Liver and Bile
Hepatology. 2022;75(6):1420–8
Effect of diabetes medications and glycemic control on risk of hepatocellular cancer in patients with non-alcoholic fatty liver disease
Background and aims: In patients with non-alcoholic fatty liver disease (NAFLD), those with type 2 diabetes mellitus (DM) have a high risk of progression to hepatocellular carcinoma (HCC). However, the determinants of HCC risk in these patients remain unclear.
Approach and results: The authors assembled a retrospective cohort of patients with NAFLD and DM diagnosed at 130 facilities in the Veterans Administration between January 1, 2004, and December 31, 2008, and followed patients from the date of NAFLD diagnosis to HCC, death, or December 31, 2018. They 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). 85,963 patients with NAFLD and DM were identified. 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 (hazard ratio [HR] = 0.80; 95% confidence interval [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 1.6–1.7-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 non-alcoholic fatty liver disease (NAFLD) and diabetes mellitus, use of metformin was associated with a reduced risk of hepatocellular carcinoma (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.