The prevention of iatrogenic hypoglycemia is similar in advanced type 2 diabetes and type 1 diabetes (6,22). Hypoglycemia risk reduction involves:

• Addressing the issue of hypoglycemia in every patient contact.
• Applying the principles of aggressive glycemic therapy - patient education, frequent self-monitoring of blood glucose,  flexible insulin (or other drug)  regimens,  individualized glycemic goals and ongoing professional guidance.
• Considering both the conventional risk factors and those indicative of compromised defenses against hypoglycemia, and adjusting the treatment regimen accordingly.

Given a history of hypoglycemia unawareness, a 2- to 3-week period of scrupulous avoidance of hypoglycemia is advisable since that often restores awareness of hypoglycemia and improves the epinephrine response. The use of insulin analogues (e.g., glargine or detemir as the basal insulin and lispro, aspart of glulisine as the prandial insulin) reduces the risk at least of nocturnal hypoglycemia. Despite its theoretical advantages, continuous subcutaneous insulin infusion has not been found to cause less hypoglycemia than a bolus-based insulin regimen with insulin analogues in type 2 diabetes. Among patients with type 2 diabetes responsive to a sulfonylurea, hypoglycemia occurs more frequently in those treated with glyburide (glibenclamide) than with glipizide or, particularly, glimepiride.

 

With these approaches it is possible to improve glycemic control substantially and reduce the risk of hypoglycemia in many patients with type 2 diabetes. Nonetheless, hypoglycemia continues to be a problem for many patients with advanced type 2 diabetes.

Ultimately,  the problem of hypoglycemia (and hyperglycemia)  will likely be solved by therapeutic methods that provide glucose-regulated insulin replacement or secretion.

Treatment of Hypoglycemia
Obviously, prevention of iatrogenic hypoglycemia, as just discussed, is preferable to treatment of hypoglycemia. Episodes of asymptomatic hypoglycemia (detected by self-monitoring of blood glucose)  and most episodes of mild to moderate symptomatic hypoglycemia,  are effectively self-treated by ingestion of glucose tablets or carbohydrate in the form of juices, soft drinks, milk, crackers, candy or a meal. A glucose dose of 20 g is reasonable (26). However, in the setting of ongoing hyperinsulinemia, the glycemic response to oral glucose is transient, typically

< 2 hours. Therefore, ingestion of a snack or meal shortly after the glucose level is raised is generally advisable.

Parenteral treatment is necessary when a hypoglycemic patient is unable or unwilling (because of neuroglycopenia) to take carbohydrate orally. While subcutaneous or intramuscular glucagon (1.0 mg in adults) is often used, by family members, to treat hypoglycemia in type 1 diabetes, glucagon is less useful in many patients with type 2 diabetes because it stimulates insulin secretion. Thus, intravenous glucose (25 g initially) is the preferable treatment for severe hypoglycemia in type 2 diabetes. Because sulfonylurea-induced hypoglycemia can persist for hours and even days, prolonged glucose infusion and frequent feedings are often required. This may require hospitalization. Clearly, it is critical that the absence of recurrent hypoglycemia is established unequivocally before the patient is discharged.

Summary and Perspective
Iatrogenic hypoglycemia is the limiting factor in the glycemic management of diabetes, and a barrier to true glycemic control and its established long-term vascular benefits. Hypoglycemia is less frequent overall in type 2 diabetes, compared with type 1 diabetes, because glucose counterregulatory defenses remain intact early in the course of type 2 diabetes. However, iatrogenic hypoglycemia becomes a progressively more frequent problem,  ultimately approaching that in type 1 diabetes, as patients approach the insulin-deficient end of the spectrum of type 2 diabetes because of compromised physiological and behavioral defenses against developing hypoglycemia. The syndromes of defective glucose counterregulation and hypoglycemia unawareness, and the concept of HAAF, in advanced (insulin deficient) type 2 diabetes are analogous to those that develop early in the course of type 1 diabetes.  By practicing hypoglycemia risk reduction, i.e., addressing the issue, applying the principles of aggressive glycemic therapy, and considering both the conventional risk factors and those indicative of compromised defenses against hypoglycemia, healthcare providers should strive to reduce mean glycemia as much as can be accomplished safely.  Clearly,  given current treatment limitations, people with diabetes need more physiological approaches to glycemic control, tailored to their degree of insulin deficiency.

Hypoglycemia should not be used, by the provider or the patient, as an excuse for poor glycemic control, particularly in view of the growing array of glucose-lowering drugs that can be used to optimize therapy and achieve the best control possible in a given patient with type 2 diabetes. Nonetheless, better methods - such as those that would provide glucose-regulated insulin replacement or secretion - are clearly needed for people with type 2 diabetes, as well as for those with type 1 diabetes, if we are to maintain euglycemia over a lifetime of diabetes.

ACKNOWLEDGMENTS
The author’s work cited in this section was supported, in part, by National Institutes of Health grants R37 DK27085, M01 RR00036, P60 DK20579, and T32 DK07120 and a fellowship award from the American Diabetes Association. The assistance of Ms. Penny Casey and Ms. Janet Dedeke in the preparation of this manuscript is gratefully acknowledged.

Philip E. Cryer
Washington University School of Medicine, St. Louis, Missouri, U.S.A.

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