A boxed warning, more commonly referred to as a “black box warning” due to the thick black border surrounding the text, is the strongest safety warning issued by the U.S. Food and Drug Administration for prescription medications. It is not assigned based on the frequency of an adverse event, but rather the potential severity of the risk. For good reason, these warnings are highly visible on medication labeling, however they may generate concern or confusion among patients. In some cases, such as medullary thyroid carcinoma (MTC), the concern is theoretical and has been only observed in animal studies rather than confirmed in humans. In today’s blog, we will review the evidence and prescribing information to be familiar with regarding MTC, which is included as a boxed warning for all GLP-1 receptor agonist–based therapies.

MTC is one of the rarer forms of cancer affecting the thyroid, accounting for only 1-4% of all thyroid cancers. It affects the parafollicular C cells that secrete calcitonin, and therefore is commonly referred to as a C-cell tumor. The majority of these neuroendocrine cells arise sporadically, however 1 in 4 are familial and associated with multiple endocrine neoplasia (MEN) syndromes type 2A or 2B. Although likely beyond the scope of ABOM boards, as a reminder, MEN2A consists of a constellation of MTC, and the following two components:

  • Pheochromocytoma: A catecholamine-producing tumor arising from the adrenal medulla. It classically presents with episodic headaches, diaphoresis, palpitations, tachycardia, and hypertension.
  • Primary hyperparathyroidism / parathyroid hyperplasia: Excessive parathyroid hormone production due to enlargement of the parathyroid glands, leading to hypercalcemia. Symptoms of hypercalcemia may include nephrolithiasis, bone pain, constipation, abdominal pain, and neuropsychiatric changes.

MEN2B is similar, except that it presents with Marfanoid habitus and mucosal neuromas rather than primary hyperparathyroidism.

Why is this relevant? Rodent trials showed both a dose and duration-dependent increased incidence of C-cell tumors (both adenomas and carcinomas) when placed on therapeutic levels of GLP-1 receptor agonists (GLP-1 RA). As mentioned before, there is no evidence that this same effect is true in humans, but given the aggressiveness of MTC, erring on the side of caution means excluding those who are potentially at higher risk of the inheritable forms of MTC, which includes those with a known personal or family history of MTC or MEN2 syndromes. Keep in mind that other thyroid cancers, including the most common, papillary thyroid cancer, are not associated with MTC and therefore irrelevant to ask about when discussing with patients. However, many patients may be unfamiliar with the different forms, so it is important to clarify that you are specifically inquiring about MTC.

What does this mean in terms of screening for MTC? Simply verifying that there is no family or personal history of MTC or MEN2 syndromes and informing patients of this potential risk is sufficient. In addition, patients should be informed on potential clinical findings that could be seen in the setting of a thyroid tumor, such as a new mass in the neck, persistent hoarseness, dyspnea, dysphonia, and dysphagia. Further evaluation with serum calcitonin or a thyroid ultrasound is not indicated and is of uncertain value in being able to detect MTC earlier. In fact, labeling specifically mentions that this additional testing may lead to unnecessary procedures, as calcitonin has a low specificity.

To provide some additional reassurance, let’s look at the evidence. Patients may be familiar with a 2023 study suggesting that GLP-1 RA increased the risk of thyroid cancer, including MTC, as this generated significant media attention. However, the study was ultimately found to have several important limitations. First, it was a case-control study, which determines correlation, not causation. The study population also was relatively small, comparing approximately 2,500 patients with thyroid cancer to a control group of about 45,000 patients. The investigators reported that GLP-1 RA use for 1–3 years was associated with an increased risk of MTC as well as other thyroid carcinomas. However, subsequent larger studies, including a Scandinavian study (145,000 patients) on GLP-1 RA did not display any increased risk of thyroid cancer.

In 2025, JAMA published a secondary analysis (review here) of study participants of over 350,000 cross-matched patients with diabetes who were initiated on glucose-lowering therapies, including GLP-1 RA, SGLT-2 inhibitors, sulfonylureas, and DPP-4 inhibitors. Across each group, the absolute incidence of thyroid cancer was low, with GLP-1 RA not showing any statistically significant increase in cancer. Interestingly, though, when hazard ratios (HR) were evaluated for individual years 1-3, the HR of thyroid cancer appeared highest within the first year of therapy and lower with longer durations of treatment. This finding is inconsistent with what is generally expected of carcinogenic exposures, in which greater cumulative exposure and longer duration are typically associated with higher cancer risk. So why would the apparent risk decrease over time? This pattern is more likely explained by surveillance bias rather than a true increased first-year cancer risk. In other words, patients started on GLP-1 RA may have undergone more medical evaluation, imaging, or thyroid testing shortly after initiation, leading to increased detection of preexisting thyroid abnormalities rather than the medication directly causing cancer. This detection bias is postulated to have occurred in the 2023 study as well.

For the exam, know the boxed warning and contraindication regarding GLP-1 RA use in patients with a personal or family history of MTC or MEN2 syndrome. Also, be familiar with counseling patients regarding symptoms of thyroid cancer, including a neck mass, persistent hoarseness, dysphonia, dysphagia, and dyspnea. Finally, remember that current human evidence has not demonstrated an increased risk of MTC or other thyroid cancers with GLP-1 RA, and the findings that led to the boxed warning were observed in rodent studies involving C-cell tumors. A general understanding of these concepts should help you answer most MTC-related questions on test day.

Sample Question

An attending physician is giving a lecture on prescribing glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and reviews the associated boxed warning regarding medullary thyroid carcinoma (MTC). A medical student asks about the clinical implications of this warning. Which of the following statements is most accurate?

A. Orforglipron does not carry the same boxed warning as injectable GLP-1 RAs
B. A family history of either MEN1 or MEN2 syndrome is a contraindication to GLP-1 RAs
C. Human studies have demonstrated an association between MTC and GLP-1 RAs
D. Testing calcitonin levels prior to initiating GLP-1 RA therapy helps risk-stratify patients who do not know their family history
E. Patients should be counseled to monitor for hoarseness or voice changes while taking GLP-1 RAs

Next Week: Monthly Knowledge Check. This is a review checklist of must-know items for ABOM exams based on the previous four blog topics. In addition, this will include a brief explanation of the correct answers to previous sample questions.

Upcoming: Discontinued Medications, Growth Hormone Deficiency, Endoscopic Therapy Guidelines and Procedures, and a Motivational Interview Question Walk Through

For more practice questions, check out the following:

  • Obesity Medicine Board Review Questions (2026): Qs 220 and 315.
  • Obesity Medicine Practice Tests (2026): Qs 417 and 419.

(Copyright 2026) Obesity Medicine Board Review Questions, LLC: obesitymedicinereview.com

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