The Impact of Diabetes and Glucose-Lowering Therapies on Hepatocellular Carcinoma Incidence and Overall Survival



      The incidence of hepatocellular carcinoma (HCC) in the United Kingdom has increased 60% in the past 10 years. The epidemics of obesity and type 2 diabetes are contributing factors. In this article, we examine the impact of diabetes and glucose-lowering treatments on HCC incidence and overall survival (OS).


      Data from 1064 patients diagnosed with chronic liver disease (CLD) (n = 340) or HCC (n = 724) were collected from 2007 to 2012. Patients with HCC were followed up prospectively. Univariate and multivariate logistic regression determined HCC risk factors. Kaplan-Meier curves were used to examine survival and Cox proportional hazards analysis estimated hazard ratios (HRs) for death according to use of glucose-lowering therapies.


      Diabetes prevalence was 39.6% and 10.6% within the HCC and CLD cohorts, respectively. The odds ratio for having HCC in patients with diabetes was 5.55 (P < 0.001). Univariate analysis found an increased association of HCC with age, sex, cirrhosis, hemochromatosis, alcohol abuse, diabetes, and Child's Pugh score. In multivariate analysis age, sex, cirrhosis, Child's Pugh score, diabetes status, and insulin use retained significance. Diabetes status did not significantly affect OS in HCC; however, in people with diabetes and HCC, metformin treatment was associated with improved OS (mean survival, 31 vs 24 months; P =0.016; HR for death = 0.75; P = 0.032).


      Diabetes is significantly associated with HCC in the United Kingdom. Metformin treatment is associated with improved OS after HCC diagnosis. Treatment of diabetes should be appropriately reviewed in high-risk populations, with specific consideration of the potential hepatoprotective effects of metformin in HCC.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Clinical Therapeutics
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Rao Kondapally Seshasai S.
        • et al.
        Diabetes Mellitus, Fasting Glucose, and Risk of Cause-Specific Death.
        N Engl J Med. 2011; 364: 829-841
        • Allen A.M.
        • Hicks S.B.
        • Mara K.C.
        • Larson J.J.
        • Therneau T.M.
        The risk of incident extrahepatic cancers is higher in non-alcoholic fatty liver disease than obesity – a longitudinal cohort study.
        J Hepatol. 2019; 71: 1229-1236
        • Wang M.
        • Yang Y.
        • Liao Z.
        Diabetes and cancer: Epidemiological and biological links.
        World J Diabetes. 2020; 11: 227-238
      1. Cancer Research UK Statistics (2015-2017).

