Do All GLP-1 Medications Cause Thyroid Cancer? Evidence Review

Do all GLP-1 medications cause thyroid cancer? This question concerns many patients and clinicians considering glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes or weight management. While rodent studies showed thyroid C-cell tumors with certain GLP-1 drugs, leading to FDA boxed warnings, over 15 years of human clinical data has not established a causal link between these medications and thyroid cancer. Not all GLP-1 agents carry the same warnings, and human thyroid cells differ significantly from rodent cells in GLP-1 receptor expression. Understanding which medications have warnings, who should avoid them, and what the evidence actually shows is essential for informed treatment decisions.

Understanding GLP-1 Medications and Thyroid Cancer Concerns

Glucagon-like peptide-1 (GLP-1) receptor agonists represent a class of medications primarily used for type 2 diabetes management and, more recently, for chronic weight management. These agents work by mimicking the action of endogenous GLP-1, an incretin hormone that enhances glucose-dependent insulin secretion, suppresses glucagon release, slows gastric emptying, and promotes satiety. Common medications in this class include semaglutide (Ozempic, Wegovy, Rybelsus), dulaglutide (Trulicity), liraglutide (Victoza, Saxenda), exenatide (Byetta, Bydureon BCise), lixisenatide (Adlyxin), and tirzepatide (Mounjaro, Zepbound), though tirzepatide is technically a dual GIP/GLP-1 receptor agonist.

Concerns about thyroid cancer risk with GLP-1 medications emerged from preclinical animal studies conducted during drug development. Specifically, rodent studies demonstrated an increased incidence of thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), at clinically relevant doses. These findings led to boxed warnings on certain GLP-1 receptor agonist labels and generated ongoing questions about human applicability.

It is important to understand that not all GLP-1 medications carry the same thyroid cancer warning, and the relevance of animal findings to human patients remains uncertain. The thyroid C-cells in rodents express significantly higher levels of GLP-1 receptors compared to human C-cells, suggesting species-specific differences in susceptibility. Despite widespread clinical use over more than 15 years, there is no established causal link between GLP-1 receptor agonists and thyroid cancer in humans. Nevertheless, the FDA has maintained precautionary labeling based on the animal data, and clinicians must carefully assess individual patient risk factors before prescribing these medications.

FDA Warnings and Thyroid Tumor Risk in Animal Studies

The FDA-mandated boxed warning for certain GLP-1 receptor agonists stems directly from carcinogenicity studies in rodents. In 2-year studies of liraglutide in rats and mice, dose-dependent and treatment-duration-dependent increases in thyroid C-cell tumors were observed at clinically relevant exposures. Similar findings occurred with semaglutide and dulaglutide in rodent models. These tumors ranged from C-cell adenomas to medullary thyroid carcinomas, a rare but aggressive form of thyroid cancer originating from calcitonin-producing parafollicular cells.

The proposed mechanism involves GLP-1 receptor activation of thyroid C-cells based on nonclinical studies. Rodent C-cells express abundant GLP-1 receptors, and chronic stimulation appears to promote cellular proliferation and neoplastic transformation in these animal models. Calcitonin levels, a biomarker of C-cell activity, were elevated in treated animals. However, human thyroid C-cells express GLP-1 receptors at substantially lower levels than rodents, raising questions about the translatability of these findings to clinical practice.

The FDA acknowledges this species difference but maintains that the human relevance of these findings cannot be definitively ruled out. Consequently, boxed warnings state that GLP-1 receptor agonists cause thyroid C-cell tumors in rodents and that it is unknown whether they cause thyroid C-cell tumors, including MTC, in humans. The warnings explicitly contraindicate these medications in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).

Not all GLP-1 medications underwent identical carcinogenicity testing, and some agents have different labeling. The specific pharmacokinetic profile of each agent may have different theoretical implications, though this remains uncertain without human evidence.

Human Clinical Data: GLP-1 Drugs and Thyroid Cancer Risk

Human clinical trial data spanning over 15 years has not demonstrated a causal association between GLP-1 receptor agonist use and thyroid cancer. Large cardiovascular outcome trials, including LEADER (liraglutide), SUSTAIN-6 (semaglutide), REWIND (dulaglutide), and EXSCEL (exenatide), involving tens of thousands of patients with median follow-up periods of 2-5 years, reported no significant increase in thyroid cancer incidence compared to placebo.

A comprehensive meta-analysis published in Diabetes Care examined data from randomized controlled trials and found no statistically significant increase in thyroid cancer risk with GLP-1 receptor agonists. However, the evidence from observational studies is mixed. While many population-based cohort studies have not identified a signal for increased thyroid malignancy, some analyses, including a French national database study, have reported small, statistically significant increases in thyroid cancer risk that require further investigation.

Medullary thyroid carcinoma remains exceptionally rare, with an annual incidence of approximately 0.2 cases per 100,000 persons in the general population. Sporadic cases have been reported in patients taking GLP-1 medications, but these occur at rates that appear consistent with background population incidence. Given MTC's typically slow growth pattern, causality assessment is challenging.

Importantly, the latency period for solid tumor development typically spans years to decades, and most clinical trials have relatively short follow-up durations. While current randomized trial evidence is reassuring, continued long-term surveillance is warranted. The American Diabetes Association and American Association of Clinical Endocrinologists acknowledge the lack of conclusive human evidence for thyroid cancer risk while respecting the contraindications based on animal data and theoretical concerns.

