Metformin use and the risk of liver cancer in a Swedish population-based cohort study

BACKGROUND: It is uncertain whether medication with metformin decreases the risk of liver cancer. This study aimed to test the hypotheses that use of metformin decreases the risk of developing both main subtypes of liver cancer, that is, hepatocellular carcinoma and intrahepatic cholangiocarcinoma. METHODS: This nationwide population-based cohort study included all individuals who had dispensed anti-diabetic medications between 2005 and 2018 in Sweden, except for those with a history of viral hepatitis. We assessed the associations between metformin use and the risk of hepatocellular carcinoma and intrahepatic cholangiocarcinoma by using Cox regression, adjusted for age, sex, calendar year, smoking-related diagnoses, alcohol-related diagnoses, non-alcoholic fatty liver disease, use of non-steroidal anti-inflammatory drugs, and use of statins. RESULTS: Among 744 173 participants, 526 859 (70.8%) were metformin users. During the follow-up of a median of 6.8 (maximum 13.5) years, 1622 participants developed hepatocellular carcinoma and 319 developed intrahepatic cholangiocarcinoma. Metformin use was associated with a slightly increased risk of hepatocellular carcinoma (hazard ratio [HR] = 1.15, 95% confidence interval [CI] = 1.02 to 1.30), but a decreased risk in participants with a prior diagnosis of obesity (HR = 0.56, 95% CI = 0.34 to 0.90). No statistically significant association was observed for intrahepatic cholangiocarcinoma (HR = 0.77, 95% CI = 0.59 to 1.01). CONCLUSION: This study found an increased risk of hepatocellular carcinoma associated with metformin use overall, while suggesting a decreased risk in individuals with obesity. No clear association was observed for intrahepatic cholangiocarcinoma.