Semaglutide and Cancer Risk: Current Evidence
Primary Recommendation
Based on the most recent and highest-quality evidence, semaglutide does not increase overall cancer risk and may actually reduce the risk of certain obesity-related cancers, with the notable exception of a theoretical thyroid C-cell tumor risk observed only in rodent studies that has not been confirmed in humans. 1, 2
Thyroid Cancer: The FDA Black Box Warning
Semaglutide carries an FDA black box warning for thyroid C-cell tumors based exclusively on rodent studies, but human relevance remains unestablished. 3
Key Evidence Points:
In mice and rats, semaglutide caused dose-dependent and treatment-duration-dependent increases in thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure at clinically relevant plasma exposures 3
It is unknown whether semaglutide causes medullary thyroid carcinoma (MTC) in humans, as the human relevance of rodent thyroid C-cell tumors has not been determined 3
Cases of MTC have been reported in patients treated with liraglutide (another GLP-1 agonist), but the data are insufficient to establish or exclude a causal relationship between MTC and GLP-1 receptor agonist use in humans 3
Recent meta-analyses of randomized controlled trials found that GLP-1 receptor agonists probably have little or no effect on thyroid cancer risk (OR 1.37,95% CI 0.82-2.31; translating to 1 fewer to 9 more cases per 10,000 patients treated) with moderate certainty of evidence 2
Notably, liraglutide showed increased thyroid cancer risk (HR 1.70,95% CI 1.03-2.82) in one large observational study, but semaglutide did not demonstrate this association 1
Absolute Contraindication:
Semaglutide is absolutely contraindicated in patients with personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) 4, 3
Patients should be counseled about symptoms of thyroid tumors including neck mass, dysphagia, dyspnea, and persistent hoarseness 3
Routine monitoring of serum calcitonin or thyroid ultrasound is of uncertain value and may increase unnecessary procedures due to low test specificity and high background incidence of thyroid disease 3
Pancreatic Cancer: Reassuring Evidence
The evidence strongly suggests semaglutide does not increase pancreatic cancer risk and may potentially reduce it. 2
Clinical Trial Data:
GLP-1 receptor agonists probably have little or no effect on pancreatic cancer risk (OR 0.84,95% CI 0.53-1.35; translating to 9 fewer to 6 more cases per 10,000 patients) with moderate certainty of evidence 2
The SUSTAIN-6 and PIONEER-6 cardiovascular outcome trials demonstrated cardiovascular safety without unexpected malignancy signals, including pancreatic cancer 5
Pancreatitis Consideration:
Acute pancreatitis has been reported in clinical trials (0.27-0.3 cases per 100 patient-years with semaglutide vs 0.2-0.33 with comparators), though causality has not been definitively established 3
Semaglutide should be used with caution in patients with a history of pancreatitis, and the FDA label states it has not been studied in this population 4, 3
If pancreatitis is suspected (persistent severe abdominal pain), semaglutide should be discontinued immediately and not restarted if confirmed 3
Obesity-Related Cancers: Protective Effects
The most compelling recent evidence demonstrates that semaglutide significantly reduces the risk of multiple obesity-related cancers, with particularly strong effects in gastrointestinal malignancies. 1, 6
Specific Cancer Risk Reductions (from 2024 nationwide analysis of 1.1 million patients):
Gastrointestinal cancers: 33% risk reduction (HR 0.67,95% CI 0.59-0.75) 1
- Semaglutide specifically showed superior protection with 55% risk reduction (HR 0.45,95% CI 0.37-0.53) 1
Skin cancers: 38% risk reduction (HR 0.62,95% CI 0.55-0.70) 1
Breast cancer: 28% risk reduction (HR 0.72,95% CI 0.64-0.82) 1
Female genital cancers: 39% risk reduction (HR 0.61,95% CI 0.53-0.71) 1
Prostate cancer: 32% risk reduction (HR 0.68,95% CI 0.58-0.80) 1
Lymphoid/hematopoietic cancers: 31% risk reduction (HR 0.69,95% CI 0.60-0.80) 1
Supporting Evidence from Type 2 Diabetes Population:
In a nationwide US cohort of 919,609 overweight or obese patients with type 2 diabetes, GLP-1 agonist users had lower incidence (7.5 vs 8.1 per 1000 person-years) and 13% lower risk of obesity-related cancer compared to other glucose-lowering drugs (adjusted HR 0.87,95% CI 0.83-0.91) 6
The protective effect was strengthened with increasing body weight: overweight (HR 0.95), mild-to-moderate obesity (HR 0.90), and severe obesity (HR 0.82) 6
Meta-Analysis Findings: Comprehensive Cancer Assessment
A 2025 systematic review and meta-analysis of 48 randomized controlled trials involving 94,245 participants provides the highest-quality evidence on cancer risk. 2
Key Findings (Moderate Certainty Evidence):
Breast cancer: probably little or no effect (OR 0.95% CI 0.60-1.49; 10 fewer to 12 more per 10,000) 2
