A population-based study of epilepsy incidence in association with type 2 diabetes and severe hypoglycaemia

  • Chin-Li Lu
    Graduate Institute of Food Safety, College of Agriculture and Natural Resources, National Chung Hsing University, Taichung, Taiwan
    Search for articles by this author
  • Ya-Hui Chang
    Department of Public Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan
    Search for articles by this author
  • Yu Sun
    Department of Neurology, En Chu Kong Hospital, Sanxia District, New Taipei City, Taiwan
    Search for articles by this author
  • Chung-Yi Li
    Corresponding author at: Department and Graduate Institute of Public Health, College of Medicine, National Cheng Kung University, #1, University Rd., Tainan 701, Taiwan.
    Department of Public Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan

    Department of Public Health, College of Public Health, China Medical University, Taichung, Taiwan
    Search for articles by this author



      This study was conducted to investigate potential link between type 2 diabetes mellitus (T2DM) and epilepsy, and the role of severe hypoglycaemia (SH) might play in the relationship.


      This was a cohort study based on Taiwan’s National Health insurance claims. Totally 751,792 people with T2DM and 824,253 matched controls were identified in 2002–2003 and followed to incidence of epilepsy or end of 2011. We used Cox proportional hazard model to relate epilepsy incidence to separate and joint effects of T2DM and SH. A possible mediation effect of SH on the association between T2DM and epilepsy was analyzed.


      Over a 10-year follow-up, patients with T2DM had a higher incidence rate of epilepsy than controls (35.0 vs 21.9 per 10,000 person-years). After controlling for potential confounders including SH, T2DM increased the hazard of epilepsy by some 50%. The stratified analysis further indicated that T2DM (hazard ratio (HR)=1.44, 95% confidence interval (CI) = 1.40–1.47), and SH (HR = 2.22, 95% CI = 1.76–2.81) were both independent risk factors for epilepsy. SH did not modify but mediated 12% of the association between T2DM and epilepsy.


      Our findings supported that SH may increase the risk of epilepsy, and that T2DM may increase risk of epilepsy independent of SH.


      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 Diabetes Research and Clinical Practice
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Chatterjee S.
        • Peters S.A.
        • Woodward M.
        • Mejia Arango S.
        • Batty G.D.
        • Beckett N.
        • et al.
        Type 2 diabetes as a risk factor for dementia in women compared with Men: a pooled analysis of 2.3 million people comprising more than 100,000 cases of dementia.
        Diabetes Care. 2016; 39: 300-307
        • Schernhammer E.
        • Hansen J.
        • Rugbjerg K.
        • Wermuth L.
        • Ritz B.
        Diabetes and the risk of developing Parkinson’s disease in Denmark.
        Diabetes Care. 2011; 34: 1102-1108
        • Sun Y.
        • Chang Y.H.
        • Chen H.F.
        • Su Y.H.
        • Su H.F.
        • Li C.Y.
        Risk of Parkinson disease onset in patients with diabetes: a 9-year population-based cohort study with age and sex stratifications.
        Diabetes Care. 2012; 35: 1047-1049
        • Hou W.H.
        • Li C.Y.
        • Chang H.H.
        • Sun Y.
        • Tsai C.C.
        A population-based cohort study suggests an increased risk of multiple sclerosis incidence in patients with type 2 diabetes mellitus.
        J Epidemiol. 2017; 27: 235-241
        • Soltesz G.
        • Acsadi G.
        Association between diabetes, severe hypoglycemia, and electroencephalographic abnormalities.
        Arch Dis Child. 1989; 64: 992-996
        • Bergey G.K.
        Autoantibodies in the patient with drug-resistant epilepsy: are we missing a treatable etiology?.
        Arch Neurol. 2012; 69: 565-566
        • Marcovecchio M.L.
        • Petrosino M.I.
        • Chiarelli F.
        Diabetes and epilepsy in children and adolescents.
        Curr Diab Rep. 2015; 15: 21
        • Kirchner A.
        • Veliskova J.
        • Velisek L.
        Differential effects of low glucose concentrations on seizures and epileptiform activity in vivo and in vitro.
        Eur J Neurosci. 2006; 23: 1512-1522
        • Maheandiran M.
        • Mylvaganam S.
        • Wu C.
        • El-Hayek Y.
        • Sugumar S.
        • Hazrati L.
        • et al.
        Severe hypoglycaemia in a juvenile diabetic rat model: presence and severity of seizures are associated with mortality.
        PLoS ONE. 2013; 8: e83168
        • Chang Y.H.
        • Ho W.C.
        • Tsai J.J.
        • Li C.Y.
        • Lu T.H.
        Risk of mortality among patients with epilepsy in southern Taiwan.
        Seizure. 2012; 21: 254-259
        • Olafsson E.
        • Ludvigsson P.
        • Gudmundsson G.
        • Hesdorffer D.
        • Kjartansson O.
        • Hauser W.A.
        Incidence of unprovoked seizures and epilepsy in Iceland and assessment of the epilepsy syndrome classification: a prospective study.
        Lancet Neurol. 2005; 4: 627-634
        • Ferlazzo E.
        • Gasparini S.
        • Beghi E.
        • Sueri C.
        • Russo E.
        • Leo A.
        • et al.
        Epilepsy in cerebrovascular diseases: review of experimental and clinical data with meta-analysis of risk factors.
        Epilepsia. 2016; 57: 1205-1214
        • Chou I.C.
        • Wang C.H.
        • Lin W.D.
        • Tsai F.J.
        • Lin C.C.
        • Kao C.H.
        Risk of epilepsy in type 1 diabetes mellitus: a population-based cohort study.
        Diabetologia. 2016; 59: 1196-1203
        • Dafoulas G.E.
        • Toulis K.A.
        • McCorry D.
        • Kumarendran B.
        • Thomas G.N.
        • Willis B.H.
        • et al.
        Type 1 diabetes mellitus and risk of incident epilepsy: a population-based, open-cohort study.
        Diabetologia. 2017; 60: 258-261
        • Ramakrishnan R.
        • Appleton R.
        Study of prevalence of epilepsy in children with type 1 diabetes mellitus.
        Seizure. 2012; 21: 292-294
        • Frier B.M.
        Hypoglycaemia in diabetes mellitus: epidemiology and clinical implications.
        Nat Rev Endocrinol. 2014; 10: 711-722
      1. National Health Insurance Administration. Statistics and surveys; 2005. [accessed 9 February 2017].

