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Management of hypoglycemia during treatment of diabetes mellitus

Author
Philip E Cryer, MD
Section Editor
Irl B Hirsch, MD
Deputy Editor
Jean E Mulder, MD

INTRODUCTION

Hypoglycemia is an important problem in type 1 diabetes, especially in patients receiving intensive therapy in whom the risk of severe hypoglycemia is increased more than threefold (figure 1) [1-4]. Less commonly, hypoglycemia may also affect patients with type 2 diabetes who take a sulfonylurea or a meglitinide or who use insulin.

Identification of patients at risk for hypoglycemia and the prevention and management of hypoglycemia are reviewed here. The clinical manifestations of hypoglycemia and the physiologic response to hypoglycemia are discussed elsewhere. (See "Hypoglycemia in adults: Clinical manifestations, definition, and causes" and "Physiologic response to hypoglycemia in normal subjects and patients with diabetes mellitus".)

BIOCHEMICAL AND CLINICAL CRITERIA

In 2013, a workgroup of the American Diabetes Association (ADA) and the Endocrine Society reconfirmed previously published criteria for the definition and clinical classification of hypoglycemia in patients with diabetes mellitus [3].

Definition — In patients with diabetes, hypoglycemia is defined as all episodes of an abnormally low plasma glucose concentration (with or without symptoms) that expose the individual to harm [3]. The workgroup recommended that people with diabetes become concerned about the possibility of hypoglycemia at a self-monitored blood glucose (SMBG) level ≤70 mg/dL (3.9 mmol/L). While that value is higher than the value used to diagnose hypoglycemia in people without diabetes, it approximates the lower limit of the physiologic fasting nondiabetic range, the normal glycemic threshold for glucose counterregulatory hormone secretion, and the highest antecedent low glucose level reported to reduce sympathoadrenal responses to subsequent hypoglycemia [1].

This cut-off value has been debated, with some favoring a value of <63 mg/dL (3.5 mmol/L) to avoid overclassification of hypoglycemia in asymptomatic patients [5-8]. However, when an SMBG value is ≤70 mg/dL, it does not mean that patients should always self-treat. Defensive options include repeating the measurement in the near term, avoiding critical tasks, such as driving, adjusting the subsequent treatment regimen, or ingesting carbohydrates. (See 'Treatment of hypoglycemia' below.)

                               