Which GLP-1 Medications Carry Thyroid Cancer Warnings

The FDA boxed warning for thyroid C-cell tumor risk applies to long-acting GLP-1 receptor agonists that demonstrated this finding in rodent carcinogenicity studies. Specifically, the following medications carry this warning:

Medications with boxed warnings:

• Liraglutide (Victoza for diabetes, Saxenda for weight management)

• Semaglutide (Ozempic, Rybelsus for diabetes; Wegovy for weight management)

• Dulaglutide (Trulicity)

• Exenatide extended-release (Bydureon BCise)

• Tirzepatide (Mounjaro for diabetes, Zepbound for weight management)

These agents share similar labeling that contraindicates their use in patients with a personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). The prescribing information for each medication includes detailed discussion of the rodent findings and the uncertain human relevance.

Medications without boxed warnings for thyroid tumors:

• Exenatide immediate-release (Byetta), a shorter-acting twice-daily formulation, does not carry a boxed warning for thyroid tumors, though the prescribing information mentions the rodent findings in the warnings and precautions section.

• Lixisenatide (Adlyxin), another short-acting GLP-1 receptor agonist, also does not carry a boxed warning for thyroid C-cell tumors.

Clinicians should review the current FDA-approved prescribing information for any GLP-1 medication before prescribing, as labeling may be updated based on emerging data. The presence of a boxed warning does not indicate proven human risk but reflects regulatory requirements based on animal carcinogenicity findings.

Who Should Avoid GLP-1 Drugs Due to Thyroid Risk

Based on FDA labeling and expert consensus, specific patient populations should avoid GLP-1 receptor agonists that carry thyroid C-cell tumor warnings. These contraindications reflect a precautionary approach given the animal data and the serious nature of medullary thyroid carcinoma, despite the absence of confirmed human risk.

Absolute contraindications include:

Personal history of medullary thyroid carcinoma (MTC): Patients with a prior diagnosis of MTC should not receive GLP-1 receptor agonists. MTC can recur, and theoretical stimulation of residual C-cells represents an unacceptable risk, even though no mechanism for GLP-1-mediated progression has been established in humans.

Family history of medullary thyroid carcinoma: First-degree relatives of patients with MTC have elevated risk for hereditary forms of the disease. Approximately 25% of MTC cases are hereditary, often associated with germline RET proto-oncogene mutations. Avoiding GLP-1 agonists in this population is prudent pending further data. Patients with suspected hereditary MTC should be referred for genetic counseling and RET mutation testing.

Multiple Endocrine Neoplasia syndrome type 2 (MEN 2): This autosomal dominant disorder, caused by RET mutations, carries a very high lifetime risk of MTC (approaching 100% in some subtypes). Patients with known or suspected MEN 2 should not receive GLP-1 receptor agonists. MEN 2A includes MTC, pheochromocytoma, and hyperparathyroidism, while MEN 2B includes MTC, pheochromocytoma, mucosal neuromas, and marfanoid habitus.

Relative considerations:

Patients with thyroid nodules or elevated calcitonin levels require careful evaluation before initiating GLP-1 therapy. Baseline calcitonin measurement is not routinely recommended by most guidelines due to low specificity, but if obtained and elevated, further investigation for MTC should occur before prescribing. Patients with a history of other thyroid cancers (papillary, follicular) do not have contraindications to GLP-1 use, as these originate from different cell types. Clinical judgment should guide decision-making, weighing the substantial metabolic benefits of GLP-1 therapy against theoretical and unproven thyroid risks in most patients.

Monitoring and Safety Guidelines for GLP-1 Therapy

Current clinical guidelines do not recommend routine thyroid monitoring specifically for GLP-1 receptor agonist therapy in patients without contraindications. The American Diabetes Association, American Association of Clinical Endocrinologists, and Endocrine Society do not advocate for baseline or serial calcitonin measurements or thyroid ultrasounds in asymptomatic patients initiating these medications. This recommendation reflects the lack of evidence for human thyroid cancer risk and the poor positive predictive value of calcitonin screening in low-risk populations. As noted in FDA prescribing information, the value of routine monitoring is uncertain.

Pre-treatment assessment should include:

• Detailed personal and family history focusing on thyroid cancer, particularly MTC, and MEN 2 syndrome

• Documentation of any known thyroid nodules or previous thyroid surgery

• Review of symptoms suggestive of thyroid disease (neck mass, dysphagia, hoarseness)

If any concerning history emerges, consider endocrinology referral before initiating therapy. Routine calcitonin testing is not recommended but may be considered in patients with thyroid nodules or strong family history of thyroid disease, recognizing that interpretation can be challenging.

Patient education should emphasize:

• The theoretical nature of thyroid cancer risk based on animal studies

• The absence of confirmed human cases causally linked to GLP-1 therapy

• Warning signs requiring immediate medical attention: neck mass or swelling, persistent hoarseness, difficulty swallowing, or shortness of breath

• The importance of disclosing any family history of thyroid cancer or MEN 2

During ongoing therapy:

Clinicians should remain alert to thyroid-related symptoms during routine follow-up visits. Any palpable thyroid abnormality warrants standard evaluation with thyroid function tests, ultrasound, and potential fine-needle aspiration biopsy based on nodule characteristics, following American Thyroid Association guidelines. If MTC is diagnosed during GLP-1 therapy, the medication should be discontinued immediately, though causality would be difficult to establish given the typical slow growth of MTC.

Physicians should maintain awareness of evolving evidence and regulatory updates. The substantial cardiovascular and metabolic benefits of GLP-1 receptor agonists generally outweigh theoretical thyroid risks in appropriate patients, but informed consent and individualized risk assessment remain essential components of safe prescribing.

Frequently Asked Questions