        • Cheng T.M.
        Taiwan’s new national health insurance program: genesis and experience so far.
        Health Aff (Millwood). 2003; 22: 61-76
        • American Diabetes Association
        Glycemic targets. Section 6 in standards of medical care in diabetes.
        Diabetes Care. 2015; 38: S33-S40
        • Ginde A.A.
        • Blanc P.G.
        • Lieberman R.M.
        • Camargo Jr., C.A.
        Validation of ICD-9-CM coding algorithm for improved identification of hypoglycaemia visits.
        BMC Endocr Disord. 2008; 8: 4
        • Liu C.Y.
        • Hung Y.T.
        • Chuang Y.L.
        • Chen Y.J.
        • Weng W.S.
        • Liu J.S.
        • et al.
        Incorporating development stratification of Taiwan townships into sampling design of large scale health interview survey.
        J Health Manag. 2006; 4: 1-22
        • Tan H.F.
        • Tseng H.F.
        • Chang C.K.
        • Lin W.
        • Hsiao S.H.
        Accessibility assessment of the Health Care Improvement Program in rural Taiwan.
        J Rural Health. 2005; 21: 372-377
        • Chen H.F.
        • Chen P.
        • Li C.Y.
        Risk of malignant neoplasms of liver and biliary tract in diabetic patients with different age and sex stratifications.
        Hepatology. 2010; 52: 155-163
        • Knol M.J.
        • VanderWeele T.J.
        Recommendations for presenting analyses of effect modification and interaction.
        Int J Epidemiol. 2012; 41: 514-520
        • VanderWeele T.J.
        Causal mediation analysis with survival data.
        Epidemiology. 2011; 22: 582-585
        • Valeri L.
        • VanderWeele T.J.
        SAS macro for causal mediation analysis with survival data.
        Epidemiology. 2015; 26: e23-e24
        • Dekker F.W.
        • de Mutsert R.
        • van Dijk P.C.
        • Zoccali C.
        • Jager K.J.
        Survival analysis: time-dependent effects and time-varying risk factors.
        Kidney Int. 2008; 74: 994-997
        • Schober E.
        • Otto K.P.
        • Dost A.
        • Jorch N.
        • Holl R.
        Association of epilepsy and type 1 diabetes mellitus in children and adolescents: is there an increased risk for diabetic ketoacidosis?.
        J Pediatr. 2012; 160: e1
        • UK Prospective Diabetes Study (UKPDS) Group
        Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34).
        The Lancet. 1998; 352: 854-865
        • van Dalem J.
        • Brouwers M.C.
        • Stehouwer C.D.
        • Krings A.
        • Leufkens H.G.
        • Driessen J.H.
        • et al.
        Risk of hypoglycaemia in users of sulphonylureas compared with metformin in relation to renal function and sulphonylurea metabolite group: population based cohort study.
        BMJ. 2016; 354: i3625
        • Sander J.W.
        • Novy J.
        • Keezer M.R.
        The intriguing relationship between epilepsy and type 1 diabetes mellitus.
        Diabetologia. 2016; 59: 1569-1570
        • Lévesque L.E.
        • Hanley J.A.
        • Kezouh A.
        • Suissa S.
        Problem of immortal time bias in cohort studies: example using statins for preventing progression of diabetes.
        BMJ. 2010; 340: b5087
        • Lipska K.J.
        • Ross J.S.
        • Wang Y.
        • Inzucchi S.E.
        • Minges K.
        • Karter A.J.
        • et al.
        National trends in US hospital admissions for hyperglycemia and hypoglycaemia among Medicare beneficiaries, 1999 to 2011.
        JAMA Intern Med. 2014; 174: 1116-1124
        • Lu C.L.
        • Shen H.N.
        • Hu S.C.
        • Wang J.D.
        • Li C.Y.
        A population-based study of all-cause mortality and cardiovascular disease in association with prior history of hypoglycaemia among patients with type 1 diabetes.
        Diabetes Care. 2016; 39: 1571-1578
        • Whitmer R.A.
        • Karter A.J.
        • Yaffe K.
        • Quesenberry Jr., C.P.
        • Selby J.V.
        Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus.
        JAMA. 2009; 301: 1565-1572