Oral Hypoglycemic Agent Toxicity

Updated: Feb 28, 2017
  • Author: David Tran, MD; Chief Editor: Timothy E Corden, MD  more...
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Overview

Practice Essentials

Oral hypoglycemic agents—sulfonylureas—which are used to treat patients with type 2 diabetes, [1] are among the most widely prescribed medications in the world. Wide availability of these medications increases the potential for either intentional or unintentional overdose in pediatric and adult populations. [2]

First-generation sulfonylurea compounds became widely available in 1955. They are acetohexamide, chlorpropamide, tolazamide, and tolbutamide. First-generation agents have long half-lives (eg, 49 hours for chlorpropamide). Second-generation sulfonylureas were introduced in 1984 and include glipizide, glyburide, and glimepiride. Second-generation sulfonylureas are more potent and have shorter half-lives than the first-generation sulfonylureas.

Other agents besides sulfonylureas are used to treat type 2 diabetes, including biguanides, alpha-glucosidase inhibitors, and thiazolidinediones. Metformin (Glucophage in the United States), a biguanide, is one such agent. [3] Even in overdose, these agents do not decrease serum glucose below euglycemia; consequently, they are appropriately referred to as antihyperglycemic agents rather than hypoglycemic agents. Although overdose of antihyperglycemic agents can have dangerous adverse effects (for example, lactic acidosis from metformin [4] ), this article focuses on acute overdose of sulfonylureas.

Hypoglycemia from sulfonylureas can result from small doses, can be delayed in onset, and can be persistent.  Prolonged observation and intensive care to restore and maintain euglycemia may be required. [5] (See Treatment and Medication.)

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Pathophysiology

Sulfonylureas are sulfonamide derivatives but do not have any antibacterial activity. The exact mechanism of sulfonylureas' hypoglycemic effect remains to be elucidated. These drugs are mainly effective in patients with functional pancreatic beta cells. Sulfonylureas bind to receptors that are associated with potassium channels sensitive to adenosine triphosphate in beta-cell membrane. The binding inhibits efflux of potassium ions from the cells, resulting in depolarization, influx of calcium ions, and release of preformed insulin. Sulfonylureas may also cause the decrease of serum glucagon and potentiate the action of insulin at the extrapancreatic tissues.

Normal hypoglycemic counterregulation is illustrated in the image below.

Normal hypoglycemic counterregulation. Normal hypoglycemic counterregulation.
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Epidemiology

Frequency

United States

The American Association of Poison Control Centers' (AAPCC) National Data Collection System compiles an annual report of human poison exposure cases. Overall, the number of exposures to oral sulfonylureas fell between 2006 and 2013 but increased in 2014. [6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16] Most exposures are in the pediatric population and are due to unintentional ingestion.

Table. Sulfonylurea exposures reported to the American Association of Poison Control Centers' National Data Collection System from 2006-2015 (Open Table in a new window)

Year Exposures <6 Years ≥6 Years Unintentional Exposures Overall Mortality* Pediatric Mortality
2006 1951 974 903 1647 1 0
2007 1975 991 890 1666 0 0
2008 1850 987 808 1571 0 0
2009 1769 922 769 1515 1 0
2010 1712 898 745 1453 0 0
2011 1687 804 807 1404 1† -
2012 1753 850 798 1449 1† -
2013 1590 778 762 1340 0 0
2014 1584 778 769 1316 2 0
2015 1659 807 852 1413 2 0
*Overall mortality includes adult and pediatric cases † Patient age not noted

Race, Sex, and Age

No racial or sex predilection has been reported in oral hypoglycemic agent exposure. Toxicity can occur in all ages, but most hypoglycemic overdoses occur in persons 6-19 years old.

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