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Hypoglycaemia in type 1 diabetes mellitus: risks and practical prevention strategies

Nature Reviews Endocrinology volume 19, pages 177–186 (2023)Cite this article

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Abstract

Hypoglycaemia, which occurs when blood levels of glucose fall below what is considered a normal range, is a well-known complication of insulin therapy in individuals with type 1 diabetes mellitus. Despite advances in diabetes mellitus management, hypoglycaemia has continued to affect the majority of these individuals, leading to suboptimal care and decreased quality of life. Multiple epidemiological studies have demonstrated the risks associated with hypoglycaemic events. With this understanding, various advances have been made in therapeutics for diabetes mellitus management. Diabetes mellitus education continues to form the foundation for management and prevention of hypoglycaemia. The advent of newer diabetes mellitus technologies and newer insulins herald improvements in management strategies and hypoglycaemia prevention. Improved understanding of these newer approaches is needed to ensure delivery of safe and effective care to individuals with type 1 diabetes mellitus, leading to reductions in both the short-term and long-term morbidity and mortality associated with hypoglycaemic events.

Key points

  • Most individuals with type 1 diabetes mellitus (T1DM) experience frequent hypoglycaemic events.

  • Long-term risks of hypoglycaemia include impaired awareness of hypoglycaemia, cognitive decline, increased cardiovascular events and increased mortality.

  • Diabetes mellitus self-management education is an important resource that should be provided to all individuals with T1DM to prevent hypoglycaemia and optimize glycaemic control.

  • Use of continuous glucose monitors and hybrid closed loop insulin pumps can lead to reductions in hypoglycaemia and improved glycaemic control.

  • Substituting newer insulins (without peak effects and with longer half-lives) for older basal insulins should be considered to reduce hypoglycaemia.

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Fig. 1: Severe hypoglycaemia during the 12-month period from the Type 1 Diabetes Patient Characteristics, Disease Burden, and Clinical Outcome in US Electronic Health Record Database (T1PCO) study, stratified by HbA1c.
Fig. 2: Severe hypoglycaemia during the 12-month period from the Type 1 Diabetes Patient Characteristics, Disease Burden, and Clinical Outcome in US Electronic Health Record Database (T1PCO) study, stratified by age group and glycaemic control.
Fig. 3: Algorithm for management and prevention of hypoglycaemia in patients with type 1 diabetes mellitus.

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References

  1. International Hypoglycaemia Study Group. Glucose concentrations of less than 3.0 mmol/L (54 mg/dL) should be reported in clinical trials: a joint position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 40, 155–157 (2017).

    Article  Google Scholar 

  2. Agiostratidou, G. et al. Standardizing clinically meaningful outcome measures beyond HbA1c for type 1 diabetes: a consensus report of the American Association of Clinical Endocrinologists, the American Association of Diabetes Educators, the American Diabetes Association, the Endocrine Society, JDRF International, The Leona M. and Harry B. Helmsley Charitable Trust, the Pediatric Endocrine Society, and the T1D Exchange. Diabetes Care 40, 1622–1630 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Pedersen-Bjergaard, U., Faerch, L., Allingbjerg, M. L., Agesen, R. & Thorsteinsson, B. The influence of new European Union Driver’s License Legislation on reporting of severe hypoglycemia by patients with type 1 diabetes. Diabetes Care 38, 29–33 (2015).

    Article  PubMed  Google Scholar 

  4. Weinstock, R. S. et al. Severe hypoglycemia and diabetic ketoacidosis in adults with type 1 diabetes: results from the T1D exchange clinic registry. J. Clin. Endocrinol. Metab. 98, 3411–3419 (2013).

    Article  CAS  PubMed  Google Scholar 

  5. Shamoon, H. et al. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes-mellitus. N. Engl. J. Med. 329, 977–986 (1993).

    Article  Google Scholar 

  6. Henriksen, M. M., Andersen, H. U., Thorsteinsson, B. & Pedersen-Bjergaard, U. Hypoglycemic exposure and risk of asymptomatic hypoglycemia in type 1 diabetes assessed by continuous glucose monitoring. J. Clin. Endocrinol. Metab. 103, 2329–2335 (2018).

    Article  PubMed  Google Scholar 

  7. Pettus, J. H. et al. Incidences of severe hypoglycemia and diabetic ketoacidosis and prevalence of microvascular complications stratified by age and glycemic control in U.S. adult patients with type 1 diabetes: a real-world study. Diabetes Care 42, 2220–2227 (2019).

