Letter to the editor: Effect of diabetes medications and glycemic control on risk of HCC in patients with NAFLD

To the editor, We have recently studied the article “Effect of Diabetes Medications and Glycemic Control on Risk of Hepatocellular Cancer in Patients with Nonalcoholic Fatty Liver Disease” published in hepatology by Kramer et al.[1] This article is a large retrospective cohort study of more than 85,000 patients with both Type 2 diabetes and NAFLD, which describes the effect of diabetes medication use and glycemic control on the development of HCC and finds that metformin alone reduces the incidence of HCC by 50%, while the combination increases it, providing strong data to support a reduction in HCC incidence. However, there are several issues to be aware of in this study. First, there were some issues with the selection of the study population. Patients with NAFLD were selected to exclude HBV simply because of the absence of HBsAg positivity. The persistence and detection of serum or liver HBV DNA in the absence of serum HBsAg are defined as occult HBV infection (OBI).[2] The status of occult infection is mainly associated with suppression of viral replication and gene expression; however, it is also seen in patients with mutant HBV whose HBsAg is undetectable. In one prospective study, multifactorial analysis confirmed that OBI is an independent risk factor for hepatocarcinogenesis in patients with cryptogenic cirrhosis.[3] This suggests the possible presence of patients with HBV among the patients with NAFLD selected for this study, which has an impact on the accuracy of the final conclusions drawn. In addition, patients with NAFLD and diabetes were selected for the study with varying degrees of severity of disease. They should be further grouped for different degrees of metabolic syndrome, using propensity score matching. If a patient has a more severe metabolic syndrome, their metabolic indications are difficult to control, and they develop HCC after the combination of drugs, it is not certain whether it is due to drug factors or their own disease. Or if the patients treated with metformin have mild disease, whether it is the anticancer properties of metformin or the mild metabolic syndrome that does not lead to HCC, we can use metformin alone and in combination for the same group of patients after group scoring and then analyze their effect on the incidence of HCC. Finally, the results of the current study are more applicable to Europeans, with study data from the US Department of Veterans Affairs (VA) Corporate Data Warehouse and the VA Central Cancer Registry.[1] In contrast, Asian or other populations from different continents may show different results depending on factors such as geography, dietary structure, and religious beliefs.[4] Therefore, we propose that multicenter studies should be conducted to refine the effect of diabetes medications and glycemic control as well as other metabolically related factors on the development of HCC in patients with NAFLD and diabetes in cohorts of different ethnic groups. Thus, the conclusion that metformin use is associated with a reduced risk of HCC while combination therapy use is associated with an increased risk needs further validation. FUNDING INFORMATION Supported by the Wang Bao 'en Liver Fibrosis Research Fund of the China Hepatitis Prevention and Control Foundation (WEB2021038) CONFLICT OF INTEREST Nothing to report. AUTHOR CONTRIBUTIONS Writing: Yibing Zhou. Writing and critical revision: Weike Chu, Xue Wu, Hui Zhou, Bin Niu, Ze Chen. Critical revision: Yuqiang Mi and Ping Li.