Although various xenobiotics and medical conditions may cause hypoglycemia, this chapter focuses on the medications used for treatment of diabetes mellitus. These medications include insulin, incretin mimetics, and oral agents: the sulfonylureas, biguanides, α-glucosidase inhibitors, thiazolidinediones, meglitinides, and gliptins. Some of the medications in these chemically heterogeneous groups of xenobiotics can cause unique toxic effects in addition to hypoglycemia.
In general, neurohormonal control of glucose production in healthy individuals maintains a fasting serum glucose concentration in the range of 60–100 mg/dL. In diabetes mellitus, the body fails to maintain normal blood glucose concentrations. The two glycemic complications of diabetes mellitus and its therapy are hyperglycemia and hypoglycemia.
Most patients with diabetes mellitus are classified as having either insulin-dependent diabetes mellitus (IDDM), also known as type I diabetes, or non—insulin-dependent diabetes mellitus (NIDDM), also known as type II diabetes. This classification scheme for diabetes mellitus is not perfect. For example, some patients with type II diabetes may require insulin in addition to oral hypoglycemics. Early in the course of type I diabetes, patients may enter a remission period during which exogenous insulin is not required.
Insulin first became available for use in 1922 after Banting and colleagues successfully treated diabetic patients with pancreatic extracts.10 In an attempt to more closely simulate physiologic conditions, additional "designer" insulins with unique kinetic properties have been developed, including an ultrashort-acting preparation known as lispro.62,130 Several oral delivery systems for insulin have been studied.87 Development of an oral delivery system for use in humans has not been successful because of poor intestinal absorption and degradation of the oral form of insulin by digestive enzymes. Using zonula occludens toxin, modulation of intestinal tight junctions in animal models has resulted in significant increases in enteral absorption of insulin.38 An inhaled form of insulin had recently become available, but has been withdrawn from the market due to poor sales.83
The hypoglycemic activity of a sulfonamide derivative used for typhoid fever was noted during World War II.70 This discovery was verified later in animals. The sulfonylureas in use today are chemical modifications of that original sulfonamide compound. In the mid-1960s, the first-generation sulfonylureas were widely used. Newer second-generation drugs differ primarily in their potency.
Although insulin is widely used for treating diabetes mellitus, sulfonylurea exposures are much more commonly reported to poison centers than are insulin exposures, based on 15 years of data from 1993 to 2007 (Chap. 135). These data likely reflect a significant percentage of intentional overdose cases. In a review of 1418 medication-related cases of hypoglycemia, sulfonylureas (especially the long-acting chlorpropamide and glyburide) alone or with a second hypoglycemic accounted for the largest percentage of cases (63%).120 Only 18 of the sulfonylurea cases in this series involved overdose with suicidal intent. However, hypoglycemia is reported in as many as 20% of patients using sulfonylureas.55...