Iatrogenic hypoglycemia as a serious medical problem

Authors: Emil Martinka 1;  Michaela Mišaníková 1,2
Authors‘ workplace: Národný endokrinologický a diabetologický ústav, n. o., Ľubochňa 1;  Jesseniova lekárska fakulta Univerzity Komenského v Martine 2
Published in: Forum Diab 2016; 5(2): 76-85
Category: Topic


Iatrogenic hypoglycemia represents a serious medical problem. This phenomenon not only limits intensification of glycemic control, but it is also associated with an increased risk of cardiovascular and overall morbidity and mortality. Furthermore it is a frequent adverse effect the frequency of which increases with intensifying the glycemic control as well as therapeutic steps. The issue of iatrogenic hypoglycemia and its relating adverse effect and potential cardiovascular as well as overall risk is a very frequently discussed topic. However these problems need to be considered from multiple points of view. Hypoglycemia, especially its severe stages, is indisputably a serious risk factor which increases both cardiovascular (CV) and overall mortality. In respect of CV mortality this mainly involves induction of ischemia and fatal cardiac arrhythmia. Overall mortality is due to accidents, falls and neurological causes (coma, spasms, cognitive dysfunction). Mortality risk related to hypoglycemia is independent of the intensity of glycemic control and the attained level of compensation. A very important factor for evaluating the risk of hypoglycemia is the patient’s “terrain”, and a need of individualization when deciding about the goals and method of glycemic control. The tendency to hypoglycemia in individual patients who receive the same treatment and reach the same levels of glycemic control is different, and according to some authors it reveals a kind of “more vulnerable, or more ill” patients with comorbidities (hepatic, renal, endocrine or oncological) and less stable body defences, which may in itself increase both the cardiovascular and overall mortality. Hypoglycemia therefore represents not only a risk factor, but also a marker identifying patients at risk. Although the relation between hypoglycemia and increased mortality remains a matter of discussion, the therapeutic procedures with a low risk of hypoglycemia and verified cardiovascular and oncological safety are preferred.

Key words:
diabetes – hypoglycemia – mortality


1. Gerstein HC, Miller ME, Byington RP et al. Action to Control Cardiovascular Risk in Diabetes Study Group. Effect of intensive glucose lowering in patients with type 2 diabetes. N Engl J Med 2008; 358(24): 2545–2559.

2. Adler KG, Bonyhay I, Failing H et al. Antecedent hypoglycemia impairs autonomic cardiovascular function. Implications for rigorous glycemic control. Diabetes 2009; 58(2): 360–366.

3. Arechavaleta R, Seck T, Chen Y et al. Efficacy and safety of treatment with sitagliptin or glimepiride in patients with type 2 diabetes inadequately controlled on metformin monotherapy: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab 2011; 13(2): 160–168.

4. Bonds DE, MillerME, Bergenstal RM 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. Dostupné z DOI: <http://dx.doi.org/10.1136/bmj.b4909>.

5. Dahlquist G, Källén B. Mortality in childhood-onset type 1 diabetes: a population-based study. Diabetes Care 2005; 28(10): 2384–2387.

6. Nathan DM, Cleary PA, Backlund JY et al. [DCCT /EDIC Study research Group]. Intensive diabetes treatment and cardiovascvular disease in patient s with type 1 diabetes. New Engl J Med 2005; 353(25): 2643–2653.

7. Desouza C, Bolli G, Fonseca V. Hypoglycemia, Diabetes, and Cardiovascular Events. Diabetes Care 2010; 33(6): 1389–1394.

8. Desouza C, Salazar H, Cheong B et al. Association of hypoglycemia and cardiac ischemia: a study based on continuous monitoring. Diabetes Care 2003; 26(5):1485–1489.

9. Dormandy JA, Charbonnel B, Eckland DJ et al. [PROactive investigators]. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005; 366(9493): 1279–1289.

