The Role of Type 2 Diabetes Mellitus–Related Risk Factors and Drugs in Hepatocellular Carcinoma

Figures & data

Table 1 Clinical trials on the relationship between diabetes mellitus and HCC

Reference	Study characteristics	Diabetes diagnosis	Covariate adjustments considered	Main findings
[5]	Meta-analysis: a total of 27 studies (23 articles, 85.2% were from Asia), inclusive of approximately 144,566 individuals	Self-report, medical records	Geographic location, alcohol intake, history of cirrhosis, or HBV and HCV infections	Strong evidence that T2DM unfavorably affects HCC progression, recurrence, and patient survival after treatment, irrespective of the approach used.
[6]	Prospective cohort study: 239 patients with T2DM who were diagnosed with nonviral HCC, and 3277 non-HCC T2DM patients from a prospective cohort study as controls. Mean follow-up 4.7 years	Medical records	Vital status, age, HBV, HCV	T2DM was associated with increased risk of incident HCC. FIB4 index in diabetes clinics can be the first step toward surveillance of HCC with a nonviral etiology.
[7]	Hospital-based retrospective case–control study: 1568 participants, of whom 716 were diagnosed with benign liver diseases and 852 diagnosed with HCC.	Fasting glucose ≥126 mg/dL or 2- hour postload glucose ≥200 mg/dL, HbA1c ≥6.5%	Age, sex, HBV and HCV infections, cirrhosis, gallstone disease, cholinesterase, alkaline phosphatase	DM patients with HBV infection represent a very high HCC risk population and should be considered for HCC close surveillance program.
[12]	Meta-analysis: 17 case–control studies (a total of nearly 6000 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	DM is associated with moderately increased risk of HCC. Meta-analysis of 7 cohort studies found a significant increased risk of HCC mortality for individuals with DM compared to those without.
[13]	Meta-analysis: a total of 25 cohort studies, enrolling 1,283,112 persons. Mean follow-up 8.8 years	Self-report, medical records	BMI, prior hepatitis, cirrhosis, alcohol intake, smoking, treatment, duration of diabetes	18 studies showed that DM was associated with an increased incidence of HCC. In addition, meta-analysis of 7 cohort studies found a significant increased risk of HCC mortality for individuals with DM.
[14]	Community-based cohort study: 63,257 middle-aged and older individuals. Prevalence of DM was 8.6%, 499 cohort participants developed HCC. Mean follow-up 14 years	Self-report	Age, sex, BMI, recruitment year, education level, smoking, alcohol intake, consumption of coffee and tea	A history of diabetes at baseline is highly associated with nonviral HCC. DM was associated with an increased risk of incident nonviral HCC.
[17]	Hospital-based case–control study: 224 HCC patients and 389 controls	Self-report	Age, sex, smoking, alcohol intake	This study confirms a doubled HCC risk in diabetics, with a stronger excess risk in diabetic subjects who are also tobacco smokers. Metformin may decrease the risk of HCC, whereas insulin may increase the risk.

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

Figure 1 Risk factors for HCC in patients with T2DM.

Figure 2 T2DM and obesity aggravate the progression of NAFL/NASHI to HCC. T2DM coexists with NAFLD, and it aggravates NAFLD to more severe forms of NASH, cirrhosis, and HCC.

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.

Figure 3 Effects of antidiabetic drugs on the occurrence and development of HCC.

Mrzljak A, Cigrovski Berković M, Giovanardi F, Lai Q. The prognostic role of diabetes mellitus type 2 in the setting of hepatocellular carcinoma: a systematic review and meta-analysis. Croat Med J. 2022;63(2):176–186. doi:10.3325/cmj.2022.63.176

 PubMed Web of Science ®Google Scholar

Tateishi R, Matsumura T, Okanoue T, et al. Hepatocellular carcinoma development in diabetic patients: a nationwide survey in Japan. J Gastroenterol. 2021;56(3):261–273. doi:10.1007/s00535-020-01754-z

 PubMed Web of Science ®Google Scholar

Zheng Z, Zhang C, Yan J, et al. Diabetes mellitus is associated with hepatocellular carcinoma: a retrospective case-control study in hepatitis endemic area. PLoS One. 2013;8(12):e84776. doi:10.1371/journal.pone.0084776

