Oral Hypoglycemic Agent Toxicity

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Oral Hypoglycemic Agent Toxicity

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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.)

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.

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

*Overall mortality includes adult and pediatric cases † Patient age not noted

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.

Hanchard B, Boulouffe C, Vanpee D. Sulfonylurea-induced hypoglycaemia: use of octreotide. Acta Clin Belg. 2009 Jan-Feb. 64(1):56-8. [Medline].

Kane MP, Abu-Baker A, Busch RS. The utility of oral diabetes medications in type 2 diabetes of the young. Curr Diabetes Rev. 2005 Feb. 1(1):83-92. [Medline].

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Pasquel FJ, Klein R, Adigweme A, Hinedi Z, Coralli R, Pimentel JL, et al. Metformin-associated lactic acidosis. Am J Med Sci. 2015 Mar. 349 (3):263-7. [Medline].

Klein-Schwartz W, Stassinos GL, Isbister GK. Treatment of sulfonylurea and insulin overdose. Br J Clin Pharmacol. 2016 Mar. 81 (3):496-504. [Medline].

Mowry JB, Spyker DA, Cantilena LR Jr, McMillan N, Ford M. 2013 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 31st Annual Report. Clin Toxicol (Phila). 2014 Dec. 52 (10):1032-283. [Medline]. [Full Text].

Mowry JB, Spyker DA, Cantilena LR Jr, Bailey JE, Ford M. 2012 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 30th Annual Report. Clin Toxicol (Phila). 2013 Dec. 51 (10):949-1229. [Medline]. [Full Text].

Bronstein AC, Spyker DA, Cantilena LR Jr, Rumack BH, Dart RC. 2011 Annual report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 29th Annual Report. Clin Toxicol (Phila). 2012 Dec. 50 (10):911-1164. [Medline]. [Full Text].

Bronstein AC, Spyker DA, Cantilena LR Jr, Green JL, Rumack BH, Dart RC. 2010 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 28th Annual Report. Clin Toxicol (Phila). 2011 Dec. 49 (10):910-41. [Medline]. [Full Text].

Bronstein AC, Spyker DA, Cantilena LR Jr, Green JL, Rumack BH, Giffin SL. 2009 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 27th Annual Report. Clin Toxicol (Phila). 2010 Dec. 48 (10):979-1178. [Medline]. [Full Text].

Bronstein AC, Spyker DA, Cantilena LR Jr, Green JL, Rumack BH, Giffin SL. 2008 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 26th Annual Report. Clin Toxicol (Phila). 2009 Dec. 47 (10):911-1084. [Medline]. [Full Text].

Bronstein AC, Spyker DA, Cantilena LR Jr, Green JL, Rumack BH, Heard SE, et al. 2007 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 25th Annual Report. Clin Toxicol (Phila). 2008 Dec. 46 (10):927-1057. [Medline]. [Full Text].

Bronstein AC, Spyker DA, Cantilena LR Jr, Green JL, Rumack BH, Heard SE, et al. 2007 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 25th Annual Report. Clin Toxicol (Phila). 2008 Dec. 46 (10):927-1057. [Medline]. [Full Text].

Bronstein AC, Spyker DA, Cantilena LR Jr, Green J, Rumack BH, Heard SE. 2006 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS). Clin Toxicol (Phila). 2007 Dec. 45 (8):815-917. [Medline]. [Full Text].

Mowry JB, Spyker DA, Brooks DE, McMillan N, Schauben JL. 2014 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 32nd Annual Report. Clin Toxicol (Phila). 2015. 53 (10):962-1147. [Medline]. [Full Text].

Mowry JB, Spyker DA, Brooks DE, Zimmerman A, Schauben JL. 2015 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 33rd Annual Report. Clin Toxicol (Phila). 2016 Dec. 54 (10):924-1109. [Medline].

Levine M, Ruha AM, Lovecchio F, et al. Hypoglycemia after accidental pediatric sulfonylurea ingestions. Pediatr Emerg Care. 2011 Sep. 27(9):846-9. [Medline].

Furukawa S, Kumagi T, Miyake T, Ueda T, Niiya T, Nishino K, et al. Suicide attempt by an overdose of sitagliptin, an oral hypoglycemic agent: a case report and a review of the literature. Endocr J. 2012. 59(4):329-33. [Medline].

Adam PA, Schwartz R. Diagnosis and treatment: should oral hypoglycemic agents be used in pediatric and pregnant patients?. Pediatrics. 1968 Nov. 42(5):819-23. [Medline].

Boyle PJ, Justice K, Krentz AJ, et al. Octreotide reverses hyperinsulinemia and prevents hypoglycemia induced by sulfonylurea overdoses. J Clin Endocrinol Metab. 1993 Mar. 76(3):752-6. [Medline].

Braatvedt GD. Octreotide for the treatment of sulphonylurea induced hypoglycaemia in type 2 diabetes. N Z Med J. 1997 May 23. 110(1044):189-90. [Medline].

Ferner RE, Chaplin S. The relationship between the pharmacokinetics and pharmacodynamic effects of oral hypoglycaemic drugs. Clin Pharmacokinet. 1987 Jun. 12(6):379-401. [Medline].

