Hypoglycemia unawareness is defined as the onset of neuroglycopenia before the appearance of autonomic warning symptoms.¹ It is difficult to study in its natural form because of its paroxysmal and unpredictable nature; therefore, well-controlled trials are limited. However, much is known regarding risk factors, biochemical causes, and populations at greatest risk for the development of hypoglycemia unawareness. Less is known regarding the impact of medications on the development or recognition of this condition in patients with diabetes. Several medications are thought to worsen or promote hypoglycemia unawareness, whereas others may have an attenuating effect on the problem. This article will review hypoglycemia unawareness and summarize the effects of medications that may influence it.

Hypoglycemic Counterregulation

In individuals without diabetes, a predictable, organized response occurs when blood glucose declines to hypoglycemic levels (Figure 1). First, insulin secretion is suppressed as glucose falls to < 81 mg/dl.¹ The suppression of insulin secretion has two effects: peripheral glucose utilization is reduced and hepatic glucose output is induced. This action typically terminates the episode. However, if glucose decline continues to < 68 mg/dl, glucagon secretion from α-cells and epinephrine secretion from the adrenals are stimulated.¹ These actions promote hepatic glucose production via gluconeogenesis and glycogenolysis. Growth hormone and cortisol are released as glucose levels decline even further (to ∼ 63 mg/dl) but are probably best characterized as responders to prolonged hypoglycemia rather than acute responders. The central nervous system triggers autonomic symptoms of hypoglycemia at plasma glucose levels between 54 and 90 mg/dl (Table 1). These symptoms are aimed at encouraging consumption of calories and are the harbinger of impending neuroglycopenia. If unchecked, the hypoglycemia will cause neuroglycopenic symptoms (Table 1) and eventually seizures and coma.

The glycemic threshold at which this counterregulatory response occurs is predictable in people without …