        • Rousseau M.C.
        • Parent M.É.
        • Pollak M.N.
        • Siemiatycki J.
        Diabetes mellitus and cancer risk in a population-based case-control study among men from Montreal, Canada.
        Int J Cancer. 2006; 118: 2105-2109
        • Wang P.
        • Kang D.
        • Cao W.
        • Wang Y.
        • Liu Z.
        Diabetes mellitus and risk of hepatocellular carcinoma: a systematic review and meta-analysis.
        Diabetes/Metabolism Res Rev. 2012; 28: 109-122
        • Miele L.
        • et al.
        Diabetes and insulin therapy, but not metformin, are related to hepatocellular cancer risk.
        Gastroenterol Res Pract. 2015;
        • Mittal S.
        • et al.
        Hepatocellular carcinoma in the absence of cirrhosis in United States veterans is associated with nonalcoholic fatty liver disease.
        Clin Gastroenterol Hepatol. 2016; 14 (e1): 124-131
        • Younossi Z.M.
        • et al.
        Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes.
        Hepatology. 2016; 64: 73-84
        • Dyal H.K.
        • et al.
        Diabetes mellitus increases risk of hepatocellular carcinoma in chronic hepatitis C virus patients: a systematic review.
        Digest Dis Sci. 2016; 61: 636-645
        • Alexander M.
        • et al.
        Risks and clinical predictors of cirrhosis and hepatocellular carcinoma diagnoses in adults with diagnosed NAFLD: real-world study of 18 million patients in four European cohorts.
        BMC Med. 2019; 17: 95
        • Wang Y.G.
        • et al.
        Diabetes mellitus and poorer prognosis in hepatocellular carcinoma: a systematic review and meta-analysis.
        PLoS One. 2014; 9
        • Zhou Y.-Y.
        • et al.
        Systematic review with network meta-analysis: antidiabetic medication and risk of hepatocellular carcinoma.
        Sci Rep. 2016; 19: 33743
        • Zhang Z.J.
        • et al.
        Metformin for liver cancer prevention in patients with type 2 diabetes: a systematic review and meta-analysis.
        J Clin Endocrinol Metab. 2012; 97: 2347-2353
        • Huang M.-Y.
        • et al.
        The role of thiazolidinediones in hepatocellular carcinoma risk reduction: a population-based cohort study in Taiwan.
        Am J Cancer Res. 2017; 7: 1606-1616
        • Chang C.H.
        • et al.
        Association of thiazolidinediones with liver cancer and colorectal cancer in type 2 diabetes mellitus.
        Hepatology. 2012; 55: 1462-1472
        • He H.
        • et al.
        Metformin, an old drug, brings a new era to cancer therapy.
        Cancer J. 2015; 21: 70-74
        • Davila J.A.
        • Morgan R.O.
        • Shaib Y.
        • McGlynn K.A.
        • El-Serag H.B.
        Diabetes increases the risk of hepatocellular carcinoma in the United States: a population based case control study.
        Gut. 2005; 54: 533-539
        • Koh W.P.
        • Wang R.
        • Jin A.
        • Yu M.C.
        • Yuan J.M.
        Diabetes mellitus and risk of hepatocellular carcinoma: Findings from the Singapore Chinese Health Study.
        Br. J. Cancer. 2013; 108: 1182-1188
        • Evans J.M.M.
        • Donnelly L.A.
        • Emslie-Smith A.M.
        • Alessi D.R.
        • Morris A.D.
        Metformin and reduced risk of cancer in diabetic patients.
        BMJ. 2005; 330: 1304-1305
        • Singh S.
        • Singh P.P.
        • Singh A.G.
        • Murad M.H.
        • Sanchez W.
        Anti-diabetic medications and the risk of hepatocellular cancer: a systematic review and meta-analysis.
        Am J Gastroenterol. 2013; 108: 881-891
        • Chen H.P.
        • et al.
        Metformin decreases hepatocellular carcinoma risk in a dose-dependent manner: population-based and in vitro studies.
        Gut. 2013; 62: 606-615
        • Thakkar B.
        • Aronis K.N.
        • Vamvini M.T.
        • Shields K.
        • Mantzoros C.S.
        Metformin and sulfonylureas in relation to cancer risk in type ii diabetes patients: a meta-analysis using primary data of published studies.
        Metab Clin Exp. 2013; 62: 922-934
        • Tsilidis K.K.
        • et al.
        Metformin does not affect cancer risk: A cohort study in the U.K. clinical practice research datalink analyzed like an intention-to-treat trial.
        Diabetes Care. 2014; 37: 2522-2532
        • Home P.D.
        • et al.
        Experience of malignancies with oral glucose-lowering drugs in the randomised controlled ADOPT (A Diabetes Outcome Progression Trial) and RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycaemia in Diabetes) clinical trials.
        Diabetologia. 2010; 53: 1838-1845
        • Schulte L.
        • et al.