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Literature review current through: Nov 2016. | This topic last updated: Tue Nov 08 00:00:00 GMT 2016.
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References
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  1. Cryer PE, Axelrod L, Grossman AB, et al. Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2009; 94:709.
  2. Cryer PE. The barrier of hypoglycemia in diabetes. Diabetes 2008; 57:3169.
  3. Seaquist ER, Anderson J, Childs B, et al. Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society. J Clin Endocrinol Metab 2013; 98:1845.
  4. Cryer PE. Hypoglycemia in Diabetes. Pathophysiology, Prevalence, and Prevention, 3rd ed. American Diabetes Association. Alexandria 2016
  5. Frier BM. Defining hypoglycaemia: what level has clinical relevance? Diabetologia 2009; 52:31.
  6. 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; 52:38.
  7. Amiel SA, Dixon T, Mann R, Jameson K. Hypoglycaemia in Type 2 diabetes. Diabet Med 2008; 25:245.
  8. Cryer PE. Preventing hypoglycaemia: what is the appropriate glucose alert value? Diabetologia 2009; 52:35.
  9. UK Hypoglycaemia Study Group. Risk of hypoglycaemia in types 1 and 2 diabetes: effects of treatment modalities and their duration. Diabetologia 2007; 50:1140.
  10. Hypoglycemia in the Diabetes Control and Complications Trial. The Diabetes Control and Complications Trial Research Group. Diabetes 1997; 46:271.
  11. Donnelly LA, Morris AD, Frier BM, et al. Frequency and predictors of hypoglycaemia in Type 1 and insulin-treated Type 2 diabetes: a population-based study. Diabet Med 2005; 22:749.
  12. Holstein A, Plaschke A, Egberts EH. Clinical characterisation of severe hypoglycaemia--a prospective population-based study. Exp Clin Endocrinol Diabetes 2003; 111:364.
  13. Leese GP, Wang J, Broomhall J, et al. Frequency of severe hypoglycemia requiring emergency treatment in type 1 and type 2 diabetes: a population-based study of health service resource use. Diabetes Care 2003; 26:1176.
  14. Gangji AS, Cukierman T, Gerstein HC, et al. A systematic review and meta-analysis of hypoglycemia and cardiovascular events: a comparison of glyburide with other secretagogues and with insulin. Diabetes Care 2007; 30:389.
  15. Zammitt NN, Frier BM. Hypoglycemia in type 2 diabetes: pathophysiology, frequency, and effects of different treatment modalities. Diabetes Care 2005; 28:2948.
  16. Phung OJ, Scholle JM, Talwar M, Coleman CI. Effect of noninsulin antidiabetic drugs added to metformin therapy on glycemic control, weight gain, and hypoglycemia in type 2 diabetes. JAMA 2010; 303:1410.
  17. Vasilakou D, Karagiannis T, Athanasiadou E, et al. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med 2013; 159:262.
  18. Bode BW, Schwartz S, Stubbs HA, Block JE. Glycemic characteristics in continuously monitored patients with type 1 and type 2 diabetes: normative values. Diabetes Care 2005; 28:2361.
  19. Raju B, Arbelaez AM, Breckenridge SM, Cryer PE. Nocturnal hypoglycemia in type 1 diabetes: an assessment of preventive bedtime treatments. J Clin Endocrinol Metab 2006; 91:2087.
  20. Amiel SA. Hypoglycemia: from the laboratory to the clinic. Diabetes Care 2009; 32:1364.
  21. McCrimmon RJ, Sherwin RS. Hypoglycemia in type 1 diabetes. Diabetes 2010; 59:2333.
  22. 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; 50:2439.
  23. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study Research Group, Jacobson AM, Musen G, et al. Long-term effect of diabetes and its treatment on cognitive function. N Engl J Med 2007; 356:1842.
  24. Feltbower RG, Bodansky HJ, Patterson CC, et al. Acute complications and drug misuse are important causes of death for children and young adults with type 1 diabetes: results from the Yorkshire Register of diabetes in children and young adults. Diabetes Care 2008; 31:922.
  25. Skrivarhaug T, Bangstad HJ, Stene LC, et al. Long-term mortality in a nationwide cohort of childhood-onset type 1 diabetic patients in Norway. Diabetologia 2006; 49:298.
  26. Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) Study Research Group. Mortality in Type 1 Diabetes in the DCCT/EDIC Versus the General Population. Diabetes Care 2016; 39:1378.
  27. Holstein A, Egberts EH. Risk of hypoglycaemia with oral antidiabetic agents in patients with Type 2 diabetes. Exp Clin Endocrinol Diabetes 2003; 111:405.
  28. Goto A, Arah OA, Goto M, et al. Severe hypoglycaemia and cardiovascular disease: systematic review and meta-analysis with bias analysis. BMJ 2013; 347:f4533.
  29. Effects of intensive diabetes therapy on neuropsychological function in adults in the Diabetes Control and Complications Trial. Ann Intern Med 1996; 124:379.
  30. Yaffe K, Falvey CM, Hamilton N, et al. Association between hypoglycemia and dementia in a biracial cohort of older adults with diabetes mellitus. JAMA Intern Med 2013; 173:1300.
