Current Diabetes Reports

, 15:117 | Cite as

Hypoglycemia and Cardiovascular Disease: Lessons from Outcome Studies

  • Frank PistroschEmail author
  • Markolf Hanefeld
Macrovascular Complications in Diabetes (VR Aroda and A Getaneh, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Macrovascular Complications in Diabetes


Severe hypoglycemia is recognized to be one of the strongest predictors of macrovascular events, adverse clinical outcomes, and mortality in patients with type 2 diabetes. Large clinical trials have reported an increased hazard ratio for all-cause mortality and cardiovascular events in patients with type 2 diabetes and severe hypoglycemia. However, these trials also reported an increased hypoglycemia-associated mortality rate in patients allocated to standard treatment by a factor of 1.5–2 despite a significant 50 % to 70 % lower incidence of hypoglycemia compared to the intensive treatment group. Although the potential for a causal relationship has been demonstrated in mechanistic studies, the evidence from large prospective studies suggest that other pre-existing cardiovascular risk factors in addition to hypoglycemia may be the major link to the final cardiovascular event, and that a low blood glucose level can trigger these events in patients with a high cardiovascular risk.


Hypoglycemia Diabetes Cardiovascular risk Outcome trials 



M.H. and F.P. prepared and reviewed the manuscript.

Compliance with Ethical Standards

Conflict of Interest

Frank Pistrosch declares that he has no conflict of interest.