        Treatment with metformin is associated with a prolonged survival in patients with hepatocellular carcinoma.
        Liver Int. 2019; 39: 714-726
        • Yin M.
        • Zhou J.
        • Gorak E.J.
        • Quddus F.
        Metformin is associated with survival benefit in cancer patients with concurrent type 2 diabetes: a systematic review and meta-analysis.
        Oncologist. 2013; 18: 1248-1255
        • Zhou J.
        • et al.
        Meta-analysis: the efficacy of metformin and other anti-hyperglycemic agents in prolonging the survival of hepatocellular carcinoma patients with type 2 diabetes.
        Ann Hepatol. 2020; 19: 320-328
        • Chang C.H.
        • Lin J.W.
        • Wu L.C.
        • Lai M.S.
        • Chuang L.M.
        Oral insulin secretagogues, insulin, and cancer risk in type 2 diabetes mellitus.
        J Clin Endocrinol. Metab. 2012; 97: E1170-E1175
        • Li C.I.
        • et al.
        Hyperglycemia and chronic liver diseases on risk of hepatocellular carcinoma in Chinese patients with type 2 diabetes - national cohort of Taiwan Diabetes Study.
        Int J Cancer. 2015; 136: 2668-2679
        • Bailey C.J.
        Metformin: historical overview.
        Diabetologia. 2017; 60: 1566-1576
        • Davies M.J.
        • et al.
        Management of hyperglycemia in type 2 diabetes, 2018.: a consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
        Diabetes Care. 2018; 41: 2669-2701
        • Saraei P.
        • Asadi I.
        • Kakar M.A.
        • Moradi-Kor N.
        The beneficial effects of metformin on cancer prevention and therapy: a comprehensive review of recent advances.
        Cancer Manag Res. 2019; 11: 3295-3313
        • Cheng J.
        • et al.
        AMP-activated protein kinase suppresses the in vitro and in vivo proliferation of hepatocellular carcinoma.
        PLoS One. 2014; 9: 93256
        • Lee C.W.
        • et al.
        AMPK promotes p53 acetylation via phosphorylation and inactivation of SIRT1 in liver cancer cells.
        Cancer Res. 2012; 72: 4394-4404
        • White D.L.
        • Ratziu V.
        • El-Serag H.B.
        Hepatitis C infection and risk of diabetes: a systematic review and meta-analysis.
        J Hepatol. 2008; 49: 831-844
        • Williams R.
        Liver disease in the UK: Startling findings & urgent need for action.
        J. Hepatol. 2015; 63: 297-299
        • Estes C.
        • Razavi H.
        • Loomba R.
        • Younossi Z.
        • Sanyal A.J.
        Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease.
        Hepatology. 2018; 67: 123-133
        • Smittenaar C.R.
        • Petersen K.A.
        • Stewart K.
        • Moitt N.
        Cancer incidence and mortality projections in the UK until 2035.
        Br J Cancer. 2016; 115: 1147-1155
        • Zoppini G.
        • et al.
        Mortality from chronic liver diseases in diabetes.
        Am J Gastroenterol. 2014; 109: 1020-1025
        • Pang Y.
        • et al.
        Diabetes, plasma glucose, and incidence of fatty liver, cirrhosis, and liver cancer: a prospective study of 0.5 million people.
        Hepatology. 2018; 68: 1308-1318
        • Campbell P.T.
        • Newton C.C.
        • Patel A.V.
        • Jacobs E.J.
        • Gapstur S.M.
        Diabetes and cause-specific mortality in a prospective cohort of one million U.S. adults.
        Diabetes Care. 2012; 35: 1835-1844
        • Schlesinger S.
        • 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: 2449-2455
        • Glyn-Owen K.
        • Böhning D.
        • Parkes J.
        • Roderick P.
        • Buchanan R.
        The combined effect of alcohol and body mass index on risk of chronic liver disease: a systematic review and meta-analysis of cohort studies.
        Liver Int. 2020;
        • Wild S.
        • et al.
        Type 2 diabetes and risk of hospital admission or deathfor chronic liver diseases.
        J Hepatol. 2016; 64: 1358-1364
      2. National Institute for Health and Care Excellence. Non-alcoholic fatty liver disease (NAFLD): assessment and management. (2016).

        • European Association for the Study of the Liver (EASL)
        European Association for the Study of Diabetes (EASD) & European Association for the Study of Obesity (EASO). EASL–EASD–EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease.
        J Hepatol. 2016; 64: 1388-1402
        • Chalasani N.
        • et al.
        The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.
        Hepatology. 2018; 67: 328-357
        • Association A.D.
        Comprehensive medical evaluation and assessment of comorbidities: standards of Medical Care in Diabetes-2020.
        Diabetes Care. 2020; 43: S37-S47