    Article  PubMed  Google Scholar 

  8. Frier, B. M. Hypoglycemia in the diabetic adult. Baillieres Clin. Endocrinol. Metab. 7, 757–777 (1993).

    Article  CAS  PubMed  Google Scholar 

  9. Khunti, K. et al. Rates and predictors of hypoglycaemia in 27 585 people from 24 countries with insulin-treated type 1 and type 2 diabetes: the global HAT study. Diabetes Obes. Metab. 18, 907–915 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Geddes, J., Schopman, J. E., Zammitt, N. N. & Frier, B. M. Prevalence of impaired awareness of hypoglycaemia in adults with type 1 diabetes. Diabet. Med. 25, 501–504 (2008).

    Article  CAS  PubMed  Google Scholar 

  11. Pedersen-Bjergaard, U. et al. Severe hypoglycaemia in 1076 adult patients with type 1 diabetes: influence of risk markers and selection. Diabetes Metab. Res. Rev. 20, 479–486 (2004).

    Article  PubMed  Google Scholar 

  12. Gonder-Frederick, L. A. et al. Cognitive function is disrupted by both hypo- and hyperglycemia in school-aged children with type 1 diabetes: a field study. Diabetes Care 32, 1001–1006 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Jauch-Chara, K. et al. Hypoglycemia during sleep impairs consolidation of declarative memory in type 1 diabetic and healthy humans. Diabetes Care 30, 2040–2045 (2007).

    Article  CAS  PubMed  Google Scholar 

  14. Lacy, M. E. et al. Severe hypoglycemia and cognitive function in older adults with type 1 diabetes: the study of longevity in diabetes (SOLID). Diabetes Care 43, 541–548 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Jacobson, A. M. et al. Cognitive performance declines in older adults with type 1 diabetes: results from 32 years of follow-up in the DCCT and EDIC study. Lancet Diabetes Endocrinol. 9, 436–445 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Jacobson, A. M. et al. Long-term effect of diabetes and its treatment on cognitive function. N. Engl. J. Med. 356, 1842–1852 (2007).

    Article  PubMed  Google Scholar 

  17. George, E. et al. Preservation of physiological cell responses to hypoglycemia 2 days after antecedent hypoglycemia in patients with IDDM. Diabetes Care 20, 1293–1298 (1997).

    Article  CAS  PubMed  Google Scholar 

  18. Cryer, P. E. Mechanisms of hypoglycemia-associated autonomic failure and its component syndromes in diabetes. Diabetes 54, 3592–3601 (2005).

    Article  CAS  PubMed  Google Scholar 

  19. Gerich, J. E., Mokan, M., Veneman, T., Korytkowski, M. & Mitrakou, A. Hypoglycemia unawareness. Endocr. Rev. 12, 356–371 (1991).

    Article  CAS  PubMed  Google Scholar 

  20. Hendrieckx, C. et al. Severe hypoglycaemia and its association with psychological well-being in Australian adults with type 1 diabetes attending specialist tertiary clinics. Diabetes Res. Clin. Pract. 103, 430–436 (2014).

    Article  CAS  PubMed  Google Scholar 

  21. Lawton, J. et al. Experiences, views, and support needs of family members of people with hypoglycemia unawareness: interview study. Diabetes Care 37, 109–115 (2014).

    Article  PubMed  Google Scholar 

  22. Rubin, N. T. et al. Relationship between hypoglycemia awareness status on Clarke/Gold methods and counterregulatory response to hypoglycemia. J. Endocr. Soc. 6, bvac107 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  23. 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 hypoglycemia among patients with type 1 diabetes. Diabetes Care 39, 1571–1578 (2016).

    Article  PubMed  Google Scholar 

  24. Khunti, K. et al. 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 38, 316–322 (2015).

    Article  PubMed  Google Scholar 

  25. Fahrmann, E. R., Adkins, L. & Driscoll, H. K. Modification of the association between severe hypoglycemia and ischemic heart disease by surrogates of vascular damage severity in type 1 diabetes during approximately 30 years of follow-up in the DCCT/EDIC study. Diabetes Care 44, 2132–2139 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Joy, N. G. et al. Acute and chronic effects of atomoxetine on symptom awareness and cognitive function during repeated hypoglycemia in healthy individuals [abstract 396-P]. Diabetes 64, A103 (2015).

    Google Scholar 

  27. Wright, R. J. et al. Effects of acute insulin-induced hypoglycemia on indices of inflammation putative mechanism for aggravating vascular disease in diabetes. Diabetes Care 33, 1591–1597 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Frier, B. M., Schernthaner, G. & Heller, S. R. Hypoglycemia and cardiovascular risks. Diabetes Care 34, S132–S137 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Snell-Bergeon, J. K. & Wadwa, R. P. Hypoglycemia, diabetes, and cardiovascular disease. Diabetes Technol. Ther. 14, S51–S58 (2012).

    Article  CAS  PubMed  Google Scholar 

  30. Robinson, R. T., Harris, N. D., Ireland, R. H., Macdonald, I. A. & Heller, S. R. Changes in cardiac repolarization during clinical episodes of nocturnal hypoglycaemia in adults with type 1 diabetes. Diabetologia 47, 312–315 (2004).

