Is there an association between Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) and cancer risk?

GLP-1 Receptor Agonists and Cancer Risk

GLP-1 receptor agonists are contraindicated only in patients with personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2 (MEN2), but there is no conclusive evidence linking these medications to increased risk of other cancers including non-medullary thyroid cancer, pancreatic cancer, or breast cancer. 1

Absolute Contraindications: Medullary Thyroid Cancer Risk

The FDA Black Box Warning specifically addresses thyroid C-cell tumors (medullary thyroid carcinoma), making GLP-1 RAs absolutely contraindicated in patients with personal or family history of MTC or MEN2. 1, 2

• GLP-1 receptor agonists cause dose-related and treatment-duration-dependent increases in thyroid C-cell tumors (adenomas and carcinomas) in rodents at clinically relevant exposures 2
• The human relevance of rodent thyroid C-cell tumors has not been determined, and it remains unknown whether GLP-1 RAs will cause MTC in humans 2
• Cases of MTC in patients treated with liraglutide have been reported in the postmarketing period, though data are insufficient to establish or exclude a causal relationship 2
• One case of MTC was reported in a patient treated with dulaglutide who had pretreatment calcitonin levels approximately 8 times the upper limit of normal 2

Evidence for Other Cancer Types: Reassuring Data

A 2025 systematic review and meta-analysis of 48 randomized controlled trials involving 94,245 participants found that GLP-1 RAs probably have little or no effect on risk for thyroid cancer, pancreatic cancer, breast cancer, or kidney cancer (moderate certainty evidence). 3

Specific Cancer Risk Estimates:

• Thyroid cancer: OR 1.37 (95% CI 0.82-2.31); translates to 1 fewer to 9 more cases per 10,000 patients treated 3
• Pancreatic cancer: OR 0.84 (95% CI 0.53-1.35); 9 fewer to 6 more per 10,000 3
• Breast cancer: OR 0.95 (95% CI 0.60-1.49); 10 fewer to 12 more per 10,000 3
• Kidney cancer: OR 1.12 (95% CI 0.78-1.60); 5 fewer to 13 more per 10,000 3

Additional Cancer Types:

• GLP-1 RAs may have little or no effect on colorectal, esophageal, liver, gallbladder, ovarian, or endometrial cancer; multiple myeloma; or meningioma (low certainty evidence) 3
• A 2025 multisite cohort study of 98,147 GLP-1 RA users found no association with increased thyroid cancer risk (pooled weighted HR 0.81,95% CI 0.59-1.12) with median follow-up of 1.8-3.0 years 4

Clinical Algorithm for Cancer Risk Assessment Before Prescribing

Step 1: Screen for Absolute Contraindications

• Personal history of medullary thyroid carcinoma → Do NOT prescribe GLP-1 RAs 1, 2
• Family history of medullary thyroid carcinoma → Do NOT prescribe GLP-1 RAs 1, 2
• Multiple endocrine neoplasia syndrome type 2 → Do NOT prescribe GLP-1 RAs 1, 2

Step 2: Assess Non-MTC Thyroid Cancer History

• For patients with non-MTC thyroid cancer history: Evaluate time since complete remission and implement regular thyroid function monitoring; GLP-1 RAs can be used 1
• The American College of Cardiology recommends close monitoring with regular thyroid function tests for these patients 1

Step 3: Proceed with Standard Prescribing for All Other Cancer Concerns

• For all other cancer concerns: Proceed with standard GLP-1 RA prescribing 1
• Follow routine cancer screening guidelines for age and sex 1
• Monitor for the actual safety concerns: gastrointestinal side effects, gallbladder disorders, and tachycardia 1

Important Caveats and Monitoring

Patient Counseling Requirements:

• Counsel patients regarding the potential risk for MTC and inform them of symptoms of thyroid tumors (mass in the neck, dysphagia, dyspnea, persistent hoarseness) 2
• Routine monitoring of serum calcitonin or thyroid ultrasound is of uncertain value for early detection of MTC and may increase the risk of unnecessary procedures 2

When to Evaluate Further:

• If serum calcitonin is measured and significantly elevated: Patients with MTC usually have calcitonin values >50 ng/L; these patients should be further evaluated 2
• If thyroid nodules are noted on physical examination or neck imaging: Further evaluation is warranted 2

Theoretical Risks Without Strong Evidence:

• GLP-1 receptor agonist treatment is not recommended in patients at risk for pancreatic cancer or pancreatitis based on theoretical risks from preclinical models, though clinical evidence does not support increased risk 5
• Real-world FAERS database analysis detected signals for certain tumors including thyroid cancers and pancreatic neoplasms, but these may reflect surveillance bias rather than causal relationships 6

Alternative Medications When GLP-1 RAs Are Contraindicated

For patients with MTC/MEN2 history who cannot use GLP-1 RAs:

• SGLT-2 inhibitors provide beneficial cardiovascular and renal protection 1
• DPP-4 inhibitors, metformin, and insulin therapy are appropriate alternatives 7
• Metformin is recommended as first-line therapy for patients with contraindications to GLP-1 RAs 7

Key Limitation: Short Follow-Up Duration

• The included trials were not designed to evaluate cancer outcomes and had short follow-up periods 3
• Evidence is insufficient to rule out excess risk with long-term use due to short follow-up in most studies 4
• Longer-term studies are needed to clarify potential risks or benefits with extended GLP-1 RA use 3