Before they settled on the 3.0-mmol/L level, the group initially considered glucose levels of <3.0 mmol/L (<54 mg/dL) and <2.8 mmol/L (<50 mg/dL), as detected by self-monitoring, continuous glucose monitoring, or laboratory measurement. Both levels have been found to lead to impairments in glucose counterregulation and patients’ awareness of hypoglycemia.3 These impairments represent “the core components of hypoglycemia-associated autonomic failure in diabetes” and may be reversed by avoiding such glucose levels, according to the current paper.
Previous findings have also shown that patients with type 1 diabetes who failed to recognize their hypoglycemia at a level of <3.0 mmol/L (<54 mg/dL) had a 4-fold increase in the risk for severe hypoglycemia, and both the 2.8 mmol/L and the 3.0 mmol/L levels have been linked with mortality in several different patient groups.4-6 For example, a post-hoc analysis of results from the Normoglycemia in Intensive Care Evaluation–Survival Using Glucose Algorithm Regulation (NICE-SUGAR) trial, which was reported in the New England Journal of Medicine in 2012, revealed that moderate hypoglycemia (defined as a value between 2.3-3.9 mmol/L) was associated with a 40% increase in the risk for death among patients in hospital intensive care units.6
“The glucose concentration suggested by the study group to be used for reporting hypoglycemia in clinical trials appears appropriate, as it is a distinctly low level that generally does not occur under physiological conditions in individuals without diabetes,” noted Dr Pantalone. While there are patients who may feel the symptoms of hypoglycemia at higher concentrations, this observation is highly variable and would be difficult to define and capture in clinical trials. “In clinical practice we alert the patients as to what glucose concentrations are considered low, but also educate them that they may feel symptoms of hypoglycemia at higher values, and that those episodes should be recorded, considered hypoglycemia, and treated accordingly.”
The study group persuaded both the ADA and the European Association for the Study of Diabetes (EASD) of the importance of this issue, as reflected by the issuance of this new recommendation as a joint statement by both organizations. The group has also presented their case to the US Food and Drug Administration (FDA) and hopes that the agency, the Europeans Medicines Agency, and “perhaps other regulatory bodies and others in the industry will now agree to adopt the same classification of hypoglycemia to be required in clinical trials,” said Dr Heller.
- 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. 2017;40(1):155-157. doi:10.2337/dc16-2215.
- 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. Diabetes Care. 2013;36:1384–1395.
- Cryer PE. Mechanisms of hypoglycemia-associated autonomic failure in diabetes. N Engl J Med. 2013;369:362–372.
- Cranston I, Lomas J, Maran A, Macdonald I, Amiel SA. Restoration of hypoglycemia awareness in patients with long-duration insulin-dependent diabetes. Lancet. 1994;344:283-287.
- Bonds DE, Miller ME, 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.
- Finfer S, Liu B, Chittock DR, et al., NICE-SUGAR Study Investigators. Hypoglycemia and risk of death in critically ill patients. N Engl J Med. 2012;367:1108–1118.