Tirzepatide is contraindicated in people with a personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).1

Thyroid disease/abnormalities (other than a personal or family history of MTC or in patients with MEN 2) are not listed contraindications to the treatment of T2D with tirzepatide.1

Counsel patients regarding the potential risk for MTC with the use of tirzepatide and inform them of symptoms of thyroid tumors (eg, a mass in the neck, dysphagia, dyspnea, persistent hoarseness).1

Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with tirzepatide. Such monitoring may increase the risk of unnecessary procedures due to the low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin values may indicate MTC, and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated.1

No clinically relevant changes in mean calcitonin levels were observed, and no cases of medullary thyroid hyperplasia or cancer were reported in the SURPASS studies.2-6 

In rats, tirzepatide causes dose-dependent and treatment duration–dependent thyroid C-cell tumors at clinically relevant exposures.1

It is unknown whether tirzepatide causes thyroid C-cell tumors, including MTC, in humans as the human relevance of tirzepatide-induced rodent thyroid C-cell tumors has not been determined.1

Evidence linking thyroid C-cell tumors to treatment with tirzepatide and products in the GLP-1 receptor agonist class is derived primarily from nonclinical studies. GLP-1 receptor expression levels on thyroid C cells differ across species with rats having high expression levels while humans and cynomolgus monkeys have low expression levels.7,8 No changes in thyroid C cells were observed in monkey studies with tirzepatide, which is also consistent with the lack of effect in monkeys for GLP-1 receptor agonists.7,9

Patients were excluded from the SURPASS 1-5 clinical studies if they had

• a family or personal history of MTC or MEN 2
• a personal history of an active or untreated malignancy or in remission from a clinically significant malignancy (other than basal or squamous cell skin cancer, in situ carcinomas of the cervix, or in situ prostate cancer) for less than 5 years
• evidence of a significant, uncontrolled endocrine abnormality (eg, thyrotoxicosis or adrenal crises), in the opinion of the investigator, or
• a serum calcitonin level of ≥35 ng/L.2-6

For rare diseases, like many cancers with long latency periods, the database is too small and duration of exposure too short to definitively conclude that there is no increased risk of malignancy. Eli Lilly and Company will continue to carefully assess for malignancies in ongoing studies and will continue to assess risk through postmarketing cases and exposure.8

A recent publication assessing incidence of thyroid cancer among patients prescribed select GLP-1 receptor agonists using a medical records database study identified an increased risk of all thyroid cancer and MTC. The relevance of these results to tirzepatide use is unknown.10

On November 10, 2022, Diabetes Care published a paper, “GLP-1 Receptor Agonists and the Risk of Thyroid Cancer.” This publication concerned findings from an analysis of GLP-1 receptor agonist use and thyroid cancer among patients treated for type 2 diabetes in France.10

Using a relatively large sample from a nationally representative database, this publication presents a quantitative measure of the association indicating an elevated risk of thyroid cancer and MTC for GLP-1 receptor agonists. The authors found that GLP-1 receptor agonist, in particular after 1 to 3 years of treatment, moderately increased risk of all thyroid cancer and MTC. The findings do not provide conclusive evidence for a causal association between GLP-1 receptor agonists exposure and thyroid cancer including MTC and should be verified with additional studies due to important limitations such as possible detection bias overestimating incidence of thyroid cancer and MTC.  Clinicians and patients should continue to balance benefit and harm.10

Use of tirzepatide is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2.10

Thyroid C cells, also referred to as parafollicular cells, and follicular cells have different embryologic origins. Differentiated thyroid cancers, including papillary and follicular thyroid cancer, develop from follicular cells and account for >90% of thyroid malignancies, while MTC develops from C cells and accounts for 1% to 2%.11,12

Follicular cells are the predominant cells of the thyroid gland. Follicular cells develop as a median endodermal downgrowth from the first and second pharyngeal pouches and secrete thyroid hormones.8,13

Thyroid C cells were historically thought to be of neural crest origin. However, more recent data may provide support that C cells directly differentiate from cells of the ultimobranchial bodies, which originate from the fourth pharyngeal pouches.14