What is the risk of medullary thyroid cancer in a patient with type 2 diabetes and obesity taking Mounjaro (tirzepatide)?

Risk of Medullary Thyroid Cancer with Mounjaro (Tirzepatide)

Tirzepatide is contraindicated in patients with a personal or family history of medullary thyroid cancer (MTC) or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2), but for patients without these risk factors, the actual human risk remains theoretical and unproven. 1

Understanding the Black Box Warning

The FDA-mandated black box warning exists because tirzepatide causes thyroid C-cell tumors (adenomas and carcinomas) in rats in a dose-dependent manner at clinically relevant plasma exposures. 1 However, the human relevance of these rodent thyroid C-cell tumors has not been determined. 1

• The biological plausibility for MTC exists in rodents but is far less clear for humans, as GLP-1 receptors are expressed in thyroid tissue but the mechanistic pathway differs between species. 2
• It remains unknown whether tirzepatide actually causes MTC in humans. 1

Clinical Evidence in Humans

Randomized controlled trials show thyroid cancer is a rare event with tirzepatide, without conclusive evidence of increased risk:

• Across the entire SURPASS clinical trial program (covering up to 2 years), thyroid cancer events were infrequent and effect estimates imprecise, with no consistent signal of increased risk. 2
• A 2024 meta-analysis of phase 2/3 randomized controlled trials found tirzepatide does not increase the risk for any cancer type, including thyroid cancer, though study durations were relatively short (36-72 weeks). 3
• The 3-year SURMOUNT-1 trial in 2539 participants with obesity identified no new safety signals related to thyroid cancer. 4

Observational and pharmacovigilance data show mixed signals:

• Real-world FAERS database analysis detected disproportionate reporting of medullary thyroid cancer (ROR 13.67,95% CI 4.35-42.96), but this was similar to the risk seen with GLP-1 receptor agonists and does not establish causality. 5
• Pharmacovigilance studies consistently show increased reporting of thyroid cancer in patients on GLP-1 receptor agonists, but these reports do not prove causation and are subject to reporting bias. 2

Practical Clinical Approach

Before prescribing tirzepatide, screen for absolute contraindications:

• Ask specifically about personal history of MTC or thyroid nodules. 1
• Ask about family history of MTC or MEN 2 syndrome in first-degree relatives. 1
• If either is present, tirzepatide is absolutely contraindicated. 1

Counsel patients on thyroid cancer symptoms:

• Inform patients about potential (though unproven) thyroid cancer risk. 1
• Educate on symptoms: neck mass, difficulty swallowing (dysphagia), difficulty breathing (dyspnea), or persistent hoarseness. 1
• Instruct patients to report these symptoms immediately if they develop. 1

Routine thyroid monitoring is NOT recommended:

• Routine serum calcitonin monitoring or thyroid ultrasound screening is of uncertain value for early MTC detection in patients on tirzepatide. 1
• Such monitoring may increase unnecessary procedures due to low test specificity and high background thyroid disease incidence. 1
• However, if calcitonin is measured and significantly elevated (typically >50 ng/L in MTC), further evaluation is warranted. 1
• If thyroid nodules are detected on physical exam or incidental imaging, pursue appropriate evaluation regardless of tirzepatide use. 1

Critical Caveats

The theoretical risk should not prevent appropriate use in eligible patients:

• For patients with type 2 diabetes and obesity without MTC/MEN 2 history, tirzepatide offers unprecedented glycemic control (HbA1c reductions of 1.87-2.59%) and weight loss (20.9% at 72 weeks with 15mg dose). 6, 7
• Excessive worry about unproven thyroid cancer risk may lead to underutilizing tirzepatide in patients who could experience substantial cardiometabolic benefits. 2
• The contraindication is based on animal data; human evidence from clinical trials does not support increased thyroid cancer risk. 2, 3

For your specific patient with type 2 diabetes and obesity:

• If no personal or family history of MTC or MEN 2 exists, tirzepatide can be safely prescribed with appropriate counseling. 1
• The proven benefits for glycemic control, weight reduction, and cardiometabolic health substantially outweigh the theoretical and unproven thyroid cancer risk. 7, 8, 6
• GLP-1 receptor agonists (including tirzepatide) should not be used in patients with personal or family history of medullary thyroid cancer or MEN 2, but this represents a small subset of the population. 9