Gjedde S, Christiansen A, Pedersen SB, Rungby J. Survival following a metformin overdose of 63 g: a case report. Pharmacol Toxicol. 2003 Aug. 93(2):98-9. [Medline].

Goldfrank LR, Flomenbaum NE, Lewin NA, eds. Goldfrank’s Toxicologic Emergencies. McGraw-Hill Professional Publishing; 1988. 671-87.

Gul M, Cander B, Girisgin S, Ayan M, Kocak S, Unlu A. The effectiveness of various doses of octreotide for sulfonylurea-induced hypoglycemia after overdose. Adv Ther. 2006 Nov-Dec. 23(6):878-84. [Medline].

Haymond MW. Hypoglycemia in infants and children. Endocrinol Metab Clin North Am. 1989 Mar. 18(1):211-52. [Medline].

Johnson SF, Schade DS, Peake GT. Chlorpropamide-induced hypoglycemia: successful treatment with diazoxide. Am J Med. 1977 Nov. 63(5):799-804. [Medline].

Little GL, Boniface KS. Are one or two dangerous? Sulfonylurea exposure in toddlers. Journal of Emergency Medicine. 2005. 28:305-10. [Medline].

Pavone L, Mollica F, Musumeci S, et al. Accidental glibenclamide ingestion in an infant: clinical and electroencephalographic aspects. Dev Med Child Neurol. 1980 Jun. 22(3):366-71. [Medline].

Ramos E, Baron S, Sentanac S. Hypoglycemia associated with oral sulfonylurea hypoglycemic agents in an 11-year-old girl. Archives de Pediatrie. 2005. 12:1109-11. [Medline].

Rao NG, Menezes RG, Nagesh KR, Kamath GS. Suicide by combined insulin and glipizide overdose in a non-insulin dependent diabetes mellitus physician: a case report. Med Sci Law. 2006 Jul. 46(3):263-9. [Medline].

Rowden AK, Fasano CJ. Emergency management of oral hypoglycemic drug toxicity. Emerg Med Clin North Am. 2007 May. 25(2):347-56; abstract viii. [Medline].

Sarmah AK, Sabadie J. Hydrolysis of sulfonylurea herbicides in soils and aqueous solutions: a review. J Agric Food Chem. 2002 Oct 23. 50(22):6253-65. [Medline].

Soderstrom J, Murray L, Daly FF, Little M. Toxicology case of the month: oral hypoglycaemic overdose. Emerg Med J. 2006 Jul. 23(7):565-7. [Medline].

Spiller HA. Management of sulfonylurea ingestions. Pediatr Emerg Care. 1999 Jun. 15(3):227-30. [Medline].

Spiller HA, Sawyer TS. Toxicology of oral antidiabetic medications. Am J Health Syst Pharm. 2006 May 15. 63(10):929-38. [Medline].

Spiller HA, Schroeder SL, Ching DS. Hemiparesis and altered mental status in a child after glyburide ingestion. J Emerg Med. 1998 May-Jun. 16(3):433-5. [Medline].

Spiller HA, Villalobos D, Krenzelok EP, et al. Prospective multicenter study of sulfonylurea ingestion in children. J Pediatr. 1997 Jul. 131(1 Pt 1):141-6. [Medline].

Szlatenyi CS, Capes KF, Wang RY. Delayed hypoglycemia in a child after ingestion of a single glipizide tablet. Ann Emerg Med. 1998 Jun. 31(6):773-6. [Medline].

Trenque T, Hoizey G, Lamiable D. Serious Hypoglycemia: Munchausen’s Syndrome?. Diabetes Care. 2001. 24:792-3.

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

*Overall mortality includes adult and pediatric cases † Patient age not noted

David Tran, MD Attending Physician, Department of Emergency Medicine, North Shore-LIJ Plainview Hospital

David Tran, MD is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Jeffrey R Tucker, MD Assistant Professor, Department of Pediatrics, Division of Emergency Medicine, University of Connecticut School of Medicine, Connecticut Children’s Medical Center

Disclosure: Received salary from Merck for employment.

Timothy E Corden, MD Associate Professor of Pediatrics, Co-Director, Policy Core, Injury Research Center, Medical College of Wisconsin; Associate Director, PICU, Children’s Hospital of Wisconsin

Timothy E Corden, MD is a member of the following medical societies: American Academy of Pediatrics, Phi Beta Kappa, Society of Critical Care Medicine, Wisconsin Medical Society

Disclosure: Nothing to disclose.

Michael E Mullins, MD Assistant Professor, Division of Emergency Medicine, Washington University in St Louis School of Medicine; Attending Physician, Emergency Department, Barnes-Jewish Hospital

Michael E Mullins, MD is a member of the following medical societies: American Academy of Clinical Toxicology, American College of Emergency Physicians

Disclosure: Received stock ownership from Johnson & Johnson for none; Received stock ownership from Savient Pharmaceuticals for none.

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author Michael Lucchesi, MD, to the original writing and development of this article.

Oral Hypoglycemic Agent Toxicity

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