Second-line antidiabetic drugs: friend or foe of the liver

Diabetes mellitus is a cardiometabolic risk factor associated with the development of various comorbidities and malignancies. It has a bidirectional relationship with chronic liver disease, promoting hepatic inflammation and fibrosis, which can ultimately progress to advanced liver diseases such as cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC). Therefore, the importance of antidiabetic treatment has been increasingly emphasized as a strategy for preventing liver-related diseases in diabetic patients. Metformin, a first-line antidiabetic agent, has been shown to be effective in improving hepatic steatosis and preventing progression to advanced liver disease. Recently updated international guidelines recommend the use of metformin as a chemopreventive agent for HCC in diabetic patients, albeit with a weak recommendation. Meanwhile, as metformin alone is often insufficient for blood glucose control and concurrent metabolic comorbidities are increasingly prevalent, new second-line antidiabetic agents have been developed: glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter-2 inhibitors, and dipeptidyl peptidase-4 inhibitors. These novel antidiabetic agents have demonstrated cardiovascular benefits, and protective effects on liver-related outcomes and mortality in previous studies. However, due to the limited number of studies and the variability in study populations, their effects remain inconsistent across different studies. Furthermore, there are no established therapeutic guidelines for diabetic patients with liver disease. Therefore, this review aims to examine the association between the use of novel second-line antidiabetic agents and the risk of liver-related outcomes and mortality in this population.