Association between Glucagon-Like Peptide-1 Receptor Agonists and Cancer

Glucagon-like peptide-1 receptor agonists, as a key therapeutic approach for type 2 diabetes and obesity, have demonstrated significant efficacy in lowering blood glucose, promoting weight loss, improving insulin resistance, and exerting anti-inflammatory effects. Beyond their established role in metabolic disease management, their potential impact on cancer risk has become a focus of research. These agents act by activating the GLP-1 receptor or, in some cases, both the GLP-1R and the glucose-dependent insulinotropic polypeptide receptor. They may influence tumorigenesis and progression through both weight-dependent and weight-independent mechanisms. This article synthesizes relevant clinical evidence, mechanisms of action, and the current state of research to provide a core perspective on the potential anticancer properties of GLP-1R agonists.

1. The Link between Metabolic Diseases and Cancer

Both type 2 diabetes and obesity are closely associated with an increased risk of various cancers. Metabolic disturbances in diabetes, such as hyperinsulinemia, elevated leptin, and decreased adiponectin, can create a tumor-promoting microenvironment. Insulin itself exhibits growth factor-like activity and has shown pro-tumor effects in preclinical models. Obesity promotes cancer development by elevating circulating growth factors, exacerbating inflammation, and altering the tumor microenvironment. Interventions leading to weight loss, such as bariatric surgery or lifestyle modification, can reduce the incidence and mortality of obesity-related cancers, providing a theoretical foundation for investigating the anticancer potential of GLP-1R agonists.

2. Core Characteristics and Mechanisms of Action of GLP-1R Agonists

2.1 Drug Classes and Clinical Applications

Approved GLP-1R agonists include exenatide, liraglutide, semaglutide, and tirzepatide (a dual GLP-1/GIP receptor agonist). They are categorized as short- or long-acting formulations. Their indications encompass T2D and obesity, with some also approved for patients with comorbid cardiovascular or renal disease. Agents like semaglutide and tirzepatide offer the convenience of once-weekly dosing, improving adherence, and provide multiple benefits including glycemic control, weight loss, and cardioprotection.

2.2 Core Modes of Action

GLP-1R agonists lower blood glucose by stimulating insulin secretion, inhibiting glucagon release, reducing food intake, and delaying gastric emptying. Long-term use leads to significant weight reduction. Their mechanisms include: direct action on the central nervous system to suppress appetite and inflammation; action on gut lymphocytes to reduce intestinal inflammation; and restoration of normal adipocyte function through weight loss, thereby improving the tumor-promoting environment. Furthermore, some drugs may exert effects via weight-independent mechanisms, such as direct anti-inflammatory action, though the specific contribution of these pathways requires further clarification.

3. Association between GLP-1R Agonists and Cancer

3.1 Trends in Clinical Research

Real-world data and cohort studies suggest a reduced incidence of several cancers among users of GLP-1R agonists, including colorectal, liver, pancreatic, ovarian, and esophageal cancers. For instance, a study involving 93 million individuals with obesity found significantly lower risks of colorectal cancer and hepatobiliary cancers among GLP-1R agonist users. Some studies also indicate lower cancer-related mortality in these patients. However, findings vary across cancer types. Evidence regarding thyroid cancer remains inconclusive. Many studies have limitations, such as lack of detailed data on drug exposure levels, adherence, and the specific impact of weight loss achieved.

3.2 Key Findings for Specific Cancer Types

• Pancreatic Cancer:​ Pancreatic cells express functional GLP-1R. Clinical studies have not found an increased risk of pancreatic cancer with GLP-1R agonist use; some even suggest a potential risk reduction. Only a few preclinical studies have hinted at a possible tumor-promoting effect, requiring validation in larger samples.

• Thyroid Cancer:​ In animal models, GLP-1R agonists can stimulate thyroid C-cell proliferation. However, GLP-1R expression in human thyroid C-cells is minimal. Current evidence does not establish a clear link with human medullary thyroid carcinoma. Any observed increased risk in some studies may be related to detection bias.

• Colorectal Cancer:​ Preclinical research shows that GLP-1R agonists can inhibit colorectal cancer cell proliferation and induce apoptosis. Real-world data indicate a reduced risk of colorectal cancer among users, with a more pronounced effect observed in populations with obesity.

• Other Cancers:​ Studies on breast, prostate, lung, and hepatobiliary cancers, among others, generally show trends toward reduced risk with GLP-1R agonist use. However, conclusions from some studies should be interpreted cautiously due to small sample sizes or short follow-up periods.

4. Potential Mechanisms and Research Challenges

4.1 Core Mechanisms

GLP-1R agonists may influence cancer through direct and indirect pathways: 1) Direct binding to GLP-1R/GIPR on tumor cell surfaces, regulating proliferation and apoptosis; 2) Indirect effects via weight loss, which improves metabolic disorders and reduces systemic inflammation, or by modifying the tumor microenvironment (e.g., modulating immune cell infiltration, reducing pro-inflammatory cytokine release). Additionally, by regulating glucose and lipid metabolism, these drugs may reduce nutrient supply to tumors, inhibiting their growth.

4.2 Major Challenges

Current research faces several limitations: Detection technologies for GLP-1R/GIPR are not yet mature, and the correlation between receptor expression levels and function is unclear. Doses used in preclinical studies often exceed human therapeutic regimens, and drug exposure within the tumor microenvironment is unknown. Many studies have small sample sizes, short follow-up, and difficulty controlling for confounding factors. The safety and tolerability of these drugs in cancer patients are not fully established, with potential risks including gastrointestinal side effects and excessive weight loss.

5. Future Directions and Outlook

Several clinical trials are currently exploring the application of GLP-1R agonists in cancer patients, including for weight management and adjuvant therapy in endometrial, breast, and prostate cancers. Future research should focus on: elucidating the core mechanisms underlying the potential anticancer effects, particularly weight-independent pathways; optimizing receptor detection techniques to identify cancer subtypes and patient populations likely to respond; and conducting large-scale, long-term clinical trials to validate anticancer efficacy and safety.

In summary, GLP-1R agonists show potential value in reducing the risk of certain cancers, but current evidence is insufficient to support their use as standalone agents for cancer prevention or treatment. As mechanistic research deepens and clinical trials progress, their role in cancer prevention and management may be clarified, potentially offering more comprehensive treatment strategies for individuals with metabolic diseases who are at increased cancer risk.

Original Article：

Yabut, Julian M., and Daniel J. Drucker. "Glucagon-like peptide-1 medicines and cancer." Nature Cancer (2026): 1-12