GLP-1 Receptor Agonists Linked to Reduced Liver Cancer Risk in Type 2 Diabetes: Study
Italy: A large meta-analysis involving 2.3 million patients has found that GLP-1 receptor agonist (GLP-1 RA) use was associated with a 42% reduction in hepatocellular carcinoma (HCC) risk among patients with type 2 diabetes. The magnitude of benefit varied depending on comparator therapies and underlying liver disease, with part of the risk reduction attributed to avoiding insulin’s potential hepatotoxic effects.
The findings were published in Cancer Medicine by Andrea Dalbeni from the Unit of General Medicine C, Medicine Department, University of Verona, and the University and Hospital Trust (AOUI) of Verona, Italy, along with colleagues.
The study addresses a critical clinical question, as patients with type 2 diabetes mellitus (T2DM) face a substantially increased risk of liver cancer, largely driven by the high prevalence of metabolic dysfunction–associated steatotic liver disease (MASLD), which affects nearly 70% of this population.
To better define the role of GLP-1 receptor agonists in HCC prevention, the researchers conducted a comprehensive meta-analysis of cohort studies comparing HCC incidence among GLP-1 RA users and nonusers with T2DM. Literature searches across PubMed, Embase, and Web of Science up to June 2025 identified nine eligible studies, encompassing more than 2.28 million patients, with over one million individuals included in the analyzed cohorts. Advanced statistical methods, including random-effects meta-analysis, network meta-analysis, and meta-regression, were used to assess treatment effects and sources of heterogeneity.
The following were the key findings:
- GLP-1 receptor agonist use was associated with a significant reduction in hepatocellular carcinoma risk (pooled HR 0.60).
- The magnitude of risk reduction varied by comparator therapy.
- The strongest protective effect was seen when GLP-1 receptor agonists were compared with insulin, showing more than a 70% relative reduction in HCC risk.
- Comparisons with oral antidiabetic agents or no treatment demonstrated smaller and statistically uncertain benefits.
- Meta-regression identified insulin as the main contributor to between-study heterogeneity, accounting for over half of the observed variation.
- Patients without cirrhosis experienced the greatest reduction in HCC risk with GLP-1 receptor agonist therapy.
- The protective effect was weaker in patients with established cirrhosis.
- Network meta-analysis ranked GLP-1 receptor agonists highest for HCC prevention, while insulin ranked lowest.
- The number needed to treat to prevent one HCC case ranged from 24 in high-risk patients to 476 in lower-risk populations.
The authors suggest that the observed benefit may be driven by both the direct hepatoprotective effects of GLP-1 RAs and the avoidance of insulin-related pathways that may promote hepatic inflammation and carcinogenesis. Importantly, the estimated preventive impact compares favorably with other accepted interventions, such as statins for cardiovascular disease.
Taken together, the findings support a shift in treatment prioritization for patients with T2DM who are at elevated risk of HCC. While metformin remains first-line therapy, the authors argue that GLP-1 receptor agonists should be favored over insulin when treatment intensification is required, particularly in patients with MASLD and without advanced cirrhosis. This strategy could help reduce the growing global burden of metabolic liver disease and hepatocellular carcinoma while delivering established cardiometabolic benefits.
Reference:
Dalbeni, A., Vicardi, M., Natola, L. A., Cattazzo, F., Auriemma, A., Lombardi, R., Cinque, F., Carbonare, L. D., Mantovani, A., & Sacerdoti, D. (2025). Glucagon-Like Peptide-1 Receptor Agonists and Hepatocellular Carcinoma Prevention: A Meta-Analysis and Clinical Decision Framework. Cancer Medicine, 14(24), e71434. https://doi.org/10.1002/cam4.71434
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