Are any GLP-1 (Glucagon-like peptide-1) or GLP-2 (Glucagon-like peptide-2) agonists not contraindicated in patients with a first-degree relative with thyroid cancer?

GLP-1 and GLP-2 Agonists in Patients with First-Degree Relatives with Thyroid Cancer

Most GLP-1 and GLP-2 receptor agonists are not contraindicated in patients who have first-degree relatives with thyroid cancer, but they are contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) or Multiple Endocrine Neoplasia syndrome type 2 (MEN2).

Contraindications and Safety Considerations

• GLP-1 receptor agonists (such as dulaglutide, liraglutide, semaglutide) are contraindicated specifically in patients with a personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN2) 1, 2
• The contraindication is specific to MTC and MEN2, not to all types of thyroid cancer 3, 1
• This contraindication appears in FDA drug labels as a black box warning due to findings in rodent studies showing an increased risk of thyroid C-cell tumors 1, 2

Evidence on Thyroid Cancer Risk

• The concern about thyroid cancer risk stems from preclinical studies in rodents where GLP-1 receptor agonists caused dose-related and treatment-duration-dependent increases in thyroid C-cell tumors 1
• Human relevance of these findings remains uncertain, as the mechanism may be rodent-specific 4
• Recent large multisite cohort studies found no evidence that GLP-1 receptor agonist use is associated with increased risk of thyroid cancer with follow-up ranging from 1.8 to 3.0 years 5
• Some pharmacovigilance studies have reported disproportionality signals for thyroid cancer with GLP-1 analogues, particularly for liraglutide and exenatide 6
• A US commercially insured population study found that after adjusting for latency, there was no significant elevated risk of thyroid cancer among liraglutide initiators 7

Clinical Decision Algorithm

1. Assess family history specifics:

   • If patient has first-degree relative with medullary thyroid carcinoma (MTC) or MEN2 → GLP-1/GLP-2 agonists are contraindicated 1, 2
   • If patient has first-degree relative with other types of thyroid cancer (papillary, follicular, etc.) → GLP-1/GLP-2 agonists are not contraindicated 1, 4

2. Consider medication options:

   • For patients without MTC/MEN2 history, all available GLP-1 receptor agonists (liraglutide, semaglutide, dulaglutide, exenatide) can be prescribed following standard guidelines 3
   • For patients with MTC/MEN2 history, consider alternative medication classes such as SGLT2 inhibitors for diabetes or other weight management options for obesity 3

3. Monitoring recommendations:

   • Follow standard monitoring practices for patients on GLP-1 receptor agonists 8
   • No special thyroid monitoring is required for patients with first-degree relatives with non-MTC thyroid cancer 8, 4
   • Routine monitoring of serum calcitonin or thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with GLP-1 receptor agonists 1

Common Pitfalls and Caveats

• Avoid confusing the specific contraindication for MTC/MEN2 with all types of thyroid cancer 4
• Be aware that significantly elevated serum calcitonin values may indicate MTC, and patients with MTC usually have calcitonin values >50 ng/L 1
• Recognize that some patients may have undiagnosed MEN2 - if there is uncertainty about the specific type of thyroid cancer in the family history, consider additional evaluation before prescribing 1
• The evidence on long-term thyroid cancer risk with GLP-1 receptor agonists remains limited due to relatively short follow-up periods in most studies 5

Practical Application

• When prescribing GLP-1 receptor agonists, document the specific type of thyroid cancer in the family history 1
• Counsel patients about the potential risk for MTC with GLP-1 receptor agonists and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness) 1
• For patients with diabetes or obesity who have a first-degree relative with non-MTC thyroid cancer, GLP-1 receptor agonists can provide significant benefits for glycemic control, weight management, and cardiovascular risk reduction 9, 3