Reply: Novel antidiabetic drugs and the risk for HCC. What else to expect from these "wonderful" drug classes?

We thank Dr. Patoulias for their interest in our review article that assessed the complex interplay between medications for diabetes and the risk of HCC.1,2 In his comments to our study, he raises an important issue related to a sort of positive “off-target activity” of novel drugs used in the management of type 2 diabetes, such as sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RAs). The recent evidence that the use of GLP-1Ras was associated with a dramatically reduced rate of any decompensating event, or of further decompensation, in previously decompensated patients with cirrhosis and type 2 diabetes as compared with other drugs such as sulfonylureas and dipeptidyl peptidase-4, but not compared with SGLT-2 inhibitors, clearly demonstrates that GLP-1Ras may have pleiotropic, positive effects in these patients who go beyond the protective effect on the development of HCC, whereas in the absence of a direct comparison, these effects cannot be definitely attributed also to SGLT-2 inhibitors.2,3 This evidence is particularly appealing as the positive effect exerted by GLP-1Ras seems to be independent of the presence of concurrent causes of liver disease (viral hepatitis and alcohol), and of concomitant medications acting on portal hypertension.3 Indeed, the use of antidiabetic drugs as disease-modifying agents may have several, downstream beneficial effects and, therefore, may act at various stages of the evolutive history of advanced chronic liver disease, not only in preventing the carcinogenetic process.2 As there are no approved drugs to treat NAFLD, a condition where diabetes prevalence is highest, selected antidiabetic medications may theoretically act at various levels—together with dietary counseling—in modifying the trajectory of liver disease progression (Figure 1), and may hypothetically be used as a tool to fine-tune surveillance strategies for HCC.4,5 Thus, we concur with the view expressed by Dr. Patoulias in his comment that the time is ripe to assess all the potential of these drugs in dedicated, prospective studies with solid outcomes in patients with chronic liver disease so as to evaluate whether they can be regarded as game-changers in the management of these patients.1FIGURE 1: Potential targets of antidiabetic drugs along the process leading to cirrhosis, liver decompensation, and HCC. Solid lines represent the positive effects of the drugs supported by the literature, dotted line indirect mechanisms of action, and dashed line potential effects that need to be explored. Abbreviation: SGLT-2, sodium-glucose cotransporter-2.