Metformin and reduced risk of hepatocellular carcinoma in diabetic patients with chronic liver disease

Background: Previous studies have reported the association between type 2 diabetes mellitus (DM2) and hepatocellular carcinoma (HCC). Aims: To explore the relationships among DM2, antidiabetic therapy and HCC risk. Methods: We recruited 610 HCC patients compared with 618 matched cirrhotic patients and 1696 Controls. The odds ratio (OR) for HCC in diabetic subjects treated with insulin, sulphonylureas and metformin was calculated. Results: DM2 prevalence was 31.2% in HCC, 23.3% in cirrhotic patients and 12.7% in Controls (P<0.0001). The OR for HCC in diabetic HCC patients vs Controls was 3.12 [confidence interval (CI) 2.40-3.90; P<0.001] in univariate analysis and 2.50 (CI 1.70-3.69; P<0.0001) in multivariate analysis. Comparing diabetic HCC patients vs liver cirrhosis (LC) cases, univariate analysis showed an OR for HCC of 2.09 (CI 1.50-2.90; P<0.001), whereas on multivariate analysis we found an OR of 1.46 (CI 1.07-1.98; P=0.02). In 84% of the cases, type 2 diabetes mellitus has been present before the HCC diagnosis. Multivariate analysis showed that metformin treatment was associated with a strong and statistically significant reduction of the risk of HCC, as compared with the use of sulphonylureas or insulin, in diabetic HCC patients vs Controls and vs LC cases (OR of 0.15; CI 0.04-0.50; P=0.005 and OR=0.16; CI 0.06-0.46; P=0.0006 respectively). Conclusions: Our study shows that DM2 is an independent risk factor for HCC and pre-exists to HCC occurrence. In DM2 patients with HCC, metformin therapy is associated with a reduced HCC risk and seems to have a protective effect on HCC development.