A large meta-analysis from Italy has found that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are linked to a 42% lower risk of hepatocellular carcinoma (HCC) in patients with type 2 diabetes (T2DM). The study, led by Andrea Dalbeni at the University of Verona, highlights the potential of these therapies to protect the liver while managing diabetes.
Patients with T2DM face a significantly higher risk of liver cancer, largely due to the high prevalence of metabolic dysfunction–associated steatotic liver disease (MASLD), which affects nearly 70% of this population. To investigate whether GLP-1 RAs can reduce this risk, researchers conducted a meta-analysis of nine cohort studies, encompassing more than 2.28 million patients, including over one million analyzed in detail.
Advanced statistical methods, including random-effects meta-analysis, network meta-analysis, and meta-regression, were used to evaluate HCC incidence among GLP-1 RA users versus nonusers.
Key findings include:
GLP-1 RA use was associated with a 40% reduction in HCC risk (pooled HR 0.60).
The strongest protective effect occurred when GLP-1 RAs were compared with insulin, showing a relative risk reduction of over 70%.
Comparisons with oral antidiabetic agents or no treatment showed smaller and less certain benefits.
Insulin was identified as the main source of study heterogeneity, accounting for more than half of observed variations.
Patients without cirrhosis experienced the greatest reduction in HCC risk, while benefits were weaker in those with advanced liver disease.
Network meta-analysis ranked GLP-1 RAs highest for HCC prevention, with insulin ranked lowest.
The number needed to treat to prevent one case of HCC ranged from 24 in high-risk patients to 476 in lower-risk populations.
The study suggests that GLP-1 RAs may reduce liver cancer risk through both direct hepatoprotective effects and by avoiding insulin-related pathways that can promote liver inflammation and carcinogenesis. The preventive impact appears comparable to other widely accepted interventions, such as statins for cardiovascular disease.
while metformin remains the first-line therapy for T2DM, GLP-1 RAs should be prioritized over insulin for patients at elevated HCC risk, particularly those with MASLD and without advanced cirrhosis. This strategy could help lower the global burden of metabolic liver disease and liver cancer while providing additional cardiometabolic benefits.
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