 PubMed Web of Science ®Google Scholar

Wang C, Wang X, Gong G, et al. Increased risk of hepatocellular carcinoma in patients with diabetes mellitus: a systematic review and meta-analysis of cohort studies. Int, J, Cancer. 2012;130(7):1639–1648. doi:10.1002/ijc.26165

 PubMed Web of Science ®Google Scholar

Wang P, Kang D, Cao W, Wang Y, Liu Z. Diabetes mellitus and risk of hepatocellular carcinoma: a systematic review and meta-analysis. Diabetes Metab Res Rev. 2012;28(2):109–122. doi:10.1002/dmrr.1291

 PubMed Web of Science ®Google Scholar

Koh WP, Wang R, Jin A, Yu MC, Yuan JM. Diabetes mellitus and risk of hepatocellular carcinoma: findings from the Singapore Chinese Health Study. Br J Cancer. 2013;108(5):1182–1188. doi:10.1038/bjc.2013.25

 PubMed Web of Science ®Google Scholar

Pfister D, Núñez NG, Pinyol R, et al. NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature. 2021;592:7854):450–456. doi:10.1038/s41586-021-03362-0

 Web of Science ®Google Scholar

Kramer JR, Natarajan Y, Dai J, et al. Effect of diabetes medications and glycemic control on risk of hepatocellular cancer in patients with nonalcoholic fatty liver disease. Hepatology. 2022;75(6):1420–1428. doi:10.1002/hep.32244

 PubMed Web of Science ®Google Scholar

Tangjarusritaratorn T, Tangjittipokin W, Kunavisarut T. Incidence and survival of hepatocellular carcinoma in type 2 diabetes patients with cirrhosis who were treated with and without metformin. Diabetes Metab Syndr Obes. 2021;14:1563–1574. doi:10.2147/DMSO.S295753

 PubMed Web of Science ®Google Scholar

Schulte L, Scheiner B, Voigtländer T, et al. Treatment with metformin is associated with a prolonged survival in patients with hepatocellular carcinoma. Liver Int. 2019;39(4):714–726. doi:10.1111/liv.14048

 PubMed Web of Science ®Google Scholar

Antwi SO, Li Z, Mody K, Roberts LR, Patel T. Independent and joint use of statins and metformin by elderly patients with diabetes and overall survival following HCC diagnosis. J Clin Gastroenterol. 2020;54(5):468–476. doi:10.1097/MCG.0000000000001182

 PubMed Web of Science ®Google Scholar

Huang M-Y, Chung C-H, Chang W-K, et al. The role of thiazolidinediones in hepatocellular carcinoma risk reduction: a population-based cohort study in Taiwan. Am J Cancer Res. 2017;7(7):1606–1616.

 PubMed Web of Science ®Google Scholar

Lai S-W, Chen P-C, Liao K-F, Muo C-H, Lin -C-C, Sung F-C. Risk of hepatocellular carcinoma in diabetic patients and risk reduction associated with anti-diabetic therapy: a population-based cohort study. Am J Gastroenterol. 2012;107(1):46–52. doi:10.1038/ajg.2011.384

 PubMed Web of Science ®Google Scholar

Lee J-Y, Jang S-Y, Nam CM, Kang ES. Incident hepatocellular carcinoma risk in patients treated with a sulfonylurea: a nationwide, nested, case-control study. Sci Rep. 2019;9(1):8532. doi:10.1038/s41598-019-44447-1

 PubMedGoogle Scholar

Schlesinger S, Aleksandrova K, Pischon T, et al. Diabetes mellitus, insulin treatment, diabetes duration, and risk of biliary tract cancer and hepatocellular carcinoma in a European cohort. Ann Oncol. 2013;24(9):2449–2455. doi:10.1093/annonc/mdt204

 PubMed Web of Science ®Google Scholar

Nakano D, Kawaguchi T, Iwamoto H, Hayakawa M, Koga H, Torimura T. Effects of canagliflozin on growth and metabolic reprograming in hepatocellular carcinoma cells: multi-omics analysis of metabolomics and absolute quantification proteomics (iMPAQT). PLoS One. 2020;15(4):e0232283. doi:10.1371/journal.pone.0232283

 PubMed Web of Science ®Google Scholar