What is the association between semaglutide (glucagon-like peptide-1 receptor agonist) and thyroid dysfunction?

Semaglutide and Thyroid Dysfunction: Clinical Implications

Semaglutide has a known association with thyroid C-cell tumors in rodents and requires caution in patients with thyroid conditions, but there is no conclusive evidence of increased thyroid cancer risk in humans with short-term use. 1, 2

Established Thyroid Concerns with Semaglutide

Risk of Thyroid C-cell Tumors

• Semaglutide caused dose-dependent and treatment-duration-dependent increases in thyroid C-cell tumors (adenomas and carcinomas) in mice and rats after lifetime exposure at clinically relevant plasma exposures 1
• This finding led to important contraindications for semaglutide use:
  • Personal or family history of medullary thyroid carcinoma (MTC)
  • Multiple Endocrine Neoplasia syndrome type 2 (MEN2) 1, 3

Monitoring Recommendations

• Patients should be counseled about potential thyroid tumor risk and informed about symptoms including:
  • Neck mass
  • Dysphagia
  • Dyspnea
  • Persistent hoarseness 1
• Routine monitoring of serum calcitonin or thyroid ultrasound has uncertain value for early MTC detection and may increase unnecessary procedures 1
• Significantly elevated calcitonin values (usually >50 ng/L) may indicate MTC and warrant further evaluation 1

Current Evidence on Thyroid Cancer Risk

Clinical Trial Data

• Thyroid cancer occurrence is infrequent in individuals exposed to GLP-1 RAs in randomized controlled trials 2
• A large international multisite cohort study found no evidence that GLP-1 RA use is associated with increased thyroid cancer risk compared to DPP-4 inhibitors (pooled weighted HR 0.81, CI 0.59-1.12) with follow-up ranging from 1.8 to 3.0 years 4

Limitations of Current Evidence

• Short follow-up periods (typically <3 years) limit conclusions about long-term thyroid cancer risk 4
• Low event rates make effect estimates imprecise 2
• Human relevance of semaglutide-induced rodent thyroid C-cell tumors has not been definitively determined 1

Thyroid Function Interactions

Interaction with Levothyroxine

• Oral semaglutide can affect levothyroxine pharmacokinetics, with a 33% increase in total T4 exposure when co-administered 5
• Case reports describe suppressed thyroid stimulating hormone (TSH) levels after initiation of subcutaneous semaglutide in post-thyroidectomy patients managed with levothyroxine 6
• Potential mechanisms include:
  • Direct effects of GLP-1 RA therapy on TSH levels
  • Changes in absorption related to delayed gastric emptying
  • Secondary effects from GLP-1 RA-associated weight loss 6

Monitoring Recommendations for Patients on Thyroid Medication

• Consider monitoring thyroid parameters when treating patients with both semaglutide and levothyroxine 5
• More frequent monitoring may be prudent for medications requiring weight-based dosing and those with a narrow therapeutic index when initiating and titrating GLP-1 RA therapies 6

Clinical Approach to Semaglutide Use in Relation to Thyroid Function

1. Absolute Contraindications:

   • Personal or family history of MTC
   • MEN2 syndrome 3, 1

2. Caution and Monitoring:

   • Patients on levothyroxine therapy: Monitor thyroid function tests more frequently after initiating semaglutide 5, 6
   • Consider dose adjustments of levothyroxine if TSH levels change significantly 6

3. Patient Education:

   • Inform patients about symptoms of thyroid tumors to report
   • Explain the theoretical risk based on animal studies while acknowledging current human data is reassuring for short-term use 2, 4

Practical Considerations

• The overall safety profile for semaglutide is similar to other GLP-1 RAs, with no unexpected thyroid safety issues arising to date 7
• Definitive conclusions for thyroid cancer risk cannot be drawn at this point due to low incidence of these conditions and limited long-term data 7
• When weighing risks and benefits, consider that semaglutide has demonstrated beneficial metabolic and cardiovascular actions with low risk for severe adverse events 7

Given the current evidence, clinicians should follow contraindication guidelines strictly while maintaining appropriate vigilance without unwarranted concern about thyroid cancer risk that might lead to underutilization of these beneficial medications in appropriate patients.