What is the evidence for a cancer preventive effect of Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs)?

GLP-1 Receptor Agonists and Cancer Prevention: Evidence Summary

Current evidence suggests GLP-1 receptor agonists demonstrate significant cancer risk reduction for multiple obesity-associated cancers, with the strongest protective effects observed for gastrointestinal, hepatocellular, pancreatic, and colorectal cancers, though thyroid cancer risk remains a specific concern requiring ongoing surveillance.

Evidence for Cancer Prevention

Obesity-Associated Cancers Show Significant Risk Reduction

The most comprehensive evidence comes from a large-scale analysis of 1.65 million patients with type 2 diabetes, demonstrating that GLP-1 RAs compared with insulin were associated with significant risk reductions in 10 of 13 obesity-associated cancers 1. The magnitude of protection varied substantially by cancer type:

• Gallbladder cancer: 65% risk reduction (HR 0.35,95% CI 0.15-0.83) 1
• Meningioma: 63% risk reduction (HR 0.37,95% CI 0.18-0.74) 1
• Pancreatic cancer: 59% risk reduction (HR 0.41,95% CI 0.33-0.50) 1
• Hepatocellular carcinoma: 53% risk reduction (HR 0.47,95% CI 0.36-0.61) 1
• Ovarian cancer: 48% risk reduction (HR 0.52,95% CI 0.03-0.74) 1
• Colorectal cancer: 46% risk reduction (HR 0.54,95% CI 0.46-0.64) 1
• Multiple myeloma: 41% risk reduction (HR 0.59,95% CI 0.44-0.77) 1
• Esophageal cancer: 40% risk reduction (HR 0.60,95% CI 0.42-0.86) 1
• Endometrial cancer: 26% risk reduction (HR 0.74,95% CI 0.60-0.91) 1
• Kidney cancer: 24% risk reduction (HR 0.76,95% CI 0.64-0.91) 1

Agent-Specific Differences Matter

Semaglutide demonstrates superior cancer-protective effects compared to other GLP-1 RAs, particularly for gastrointestinal malignancies 2. A nationwide analysis of 1.1 million patients with obesity revealed:

• Gastrointestinal cancers overall: 33% risk reduction (HR 0.67,95% CI 0.59-0.75) with GLP-1 RAs generally 2
• Gastrointestinal cancers with semaglutide specifically: 55% risk reduction (HR 0.45,95% CI 0.37-0.53) 2
• Skin cancers: 38% risk reduction (HR 0.62,95% CI 0.55-0.70) 2
• Breast cancer: 28% risk reduction (HR 0.72,95% CI 0.64-0.82) 2
• Female genital cancers: 39% risk reduction (HR 0.61,95% CI 0.53-0.71) 2
• Prostate cancer: 32% risk reduction (HR 0.68,95% CI 0.58-0.80) 2
• Lymphoid/hematopoietic cancers: 31% risk reduction (HR 0.69,95% CI 0.60-0.80) 2

Critical Exception: Thyroid Cancer Concerns

Liraglutide specifically shows increased thyroid cancer risk, creating an important safety distinction within the GLP-1 RA class 2. The evidence reveals:

• Liraglutide and thyroid cancer: 70% increased risk (HR 1.70,95% CI 1.03-2.82) 2
• Liraglutide and respiratory cancers: 62% increased risk (HR 1.62,95% CI 1.13-2.32) 2

However, overall thyroid cancer risk with GLP-1 RAs as a class remains reassuring. A multisite international cohort study of 98,147 GLP-1 RA users found no increased thyroid cancer risk compared to DPP-4 inhibitor users (pooled weighted HR 0.81,95% CI 0.59-1.12) over median follow-up of 1.8-3.0 years 3. Evidence from randomized controlled trials indicates thyroid cancer occurrence is infrequent in individuals exposed to GLP-1 RAs, with observational studies yielding inconsistent results 4.

Comparison with Other Diabetes Medications

GLP-1 RAs vs. Metformin

When compared to metformin, GLP-1 RAs show less consistent cancer-protective effects 1. The comparison reveals:

• Colorectal and gallbladder cancers: Risk reduction trends exist but lack statistical significance 1
• Kidney cancer: GLP-1 RAs associated with 54% increased risk compared to metformin (HR 1.54,95% CI 1.27-1.87) 1
• No decreased risk for any cancers when directly compared to metformin 1

This suggests metformin may have independent cancer-protective properties that should be considered when selecting diabetes therapies.

GLP-1 RAs vs. Insulin

GLP-1 RAs demonstrate clear superiority over insulin for cancer prevention across multiple malignancies 1. This comparison is particularly relevant given insulin's known association with cancer promotion through IGF-1 pathway activation.

Mechanisms and Clinical Context

The cancer-protective effects likely operate through multiple pathways beyond simple weight reduction 1. These include:

• Direct anti-inflammatory effects
• Improved insulin sensitivity reducing hyperinsulinemia
• Modulation of cellular proliferation pathways
• Weight loss-mediated hormonal changes

Real-world effectiveness shows substantial benefits when patients maintain adherence, though discontinuation rates of 20-50% within the first year remain problematic 5. The observed cancer risk reductions occurred despite these adherence challenges, suggesting robust protective effects.

Clinical Implications

For patients with obesity or type 2 diabetes requiring pharmacotherapy, semaglutide should be prioritized when cancer prevention is a consideration, given its superior protective profile across multiple cancer types 2. Liraglutide should be avoided in patients with personal or family history of thyroid cancer or multiple endocrine neoplasia syndrome type 2 2.

The 15-year follow-up data provides confidence in medium-term cancer prevention benefits 1, though longer-term surveillance remains necessary given cancer's prolonged latency periods. The multisite international study acknowledges that evidence remains insufficient to rule out excess risk with very long-term use beyond 3 years 3.

These cancer-protective effects represent an additional benefit beyond the established cardiovascular and renal protective effects documented in cardiovascular outcomes trials 6, though guidelines have not yet incorporated cancer prevention into treatment algorithms 6.