Table S1. Principal observational studies and meta-analyses that have explored the association between type 2 diabetes and risk of hepatocellular carcinoma (ordered by publication year).
| Study | Study characteristics | Diabetes diagnosis | Covariate adjustment considered | Main findings |
|---|---|---|---|---|
| Adami HO et al. Cancer Causes Control 1991;2:307-14 | Hospital-based cohort: 51,008 patients with DM. Mean follow-up: 9 years | Hospital discharge diagnosis | None | DM was associated with increased risk of incident HCC |
| Adami HO et al. J Natl Cancer Inst 1996;88:1472-7 | Hospital-based cohort: 153,852 patients with DM. Follow-up: from 1 to 24 years | Hospital discharge diagnosis | None | DM was associated with increased risk of incident HCC |
| La Vecchia et al. Int J Cancer 1997;73:204-7 | Case-control study: 428 HCC cases, 59 with gallbladder and bile duct cancers, and 1,502 control subjects from hospital | Self-reported | Age, sex, area of residence, education level, alcohol intake, BMI, smoking, history of chronic hepatitis and cirrhosis, family history of liver cancer | DM was associated with increased risk of incident HCC |
| Huo TI et al. Eur J Gastroenterol Hepatol 2003;15:1203-8 | Prospective study: 239 HCC patients (16.3% of whom had DM). Mean follow-up: 2.6 years | Fasting glucose ≥126 mg/dL or 2-hour post-load glucose ≥200 mg/dL, or past history | Age, sex, tumor size, anti-HCV-Ab positivity, HBeAg-positivity, cirrhosis, alcohol intake, alpha-fetoprotein, albumin, bilirubin | DM did not affect long-term survival in HCV-related HCC, but was a recurrence-independent prognostic factor for HBV-related HCC |
| Coughlin SS et al. Am J Epidemiol 2004;159:1160-7 | Population cohort study: 467,922 men and 588,321 women without history of cancer at baseline. Mean follow-up: 16 years | Self-reported | BMI | DM was associated with increased risk of incident HCC only in men |
| El-Serag HB et al. Gastroenterology 2004;126:460-8 | Prospective study: 73,643 patients with DM and 650,620 patients without DM. Mean follow-up: 5 years | Self-reported | Alcoholic liver disease, viral chronic hepatitis, demographic variables | DM was associated with an increased risk of incident HCC. DM carried the highest risk among patients with a follow-up longer than 10 years |
| Davilla JA et al. Gut 2005;54:533-9 | Population based case-control study: 2,061 HCC patients (of whom 43% with DM) and 6,183 non-cancer controls (of whom 19% with DM) | Electronic register | Age, sex, race, HCV, HBV, alcoholic liver disease, and hemochromatosis | DM was associated with a nearly three-fold increased risk of HCC |
| Inoue M et al. Arch Intern Med 2006;166:1871-7 | Prospective study: 97,771 Japanese adult individuals followed-up for cancer incidence over 5 years. At baseline, 4.7% of them had DM | Self-reported | Age, study area, BMI, prior cardiovascular disease, smoking, alcohol intake, leisure-time physical activity, green vegetable intake, coffee intake | DM was associated with increased risk of total cancer and cancer in specific sites, including HCC |
| El-Serag HB et al. Clin Gastroenterol Hepatol 2006;4:369-80 | Meta-analysis: a total of 26 studies (of whom 13 case-control studies and 13 cohort studies), inclusive of approximately 3 million of individuals | Self-reported | Alcohol intake, chronic viral hepatitis, diet, BMI | Among 13 cohort studies, DM was associated with an increased risk of HCC |
| Kawamura Y et al. J Gastroenterol Hepatol 2008;23:1739-46 | Prospective study: 40 consecutive HCC patients (with HCC associated with non-B, non-C hepatitis), and later underwent surgical resection or radiofrequency ablation. Prevalence of DM was 45%. Mean follow-up: 5 years | Fasting glucose ≥126 mg/dL or past history | Age, sex, dyslipidemia, smoking, alcohol intake, history of blood transfusion, state of liver disease (chronic hepatitis or cirrhosis), AST, albumin, bilirubin, alpha-fetoprotein, pro-thrombin time, tumor size, multiplicity, hyper-vascularity and portal vein invasion of HCC | DM was a significant predictor of tumor recurrence after potentially curative therapy for HCC |
| Donadon V et al. World J Gastroenterol 2009;15:2506-11 | Case-control study: 465 HCC patients, 618 with cirrhosis and 490 control subjects. The prevalence of DM was 31.2% in HCC, 23.3% in cirrhotic patients and 12.7% in control group | Self-reported | Age, sex, BMI, alcohol abuse, HBV and HCV | DM was an independent risk factor for HCC. Among male patients with DM, there was a positive association of HCC with insulin/sulphonylurea treatment and an inverse association with metformin |
| Hassan MM et al. Cancer 2010;116:1938-46 | Hospital-based case-control study: 420 patients with HCC and 1,104 healthy controls. The prevalence of DM was 33.3% in patients with HCC and 10.4% in controls | Self-reported | Age, sex, race, educational level, smoking, alcohol intake, HCV, HBV, family history of cancer | DM increased the risk of HCC. Treatments with sulfonylureas or insulin were associated with higher HCC risk, whereas treatments with metformin or glitazones were associated with lower HCC risk |
