Tirzepatide is contraindicated in patients 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 overweight or obesity with tirzepatide.1

Counsel patients regarding the potential risk of 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 cases of medullary thyroid carcinoma were reported in the completed SURMOUNT studies.2-5

In rats, tirzepatide caused a dose-dependent and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) in a 2-year study at clinically relevant plasma exposures.1

It is unknown whether tirzepatide causes thyroid C-cell tumors, including MTC, in humans as 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.6,7 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.6,8

Patients were excluded from the SURMOUNT studies if they had

• a family or personal history of MTC or MEN 2
• a history of an active or untreated malignancy or are 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, or
• a serum calcitonin level of ≥20 ng/L at Visit 1, if eGFR ≥60 mL/min/1.73 m2 or ≥35 ng/L at Visit 1, if eGFR <60 mL/min/1.73 m2. 2-5,9

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

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.7,13

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