Why are GLP-1 (Glucagon-like peptide-1) receptor agonists contraindicated in patients with medullary thyroid cancer?

GLP-1 Receptor Agonists Are Contraindicated in Medullary Thyroid Cancer Due to Increased Cancer Risk

GLP-1 receptor agonists are absolutely contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2 due to their potential to stimulate C-cell tumor growth. 1

Mechanism and Evidence

GLP-1 receptor agonists carry an FDA Black Box Warning regarding thyroid C-cell tumors for important biological reasons:

• Receptor Expression: Human thyroid C-cells express GLP-1 receptors, particularly in neoplastic and hyperplastic lesions 2
• Molecular Pathway: GLP-1 receptor activation can stimulate C-cell proliferation, potentially accelerating tumor growth in susceptible individuals
• Preclinical Evidence: Animal studies demonstrated that GLP-1 receptor agonists induced C-cell hyperplasia and medullary thyroid carcinoma in rodents 3
• Human Studies: Research has confirmed GLP-1 receptor expression in:
  • 100% of medullary thyroid carcinomas
  • 100% of C-cell hyperplasia cases
  • Approximately 35% of normal C-cells in human thyroid tissue 2

Clinical Evidence and Risk

Recent clinical data reinforces this contraindication:

• A 2023 nested case-control study using the French national healthcare database found that GLP-1 receptor agonist use for 1-3 years was associated with:
  • 58% increased risk of all thyroid cancers (adjusted HR 1.58)
  • 78% increased risk of medullary thyroid cancer specifically (adjusted HR 1.78) 4

Regulatory and Guideline Position

The FDA Black Box Warning explicitly states that "GLP-1 receptor agonists can increase the risk of thyroid C-cell tumors. They are contraindicated in patients with a personal or family history of medullary thyroid carcinoma and in patients with multiple endocrine neoplasia syndrome type 2A or 2B." 1

Clinical Approach to GLP-1 RA Use

When considering GLP-1 receptor agonist therapy:

1. Mandatory Screening:

   • Obtain detailed family history of thyroid cancer
   • Screen for personal history of MTC or MEN2
   • Consider baseline calcitonin in high-risk patients

2. Absolute Contraindications:

   • Personal history of MTC
   • Family history of MTC
   • Known MEN2 syndrome
   • Suspicious thyroid nodules requiring evaluation

3. Monitoring During Treatment:

   • Patients should be educated about symptoms of thyroid tumors (neck mass, dysphagia, hoarseness)
   • Any concerning thyroid findings during treatment should prompt immediate evaluation

Alternative Therapies for Patients with MTC History

For patients with type 2 diabetes who cannot use GLP-1 receptor agonists due to MTC risk:

• SGLT-2 inhibitors (preferred alternative with cardiovascular and renal benefits)
• Metformin (if not contraindicated by renal function)
• DPP-4 inhibitors (with caution in heart failure)
• Insulin therapy when necessary

Conclusion

The contraindication of GLP-1 receptor agonists in patients with MTC is based on solid biological plausibility and clinical evidence. The presence of GLP-1 receptors on thyroid C-cells and the demonstrated risk of stimulating tumor growth make this an absolute contraindication where patient safety must take precedence over potential metabolic benefits.