Skip to main content

Association of severe hypoglycemia with mortality for people with diabetes mellitus during a 20-year follow-up in Denmark: a cohort study



Severe hypoglycemia has a significant deteriorating effect on quality of life of the individual and has been associated with increased mortality. The aim of this study was to investigate the mortality among people with type 1 and type 2 diabetes suffering from severe hypoglycemia in Denmark in the last two decades.


People diagnosed with type 1 (n = 44,033) and type 2 diabetes (n = 333,581) were extracted from the complete population of Denmark from 1996 to 2017 via ICD-10 diabetes codes and ATC diabetes medication codes. People suffering from severe hypoglycemia (type 1 diabetes n = 8808, type 2 diabetes n = 5605) as identified from ICD-10 codes were then matched 1:1 by year of birth, gender and year of diabetes diagnosis with those without severe hypoglycemia. Cox proportional hazards models were constructed to analyze the effect of severe hypoglycemia on mortality.


For both people with type 1 (HR 1.11, CI 95% 1.06 to 1.17) and type 2 diabetes (HR 1.77, CI 95% 1.67 to 1.87) suffering from hypoglycemia, an increased mortality risk was observed, compared to people without severe hypoglycemia. An investigation of the death causes did not indicate an association between the severe hypoglycemic episodes and death.


In this study, severe hypoglycemic episodes increased the mortality risk for people with type 1 and type 2 diabetes. The risk was higher among people with type 2 diabetes. Whether severe hypoglycemia is a symptom of other underlying illnesses increasing mortality risk or a risk factor itself needs further investigation.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2


  1. Lachin JM, White NH, Hainsworth DP, Sun W, Cleary PA, Nathan DM (2015) Effect of intensive Diabetes therapy on the progression of diabetic retinopathy in patients with type 1 diabetes: 18 years of follow-up in the DCCT/EDIC. Diabetes 64:631–642

    Article  CAS  PubMed  Google Scholar 

  2. UK Prospective Diabetes Study (UKPDS) Group (1998) Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 352(9131):837–853

    Article  Google Scholar 

  3. Bailey CJ, Day C (2008) Glycaemic memory. Br J Diabetes Vasc Dis 8:242–247

    Article  Google Scholar 

  4. Gubitosi-Klug RA, Braffett BH, White NH et al (2017) Risk of severe hypoglycemia in type 1 diabetes over 30 years of follow-up in the DCCT/EDIC study. Diabetes Care 40:1010–1016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Zoungas S, Patel A, Chalmers J et al (2010) Severe hypoglycemia and risks of vascular events and death. N Engl J Med. 363(15):1410–1418

    Article  CAS  PubMed  Google Scholar 

  6. Sejling A, Schouwenberg B, Faerch L, Thorsteinsson B, de Galan B, Pedersen-Bjergaard U (2015) Association between hypoglycaemia and impaired hypoglycaemia awareness and mortality in people with Type 1 diabetes mellitus. Diabet Med 33(1):77–83

    Article  PubMed  Google Scholar 

  7. American Diabetes Association Workgroup on Hypoglycemia (2005) Defining and reporting hypoglycemia in diabetes. Diabetes Care 28(5):1245–1249

    Article  Google Scholar 

  8. Bonaventura A, Montecucco F, Dallegri F (2015) Update on strategies limiting iatrogenic hypoglycemia. Endocr Connect 4(3):R37–R45

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Oyer DS (2013) The science of hypoglycemia in patients with diabetes. Curr Diabetes Rev 9:195–208

    Article  PubMed  Google Scholar 

  10. Morales J, Schneider D (2014) Hypoglycemia. Am J Med 127(10 Suppl):S17–24

    Article  CAS  PubMed  Google Scholar 

  11. Van Dalem J, Brouwers MCGJ, Stehouwer CDA et al (2016) Risk of hypoglycaemia in users of sulphonylureas compared with metformin in relation to renal function and sulphonylurea metabolite group: population based cohort study. BMJ 354:1–8

    Google Scholar 

  12. Heller SR, Frier BM, Hersløv ML, Gundgaard J, Gough SCL (2016) Severe hypoglycaemia in adults with insulin-treated diabetes: impact on healthcare resources. Diabet Med 33(4):471–477

    Article  CAS  PubMed  Google Scholar 

  13. McCoy R, Van Houten H, Ziegenfuss J, Shah N, Wermers R, Smith S (2012) Increased mortality of patients with diabetes reporting severe hypoglycemia. Diabetes Care 35(9):1897–1901

    Article  PubMed  PubMed Central  Google Scholar 

  14. Zaccardi F, Dhalwani NN, Webb DR, Davies MJ, Khunti K (2018) Global burden of hypoglycaemia-related mortality in 109 countries, from 2000 to 2014: an analysis of death certificates. Diabetologia 61(7):1592–1602

    Article  PubMed  PubMed Central  Google Scholar 

  15. Tella SH, Rendell MS (2015) DPP-4 inhibitors: focus on safety. Expert Opin Drug Saf 14(1):127–140

    Article  CAS  PubMed  Google Scholar 

  16. Abd El Aziz MS, Kahle M, Meier JJ, Nauck MA (2017) A meta-analysis comparing clinical effects of short- or long-acting GLP-1 receptor agonists versus insulin treatment from head-to-head studies in type 2 diabetic patients. Diabetes, Obes Metab. 2017;19(2):216–27

  17. Bonaventura A, Carbone S, Dixon DL, Abbate A, Montecucco F (2019) Pharmacologic strategies to reduce cardiovascular disease in type 2 diabetes mellitus: focus on SGLT-2 inhibitors and GLP-1 receptor agonists. J Intern Med 286(1):16–31

