Glucose Variability and Risk of Hepatocellular Carcinoma in Patients with Diabetes: A Nationwide Population-Based Study.

Background: Although diabetes is a well-known risk factor for hepatocellular carcinoma, exactly which metabolic parameters of diabetes are associated with hepatocellular carcinoma remain unexplored. In this study, we investigated the relationship between glucose variability (GV) and hepatocellular carcinoma in patients with diabetes through a nationwide population-based study. Methods: A population-based cohort study including 674,178 diabetic subjects participating in more than three health examinations within 5 years from the index year (2009 and 2010) were followed until the end of 2017. The coefficient of variation, SD, variability independent of the mean, and average real variability were calculated as GV indices. Results: During a median follow-up of 6.7 years, there were 5,494 cases of hepatocellular carcinoma. When groups were classified according to glucose level, the highest risk for hepatocellular carcinoma was observed when the basal blood glucose level was 180 mg/dL or greater [adjusted HR (aHR), 1.19; 95% confidence interval (CI), 1.08–1.31]. We observed increasing trends for the relationship between GV and hepatocellular carcinoma in multivariable Cox proportional analyses. The risk of hepatocellular carcinoma increased by 27% (aHR, 1.27; 95% CI, 1.17–1.38) for the highest quartile of GV relative to the lowest quartile. These findings were consistent regardless of the presence of chronic viral hepatitis or cirrhosis, alcohol consumption, or body mass index. Conclusions: GV was an independent predictor of hepatocellular carcinoma, even after adjusting for confounding factors. There was a linear relationship between increase in GV and prevalence of hepatocellular carcinoma. Impact: Visit-to-visit GV might be helpful for identifying patients with diabetes at high risk of hepatocellular carcinoma.