Markolf Hanefeld reports grants from Sanofi and nonfinancial support from Medtronic.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Bonds DE, Miller ME, Bergenstal RM, Buse JB, Byington RP, Cutler JA, et al. The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study. BMJ. 2010;340:b4909.PubMedCentralCrossRefPubMedGoogle Scholar
  2. 2.
    McCoy RG, Van Houten HK, Ziegenfuss JY, Shah ND, Wermers RA, Smith SA. Increased mortality of patients with diabetes reporting severe hypoglycemia. Diabetes Care. 2012;35:1897–901.PubMedCentralCrossRefPubMedGoogle Scholar
  3. 3.••
    Mellbin LG, Ryden L, Riddle MC, Probstfield J, Rosenstock J, Diaz R, et al. Does hypoglycaemia increase the risk of cardiovascular events? A report from the ORIGIN trial. Eur Heart J. 2013;34:3137–44. An excellent analysis of CV events, treatments, and CV risk factors of patients from the ORIGIN trial with vs without hypoglycemia.CrossRefPubMedGoogle Scholar
  4. 4.
    Yakubovich N, Gerstein HC. Serious cardiovascular outcomes in diabetes: the role of hypoglycemia. Circulation. 2011;123:342–8.CrossRefPubMedGoogle Scholar
  5. 5.
    Zoungas S, Patel A, Chalmers J, de Galan BE, Li Q, Billot L, et al. Severe hypoglycemia and risks of vascular events and death. N Engl J Med. 2010;363:1410–8.CrossRefPubMedGoogle Scholar
  6. 6.
    Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360:129–39.CrossRefPubMedGoogle Scholar
  7. 7.
    Goto A, Arah OA, Goto M, Terauchi Y, Noda M. Severe hypoglycaemia and cardiovascular disease: systematic review and meta-analysis with bias analysis. BMJ. 2013;347:f4533.CrossRefPubMedGoogle Scholar
  8. 8.
    Gruden G, Barutta F, Chaturvedi N, Schalkwijk C, Stehouwer CD, Witte DR, et al. Severe hypoglycemia and cardiovascular disease incidence in type 1 diabetes: the EURODIAB Prospective Complications Study. Diabetes Care. 2012;35:1598–604.PubMedCentralCrossRefPubMedGoogle Scholar
  9. 9.•
    Orchard TJ, Nathan DM, Zinman B, Cleary P, Brillon D, Backlund JY, et al. Association between 7 years of intensive treatment of type 1 diabetes and long-term mortality. JAMA. 2015.Google Scholar
  10. 10.
    Khunti K, Davies M, Majeed A, Thorsted BL, Wolden ML, Paul SK. Hypoglycemia and risk of cardiovascular disease and all-cause mortality in insulin-treated people with type 1 and type 2 diabetes: a cohort study. Diabetes Care. 2015;38:316–22.CrossRefPubMedGoogle Scholar
  11. 11.
    Gerstein HC, Miller ME, Genuth S, Ismail-Beigi F, Buse JB, Goff Jr DC, et al. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med. 2011;364:818–28.CrossRefPubMedGoogle Scholar
  12. 12.
    Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577–89.CrossRefPubMedGoogle Scholar
  13. 13.
    Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560–72.CrossRefPubMedGoogle Scholar
  14. 14.
    The Diabetes Control and Complications Trial Research Group. Hypoglycemia in the Diabetes Control and Complications Trial. Diabetes. 1997;46:271–86.CrossRefGoogle Scholar
  15. 15.•
    Holman RR, Sourij H, Califf RM. Cardiovascular outcome trials of glucose-lowering drugs or strategies in type 2 diabetes. Lancet. 2014;383:2008–17. Interesting review which address the problems and limitations of recent outcome trials.CrossRefPubMedGoogle Scholar
  16. 16.
    The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993;329:977–86.CrossRefGoogle Scholar
  17. 17.
    UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837–53.CrossRefGoogle Scholar
  18. 18.
    Gerstein HC, Miller ME, Byington RP, Goff Jr DC, Bigger JT, Buse JB, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545–59.CrossRefPubMedGoogle Scholar
  19. 19.
    Miller ME, Bonds DE, Gerstein HC, Seaquist ER, Bergenstal RM, Calles-Escandon J, et al. The effects of baseline characteristics, glycaemia treatment approach, and glycated haemoglobin concentration on the risk of severe hypoglycaemia: post hoc epidemiological analysis of the ACCORD study. BMJ. 2010;340:b5444.PubMedCentralCrossRefPubMedGoogle Scholar
  20. 20.
    Origin Trial Investigators. Predictors of nonsevere and severe hypoglycemia during glucose-lowering treatment with insulin glargine or standard drugs in the ORIGIN trial. Diabetes Care. 2015;38:22–8.CrossRefGoogle Scholar
  21. 21.
    Wright AD, Cull CA, Macleod KM, Holman RR. Hypoglycemia in Type 2 diabetic patients randomized to and maintained on monotherapy with diet, sulfonylurea, metformin, or insulin for 6 years from diagnosis: UKPDS73. J Diabetes Complicat. 2006;20:395–401.CrossRefPubMedGoogle Scholar
  22. 22.
    Pistrosch F, Ganz X, Bornstein SR, Birkenfeld AL, Henkel E, Hanefeld M. Risk of and risk factors for hypoglycemia and associated arrhythmias in patients with type 2 diabetes and cardiovascular disease: a cohort study under real-world conditions. Acta Diabetol. 2015.Google Scholar
  23. 23.
    Fisher BM, Gillen G, Hepburn DA, Dargie HJ, Frier BM. Cardiac responses to acute insulin-induced hypoglycemia in humans. Am J Physiol. 1990;258:H1775–9.PubMedGoogle Scholar
  24. 24.
    Hilsted J, Bonde-Petersen F, Norgaard MB, Greniman M, Christensen NJ, Parving HH, et al. Haemodynamic changes in insulin-induced hypoglycaemia in normal man. Diabetologia. 1984;26:328–32.CrossRefPubMedGoogle Scholar
  25. 25.
