without these risk factors.
• This recommendation stems from preclinical studies showing that GLP-1 agonists caused C-cell hyperplasia and medullary thyroid tumors in rodents, although the relevance to humans remains uncertain as human thyroid C-cells express far fewer GLP-1 receptors than rodent cells.

Clinical Implications

• Patients should be counseled about the symptoms of thyroid tumors, including a mass in the neck, dysphagia, dyspnea, or persistent hoarseness, and advised to seek prompt medical evaluation if these develop while on GLP-1 agonist therapy.
• The 2020 update to the management of hyperglycemia in type 2 diabetes also supports the use of GLP-1 receptor agonists to reduce major adverse cardiovascular events, hospitalization for heart failure, cardiovascular death, or chronic kidney disease progression 1.
• The most recent guideline from 2024 recommends adding a GLP-1 agonist to metformin and lifestyle modifications in adults with type 2 diabetes and inadequate glycemic control to reduce the risk for all-cause mortality, major adverse cardiovascular events, and stroke 1.

From the FDA Drug Label

WARNING: RISK OF THYROID C-CELL TUMORS • In rodents, semaglutide causes thyroid C-cell tumors. It is unknown whether OZEMPIC causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as the human relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined (5.1,13. 1). • OZEMPIC is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC and symptoms of thyroid tumors (4,5.1).

The current recommendation for GLP-1 agonist and the thyroid is to:

• Contraindicate the use of semaglutide in patients with a personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) 2.
• Counsel patients regarding the potential risk of MTC and symptoms of thyroid tumors. Key points to consider:
• The human relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined.
• Semaglutide causes thyroid C-cell tumors in rodents. It is essential to carefully evaluate the benefits and risks of using semaglutide in patients with a history of thyroid disease or those at risk of developing thyroid tumors 2.

From the Research

Current Recommendations for GLP-1 Agonist and Thyroid Cancer

The current recommendations for GLP-1 agonist and thyroid cancer are based on various studies that have investigated the potential link between the two.

• The use of GLP-1 receptor agonists (GLP-1 RAs) has been associated with a potential increased risk of thyroid cancer, particularly medullary thyroid cancer (MTC) in rodents 3.
• However, clinical evidence from randomized trials and observational studies in humans has yielded inconsistent results, with some studies suggesting a potential increased risk of thyroid cancer 4, while others have found no conclusive evidence of an elevated risk 3, 5.
• A recent multisite cohort study found no evidence of an increased risk of thyroid cancer with the use of GLP-1 RAs compared to dipeptidyl peptidase-4 inhibitors (DPP-4is) 5.
• The American Thyroid Association and other organizations have not issued specific guidelines on the use of GLP-1 RAs in patients with thyroid cancer or those at high risk of developing thyroid cancer.

Considerations for Clinical Practice

• Clinicians should be aware of the potential risks and benefits of GLP-1 RAs in patients with type 2 diabetes and consider alternative treatments for those with a history of thyroid cancer or at high risk of developing thyroid cancer 6.
• Patients with a history of medullary thyroid cancer should not use GLP-1 RAs, and those with a history of pancreatitis should use them with caution 6.
• Further research is needed to fully understand the relationship between GLP-1 RAs and thyroid cancer, particularly in humans, and to inform clinical practice guidelines 3, 7.