    Article  CAS  PubMed  Google Scholar 

  31. Murphy, N. P. et al. Prolonged cardiac repolarisation during spontaneous nocturnal hypoglycaemia in children and adolescents with type 1 diabetes. Diabetologia 47, 1940–1947 (2004).

    Article  CAS  PubMed  Google Scholar 

  32. Gruden, G. et al. QTc interval prolongation is independently associated with severe hypoglycemic attacks in type 1 diabetes from the EURODIAB IDDM complications study. Diabetes Care 35, 125–127 (2012).

    Article  PubMed  Google Scholar 

  33. Tanenberg, R. J., Newton, C. A. & Drake, A. J. Confirmation of hypoglycemia in the “dead-in-bed” syndrome, as captured by a retrospective continuous glucose monitoring system. Endocr. Pract. 16, 244–248 (2010).

    Article  PubMed  Google Scholar 

  34. Tattersall, R. B. & Gill, G. V. Unexplained deaths of type 1 diabetic patients. Diabet. Med. 8, 49–58 (1991).

    Article  CAS  PubMed  Google Scholar 

  35. Gill, G. V., Woodward, A., Casson, I. F. & Weston, P. J. Cardiac arrhythmia and nocturnal hypoglycaemia in type 1 diabetes – the ‘dead in bed’ syndrome revisited. Diabetologia 52, 42–45 (2009).

    Article  CAS  PubMed  Google Scholar 

  36. Novodvorsky, P. et al. Diurnal differences in risk of cardiac arrhythmias during spontaneous hypoglycemia in young people with type 1 diabetes. Diabetes Care 40, 655–662 (2017).

    Article  PubMed  Google Scholar 

  37. Laing, S. P. et al. The British Diabetic Association Cohort Study, II: cause-specific mortality in patients with insulin-treated diabetes mellitus. Diabet. Med. 16, 466–471 (1999).

    Article  CAS  PubMed  Google Scholar 

  38. American Diabetes Association Professional Practice Committee. 6. Glycemic targets: standards of medical care in diabetes–2022. Diabetes Care 45, S83–S96 (2022).

    Article  Google Scholar 

  39. Bailey, T. S. et al. Dasiglucagon, a next-generation glucagon analogue, for treatment of severe hypoglycaemia via an autoinjector device: results of a phase 3, randomized, double-blind trial. Diabetes Obes. Metab. 23, 2329–2335 (2021).

    Article  CAS  PubMed  Google Scholar 

  40. Rickels, M. R. et al. Intranasal glucagon for treatment of insulin-induced hypoglycemia in adults with type 1 diabetes: a randomized crossover noninferiority study. Diabetes Care 39, 264–270 (2016).

    Article  CAS  PubMed  Google Scholar 

  41. Seaquist, E. R. et al. Prospective study evaluating the use of nasal glucagon for the treatment of moderate to severe hypoglycaemia in adults with type 1 diabetes in a real-world setting. Diabetes Obes. Metab. 20, 1316–1320 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Seaquist, E. R. et al. Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society. Diabetes Care 36, 1384–1395 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Hopkins, D. et al. Improved biomedical and psychological outcomes 1 year after structured education in flexible insulin therapy for people with type 1 diabetes: the U.K. DAFNE experience. Diabetes Care 35, 1638–1642 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Cox, D. J. et al. Blood glucose awareness training (BGAT-2): long-term benefits. Diabetes Care 24, 637–642 (2001).

    Article  CAS  PubMed  Google Scholar 

  45. Cox, D. J. 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. 11, 212–218 (2004).

    Article  PubMed  Google Scholar 

  46. Amiel, S. A. et al. A parallel randomised controlled trial of the Hypoglycaemia Awareness Restoration Programme for adults with type 1 diabetes and problematic hypoglycaemia despite optimised self-care (HARPdoc). Nat. Commun. 13, 2229 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Beck, R. W. et al. Effect of continuous glucose monitoring on glycemic control in adults with type 1 diabetes using insulin injections: the DIAMOND randomized clinical trial. JAMA 317, 371–378 (2017).

    Article  CAS  PubMed  Google Scholar 

  48. Heinemann, L. et al. Real-time continuous glucose monitoring in adults with type 1 diabetes and impaired hypoglycaemia awareness or severe hypoglycaemia treated with multiple daily insulin injections (HypoDE): a multicentre, randomised controlled trial. Lancet 391, 1367–1377 (2018).

