GLP-1 drugs associated with modest but significant 31% increased risk of liver cancer in large veterans study | Research

The takeaway

In 200,496 propensity-matched veterans, GLP-1 drug use was associated with 31% higher hepatocellular carcinoma risk versus DPP4i (OR 1.31, p<0.001), primarily with use >6 months, though overall benefits likely outweigh this modest risk.

31% higher HCC risk signal
Large propensity-matched study finds GLP-1 drugs associated with modestly increased hepatocellular carcinoma risk—a safety signal warranting monitoring in the millions now taking these drugs

What the researchers found

GLP-1RA vs DPP4i: HCC OR 1.31 (1.11-1.56, p<0.001). >6 months use: increased risk. <6 months: OR 0.96 (NS). HCC: 302 (0.30%) GLP-1RA vs 230 (0.23%) DPP4i. 100,248 matched pairs. 133 PS variables.

Why it matters

This is the first large study finding a statistically significant HCC risk increase with GLP-1 drugs. While modest, it warrants monitoring given millions of users and expanding indications.

How the study worked

Retrospective PS-matched cohort from VHA (2006-2021). New-user active comparator design. 133-variable propensity score. 100,248 matched pairs. Secondary analysis by duration.

What this study cannot tell us

Veterans population (predominantly male, older). DPP4i comparator may itself affect HCC risk. 133 PS variables cannot fully control confounding. HCC is rare. Duration analysis suggests confounding by indication (sicker patients use longer).

How to read the evidence

Large PS-matched retrospective study with 133 variables. Strong methodology but cannot exclude residual confounding.

When this study was published

Published in 2025; VHA data 2006-2021.

The bigger picture

This HCC signal contrasts with the MASLD protection data showing GLP-1 drugs reduce liver disease. The paradox may reflect different effects on normal hepatocytes versus established liver pathology.

Questions still open

Does the HCC risk increase reflect GLP-1 effects or confounding by indication?
Should patients with liver disease be monitored more closely on GLP-1 drugs?
Does the MASLD protective effect reduce HCC long-term despite short-term risk signal?

Common questions

Can GLP-1 drugs cause liver cancer?

This large study found a modest 31% increase in hepatocellular carcinoma risk with GLP-1 drug use compared to DPP4 inhibitors. However, the absolute risk remains very low (0.30% vs 0.23% over the study period). The overall cardiovascular and metabolic benefits of GLP-1 drugs likely far outweigh this small risk for most patients.

Should I be worried about liver cancer on semaglutide?

The risk is very small and may reflect patients with pre-existing liver disease being more likely to use GLP-1 drugs long-term. Interestingly, GLP-1 drugs also protect against fatty liver disease, which itself is a risk factor for liver cancer. Discuss any liver concerns with your doctor, but this finding should not prevent most patients from benefiting from GLP-1 therapy.

Read the original research

Association of GLP1-Receptor Agonists with Risk of Hepatocellular Carcinoma: A Retrospective Cohort Study.

Drug safety, 48(10), 1089-1101

View on PubMed ↗Publisher’s paper ↗

Citation

Titus, Joane; Katukuri, Vinay; Boktor, Moheb; Mansi, Ishak A. (2025). Association of GLP1-Receptor Agonists with Risk of Hepatocellular Carcinoma: A Retrospective Cohort Study.. Drug safety, 48(10), 1089-1101. https://doi.org/10.1007/s40264-025-01558-1