What are the risks and considerations for using Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) in a patient with a history of medullary thyroid cancer and type 2 diabetes?

GLP-1 Receptor Agonists Are Absolutely Contraindicated in Medullary Thyroid Cancer

GLP-1 receptor agonists (GLP-1 RAs) are contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2 (MEN 2). This is an FDA Black Box Warning that applies to all agents in this class, including semaglutide, tirzepatide, liraglutide, and dulaglutide 1, 2, 3.

The Evidence Behind the Contraindication

Animal Data and Biological Plausibility

• In male and female rats, GLP-1 RAs cause dose-related and treatment-duration-dependent increases in thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure 2, 3
• GLP-1 receptors are expressed in the thyroid gland, which may explain the pleiotropic effects of these medications 4
• The biological plausibility for an association between GLP-1 RAs and MTC in rodents is well-established, though the human relevance remains uncertain 5

Human Clinical Evidence

The actual risk in humans remains controversial and likely very low:

• One case of MTC was reported in a patient treated with dulaglutide in clinical trials, though this patient had pretreatment calcitonin levels approximately 8 times the upper limit of normal 2
• A French nationwide study found increased risk of MTC with 1-3 years of GLP-1 RA use (adjusted HR 1.78,95% CI 1.04-3.05) 6
• However, a Korean nationwide cohort study showed no increased risk of medullary thyroid cancer (IRR 0.34) in the GLP-1 RA group compared with diabetes controls 7
• Meta-analyses of randomized controlled trials show thyroid cancer as a rare event with imprecise effect estimates and no conclusive evidence of increased risk 5

Clinical Decision Algorithm for Your Patient

For a patient with a history of medullary thyroid cancer and type 2 diabetes:

Step 1: Absolute Exclusion of GLP-1 RAs

• Do not prescribe any GLP-1 RA (semaglutide, tirzepatide, liraglutide, dulaglutide, exenatide, lixisenatide) 1, 2, 3
• This contraindication is absolute and non-negotiable regardless of potential cardiovascular or weight loss benefits 1

Step 2: Alternative Glucose-Lowering Strategies

Prioritize SGLT-2 inhibitors as the preferred second-line agent:

• SGLT-2 inhibitors (empagliflozin, canagliflozin, dapagliflozin) provide cardiovascular and renal protection without thyroid cancer concerns 1, 8
• These agents reduce heart failure hospitalization and cardiovascular mortality 1
• Contraindicated if eGFR <30 mL/min/1.73 m² (canagliflozin not recommended if eGFR <45) 1

If SGLT-2 inhibitors are contraindicated or not tolerated:

• Metformin remains first-line if eGFR ≥30 mL/min/1.73 m² 1
• DPP-4 inhibitors (sitagliptin, linagliptin) are safe alternatives, though saxagliptin increases heart failure risk 1
• Insulin therapy if glycemic targets are not met, though it causes weight gain 1
• Avoid thiazolidinediones due to fluid retention and heart failure risk 1

Step 3: Monitoring Considerations

• No routine calcitonin monitoring is recommended, as it has uncertain value and low specificity 2
• If calcitonin is measured and found elevated (>50 ng/L typically indicates MTC), further evaluation is warranted 2
• Physical examination for thyroid nodules should be performed, with further evaluation if detected 2

Critical Pitfalls to Avoid

Do not rationalize GLP-1 RA use based on:

• The low absolute risk in human studies—the FDA contraindication is absolute 1, 2, 3
• Potential cardiovascular benefits—SGLT-2 inhibitors provide comparable protection 1, 8
• Weight loss needs—other strategies exist, including lifestyle modification and metabolic surgery if BMI criteria are met 1

Do not confuse MTC with other thyroid cancers:

• The contraindication specifically applies to medullary thyroid cancer (C-cell derived) 2, 3
• Patients with history of papillary or follicular thyroid cancer do not have this absolute contraindication, though clinical judgment and shared decision-making are warranted 5

The Bottom Line

Your patient with medullary thyroid cancer history should receive metformin plus an SGLT-2 inhibitor for cardiovascular and renal protection, with insulin added if needed for glycemic control. GLP-1 RAs are absolutely off the table regardless of their potential benefits 1, 2, 3, 8.