GLP-1 RA Use Linked to 42% Hepatocellular Carcinoma Risk Reduction in T2DM

New research is shedding light on the hepatic benefits of glucagon-like peptide-1 receptor agonist (GLP-1 RA) use among patients with type 2 diabetes (T2DM), particularly for hepatocellular carcinoma (HCC) risk reduction.1

The systematic review and meta-analysis drew data from a pooled population of 2.3 million patients and demonstrated a clinically meaningful 42% reduction in HCC risk among patients with T2DM using GLP-1 RAs. Of note, the magnitude of benefit varied by comparator drug and baseline liver disease status.1

“HCC represents a growing global health burden, with T2DM recognized as an independent risk factor conferring a 2–3 fold increased risk,” David Sacerdoti, MD, an associate professor in the department of medicine at the University of Verona and colleagues wrote.1 “The rising prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), affecting 30% of adults worldwide and 70% of those with T2DM, has created an urgent need for effective HCC prevention strategies.”

GLP-1 RAs have had a profound impact across multiple disciplines in medicine, among the earliest and most transformative being T2DM. Emerging evidence suggests that these agents may also confer hepatoprotective effects, as demonstrated by semaglutide (Wegovy) injection 2.4 mg’s 2025 US Food and Drug Administration approval for the treatment of adults with metabolic dysfunction-associated steatohepatitis (MASH). Existing research on the benefit of GLP-1 RAs in the context of HCC prevention have yielded mixed results and are constrained by notable methodological limitations.1,2

To explore the association between GLP-1RA use and HCC risk in patients with T2DM, investigators searched PubMed, Embase, Web of Science, Cochrane Library, and conference abstracts from inception through June 2025. Inclusion criteria were cohort studies comparing GLP-1RA users to non-users, patients with T2DM, HCC incidence as outcome, and hazard ratios (HR) with 95% confidence intervals (CI) reported or calculable.1

The search yielded 606 potentially relevant articles across 4 databases, of which 9 encompassing 2,283,835 total patients ultimately met the inclusion criteria. These studies were published between 2022 and 2025 and utilized large administrative databases or electronic health records from the United States (n = 4), Sweden (n = 1), Korea (n = 1), and Taiwan (n = 3). All included studies were retrospective observational, and 7 out of 9 employed propensity score methods to address confounding.1

Upon analysis, GLP-1RA use was associated with a 42% reduced HCC risk (pooled HR, 0.60; 95% CI, 0.41 to 0.88), with substantial heterogeneity (I2 = 86.2%; P <.001). Investigators noted the protective association was consistent across most studies, though effect magnitudes varied considerably by comparator:

• Versus insulin (HR, 0.29; 95% CI, 0.13 to 0.67)
• Versus oral agents (HR, 0.81; 95% CI, 0.63 to 1.05)
• Versus no treatment (HR, 0.77; 95% CI, 0.52 to 1.14)

Meta-regression identified the use of insulin as a comparator as the strongest predictor of effect size (β = −0.74; SE, 0.27; P = .025), explaining 55% of between-study variance. Additionally, baseline cirrhosis showed a trend toward reduced efficacy (HR, 0.41; SE, 0.23; P = .075).1

Network meta-analysis ranked GLP-1RAs highest for HCC prevention (SUCRA, 0.89; mean rank, 1.7), followed by SGLT-2 inhibitors (SUCRA, 0.78; rank, 2.3), DPP-4 inhibitors (SUCRA, 0.70; rank, 3.0), mixed agents (SUCRA, 0.45; rank, 4.0), sulfonylureas (SUCRA, 0.11; rank, 5.7), and insulin (SUCRA, 0.08; rank, 5.9). Further head-to-head comparisons showed GLP-1RAs were superior to insulin (HR, 0.29; 95% CI, 0.13 to 0.67), sulfonylureas (HR, 0.54; 95% CI, 0.31 to 0.94), and additionally indicated a nonsignificant trend toward superiority over SGLT-2 inhibitors (HR, 0.87; 95% CI, 0.52 to 1.45).1

“These findings, combined with GLP-1RAs' established cardiovascular benefits, support the preferential use of GLP-1RAs in T2DM patients at risk for HCC,” investigators concluded.1 “Application of these findings could potentially reduce the rising global burden of metabolic-associated liver disease and HCC.”

References

1. Dalbeni A, Vicardi M, Natola LA, et al. Glucagon-Like Peptide-1 Receptor Agonists and Hepatocellular Carcinoma Prevention: A Meta-Analysis and Clinical Decision Framework. Cancer Medicine. https://doi.org/10.1002/cam4.71434

2. Brooks A. FDA Approves Semaglutide (Wegovy) Injection 2.4 mg for Noncirrhotic MASH. HCPLive. August 15, 2025. Accessed December 15, 2025. https://www.hcplive.com/view/fda-approves-semaglutide-wegovy-injection-2-4-mg-for-noncirrhotic-mash