A comprehensive analysis of clinical and preclinical data reveals that GLP-1 receptor agonists, previously suspected of increasing cancer risk, are generally safe and may even reduce the incidence of certain cancers through improved insulin regulation and immune modulation.
Review: GLP-1 receptor agonists and cancer: current clinical evidence and translational opportunities for preclinical research. Image Credit: Love Employee / Shutterstock
In a recent review published in The Journal of Clinical Investigation, researchers summarized current clinical evidence and relevant preclinical studies to assess the connection between glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) and cancer outcomes.
Study findings revealed that, despite early concerns and warnings related to specific cancer types, the bulk of evidence from large-scale meta-analyses does not show an increased cancer incidence. In contrast, some analyses report lower risk for specific cancers, particularly hepatocellular, colorectal, and prostate cancers.
Global Burden of Obesity, Diabetes, and Cancer Risk
Obesity and type 2 diabetes (T2D) represent a pressing global health crisis, demonstrating an alarming surge in global prevalence. These intertwined epidemics have previously been strongly associated with cardiovascular complications, but more recent research suggests that these metabolic conditions may further trigger or exacerbate malignancy (cancers).
Consequently, the World Health Organization (WHO) and other public health bodies have now associated obesity with an elevated risk for at least 13 different types of cancer, including colorectal, postmenopausal breast, pancreatic, and endometrial cancers.
Biological Pathways Linking Metabolic Disease and Cancer
Mechanistic research suggests that obesity and T2D often lead to a state of chronic, low-grade inflammation and, crucially, sustained hyperinsulinemia (excessively high insulin levels). While vital for glucose control, insulin is also a potent growth factor that can "fuel" the proliferation and survival of cancer cells.
GLP-1 Receptor Agonists as a Breakthrough in Metabolic Therapy
The current gold-standard pharmacological interventions against obesity and T2D are glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) such as semaglutide and liraglutide. These drugs mimic a natural gut hormone (GLP-1) that stimulates insulin secretion, slows digestion, and reduces appetite. Their success in managing both diabetes and obesity has been revolutionary, with GLP-1 RAs demonstrating substantially improved efficacy over last-generation interventions.
However, since the GLP-1 receptor is expressed in many tissues beyond its primary target (e.g., the brain, heart, and lungs), current research aims to investigate the comprehensive systemic effects of these drugs, particularly on cancer.
Scope and Objectives of the Review
The present comprehensive review aims to address mounting fears of GLP-1 RA, cancer associations by synthesizing and evaluating the existing body of evidence from dozens of independent clinical and preclinical studies across: (1) preclinical investigations, (2) observational data, (3) retrospective cohort studies, and (4) meta-analyses.
The review’s approach allows for a broad, "state-of-the-union" summary of the evidence, particularly regarding the two most controversial areas in clinical conversation, thyroid and pancreatic cancer.
Evidence on Thyroid and Pancreatic Cancer Risks
Review findings suggest that while early studies sparked fears of GLP-1 RAs increasing cancer risks or exacerbating malignancy outcomes, these fears have now been largely tempered by a growing body of reassuring and even positive data.
The thyroid cancer debate has been one of the most significant GLP-1 RA-associated safety concerns. This fear originated from preclinical data showing that these drugs could make thyroid C-cells proliferate in rodent models.
Thyroid cancer fears were exacerbated by reports from the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) and a nested case-control study (Bezin et al., 2023) that reported increased risk for thyroid cancer following GLP-1 RA-based interventions. This led to an FDA warning that remains on GLP-1 RA drugs today, advising against their use in patients with a personal or family history of medullary thyroid carcinoma.
However, the present review highlights critical demerits of these lines of evidence: the FAERS data were voluntary and clinically unverified, and the Bezin et al. study likely suffered from detection bias and confounding by obesity, as patients taking GLP-1s tend to see their doctors more frequently, leading to higher detection rates of slow-growing thyroid nodules.
The authors also note that while most meta-analyses show no increase in risk, a few report elevated thyroid cancer incidence, but these analyses exhibit methodological fragility. Multiple large-scale meta-analyses (2012–2022) found no significant increase in thyroid cancer risk.
A similar pattern was observed for pancreatic cancer. An early FAERS analysis suggested an elevated risk, prompting the FDA to investigate. However, subsequent meta-analyses and cohort studies found mixed or null results. One large retrospective cohort found that GLP-1 agonist use was associated with a lower risk of pancreatic cancer compared to treatment with other antihyperglycemic drugs, particularly insulin.
Broader Cancer Outcomes and Mechanistic Insights
For most other cancers, recent clinical evidence demonstrates largely positive outcomes, with several meta-analyses showing no excess risk and even a reduced risk for hepatocellular carcinoma and colorectal cancer (relative to insulin users). Positive outcomes were also observed in studies investigating associations between GLP-1 RAs and prostate cancer (lower risk in meta-analyses), while breast cancer shows no effect.
The review highlights sustained hyperinsulinemia as a key driver of obesity- and T2D-related cancer risk and notes that GLP-1RA-mediated reductions in insulin could partly explain the observed benefits. Preclinical data also indicate potential anticancer effects independent of weight loss, such as modulation of tumor cell metabolism and inflammation, as well as reprogramming of tumor-associated macrophages toward anti-tumor (M1-like) phenotypes and enhanced cytotoxic T-cell infiltration in animal models.
Research Gaps and Future Directions in GLP-1, Cancer Studies
Most clinical evidence pertains to cancer incidence rather than progression, and the review calls for additional trials specifically in patients undergoing cancer treatment or in remission. Several such studies are ongoing or planned, including those exploring weight management and metabolic support during therapy.
The authors emphasize that interpreting preclinical tumor progression data requires caution, as mechanisms affecting incidence may not accurately predict tumor behavior once established.
The present review ultimately weighs early concerns against increasingly consistent evidence that GLP-1 RA use does not raise overall cancer risk, clarifies that breast cancer risk appears neutral, and further highlights key mechanisms, such as the reduction of hyperinsulinemia and immune-microenvironment modulation, through which these drugs may improve rather than exacerbate malignancy outcomes.
Preclinical evidence also suggests direct anticancer effects, even in non-obese models, though translational confirmation is needed.
Journal reference:
- Valencia-Rincón, E., Rai, R., Chandra, V., & Wellberg, E. A. (2025). GLP-1 receptor agonists and cancer: current clinical evidence and translational opportunities for preclinical research. Journal of Clinical Investigation, 135(21). DOI – 10.1172/jci194743. https://www.jci.org/articles/view/194743