10. Duckworth W, Abraira C, Moritz T et al. Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes. N Engl J Med 2009; 360(2): 129–139. Erratum in N Engl J Med 2009; 361(10): 1028.

11. Dotson S, Freeman R, Failing HJ et al. Hypoglycemia increases serum interleukin-6 levels in healthy men and women. Diabetes Care 2008; 31(6): 1222–1223.

12. Egi M, Krinsley JS, Maurer P et al. Pre-morbid glycemic control modifies the interaction between acute hypoglycemia and mortality. Intensive Care Med 2016; 42(4): 562–571. Dostupné z DOI: <http://dx.doi.org/10.1007/s00134–016–4216–8>.

13. Frier BM, Schernthaner G, Heller SR. Hypoglycemia and Cardiovascular Risks. Diabetes Care 2011; 34(Suppl 2): S132-S137.

14. Gejl M, Søndergaard HM, Stecher C et al. Exenatide alters myocardial glucose transport and uptake depending on insulin resistance and increases myocardial blood flow in patients with type 2 diabetes. J Clin Endocrinol Metab 2012; 97(7): E1165-E1169. Dostupné z DOI: <http://dx.doi.org/10.1210/jc.2011–3456>.

15. Gill GV, Woodward A, Casson IF et al. Cardiac arrhythmia and nocturnal hypoglycemia in type-1 diabetes – the dead in bed syndrome revisited. Diabetologia 2009; 52(1): 42–45.

16. Goto A, Arah OA, Goto M et al. Severe hypoglycemia and cardiovascular disease: systematic review and meta-analysis with bias analysis. BMJ 2013; 347: f4533. Dostupné z DOI: <http://dx.doi.org/10.1136/bmj.f4533>.

17. Graveling AJ, Frier BM. Review: Does hypoglycaemia cause cardiovascular events? Br J Diabetes Vasc Dis 2010; 10(1): 5–13.

18. Green JB, Bethel MA, Armstrong PW et al. Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2015; 373(3): 232–242.

19. Gruden G, Barutta F, Chaturvedi N et al. Severe hypoglycemia and cardiovascular disease incidence in type 1 diabetes. The EURODIAB Prospective Complications Study. Diabetes Care 2012; 35(7): 1598–1604.

20. Holman R, Paul SK, Bethel MA et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008; 359(15): 1577–1589.

21. Informácie dostupné z WWW: <http://www.medscape.com/viewarticle/859905>.

22. Ishihara M, Kojima S, Sakamoto T et al. Comparison of blood glucose values on admission for acute myocardial infarction in patients with versus without diabetes mellitus. Am J Cardiol 2009; 104(6): 769–774.

23. Joy NG, Hedrington MS, Briscoe VJ et al. Effects of Acute Hypoglycemia on Inflammatory and Pro-atherothrombotic Biomarkers in Individuals with Type 1 Diabetes and Healthy Individuals. Diabetes Care 2010; 33(7): 1529–1535. Erratum in Diabetes Care 2010; 33(9): 2129.

24. Kosiborod M, Inzucchi SE, Goyal A et al. Relationship between spontaneous and iatrogenic hypoglycemia and mortality in patients hospitalized with acute myocardial infarction. JAMA 2009; 301(15): 1556–1564. Dostupné z DOI: <http://dx.doi.org/10.1001/jama.2009.496>.

25. Lindström T, Jorfeldt L, Tegler L et al. Hypoglycaemia and cardiac arrhythmias in patients with type 2 diabetes mellitus. Diabet Med 1992; 9(6): 536–541.

26. Malmberg K, Ryden L, Wedel H et al. [DIGAMI-2 investigators]. Intense metabolic control by mof nsulin in paicetients with diabetes mellitus and acute myocardial infarction (DIGAMI-2): effects on mortality and morbidity. Eur Heart J 2005; 26(7): 650–661.

