Can I prescribe trizepatide (a glucagon-like peptide-1 receptor agonist) to a patient with a family history of thyroid cancer?

Tirzepatide Contraindication with Family History of Thyroid Cancer

Tirzepatide is contraindicated 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). 1

Understanding the Contraindication

The FDA label for tirzepatide (Zepbound) contains a boxed warning regarding the risk of thyroid C-cell tumors. This warning is based on the following evidence:

1. In rat studies, tirzepatide causes thyroid C-cell tumors
2. The human relevance of these findings is unknown
3. Due to this potential risk, tirzepatide is specifically contraindicated in:
   • Patients with a personal history of MTC
   • Patients with a family history of MTC
   • Patients with MEN 2 1

Clinical Decision Algorithm

When considering tirzepatide for a patient whose mother had thyroid cancer:

1. Determine the type of thyroid cancer the mother had:

   • If medullary thyroid cancer (MTC): DO NOT prescribe tirzepatide
   • If non-medullary thyroid cancer (papillary, follicular, anaplastic, etc.):

2. Screen for MEN 2 syndrome:

   • Assess for clinical features of MEN 2 (pheochromocytoma, hyperparathyroidism, mucosal neuromas)
   • If MEN 2 is suspected: DO NOT prescribe tirzepatide
   • If no features of MEN 2: Proceed to next step

3. Evaluate family history more broadly:

   • Multiple family members with thyroid cancer suggests hereditary risk
   • Single case of non-MTC in a first-degree relative without other concerning features: May proceed with caution

Important Considerations

• Medullary thyroid cancer (MTC) accounts for only about 5% of all thyroid cancers 2, but it is the specific type mentioned in the contraindication
• Family history of thyroid cancer is an indicator of potential malignancy risk 2
• The AGA clinical practice guideline specifically states that tirzepatide is "contraindicated in patients with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 based on animal studies" 2

Monitoring and Patient Education

If you determine tirzepatide is appropriate (i.e., mother had non-MTC thyroid cancer and no features of MEN 2):

• Counsel the patient about the potential risk and symptoms of thyroid tumors
• Consider baseline calcitonin measurement (although this remains controversial) 2
• Maintain vigilance for symptoms suggestive of thyroid tumors

Current Evidence on GLP-1 RAs and Thyroid Cancer Risk

Recent research provides some reassurance regarding the short-term risk:

• A 2025 international multisite cohort study found no increased risk of thyroid cancer with GLP-1 receptor agonist use compared to DPP-4 inhibitors 3
• A systematic review and meta-analysis of 13 RCTs with 13,761 participants found no increased overall or specific cancer risk with tirzepatide use over 26-72 weeks 4
• However, pharmacovigilance data from the FDA Adverse Event Reporting System did show disproportionate reporting of medullary thyroid cancer with tirzepatide (ROR 13.67,95% CI 4.35-42.96) 5

Bottom Line

The contraindication specifically applies to medullary thyroid cancer, not all thyroid cancers. If the patient's mother had a different type of thyroid cancer (papillary, follicular, etc.) and there are no features suggestive of MEN 2 syndrome, tirzepatide may be prescribed with appropriate counseling and monitoring.