    Sommerfield AJ, Wilkinson IB, Webb DJ, Frier BM. Vessel wall stiffness in type 1 diabetes and the central hemodynamic effects of acute hypoglycemia. Am J Physiol Endocrinol Metab. 2007;293:E1274–9.CrossRefPubMedGoogle Scholar
  26. 26.
    Hanefeld M, Duetting E, Bramlage P. Cardiac implications of hypoglycaemia in patients with diabetes— a systematic review. Cardiovasc Diabetol. 2013;12:135.PubMedCentralCrossRefPubMedGoogle Scholar
  27. 27.
    Wright RJ, Frier BM. Vascular disease and diabetes: is hypoglycaemia an aggravating factor? Diabetes Metab Res Rev. 2008;24:353–63.CrossRefPubMedGoogle Scholar
  28. 28.
    Tsujimoto T, Yamamoto-Honda R, Kajio H, Kishimoto M, Noto H, Hachiya R, et al. Vital signs, QT prolongation, and newly diagnosed cardiovascular disease during severe hypoglycemia in type 1 and type 2 diabetic patients. Diabetes Care. 2014;37:217–25.CrossRefPubMedGoogle Scholar
  29. 29.
    Leitch A. Sudden death in insulin coma treatment for schizophrenia. J Nerv Ment Dis. 1955;121:267–9.CrossRefPubMedGoogle Scholar
  30. 30.
    Tanenberg RJ, Newton CA, Drake AJ. Confirmation of hypoglycemia in the "dead-in-bed" syndrome, as captured by a retrospective continuous glucose monitoring system. Endocr Pract. 2010;16:244–8.CrossRefPubMedGoogle Scholar
  31. 31.
    Tattersall RB, Gill GV. Unexplained deaths of type 1 diabetic patients. Diabet Med. 1991;8:49–58.CrossRefPubMedGoogle Scholar
  32. 32.
    Gill GV, Woodward A, Casson IF, Weston PJ. Cardiac arrhythmia and nocturnal hypoglycaemia in type 1 diabetes—the 'dead in bed' syndrome revisited. Diabetologia. 2009;52:42–5.CrossRefPubMedGoogle Scholar
  33. 33.
    Landstedt-Hallin L, Englund A, Adamson U, Lins PE. Increased QT dispersion during hypoglycaemia in patients with type 2 diabetes mellitus. J Intern Med. 1999;246:299–307.CrossRefPubMedGoogle Scholar
  34. 34.
    Marques JL, George E, Peacey SR, Harris ND, Macdonald IA, Cochrane T, et al. Altered ventricular repolarization during hypoglycaemia in patients with diabetes. Diabet Med. 1997;14:648–54.CrossRefPubMedGoogle Scholar
  35. 35.
    Al Khatib SM, LaPointe NM, Kramer JM, Califf RM. What clinicians should know about the QT interval. JAMA. 2003;289:2120–7.CrossRefPubMedGoogle Scholar
  36. 36.
    Chow E, Bernjak A, Williams S, Fawdry RA, Hibbert S, Freeman J, et al. Risk of cardiac arrhythmias during hypoglycemia in patients with type 2 diabetes and cardiovascular risk. Diabetes. 2014;63:1738–47.CrossRefPubMedGoogle Scholar
  37. 37.
    Stahn A, Pistrosch F, Ganz X, Teige M, Koehler C, Bornstein S, et al. Relationship between hypoglycemic episodes and ventricular arrhythmias in patients with type 2 diabetes and cardiovascular diseases. silent hypoglycemias and silent arrhythmias. Diabetes Care. 2014;37:516–20.CrossRefPubMedGoogle Scholar
  38. 38.•
    Frier BM. Hypoglycaemia in diabetes mellitus: epidemiology and clinical implications. Nat Rev Endocrinol. 2014;10:711–22. Comprehensive review of the topic.CrossRefPubMedGoogle Scholar
  39. 39.
    Hutton RA, Mikhailidis D, Dormandy KM, Ginsburg J. Platelet aggregation studies during transient hypoglycaemia: a potential method for evaluating platelet function. J Clin Pathol. 1979;32:434–8.PubMedCentralCrossRefPubMedGoogle Scholar
  40. 40.
    Wright RJ, Newby DE, Stirling D, Ludlam CA, Macdonald IA, Frier BM. Effects of acute insulin-induced hypoglycemia on indices of inflammation: putative mechanism for aggravating vascular disease in diabetes. Diabetes Care. 2010;33:1591–7.PubMedCentralCrossRefPubMedGoogle Scholar
  41. 41.
    Dalsgaard-Nielsen J, Madsbad S, Hilsted J. Changes in platelet function, blood coagulation and fibrinolysis during insulin-induced hypoglycaemia in juvenile diabetics and normal subjects. Thromb Haemost. 1982;47:254–8.PubMedGoogle Scholar
  42. 42.
    Dandona P, Chaudhuri A, Dhindsa S. Proinflammatory and prothrombotic effects of hypoglycemia. Diabetes Care. 2010;33:1686–7.PubMedCentralCrossRefPubMedGoogle Scholar
  43. 43.
    Gogitidze JN, Hedrington MS, Briscoe VJ, Tate DB, Ertl AC, Davis SN. Effects of acute hypoglycemia on inflammatory and pro-atherothrombotic biomarkers in individuals with type 1 diabetes and healthy individuals. Diabetes Care. 2010;33:1529–35.CrossRefGoogle Scholar
  44. 44.
    Turnbull FM, Abraira C, Anderson RJ, Byington RP, Chalmers JP, Duckworth WC, et al. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia. 2009;52:2288–98.CrossRefPubMedGoogle Scholar
  45. 45.
    Hanefeld M, Ganz X, Nolte C. Hypoglycemia and cardiac arrhythmia in patients with diabetes mellitus type 2. Herz. 2014;39:312–9.CrossRefPubMedGoogle Scholar
  46. 46.
    Mellbin LG, Malmberg K, Norhammar A, Wedel H, Ryden L. Prognostic implications of glucose-lowering treatment in patients with acute myocardial infarction and diabetes: experiences from an extended follow-up of the Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) 2 Study. Diabetologia. 2011;54:1308–17.CrossRefPubMedGoogle Scholar
  47. 47.
    Riveline JP, Danchin N, Ledru F, Varroud-Vial M, Charpentier G. Sulfonylureas and cardiovascular effects: from experimental data to clinical use. Available data in humans and clinical applications. Diabetes Metab. 2003;29:207–22.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Study Center Professor HanefeldGWT TU-Dresden GmbHDresdenGermany
  2. 2.Medical Clinic IIIUniversitätsklinikum “Carl Gustav Carus”DresdenGermany

Personalised recommendations