What are the risks of using tirzepatide (GLP-1 receptor agonist) in patients with a history of medullary thyroid cancer?

Tirzepatide and Medullary Thyroid Cancer: Risk Assessment and Management

Tirzepatide is contraindicated in patients with a personal or family history of medullary thyroid cancer (MTC) or multiple endocrine neoplasia syndrome type 2 (MEN2) due to significant safety concerns identified in animal studies. 1, 2

Risk Assessment

Biological Basis for Concern

• GLP-1 receptor agonists, including tirzepatide, have shown potential thyroid C-cell proliferation in rodent studies
• GLP-1 receptors are expressed in multiple organs including the thyroid 2
• This biological mechanism forms the basis for the contraindication in patients with MTC or MEN2

Evidence from Clinical Data and Pharmacovigilance

• Recent pharmacovigilance analysis of the FDA Adverse Event Reporting System (FAERS) showed disproportionate reporting of medullary thyroid cancer with tirzepatide (ROR 13.67,95% CI 4.35-42.96) 3
• However, tirzepatide exhibited a similar risk profile for medullary thyroid cancer compared to other GLP-1 receptor agonists 3
• A large Scandinavian cohort study found no statistically significant increased risk of medullary thyroid cancer with GLP-1 receptor agonists (HR 1.19,95% CI 0.37-3.86) 4
• European pharmacovigilance data showed disproportionality for medullary thyroid cancer with GLP-1 analogues (PRR 221.5,95% CI 155.7-315.1) 5

Management Recommendations

Absolute Contraindications

• Do not prescribe tirzepatide to patients with:
  • Personal history of medullary thyroid cancer
  • Family history of medullary thyroid cancer
  • Multiple endocrine neoplasia syndrome type 2 (MEN2)

Pre-Treatment Screening

1. Comprehensive thyroid history:

   • Personal or family history of thyroid cancer
   • History of MEN2 syndrome
   • Previous thyroid surgery or radiation

2. Screening for MEN2-related conditions:

   • Assess for pheochromocytoma
   • Evaluate for hyperparathyroidism 1

3. Physical examination:

   • Thyroid examination for nodules
   • Assess for symptoms like dysphagia or persistent hoarseness 2

Monitoring During Treatment

For patients without contraindications who are receiving tirzepatide:

1. Regular thyroid monitoring:

   • Physical examination of the neck
   • Vigilance for symptoms such as:
     • New thyroid nodules
     • Voice changes
     • Dysphagia
     • Persistent hoarseness

2. Consider baseline calcitonin:

   • While routine measurement is debated, it may be considered in high-risk patients
   • The ATA is equivocal about measuring serum calcitonin 1

Special Considerations

Risk-Benefit Assessment

• For patients without contraindications, the cardiovascular and metabolic benefits of tirzepatide often outweigh theoretical thyroid cancer risks 2
• GLP-1 receptor agonists significantly reduce major adverse cardiovascular events by 13-26% in patients with type 2 diabetes and established cardiovascular disease 2

Alternative Medications

• For patients with absolute contraindications to tirzepatide, consider:
  • Non-GLP-1 receptor agonist weight loss medications
  • Other diabetes management strategies if treating T2DM

Conclusion

The risk of medullary thyroid cancer with tirzepatide remains a significant concern based on animal studies, leading to absolute contraindication in patients with personal or family history of MTC or MEN2. While pharmacovigilance data shows disproportionate reporting, large cohort studies have not demonstrated a definitive increased risk. Nevertheless, caution and appropriate screening remain essential when considering tirzepatide therapy.