Effect of diabetes medications and glycemic control on risk of hepatocellular cancer in patients with nonalcoholic fatty liver disease

Hepatology. 2022 Jun;75(6):1420-1428. doi: 10.1002/hep.32244. Epub 2021 Dec 19.


Background and aims: In patients with NAFLD, those with type 2 diabetes mellitus (DM) have a high risk of progression to HCC. However, the determinants of HCC risk in these patients remain unclear.

Approach and results: We assembled a retrospective cohort of patients with NAFLD and DM diagnosed at 130 facilities in the Veterans Administration between 1/1/2004 and 12/31/2008. We followed patients from the date of NAFLD diagnosis to HCC, death, or 12/31/2018. We used landmark Cox proportional hazards models to determine the effects of anti-DM medications (metformin, insulin, sulfonylureas) and glycemic control (percent of follow-up time with hemoglobin A1c < 7%) on the risk of HCC while adjusting for demographics and other metabolic traits (hypertension, obesity, dyslipidemia). We identified 85,963 patients with NAFLD and DM. In total, 524 patients developed HCC during a mean of 10.3 years of follow-up. Most common treatments were metformin monotherapy (19.7%), metformin-sulfonylureas (19.6%), insulin (9.3%), and sulfonylureas monotherapy (13.6%). Compared with no medication, metformin was associated with 20% lower risk of HCC (HR, 0.80; 95% CI, 0.93-0.98). Insulin had no effect on HCC risk (HR, 1.02; 95% CI, 0.85-1.22; p = 0.85). Insulin in combination with other oral medications was associated with a 1.6 to 1.7-fold higher risk of HCC. Adequate glycemic control was associated with a 31% lower risk of HCC (HR, 0.69; 95% CI, 0.62-0.78).

Conclusions: In this large cohort of patients with NAFLD and DM, use of metformin was associated with a reduced risk of HCC, whereas use of combination therapy was associated with increased risk. Glycemic control can serve as a biomarker for HCC risk stratification in patients with NAFLD and diabetes.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural

MeSH terms

  • Carcinoma, Hepatocellular* / epidemiology
  • Carcinoma, Hepatocellular* / etiology
  • Carcinoma, Hepatocellular* / prevention & control
  • Diabetes Mellitus, Type 2* / complications
  • Diabetes Mellitus, Type 2* / drug therapy
  • Glycemic Control
  • Humans
  • Insulin
  • Liver Neoplasms* / epidemiology
  • Liver Neoplasms* / etiology
  • Liver Neoplasms* / prevention & control
  • Metformin* / therapeutic use
  • Non-alcoholic Fatty Liver Disease* / chemically induced
  • Non-alcoholic Fatty Liver Disease* / complications
  • Non-alcoholic Fatty Liver Disease* / drug therapy
  • Retrospective Studies
  • Risk Factors


  • Insulin
  • Metformin