Is there a link between GLP-1 drugs and cancer? A recent review says no, and may even suggest protective effects.
A comprehensive analysis of clinical and preclinical data reveals that GLP-1 receptor agonists, once suspected of increasing cancer risk, are generally safe and may even reduce the incidence of certain cancers through improved insulin regulation and immune modulation. The review, published in The Journal of Clinical Investigation, summarizes current clinical evidence and relevant preclinical studies to assess the connection between glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) and cancer outcomes.
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 fact, some analyses report lower risk for certain cancers, particularly hepatocellular, colorectal, and prostate cancers.
Obesity and type 2 diabetes (T2D) are global health crises, strongly associated with cardiovascular complications. Recent research suggests these metabolic conditions may also trigger or exacerbate malignancy (cancers). The World Health Organization (WHO) and other public health bodies have linked obesity with an elevated risk for at least 13 different types of cancer, including colorectal, postmenopausal breast, pancreatic, and endometrial cancers.
Mechanistic research indicates that obesity and T2D often lead to chronic, low-grade inflammation and sustained hyperinsulinemia (excessively high insulin levels). While insulin is vital for glucose control, it's also a potent growth factor that can 'fuel' cancer cell proliferation and survival.
GLP-1 receptor agonists, such as semaglutide and liraglutide, are the gold standard for treating obesity and T2D. These drugs mimic a natural gut hormone (GLP-1) that stimulates insulin secretion, slows digestion, and reduces appetite. Their success in managing 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, current research aims to investigate the comprehensive systemic effects of these drugs, particularly on cancer.
The review's scope and objectives 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 preclinical investigations, observational data, retrospective cohort studies, and meta-analyses.
The review finds that while early studies sparked fears of GLP-1 RAs increasing cancer risks or exacerbating malignancy outcomes, these fears have been largely tempered by a growing body of reassuring and even positive data.
The thyroid cancer debate has been a significant safety concern. This fear originated from preclinical data showing that these drugs could make thyroid C-cells proliferate in rodent models. However, the review highlights critical demerits of these lines of evidence, including the voluntary and clinically unverified nature of FAERS data, and the potential for detection bias and confounding by obesity.
Multiple large-scale meta-analyses (2012-2022) found no significant increase in thyroid cancer risk. A similar pattern was observed for pancreatic cancer. Early FAERS analysis suggested an elevated risk, but subsequent meta-analyses and cohort studies found mixed or null results.
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.
The review calls for additional trials specifically in patients undergoing cancer treatment or in remission, as most clinical evidence pertains to cancer incidence rather than progression. The authors emphasize the need for caution when interpreting preclinical tumor progression data, as mechanisms affecting incidence may not accurately predict tumor behavior once established.
Ultimately, the review concludes that early concerns are weighed against increasingly consistent evidence that GLP-1 RA use does not raise overall cancer risk, clarifies that breast cancer risk appears neutral, and 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. The review's DOI is 10.1172/jci194743.