| Hense HW et al. Diabetol Metab Syndr 2011;3:15 | Community-based study: 26,742 DM patients, who were 40 to 79 years old, resided in the Muenster district. Mean follow-up: 3.3 years | Self-reported | Sex, diabetes duration, BMI, insulin treatment | Risk of any incident cancer in DM was increased, in particular for HCC. Insulin therapy was related to higher cancer risk, while metformin was not |
| Johnson et al. Diabetologia 2011;54:2263-71 | Population-based retrospective cohort study: 185,100 individuals with DM and 185,100 without DM, matched by sex and age. Mean follow-up: 10 years | Electronic register | Age, sex, socio-economic status, number of physician visits, year of diagnosis | DM was associated with increased risk of selected cancers, including HCC |
| Li Q et al. Int J Canc 2012;131:1197-202 | Hospital-based case-control study: 1,105 patients with HBV-related HCC and 5,170 patients with chronic HBV. The whole prevalence of DM was 6.7% | Fasting glucose ≥126 mg/dL or past history | Age, family history of HCC, city of residence, HBV-Ag and cirrhosis | DM was associated with increased risk of HCC, only in women |
| Wang C et al. Int J Cancer 2012;130:1639-48 | Meta-analysis: a total of 25 cohort studies, enrolling 1,283,112 persons. Mean follow-up: 8.8 years | Self-report, medical records | Geographic location, alcohol intake, history of cirrhosis, or HBV and HCV infections | DM was associated with increased risk of incident HCC and higher HCC mortality. Longer diabetes duration and use of sulphonylureas or insulin were associated with increased risk of HCC. Metformin treatment was protective |
| Wang P et al. Diabetes Metab Res Rev 2012;28:109-22 | Meta-analysis: 17 case-control studies (a total of nearly 6,000 HCC cases and 74,000 controls) and 32 cohort studies (a total of nearly 6,500,000 individuals) | Self-report, medical records | BMI, prior hepatitis, cirrhosis, alcohol intake, smoking, treatment, duration of diabetes | The combined risk estimate of all studies showed a significant increased risk of HCC among DM individuals. In addition, meta-analysis of 7 cohort studies found a significant increased risk of HCC mortality for individuals with DM compared to those without |
| Lai SW et al. Am J Gastroenterol 2012;107:46-52 | Population-based cohort study: 19,349 newly diagnosed DM patients and 77,396 control subjects without DM. Mean follow-up: 5 years | Electronic register | Age, sex, cirrhosis, alcoholic liver damage, viral hepatitis | DM was associated with increased risk of incident HCC. Use of metformin or glitazones was associated with reduced HCC risk |
| Schlesinger S et al. Ann Oncol 2013;24:2449-55 | Community-based cohort study: 363,426 participants, after excluding those with cancer at baseline. Mean follow-up: 8.5 years | Self-reported | Age, sex, center, education level, smoking, alcohol intake, BMI, waist-to-height ratio | DM was independently associated with higher risk of incident HCC and biliary tract cancer. HCC risk was higher in those treated with insulin. Results were similar in HCV/HBV-negative individuals |
| Zheng Z et al. PLoS One 2013;8:e84776 | Hospital-based retrospective case-control study: 1,568 participants of whom 716 patients were diagnosed with benign liver diseases, and 852 patients were diagnosed with HCC. The prevalence of DM was 7.6% | Fasting glucose ≥126 mg/dL or 2-hour post-load glucose ≥200 mg/dL, HbA1c≥6.5% | Age, sex, HBV and HCV infections, cirrhosis, gallstone disease, cholinesterase, alkaline phosphatase | DM was associated with increased risk of HCC. However, there was significant interaction between DM and HBV on HCC occurrence |
| Koh WP et al. Br J Cancer 2013;108:1182-8 | Community-based cohort study: 63,257 middle-aged and older individuals. The prevalence of DM was 8.6%. Mean follow-up: 14 years | Self-reported | Age, sex, BMI, recruitment year, education level, smoking, alcohol intake, consumption of coffee and tea | DM was associated with an increased risk of incident non-viral HCC |
| Miele L et al. Gastroenterol Res Pract 2015;2015:570356 | Hospital-based case-control study: 224 HCC patients and 389 controls. The prevalence of DM was 19.7% | Self-reported | Age, sex, smoking, alcohol intake | DM was associated with increased risk of HCC. Treatment with any glucose-lowering drugs was not associated with increased HCC risk |
| Dyal HK et al. Dig Dis Sci 2016;61:636-45 | Meta-analysis: 9 studies (7 cohorts and 2 case-controls) with a total of nearly 10,000 adults with chronic HCV. The prevalence of DM was 8% | Self-reported | Age, sex, BMI, hypertension, smoking, alcohol intake, liver enzymes, albumin, lipids, platelet count, cirrhosis, HCV treatment, HCV genotype, hepatic steatosis | DM was associated with increased risk of HCC |
ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; DM, diabetes mellitus; GGT, gamma-glutamyltransferase; HBV, hepatitis B virus; HCV, hepatitis C virus; HCC, hepatocellular carcinoma.