27. Mahmoodpoor A, Hamishehkar H, Beigmohammadi M et al. Predisposing Factors for Hypoglycemia and Its Relation With Mortality in Critically Ill Patients Undergoing Insulin Therapy in an Intensive Care Unit. Anesth Pain Med 2016; 6(1): e33849. Dostupné z DOI: <http://dx.doi.org/10.5812/aapm.33849>.

28. Martinka E, Uličiansky V, Mokáň M et al (v spolupráci členov výboru Slovenskej diabetologickej spoločnosti). Konsenzuálny terapeutický algoritmus pre diabetes mellitus 2. typu (v súlade s SPC, aktuálnym znením indikačných obmedzení a odporúčaní ADA/EASD). Diabetes a obezita 2016 (v tlači).

29. McCoy RG, Van Houten HK, Ziegenfuss JY et al. Increased mortality of patients with diabetes reporting severe hypoglycemia. Diabetes Care 2012; 35(9): 1897–1901.

30. Miller ME, Bonds DE, Gerstein HC et al. [ACCORD Investigators]. 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. Dostupné z DOI: <http://dx.doi.org/10.1136/bmj.b5444>.

31. Mitrakou A, Ryan C, Veneman T et al. Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms, and cerebral dysfunction. Am J Physiol 1991; 260(1 Pt 1): E67-E74.

32. Patterson CC, Dahlquist G, Harjutsalo V et al. Early mortality in EURODIAB population-based cohorts of type 1 diabetes diagnosed in childhood since 1989. Diabetologia 2007; 50(12): 2439–2442.

33. Pinto DS, Kirtane AJ, Pride YB et al. Association of blood glucose with angiographic and clinical outcomes among patients with ST-segment elevation myocardial infarction (from the CLARITYTIMI 28 study). Am J Cardiol 2008; 101(3): 303–307.

34. Ravassa S, Zudaire A, Diez J. GLP-1 and cardioprotection: from bench to bedside. Cardiovasc Res 2012; 94(2): 316–323. Dostupné z DOI: <http://dx.doi.org/10.1093/cvr/cvs123> .

35. Raz I, Wilson PW, Strojek K et al. Effects of prandial versus fasting glycemia on cardiovascular outcomes in tye 2 diabetes: the HEART2D trial. Diabetes Care 2009; 32(3): 381–386.

36. Riddle MC, Ambrosius WT, Brillon DJ et al. Epidemiologic relationships between A1C and all-cause mortality during a median 3.4-year follow-up of glycemic treatment in the ACCORD trial. Diabetes Care 2010; 33(5): 983–990.

37. Riddle M. New analyses of glycemic control in ORIGIN. 48th annual meeting of Euroapean Association for study of diabetes. Berlin 2012. Dostupné z WWW: <http://www.easdvirtualmeeting.org/resources/2946>.

38. Skrivarhaug T, Bangstad HJ, Stene LC et al. Longterm mortality in a nationwide cohort of childhood-onset type 1 diabetic patients in Norway. Diabetologia 2006; 49(2): 298–305.

39. Saremi A, Bahn GD, Reaven PE et al. [Veterans Affairs Diabetes Trial (VADT)].A Link Between Hypoglycemia and Progression of Atherosclerosis in the Veterans Affairs Diabetes Trial (VADT) Diabetes Care 2016; 39(3): 448–454. Dostupné z DOI: <http://dx.doi.org/10.2337/dc15–2107>.

40. Sartor G, Dahlquist G. Short-term mortality in childhood onset insulin-dependent diabetes mellitus: a high frequency of unexpected deaths in bed. Diabet Med 1995; 12(7): 607–611.

41. Scirica BM, Bhatt DL, Braunwald E et al. [SAVOR-TIMI 53 Steering Committee and Investigators]. Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus. N Engl J Med 2013; 369(14): 1317–1326.

42. Snell-Bergeon JK, Wadwa RP. Hypoglycemia, diabetes, and cardiovascular disease. Diabetes Technol Ther 2012; 14(Suppl 1): S51-S58.

