Organizations publish recommendations for identifying and reporting hypoglycemia in clinical studies.
Current research on hypoglycemia was examined by the International Hypoglycemia Study group to create proposed hypoglycemia levels. The study group also formed recommendations for which levels of hypoglycemia should be reported.
Simon R. Heller, MD, professor of clinical diabetes, University of Sheffield, and director of research and development and honorary consultant physician at Sheffield Teaching Hospitals NHS Foundation Trust in the United Kingdom, said in a press release that, “We formed our multi-disciplinary group 3 years ago with a goal to increase awareness of hypoglycemia as a major side effect of current treatment in diabetes by educational activities among the diabetes community — including patients, their families and professionals — to benefit patient care….We developed the idea that a reclassification of hypoglycemia would be useful and are delighted that both the ADA and European Association for the Study of Diabetes have agreed.”
A Joint Position Statement of the American Diabetes Association and the European Association for the Study of Diabetes agreed that a glucose concentration of less than 54 mg/dL. or 3.0 mmol/L should be reported in clinical trials of glucose-lowering drugs evaluated for the treatment of diabetes.
The glycemic thresholds for symptoms of hypoglycemia and for glucose counterregulatory (including sympathoadrenal) responses to hypoglycemia, as plasma glucose concentrations fall, are not fixed in patients with insulin, sulfonylurea, or meglitinide (glinide)-treated diabetes. They are at higher glucose concentrations in those with poor glycemic control and at lower glucose concentrations in those with tight glycemic control. The shifts in glycemic threshold to lower glucose concentrations are largely the result of more frequent episodes of iatrogenic hypoglycemia during intensive glycemic therapy. 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; it is therefore not appropriate to cite a specific glucose concentration that defines hypoglycemia in diabetes. As a consequence, the American Diabetes Association has defined hypoglycemia in diabetes non numerically as “all episodes of an abnormally low plasma glucose concentration that expose the individual to potential harm.”
Nonetheless, the International Hypoglycemia Study Group believes that it is important to identify and record a level of hypoglycemia that needs to be avoided because of its immediate and long-term danger to the individual. A single glucose level should be agreed to that has serious clinical and health-economic consequences. This would enable the diabetes and regulatory communities to compare the effectiveness of interventions in reducing hypoglycemia, be they pharmacological, technological, or educational. It would also permit the use of meta-analysis as a statistical tool to increase power when comparing interventions.
In its discussion, the International Hypoglycemia Study Group considered glucose concentration levels of <54 mg/dL (3.0 mmol/L), and 50 mg/dL(2.8 mmol/L), detected by self-monitoring of plasma glucose, continuous glucose monitoring (for at least 20 minutes), or a laboratory measurement of plasma glucose. Both of these levels are distinctly low glucose concentrations that do not occur under physiological conditions in nondiabetic individuals. Thus, they are unequivocally hypoglycemic values. They approximate the upper and lower limits, respectively, of the nondiabetic glycemic threshold for symptoms of insulin-induced hypoglycemia. The generic nondiabetic glycemic threshold for impairment of cognitive function is <50 mg/dL (2.8 mmol/L), but higher glucose levels have been reported for some tests.
Glucose concentrations of both <54 mg/dL (3.0mmol/L) and <50 mg/dL (2.8 mmol/L) cause defective glucose counterregulation and impaired awareness of hypoglycemia, the core components of hypoglycemia associated autonomic failure in diabetes. Avoiding these glucose levels could reverse impaired awareness of hypoglycemia, and some aspects of defective glucose counterregulation, in many affected patients. In type 1 diabetes, failure to recognize one’s own hypoglycemia at a glucose concentration <54 mg/dL (3.0 mmol/L) increased the risk of severe hypoglycemia (defined as needing the help of another person for recovery) fourfold. In type 2 diabetes, both glucose concentrations were associated with cardiac arrhythmias. Finally, a glucose concentration <50 mg/dL, (2.8 mmol/L) was associated with mortality in patients with type 2 diabetes in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial (NCT00000620), and possibly in the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial (NCT00069784), and among patients treated in intensive care units in the Normoglycemia in Intensive Care Evaluation Survival Using Glucose Algorithm Regulation (NICE-SUGAR) trial (NCT00220987). A glucose concentration <54 mg/dL, (3.0 mmol/L) was associated with mortality in the NICE-SUGAR trial and, possibly, in the ORIGIN trial.
Ultimately, the International Hypoglycemia Study Group members agreed that a glucose concentration <54 mg/dL (3.0 mmol/L) is sufficiently low to indicate serious, clinically important hypoglycemia. Possible terms used to describe this condition include “serious,” “clinically important,” “major,” or “clinically significant.” The group decided not to describe “severe hypoglycemia” in terms of glucose concentration since there is currently widespread agreement that severe hypoglycemia, as defined by the American Diabetes Association, denotes severe cognitive impairment requiring external assistance for recovery. The group also proposed that the frequency of detection of the glucose alert value of 70 mg/dL (3.9 mmol/L) or less need not be reported routinely in clinical trials.
In conclusion, the table below (Table 1) shows the glucose levels that have been proposed for adoption by the diabetes community to address the issue of hypoglycemic risk.
Table 1 — Proposed glucose levels when reporting hypoglycemia in clinical trials
Level 1: A glucose alert value of 70mg/dL. (3.9 mmol/L) or less.
Level 2: A glucose level of 54mg/dL. (3.0 mmol/L) is sufficiently low to indicate serious, clinically important hypoglycemia
Level 3: Severe hypoglycemia, as defined by the ADA, denotes severe cognitive impairment requiring external assistance for recovery clinical studies, although this would depend on the purpose of the study
The position statement was simultaneously published in Diabetologia.