Hypoglycaemia unawareness: causes, consequences and treatment.

Fear of hypoglycaemia is a powerful emotion among patients treated with insulin, and hypoglycaemia remains the major factor limiting attempts to achieve and sustain normoglycaemia with intensive insulin therapy. The Diabetes Control and Complications Trial (DCCT) reported a threefold greater risk of severe hypoglycaemia in those randomised to intensive insulin therapy1,2, with most of the episodes occurring during sleep (Table 1). The DCCT feasibility study had previously identified a history of severe hypoglycaemia before study entry and longer duration of diabetes to be predictive of severe hypoglycaemia; patients with these characteristics were excluded from the major prospective randomisation. The risk of severe hypoglycaemia which accompanies attempts to tighten glycaemic control in a less highly selected patient population may therefore be even greater. In a four-year prospective study of a large clinic population of children with type 1 diabetes, tight glycaemic control, as evidenced by a reduction in the mean glycated haemoglobin from 10.2% to 8.8%, was associated with a dramatic increase in the rate of hypoglycaemia-related coma or convulsion from 4.8 to 15.6 episodes/100 patientyears. The increase was particularly marked in children below the age of six years, in whom the rate increased from 14.9 to 42.1 episodes/100 patientyears3. Although the absolute frequency of hypoglycaemia is considerably lower in patients with type 2 diabetes, even in this group efforts to intensify glycaemic control have been associated with a significantly increased prevalence of hypoglycaemia, particularly in those treated with insulin. It is self-evident that the risks of hypoglycaemia will be increased in patients achieving blood glucose concentrations close to normality. In contrast to those with poorer glycaemic control in whom the margins for error are proportionately greater, in tightly controlled patients even a modest mismatch in insulin dose, energy expenditure and carbohydrate consumption will risk hypoglycaemia. The degree of increased risk is, however, unexpected and occurs because ‘hypoglycemia begets hypoglycemia in IDDM’4; in other words, preceding hypoglycaemia promotes reduced symptomatic awareness and neuroendocrine responsiveness to subsequent hypoglycaemia, resulting in a progressive reduction in awareness of hypoglycaemia and an increase in hypoglycaemic risk . Impaired awareness of hypoglycaemia is a critical acquired defect in the defences against hypoglycaemia for patients with diabetes.