43. Svensson AM, McGuire DK, Abrahamsson P et al. Association between hyperand hypoglycaemia and 2 year all-cause mortality risk in diabetic patients with acute coronary events. Eur Heart J 2005; 26(13): 1255–1261.

44. Schernthaner G. Diabetes and cardiovascular disease: is intensive glucose control beneficial or deadly? Lessons from ACCORD, ADVANCE, VADT, UKPDS, PROactive, and NICE-SUGAR. Wien Med Wochenschr 2010; 160(1–2): 8–19.

45. Streja D. Can continuous glucose monitoring provide objective documentation of hypoglycemia unawareness? Endocr Pract 2005; 11(2): 83–90.

46. Swinnen SG, Mullins P, Miller M et al.: Changing the glucose cut-off values that define hypoglycaemia has a major effect on reported frequencies of hypoglycaemia. Diabetologia 2009; 52(1): 38–41. Dostupné z DOI: <http://dx.doi.org/10.1007/s00125–008–1147–0>.

47. Tattersall RB, Gill GV. Unexplained deaths of type 1 diabetic patients. Diabet Med 1991; 8(1): 49–58.

48. Tatti P, Di Mauro P, Neri M. Effect of a slow release formula (Glucerna SR) on the risk of Hypoglycemia and blood glucose profile. Seventh Annual Diabetes Technology Meeting. San Francisco, CA, October 2007. A167. Dostupné z WWW: <http://chinacdn.abbottnutrition.com/cms/GLU_CN/MEDIA/Glucerna_Tatti2007_External.pdf>.

49. Patel A, MacMahon S, Chalmers J et al. ADVANCE Collaborative Group. Intensive Blood Glucose Control and VascularOutcomes in Patients with Type 2 Diabetes. N Engl J Med 2008; 358(24): 2560–2572.

50. Frye RL, August P, Brooks MM et al. [BARI-2D Study Goup]. A randomized trial of therapies for type 2 diabwetes and coronary artery disease. N Eng J Med 2009; 360(24): 2503–2515.

51. Finfer S, Chittock DR, Su SY et al. [NICE-SUGAR Study Investigators]. Intensive versus conventional glucose control in critically ill patients. N Engl J Med 2009; 360(13): 1283–1297.

52. Gerstein HC, Bosch J, Dagenais GR et al. [Origin Trial Investigators] Basal Insulin and Cardiovascular and Other Outcomes in Dysglycemia. N Engl J Med, 2012; 367(4): 319–328.

53. Tschope D, Bramlage P, Binz C et al. Incidence and predictors of hypoglycaemia in type 2 diabetes – an analysis of the prospective DiaRegis registry. BMC Endocr Disord 2012; 12: 23. Dostupné z DOI: <http://dx.doi.org/10.1186/1472–6823–12–23>.

54. Yakubovich N, Gerstein H. Serious cardiovascular outcomes in diabetes. The role of hypoglycaemia. Circulation 2011; 123(3): 342–348.

55. White VB, Cannon CP, Heller SR et al. [EXAMINE Investigators]. Alogliptin after Acute Coronary Syndrome in Patients with Type 2 Diabetes. N Engl J Med 2013; 369(14): 1327–1335.

56. Wright RJ, Frier BM. Vascular disease and diabetes: is hypoglycaemia an aggravating factor? Diabetes Metab Res Rev 2008; 24(5): 353–363.

57. Wright AD, Cull CA, MacLeod KM et al. [UKPDS Group]. Hypoglycemia in type 2 diabetic patients randomized to and maintained on monotherapy with diet, sulfonylurea, metformin, or insulin for 6 years from diagnosis (UKPDS 73). J Diabetes Complications 2006; 20(6): 395–401.

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

59. Zinman B, Wanner C, Lachin JM et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med 2015; 373(22): 2117–2128.

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