  31. Cryer PE. Mechanisms of hypoglycemia-associated autonomic failure in diabetes. N Engl J Med 2013; 369:362.
  32. Murad MH, Coto-Yglesias F, Wang AT, et al. Clinical review: Drug-induced hypoglycemia: a systematic review. J Clin Endocrinol Metab 2009; 94:741.
  33. Cox DJ, Gonder-Frederick L, Ritterband L, et al. Prediction of severe hypoglycemia. Diabetes Care 2007; 30:1370.
  34. Cryer PE, Davis SN, Shamoon H. Hypoglycemia in diabetes. Diabetes Care 2003; 26:1902.
  35. Pogach L, Aron D. Balancing hypoglycemia and glycemic control: a public health approach for insulin safety. JAMA 2010; 303:2076.
  36. Yudkin JS, Richter B, Gale EA. Intensified glucose lowering in type 2 diabetes: time for a reappraisal. Diabetologia 2010; 53:2079.
  37. Cryer PE. Elimination of hypoglycemia from the lives of people affected by diabetes. Diabetes 2011; 60:24.
  38. Cryer PE. Glycemic goals in diabetes: trade-off between glycemic control and iatrogenic hypoglycemia. Diabetes 2014; 63:2188.
  39. Cox DJ, Gonder-Frederick L, Antoun B, et al. Perceived symptoms in the recognition of hypoglycemia. Diabetes Care 1993; 16:519.
  40. Hirsch IB, Boyle PJ, Craft S, Cryer PE. Higher glycemic thresholds for symptoms during beta-adrenergic blockade in IDDM. Diabetes 1991; 40:1177.
  41. Cox DJ, Kovatchev B, Koev D, et al. Hypoglycemia anticipation, awareness and treatment training (HAATT) reduces occurrence of severe hypoglycemia among adults with type 1 diabetes mellitus. Int J Behav Med 2004; 11:212.
  42. de Zoysa N, Rogers H, Stadler M, et al. A psychoeducational program to restore hypoglycemia awareness: the DAFNE-HART pilot study. Diabetes Care 2014; 37:863.
  43. Fanelli CG, Epifano L, Rambotti AM, et al. Meticulous prevention of hypoglycemia normalizes the glycemic thresholds and magnitude of most of neuroendocrine responses to, symptoms of, and cognitive function during hypoglycemia in intensively treated patients with short-term IDDM. Diabetes 1993; 42:1683.
  44. Cranston I, Lomas J, Maran A, et al. Restoration of hypoglycaemia awareness in patients with long-duration insulin-dependent diabetes. Lancet 1994; 344:283.
  45. Fanelli C, Pampanelli S, Epifano L, et al. Long-term recovery from unawareness, deficient counterregulation and lack of cognitive dysfunction during hypoglycaemia, following institution of rational, intensive insulin therapy in IDDM. Diabetologia 1994; 37:1265.
  46. Dagogo-Jack S, Rattarasarn C, Cryer PE. Reversal of hypoglycemia unawareness, but not defective glucose counterregulation, in IDDM. Diabetes 1994; 43:1426.
  47. Lingenfelser T, Buettner U, Martin J, et al. Improvement of impaired counterregulatory hormone response and symptom perception by short-term avoidance of hypoglycemia in IDDM. Diabetes Care 1995; 18:321.
  48. Fritsche A, Stefan N, Häring H, et al. Avoidance of hypoglycemia restores hypoglycemia awareness by increasing beta-adrenergic sensitivity in type 1 diabetes. Ann Intern Med 2001; 134:729.
  49. Fanelli C, Pampanelli S, Lalli C, et al. Long-term intensive therapy of IDDM patients with clinically overt autonomic neuropathy: effects on hypoglycemia awareness and counterregulation. Diabetes 1997; 46:1172.
  50. Gray RO, Butler PC, Beers TR, et al. Comparison of the ability of bread versus bread plus meat to treat and prevent subsequent hypoglycemia in patients with insulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1996; 81:1508.
  51. Bergenstal RM, Klonoff DC, Garg SK, et al. Threshold-based insulin-pump interruption for reduction of hypoglycemia. N Engl J Med 2013; 369:224.
  52. Irvine AA, Cox D, Gonder-Frederick L. Fear of hypoglycemia: relationship to physical and psychological symptoms in patients with insulin-dependent diabetes mellitus. Health Psychol 1992; 11:135.
  53. Pontiroli AE. Intranasal glucagon: a promising approach for treatment of severe hypoglycemia. J Diabetes Sci Technol 2015; 9:38.
  54. Rickels MR, Ruedy KJ, Foster NC, et al. Intranasal Glucagon for Treatment of Insulin-Induced Hypoglycemia in Adults With Type 1 Diabetes: A Randomized Crossover Noninferiority Study. Diabetes Care 2016; 39:264.
  55. Haymond MW, Redondo MJ, McKay S, et al. Nonaqueous, Mini-Dose Glucagon for Treatment of Mild Hypoglycemia in Adults With Type 1 Diabetes: A Dose-Seeking Study. Diabetes Care 2016; 39:465.
  56. Gunning RR, Garber AJ. Bioactivity of instant glucose. Failure of absorption through oral mucosa. JAMA 1978; 240:1611.
  57. Barennes H, Valea I, Nagot N, et al. Sublingual sugar administration as an alternative to intravenous dextrose administration to correct hypoglycemia among children in the tropics. Pediatrics 2005; 116:e648.
  58. Graz B, Dicko M, Willcox ML, et al. Sublingual sugar for hypoglycaemia in children with severe malaria: a pilot clinical study. Malar J 2008; 7:242.