Table 2.

Effects of antidiabetic drugs on the occurrence and development of HCC

Reference	Study characteristics	Diabetes diagnosis	Covariate adjustments considered	Main findings
[69]	Hospital-based case–control study: 224 HCC patients and 389 controls	Self-report	Age, sex, smoking, alcohol intake	More than doubled HCC risk in diabetics, with stronger excess risk in diabetic subjects who are also tobacco smokers. Metformin may decrease the risk of HCC, whereas insulin may increase the risk.
[70]	Hospital-based retrospective case–control study: 85,963 patients with NAFLD and DM, and 852 patients were diagnosed with HCC, mean follow-up 10.3 years	Self-report, medical records	Age, sex, cirrhosis, alcoholic liver damage, viral hepatitis, hereditary hemochromatosis, primary biliary cirrhosis, primary sclerosing cholangitis, α1 antitrypsin disease, or autoimmune hepatitis	In this large cohort of patients with NAFLD and DM, use of metformin was associated with a reduced risk of HCC, whereas use of combination therapy was associated with increased risk.
[71]	Retrospective multicenter study: among 5093 patients with HCC, 1917 (37.6%) were diagnosed with T2DM, of which 338 (17.6%) received treatment with metformin	Medical records	Geographic location, alcohol intake, history of cirrhosis, or HBV and HCV infections	Treatment with metformin was associated with improved survival in patients with T2DM and HCC.
[72]	Retrospective cohort study: 2499 elderly diabetic HCC patients	Medical records	Age, sex, and pre- and postdiagnosis medication use	Prediagnosis use of metformin ≤1500 mg/day may improve overall survival of elderly diabetic HCC patients.
[73]	Population-based case–control study: 76,349 newly diagnosed DM patients were identified from claims; among diabetics, 3026 and 12,104 patients, respectively, received or did not receive TZDs	Self-report, medical records	Age, sex, comorbidities of diabetes, HBV, HCV, cirrhosis, alcoholic liver disease, NAFLD, end-stage renal disease, hypertension, and hyperlipidemia	The use of TZDs may reduce the risk of developing HCC among DM patients.
[74]	Population-based cohort study: 19,349 newly diagnosed DM patients and 77,396 control subjects without DM, nean follow-up 5 years	Electronic register	Age, sex, cirrhosis, alcoholic liver damage, viral hepatitis	The use of metformin or thiazolidinediones may reduce the risk of developing HCC.
[75]	Retrospective case–control study: 47,738, participants of whom 241 were diagnosed with HCC	Hospital discharge diagnosis	Age, sex, area of residence, education, alcohol intake, BMI, smoking, history of chronic hepatitis and cirrhosis, family history of liver cancer	Compared to patients never treated with a sulfonylurea, those treated with a sulfonylurea had a 1.7-fold increased risk of HCC development.
[76]	Community-based cohort study: 363,426 participants, after excluding those with cancer at baseline, mean follow-up 8.5 years, 176 HCC cases identified	Self-report	Age, sex, center, education, smoking, alcohol intake, BMI, waist:height ratio	DM was independently associated with higher risk of incident HCC and biliary tract cancer. The risk of HCC was particularly higher in participants treated with insulin.
[77]	Population-based retrospective cohort study, 3185 HCC patients, mean follow-up 3.5 years	Self-report, medical records	Cirrhosis, HBV, HCV, and alcohol-related diseases	HCC patients with preexisting T2DM treated with SGLT2 inhibitors had significantly lower risk of mortality, especially among those treated >12 months.

Abbreviations: T2DM, type 2 diabetes mellitus; HCC, hepatocellular carcinoma; HBV, hepatitis B virus; HCV, hepatitis C virus.