    Article  CAS  PubMed  Google Scholar 

  18. Filippas-Ntekouan S, Filippatos TD, Elisaf MS (2018) SGLT2 inhibitors: are they safe? Postgrad Med 130(1):72–82

    Article  PubMed  Google Scholar 

  19. Marso SP, McGuire DK, Zinman B et al (2017) Efficacy and safety of degludec versus glargine in type 2 diabetes. N Engl J Med 377(8):723–732

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ritzel R, Roussel R, Giaccari A, Vora J, Brulle-Wohlhueter C, Yki-Järvinen H (2018) Better glycaemic control and less hypoglycaemia with insulin glargine 300 U/mL vs glargine 100 U/mL: 1-year patient-level meta-analysis of the EDITION clinical studies in people with type 2 diabetes. Diabetes Obes Metab 20(3):541–548

    Article  CAS  PubMed  Google Scholar 

  21. Schmidt M, Alba S, Schmidt J et al (2015) The Danish National Patient Registry: a review of content, data quality, and research potential. Clin Epidemiol. 7:449–490

    Article  PubMed  PubMed Central  Google Scholar 

  22. Schmidt M, Pedersen L, Sørensen H (2014) The Danish Civil Registration System as a tool in epidemiology. Eur J Epidemiol 29(8):541–549

    Article  PubMed  Google Scholar 

  23. Charlson ME, Pompei P, Ales KL, MacKenzie CR (1987) A new method for classifying prognostic comorbidity in longitudinal studies. J Chron Dis 40:373–384

    Article  CAS  PubMed  Google Scholar 

  24. Ilic M, Ilic I (2016) Epidemiology of pancreatic cancer. World J Gastroenterol 22(44):9694–9705

    Article  PubMed  PubMed Central  Google Scholar 

  25. Kittah NE, Vella A (2017) Pathogenesis and management of hypoglycemia. Eur J Endocrinol 177(1):R37–R47

    Article  CAS  PubMed  Google Scholar 

  26. Quaresma M, Coleman MP, Rachet B (2015) 40-year trends in an index of survival for all cancers combined and survival adjusted for age and sex for each cancer in England and Wales, 1971–2011: a population-based study. Lancet 385(9974):1206–1218

    Article  PubMed  Google Scholar 

  27. Cryer PE (2017) Individualized glycemic goals and an expanded classification of severe hypoglycemia in diabetes. Diabetes Care 40(12):1641–1643

    Article  CAS  PubMed  Google Scholar 

  28. Kakei M, Tsujimoto T, Noto H et al (2013) Vital signs, QT prolongation, and newly diagnosed cardiovascular disease during severe hypoglycemia in type 1 and type 2 diabetic patients. Diabetes Care 37(1):217–225

    PubMed  Google Scholar 

  29. Simpson SH, Lee J, Choi S, Vandermeer B, Abdelmoneim AS, Featherstone TR (2015) Mortality risk among sulfonylureas: a systematic review and network meta-analysis. Lancet Diabetes Endocrinol 3(1):43–51

    Article  CAS  PubMed  Google Scholar 

  30. Inzucchi SE, Bergenstal RM, Buse JB et al. Management of hyperglycaemia in type 2 diabetes, 2015: a patient-centred approach. Update to a Position Statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia. 2015;58(3):429–42

  31. Lynge E, Sandegaard JL, Rebolj M (2011) The Danish national patient register. Scand J Public Health 39(7):30–33

    Article  PubMed  Google Scholar 

  32. Mosbech J, Jørgensen J, Madsen M, Rostgaard K, Thornberg K, Poulsen T (1995) The national patient registry. Evaluation of data quality. Ugeskr Laeger 157(26):3741–3745

    CAS  PubMed  Google Scholar 

  33. Vestergaard P, Mosekilde L (2002) Fracture risk in patients with celiac disease, Crohn’s disease, and ulcerative colitis: a nationwide follow-up study of 16,416 patients in Denmark. Am J Epidemiol 156(1):8–10

    Article  Google Scholar 

  34. Bonaventura A, Gallo F, Carbone F et al (2017) Low serum C-reactive protein levels predict 90-day mortality in hypoglycaemic patients. Diabetes Metab 43(6):554–556

    Article  CAS  PubMed  Google Scholar 

  35. Bonaventura A, Gallo F, Carbone F et al (2018) Levels of serum uric acid at admission for hypoglycaemia predict 1-year mortality. Acta Diabetol. 55(4):323–330

    Article  CAS  PubMed  Google Scholar 

Download references


This study was not funded.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Morten Hasselstrøm Jensen.

Ethics declarations

Conflict of interest

Author Vestergaard has received unrestricted Grants from MSD and Servier and travel grants from Amgen, Eli Lilly, Novartis, Sanofi Aventis and Servier. Auther Dethlefsen is employed at Novo Nordisk A/S. Author Jensen is former employee at Novo Nordisk A/S and holds shares in the company.

Ethical approval

All data was handled in accordance with the General Data Protection Regulation (EU) 2016/679. No ethical approval is necessary in Denmark when handling registry data only.

Informed consent

For this study, formal consent was not required.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Jensen, M.H., Dethlefsen, C., Hejlesen, O. et al. Association of severe hypoglycemia with mortality for people with diabetes mellitus during a 20-year follow-up in Denmark: a cohort study. Acta Diabetol 57, 549–558 (2020).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


  • Severe hypoglycemia
  • Mortality
  • Type 1 diabetes
  • Type 2 diabetes
  • Denmark