Hepatocellular carcinoma (HCC) associated mortality is increasing at an alarming rate and there is a readily identifiable cohort of at risk patients with cirrhosis, viral hepatitis, non-alcoholic fatty liver disease, and diabetes. These patients are candidates for chemoprevention. Metformin is an attractive agent for chemoprevention since it is inexpensive, has a favorable safety profile and is well tolerated over long time periods.
We studied the efficacy of metformin as a prevention agent in a clinically relevant rat model of HCC, where tumors develop in the setting of chronic inflammation and cirrhosis. We used repeated injections of diethylnitrosamine to induce sequential cirrhosis and HCC and administered metformin either at the first signs of fibrosis or cirrhosis.
Prolonged metformin exposure was safe and associated with decreases in fibrotic and inflammatory markers especially when administered early at the first signs of fibrosis. In addition, early metformin treatment led to a 44% decrease in HCC incidence, while tumor burden was unchanged when metformin was administered at the first signs of cirrhosis. Interestingly, activation of the hepatic progenitor/stem cell compartment was first observed at the onset of cirrhosis and therefore only early metformin treatment suppressed receptor for advanced glycation end products and inhibited the activation of hepatic progenitor cells.