What are the risks of using Glucagon-like peptide-1 (GLP-1) receptor agonists, such as liraglutide (Victoza) and semaglutide (Ozempic), in patients with medullary thyroid carcinoma?

GLP-1 Receptor Agonists and Medullary Thyroid Carcinoma

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 (MEN2). 1, 2, 3

Absolute Contraindications

The FDA mandates a black box warning for all GLP-1 receptor agonists regarding thyroid C-cell tumors. 3, 4 This stems from rodent studies where semaglutide and other GLP-1 agonists caused dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures. 3

Do not prescribe GLP-1 receptor agonists if the patient has:

• Personal history of medullary thyroid carcinoma 1, 2, 3
• Family history of medullary thyroid carcinoma 1, 2, 3
• Multiple Endocrine Neoplasia syndrome type 2 (MEN2) 1, 2, 3

Clinical Evidence on Thyroid Cancer Risk

Human Data vs. Rodent Studies

The biological mechanism observed in rodents has uncertain relevance to humans. 3, 5 Rodents have substantially higher expression of GLP-1 receptors on thyroid C-cells compared to humans, which may explain the species-specific tumor development. 5

Randomized Controlled Trial Evidence

Large cardiovascular outcomes trials show thyroid cancer is a rare event with GLP-1 receptor agonists, and meta-analyses demonstrate no conclusive evidence of increased risk. 5 The EXSCEL trial with extended-release exenatide found no significant difference in medullary thyroid carcinoma incidence between treatment and placebo groups over 3.2 years of follow-up. 1

Observational Studies Show Conflicting Results

Evidence suggesting potential risk:

• A French nested case-control study (2023) found increased risk of all thyroid cancer (adjusted HR 1.58,95% CI 1.27-1.95) and medullary thyroid cancer (adjusted HR 1.78,95% CI 1.04-3.05) after 1-3 years of GLP-1 receptor agonist use. 6
• European pharmacovigilance data showed disproportionate reporting of medullary thyroid cancer with GLP-1 analogues (PRR 221.5,95% CI 155.7-315.1), with liraglutide showing the strongest association (PRR 27.5). 7

Evidence suggesting no increased risk:

• A large Scandinavian cohort study (2024) with mean follow-up of 3.9 years found no association between GLP-1 receptor agonist use and thyroid cancer (HR 0.93,95% CI 0.66-1.31) or medullary thyroid cancer specifically (HR 1.19,95% CI 0.37-3.86). 8
• A 2025 TriNetX database study of patients with thyroid nodules showed no significant difference in thyroid cancer risk between GLP-1 analogue users and metformin users (risk ratio 0.99,95% CI 0.96-1.03). 9

Practical Clinical Approach

Before Prescribing

Screen every patient for:

• Personal history of any thyroid cancer, specifically asking about medullary thyroid carcinoma 1, 2
• Family history of medullary thyroid carcinoma in first-degree relatives 1, 2
• History of Multiple Endocrine Neoplasia syndrome type 2 1, 2

If any of these are present, do not prescribe GLP-1 receptor agonists under any circumstances. 1, 2, 3

Patient Counseling

Inform patients about the potential risk of thyroid tumors and instruct them to report symptoms including: 3

• Neck mass or lump
• Persistent hoarseness
• Dysphagia (difficulty swallowing)
• Dyspnea (shortness of breath)

Monitoring Considerations

Routine calcitonin monitoring or thyroid ultrasound screening is not recommended for patients on GLP-1 receptor agonists, as this may lead to unnecessary procedures and overdiagnosis. 5 The FDA label does not require routine calcitonin testing. 3, 4

Critical Pitfalls to Avoid

Do not:

• Dismiss family history as irrelevant—always ask specifically about medullary thyroid carcinoma, not just "thyroid problems" 2
• Prescribe GLP-1 receptor agonists to patients with known MEN2, even if they haven't developed MTC yet 1, 2
• Order routine calcitonin levels or thyroid ultrasounds in asymptomatic patients, as this creates unnecessary anxiety and potential harms from overdiagnosis 5

When Benefits Outweigh Theoretical Risks

For patients without personal/family history of MTC or MEN2, the substantial cardiovascular and mortality benefits of GLP-1 receptor agonists (particularly liraglutide, semaglutide, and dulaglutide) far outweigh the unproven thyroid cancer risk in humans. 1, 5 These agents reduce major adverse cardiovascular events and should not be withheld due to excessive concern about thyroid cancer in appropriate candidates. 1, 5