    Article  CAS  PubMed  Google Scholar 

  49. Laffel, L. M. et al. Effect of continuous glucose monitoring on glycemic control in adolescents and young adults with type 1 diabetes: a randomized clinical trial. JAMA 323, 2388–2396 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Pratley, R. E. et al. Effect of continuous glucose monitoring on hypoglycemia in older adults with type 1 diabetes: a randomized clinical trial. JAMA 323, 2397–2406 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Little, S. A. et al. Recovery of hypoglycemia awareness in long-standing type 1 diabetes: a multicenter 2 x 2 factorial randomized controlled trial comparing insulin pump with multiple daily injections and continuous with conventional glucose self-monitoring (HypoCOMPaSS). Diabetes Care 37, 2114–2122 (2014).

    Article  CAS  PubMed  Google Scholar 

  52. Ratner, R. E. et al. Less hypoglycemia with insulin glargine in intensive insulin therapy for type 1 diabetes. Diabetes Care 23, 639–643 (2000).

    Article  CAS  PubMed  Google Scholar 

  53. Heise, T. et al. Insulin degludec: four times lower pharmacodynamic variability than insulin glargine under steady-state conditions in type 1 diabetes. Diabetes Obes. Metab. 14, 859–864 (2012).

    Article  CAS  PubMed  Google Scholar 

  54. Lane, W. et al. Effect of insulin degludec vs insulin glargine U100 on hypoglycemia in patients with type 1 diabetes: the SWITCH 1 randomized clinical trial. JAMA 318, 33–44 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Becker, R. H. A. et al. New insulin glargine 300 units.mL−1 provides a more even activity profile and prolonged glycemic control at steady state compared with insulin glargine 100 units.mL−1. Diabetes Care 38, 637–643 (2015).

    Article  CAS  PubMed  Google Scholar 

  56. Home, P. D. et al. Glycaemic control and hypoglycaemia during 12 months of randomized treatment with insulin glargine 300 U/mL versus glargine 100 U/mL in people with type 1 diabetes (EDITION 4). Diabetes Obes. Metab. 20, 121–128 (2018).

    Article  CAS  PubMed  Google Scholar 

  57. Malecki, M. T. et al. Ultra-rapid lispro improves postprandial glucose control and time in range in type 1 diabetes compared to lispro: PRONTO-T1D continuous glucose monitoring substudy. Diabetes Technol. Ther. 22, 853–860 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Hering, B. J. et al. Single-donor, marginal-dose islet transplantation in patients with type 1 diabetes. J. Am. Med. Assoc. 293, 830–835 (2005).

    Article  CAS  Google Scholar 

  59. Rickels, M. R. et al. Long-term improvement in glucose control and counterregulation by islet transplantation for type 1 diabetes. J. Clin. Endocrinol. Metab. 101, 4421–4430 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Hering, B. J. et al. Phase 3 trial of transplantation of human islets in type 1 diabetes complicated by severe hypoglycemia. Diabetes Care 39, 1230–1240 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Bergenstal, R. M. et al. Threshold-based insulin-pump interruption for reduction of hypoglycemia. N. Engl. J. Med. 369, 224–232 (2013).

    Article  CAS  PubMed  Google Scholar 

  62. Forlenza, G. P. et al. Predictive low-glucose suspend reduces hypoglycemia in adults, adolescents, and children with type 1 diabetes in an at-home randomized crossover study: results of the PROLOG trial. Diabetes Care 41, 2155–2161 (2018).

    Article  CAS  PubMed  Google Scholar 

  63. Brown, S. A. et al. Six-month randomized, multicenter trial of closed-loop control in type 1 diabetes. N. Engl. J. Med. 381, 1707–1717 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Tauschmann, M. et al. Closed-loop insulin delivery in suboptimally controlled type 1 diabetes: a multicentre, 12-week randomised trial. Lancet 392, 1321–1329 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Brown, S. A. et al. Multicenter trial of a tubeless, on-body automated insulin delivery system with customizable glycemic targets in pediatric and adult participants with type 1 diabetes. Diabetes Care 44, 1630–1640 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Hepburn, D. A. et al. Symptoms of acute insulin-induced hypoglycemia in humans with and without IDDM. Factor-analysis approach. Diabetes Care 14, 949–957 (1991).

    Article  CAS  PubMed  Google Scholar 

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  1. Department of Medicine, Division of Endocrinology and Diabetes, University of Minnesota, Minneapolis, MN, USA

    Jasleen Kaur & Elizabeth R. Seaquist

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E.R.S. researched data for the article, wrote the manuscript and reviewed and/or edited the manuscript before submission. J.K. researched data for the article and wrote the article. E.R.S and J.K. contributed to discussion of the content.

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Correspondence to Elizabeth R. Seaquist.

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Kaur, J., Seaquist, E.R. Hypoglycaemia in type 1 diabetes mellitus: risks and practical prevention strategies. Nat Rev Endocrinol 19, 177–186 (2023). https://doi.org/10.1038/s41574-022-00762-8

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