In the January 2017 issue of Diabetes Care, the International Hypoglycaemia Study Group published a recommendation that glucose levels lower than 3.0 mmol/L (54 mg/dL) be documented in clinical trials of glucose-lowering diabetes drugs.1 The group consists of experts from numerous international and US institutions, including Washington University, the University of Virginia, and the University of Minnesota.
“Hypoglycemia is perhaps one of the most important barriers to glycemic control in patients with diabetes, as hypoglycemic episodes can not only limit the ability to obtain the glycemic target, but they may also result in harm to the patient,” Kevin M. Pantalone, DO, staff endocrinologist and director of clinical research at the Cleveland Clinic in Ohio, told Endocrinology Advisor. “
It would thus be very important to recognize the frequency of hypoglycemia in a standardized manner when conducting clinical trials, particularly when evaluating the efficacy and safety of antidiabetic therapies.”
The American Diabetes Association (ADA) previously defined hypoglycemia as any episode of abnormally low glucose that could result in harm to an individual.2 It had not been defined numerically because glycemic “thresholds for responses to hypoglycemia vary, not only among individuals with diabetes but also in the same individual with diabetes as a function of their HbA1c levels and hypoglycemic experience,” wrote the authors of the new paper.
During intensive glycemic treatment, for example, an increased frequency of iatrogenic hypoglycemia can cause the glycemic threshold for hypoglycemia and related glucose counterregulatory responses to shift to lower glucose concentrations.
Despite such variability, the study group emphasized the importance of identifying a specific glucose concentration indicative of a level of hypoglycemia that clearly presents the risk for harm and thus should be avoided.
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“Increasingly in our discussions, our group felt that the diabetes community was failing to appreciate the potentially serious consequences of glucose levels, which were not considered ‘severe'—meaning needing the help of another person to recover—and which were not captured systematically in clinical studies,” co-author Simon Heller, MD, a professor of clinical diabetes at the University of Sheffield in the UK, said in an interview.
Additionally, the use of different classification systems by various groups such as pharmaceutical companies has led to difficulty in comparing treatments.
“We feel that if the diabetes community can agree on a glucose level that captures this information, we can both calculate the clinical risk to patients and more effectively compare treatment approaches that aim to reduce rates of hypoglycemia. This would be an important advance,” said Dr Heller.
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.3These 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.
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