Defining hypoglycaemia: what level has clinical relevance?

Abstract

A wide range of glucose concentrations could therefore represent biochemical hypoglycaemia; the difficulty arises in determining at what level it starts. To address this and other problems of defining hypoglycaemia, a Workgroup of the American Diabetes Association (ADA) published an erudite report in 2005 [2] in which the methods of identifying and measuring hypoglycaemia were reviewed and a classification of hypoglycaemia was proposed. Much of the report and recommendations are sound, sensible and justifiable, based on available evidence. The one contentious issue is their proposal that any blood glucose value equal to, or below, 3.9 mmol/l (70 mg/dl) should represent hypoglycaemia, whether or not symptoms are present. Many clinicians would regard a blood glucose of this concentration in a non-diabetic adult as being within the normal fasting range, and would not consider it to indicate significant hypoglycaemia. This is an important consideration as it is evident that the glucose level that is selected to define hypoglycaemia can influence estimates of the frequency of this therapeutic side effect—a choice that could have important clinical and commercial implications. To illustrate this, Swinnen et al. [3] applied a range of different glucose levels defining hypoglycaemia to the blood glucose data from two large prospective trials of people with type 2 diabetes who had commenced treatment with insulin. As reported in this issue of Diabetologia, they unequivocally demonstrate how changing the glucose cut-off level can profoundly influence the estimated frequency of hypoglycaemia. The higher the cut-off level for hypoglycaemia, the greater the reported frequency, predominantly of asymptomatic events. The sensitivity to identify severe hypoglycaemia was not greatly enhanced by setting the definition of hypoglycaemia at a higher blood glucose level, but the specificity was lowered considerably. The authors suggest that exposure to blood glucose levels between 3.5 and 3.9 mmol/l is unlikely to be of great clinical consequence and argue that the ADA definition of 3.9 mmol/l is set at too high a level to have clinical credibility. It is timely therefore to re-examine the ADA definition with respect to this designated blood glucose level of 3.9 mmol/l [2]. Why was this level chosen? The ADA Workgroup argued that this is the glycaemic level at which hormonal counter-regulation is activated in non-diabetic adults [4, 5], and that antecedent hypoglycaemia of this modest degree can reduce the secretion of the counter-regulatory hormones glucagon and adrenaline (epinephrine) in response to a subsequent episode of hypoglycaemia [6].