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

Semaglutide and Medullary Thyroid Cancer: Risk Assessment

Semaglutide is contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2 (MEN2) due to established risk of thyroid C-cell tumors in rodent studies and potential risk in humans. 1, 2

Risk Profile and Evidence Base

Established Contraindications

• Semaglutide carries an FDA Black Box Warning regarding the risk of thyroid C-cell tumors 1
• The contraindication applies to:
  • Patients with personal history of MTC
  • Patients with family history of MTC
  • Patients with MEN2 syndrome 2, 1

Mechanism of Risk

• In rodent studies, semaglutide causes thyroid C-cell tumors, though human relevance remains uncertain 1
• GLP-1 receptor expression has been detected in human thyroid C-cells, with significant differences in expression between MTC and non-neoplastic thyroid tissue 3

Clinical Evidence

• Recent observational research (2023) found increased risk of all thyroid cancer (adjusted HR 1.58,95% CI 1.27-1.95) and specifically medullary thyroid cancer (adjusted HR 1.78,95% CI 1.04-3.05) with GLP-1 RA use for 1-3 years 4
• However, evidence from randomized controlled trials indicates thyroid cancer occurrence is infrequent in individuals exposed to GLP-1 RAs 5

Clinical Approach to Patients Without MTC History

For patients without a personal or family history of MTC or MEN2:

1. Risk Communication:

   • Counsel patients about the potential risk of MTC and symptoms of thyroid tumors (neck mass, dysphagia, hoarseness, persistent cough) 1
   • Explain that while there's a theoretical risk based on animal studies, conclusive human evidence is limited 5

2. Monitoring:

   • No specific thyroid monitoring protocol is mandated for patients without MTC risk factors
   • Routine thyroid cancer screening is not recommended solely based on GLP-1 RA use, as this could lead to overdiagnosis 5

3. Special Considerations:

   • For patients on levothyroxine after thyroidectomy, monitor thyroid function more frequently when initiating semaglutide, as cases of suppressed TSH have been reported 6
   • Consider dose adjustments of thyroid medication if changes in thyroid function are observed

Clinical Decision Algorithm

1. Absolute Contraindications - Do NOT prescribe semaglutide if:

   • Personal history of MTC
   • Family history of MTC
   • MEN2 syndrome

2. Relative Cautions - Use with increased monitoring if:

   • History of non-medullary thyroid disorders
   • Post-thyroidectomy patients on thyroid hormone replacement
   • History of pancreatitis (semaglutide not studied in this population) 1, 7

3. Benefit-Risk Assessment - For eligible patients:

   • Consider cardiovascular and renal benefits of semaglutide 2, 8
   • Weigh against theoretical thyroid cancer risk
   • Implement appropriate dose titration to minimize adverse effects 2

Practical Recommendations

• Document discussion of thyroid cancer risk with patients prior to initiating therapy
• Instruct patients to report any symptoms suggestive of thyroid tumors promptly
• For patients with thyroid disease but without MTC/MEN2 history, coordinate care with endocrinology when appropriate
• Follow standard dose escalation protocols to minimize gastrointestinal side effects 2

The benefit-risk profile remains favorable for most patients without MTC risk factors, given the established cardiovascular and metabolic benefits of semaglutide.