Defining hypoglycaemia: what level has clinical relevance?

Abstract

Never let the facts get in the way of a carefully thoughtout bad decision.John Marshall (1755Marshall ( -1835 Because hypoglycaemia is so common in insulin-treated diabetes and remains the greatest impediment to strict glycaemic control, its evaluation is mandatory as an outcome measure of studies assessing new therapies for diabetes and those comparing insulin regimens or management strategies. Regrettably, the lack of consensus as to how hypoglycaemia should be defined has permitted, if not actively encouraged, a plethora of eccentric, vague and clinically irrelevant definitions to be applied in many therapeutic trials. The practical definition (from a clinical viewpoint) of severe (requiring external help for recovery) and mild (self-treated) hypoglycaemia, as described in the DCCT [1], has been widely adopted for epidemiological and clinical use, but its reliance on ascertaining the ability to self-treat hypoglycaemia does not capture events that do not generate symptoms-socalled asymptomatic 'biochemical' hypoglycaemia. This is a common problem in people with impaired awareness of hypoglycaemia, but is recognised to occur in all people treated with insulin, either because the glycaemic thresholds that trigger symptomatic and physiological responses are not broached, or warning symptoms are not subjectively perceived. The frequency with which biochemical hypoglycaemia appears to occur is dependent on how often it is measured. Estimates based on continuous glucose monitoring systems cannot be included because the sensors measure interstitial tissue glucose, and the inter-relationship between this and blood glucose is unclear. Rationale for the American Diabetes Association definition of biochemical hypoglycaemiaA 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 fr...

Regional variations in definitions and rates of hypoglycaemia: findings from the global HAT observational study of 27 585 people with Type 1 and insulin‐treated Type 2 diabetes mellitus

“…Despite the potentially serious consequences, it remains unclear how people with diabetes understand and define hypoglycaemia 6. Hypoglycaemia definitions, including symptomatic vs. blood glucose measured and the use of different blood glucose cut‐off points, vary in different studies, regions and guidelines 7, 8, 9.…”

“…Hypoglycaemia definitions, including symptomatic vs. blood glucose measured and the use of different blood glucose cut‐off points, vary in different studies, regions and guidelines 7, 8, 9. For example, the ADA and American Academy of Clinical Endocrinologists consider blood glucose values ≤ 3.9 mmol/l as hypoglycaemia 5, 8; the International Hypoglycaemia Study Group and ADA/EASD recommend reporting all events with blood glucose < 3.0 mmol/l 10; the Canadian Diabetes Association use a cut‐off of 4 mmol/l 7; whereas a cut‐off of 3.5 mmol/l has been used to define clinically meaningful hypoglycaemia 6. The use of different hypoglycaemia definitions has a major effect on reported hypoglycaemia incidence 10, 11, 12.…”

Preventing hypoglycaemia: what is the appropriate glucose alert value?

“…Swinnen et al [1], Frier [2] and Amiel et al [3] opine that a lower plasma glucose concentration alert value would be preferable. Collectively, they raise four points.…”

“…However, its relevance to people with diabetes, in whom lower glucose levels predict subsequent severe hypoglycaemia [13], is questionable. Second, use of a glucose cut-off value of ≤3.9 mmol/l (70 mg/dl) would overestimate the frequency of clinically important hypoglycaemia [1,3] or inflate the frequency of clinically meaningless biochemical hypoglycaemia [2]. This criticism is wide of the mark.…”

“…Frier raises additional issues [2]. His points about the technical aspects of glucose measurements are true, but, in my view, clinically irrelevant given the limited accuracy of devices for self-monitoring blood glucose-generally calibrated to provide estimates of plasma glucose concentrations-at low glucose levels.…”