Kidney cancer: probably little or no effect (OR 1.12,95% CI 0.78-1.60; 5 fewer to 13 more per 10,000) 2
Low Certainty Evidence (may have little or no effect):
Colorectal, esophageal, liver, gallbladder, ovarian, endometrial cancer, multiple myeloma, and meningioma 2
The effect on gastric cancer remains very uncertain 2
Important Limitations:
The included trials were not designed to evaluate cancer outcomes and had relatively short follow-up periods 2
Longer-term studies are needed to clarify potential risks or benefits 2
Neuroendocrine Tumors: An Emerging Concern
Recent preclinical evidence suggests potential risk for GLP-1 receptor-expressing neuroendocrine neoplasms, though clinical significance remains unclear. 7
Laboratory Findings:
Semaglutide promoted growth of neuroendocrine neoplasm cell lines expressing GLP-1 receptors by 19-22% in vitro 7
In mouse xenograft models, semaglutide promoted tumor growth by 72% in GLP-1 receptor-expressing neuroendocrine tumors 7
Approximately 50% of tested neuroendocrine neoplasm cell lines expressed GLP-1 receptors 7
Clinical Implications:
This represents a potential risk in patients with known neuroendocrine neoplasms expressing GLP-1 receptors, though human clinical data are lacking 7
Insulin-secreting pancreatic neuroendocrine neoplasms have been reported to express high levels of GLP-1 receptor protein 7
Further investigation in larger sets of neuroendocrine neoplasms is needed, as these tumors are highly heterogeneous 7
Mechanisms of Cancer Protection
The anticancer effects of semaglutide likely result from multiple mechanisms beyond simple weight loss. 8
Direct and Indirect Effects:
Immune-modulating effects have been reported in preclinical cancer studies, potentially reflecting direct action on immune cells or improved metabolic function 8
Weight loss itself provides protective effects for cancer prevention, as cancer diagnoses are prevalent in people with obesity and type 2 diabetes 8
Improvements in inflammatory markers like C-reactive protein may contribute to cancer risk reduction 4
Enhanced metabolic function, improved insulin sensitivity, and reduced chronic inflammation all contribute to lower cancer risk 8
Clinical Decision-Making Algorithm
For Patients WITHOUT Cancer History:
Screen for absolute contraindications:
If contraindications absent, proceed with semaglutide for appropriate indications (obesity, type 2 diabetes, cardiovascular disease) 4
Counsel patients about:
For Patients WITH Cancer History:
History of medullary thyroid carcinoma or MEN 2: absolute contraindication 3
History of neuroendocrine tumors: exercise caution
History of other obesity-related cancers: semaglutide may be preferred
For Patients WITH Pancreatitis History:
Consider alternative antidiabetic therapies, as semaglutide has not been studied in patients with history of pancreatitis 4, 3
If semaglutide is used, monitor closely for signs of recurrent pancreatitis 3
Common Pitfalls to Avoid
Do not withhold semaglutide based solely on theoretical thyroid cancer risk from rodent studies - human relevance has not been established, and recent meta-analyses show no increased risk 3, 2
Do not ignore the absolute contraindication for personal/family history of MTC or MEN 2 - this is based on FDA black box warning and should never be overlooked 3
Do not assume all GLP-1 agonists have identical cancer profiles - liraglutide showed increased thyroid and respiratory cancer risk in observational studies, while semaglutide demonstrated protective effects 1
Do not rely on routine calcitonin monitoring - it has uncertain value and may lead to unnecessary procedures 3
Do not dismiss the emerging neuroendocrine tumor concern - while based on preclinical data, it warrants consideration in patients with known neuroendocrine neoplasms 7
Monitoring Recommendations
Baseline Assessment:
Screen for personal and family history of medullary thyroid carcinoma and MEN 2 3
Document any history of pancreatitis 3
Assess for known neuroendocrine tumors 7
Ongoing Monitoring:
Do not perform routine calcitonin monitoring or thyroid ultrasound - uncertain value and may increase unnecessary procedures 3
Educate patients about thyroid tumor symptoms (neck mass, dysphagia, dyspnea, persistent hoarseness) 3
If serum calcitonin is measured and significantly elevated (>50 ng/L), further evaluation is warranted 3
Monitor for signs of pancreatitis (persistent severe abdominal pain) 3
Strength of Evidence Summary
Highest Quality Evidence (Moderate Certainty):
- No increased risk for thyroid, pancreatic, breast, or kidney cancer 2
- Protective effects against multiple obesity-related cancers 1, 6
Lower Quality Evidence (Low Certainty):
- Effects on colorectal, esophageal, liver, gallbladder, ovarian, endometrial cancer 2
Preclinical Evidence Only:
- Potential risk for GLP-1 receptor-expressing neuroendocrine tumors 7
- Immune-modulating anticancer effects 8
Rodent Studies (Human Relevance Unknown):
- Thyroid C-cell tumor risk 3