Practice Essentials

Sulfonylureas are oral hypoglycemic agents extensively used in the treatment of type 2 diabetes,^[1]The wide availability of these medications increases the potential for intentional or unintentional overdose in pediatric and adult populations.

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 oral agents besides sulfonylureas are used to treat type 2 diabetes, including biguanides, alpha-glucosidase inhibitors, thiazolidinediones, selective sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) agonists, and dipeptidyl peptidase IV (DPP-4) inhibitors.^[2]Metformin, a biguanide, is one such agent. Even in overdose, for the most part those agents do not decrease serum glucose below euglycemia; consequently, they are appropriately referred to as antihyperglycemic agents rather than hypoglycemic agents. Overdose of antihyperglycemic agents can have other dangerous adverse effects (for example, lactic acidosis from metformin,^[3]decreased kidney function from an SGLT2 inhibitor^[4]). However, 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. The risk of hypoglycemia varies by drug and patient populations. For example, glyburide has greater hypoglycemic effects than glipizide and glimepiride, particularly in patients with kidney dysfunction and in the elderly.^[5]

Prolonged observation and intensive care to restore and maintain euglycemia may be required.^[6](See Treatment and Medication.)

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.

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 from 2012 to 2022.^{[7, 8, 9, 10, 11, 12, 13, 14, 15, 16]} Approximately half of 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 2012-2022 (Open Table in a new window)

Year	Exposures	< 6 Years	≥6 Years	Unintentional Exposures	Overall Mortality*	Pediatric Mortality
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
2016	1582	677	905	1295	2†	-
2017	1471	693	778	1240	2†	-
2018	1512	613	899	1199	1†
2019	1370	570	800	1113	0
2020	1189	482	707	957	1†
2021	1084	409	640	844	2†
2022	1098	416	649	840	2†
*Overall mortality includes adult and pediatric cases † Patient age not noted

Race, Sex, and Age

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

Prognosis

Prognosis depends mainly on the early recognition of sulfonylurea exposures, the amount ingested, and the half-life of the drug. Most patients with oral hypoglycemic poisoning recover without any complications. In severe cases, possible complications include coma, recurrent seizures, permanent neurologic deficits, intellectual disability, and death.

Patient Education

Parents should keep medication inaccessible to children. For patient education resources, see the Poisoning - First Aid and Emergency Center, as well as Poisoning, Activated Charcoal, and Poison Proofing Your Home.

Clinical Presentation

Sola D, Rossi L, Schianca GP, Maffioli P, Bigliocca M, Mella R, et al. Sulfonylureas and their use in clinical practice. Arch Med Sci. 2015 Aug 12. 11 (4):840-8. [QxMD MEDLINE Link]. [Full Text].
Ahmad E, Lim S, Lamptey R, Webb DR, Davies MJ. Type 2 diabetes. Lancet. 2022 Nov 19. 400 (10365):1803-1820. [QxMD MEDLINE Link].
Fadden EJ, Longley C, Mahambrey T. Metformin-associated lactic acidosis. BMJ Case Rep. 2021 Jul 8. 14 (7):263-7. [QxMD MEDLINE Link]. [Full Text].
Nakamura M, Nakade J, Toyama T, Okajima M, Taniguchi T. Severe intoxication caused by sodium-glucose cotransporter 2 inhibitor overdose: a case report. BMC Pharmacol Toxicol. 2020 Jan 9. 21 (1):5. [QxMD MEDLINE Link]. [Full Text].
Vaughan EM, Rueda JJ, Samson SL, Hyman DJ. Reducing the Burden of Diabetes Treatment: A Review of Low-cost Oral Hypoglycemic Medications. Curr Diabetes Rev. 2020. 16 (8):851-858. [QxMD MEDLINE Link]. [Full Text].
Klein-Schwartz W, Stassinos GL, Isbister GK. Treatment of sulfonylurea and insulin overdose. Br J Clin Pharmacol. 2016 Mar. 81 (3):496-504. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link]. [Full Text].
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. [QxMD MEDLINE Link]. [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. [QxMD MEDLINE Link]. [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. [QxMD MEDLINE Link]. [Full Text].
Gummin DD, Mowry JB, Spyker DA, Brooks DE, Fraser MO, Banner W. 2016 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 34th Annual Report. Clin Toxicol (Phila). 2017 Dec. 55 (10):1072-1252. [QxMD MEDLINE Link]. [Full Text].
Gummin DD, Mowry JB, Spyker DA, Brooks DE, Osterthaler KM, Banner W. 2017 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 35th Annual Report. Clin Toxicol (Phila). 2018 Dec. 56 (12):1213-1415. [QxMD MEDLINE Link]. [Full Text].
Gummin DD, Mowry JB, Spyker DA, Brooks DE, Beuhler MC, Rivers LJ, et al. 2018 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 36th Annual Report. Clin Toxicol (Phila). 2019 Dec. 57 (12):1220-1413. [QxMD MEDLINE Link]. [Full Text].
Gummin DD, Mowry JB, Beuhler MC, Spyker DA, Brooks DE, Dibert KW, et al. 2019 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 37th Annual Report. Clin Toxicol (Phila). 2020 Dec. 58 (12):1360-1541. [QxMD MEDLINE Link]. [Full Text].
Gummin DD, Mowry JB, Beuhler MC, Spyker DA, Bronstein AC, Rivers LJ, et al. 2020 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 38th Annual Report. Clin Toxicol (Phila). 2021 Dec. 59 (12):1282-1501. [QxMD MEDLINE Link]. [Full Text].
Gummin DD, Mowry JB, Beuhler MC, Spyker DA, Rivers LJ, Feldman R, et al. 2021 Annual Report of the National Poison Data System(©) (NPDS) from America's Poison Centers: 39th Annual Report. Clin Toxicol (Phila). 2022 Dec. 60 (12):1381-1643. [QxMD MEDLINE Link]. [Full Text].
Levine M, Ruha AM, Lovecchio F, et al. Hypoglycemia after accidental pediatric sulfonylurea ingestions. Pediatr Emerg Care. 2011 Sep. 27(9):846-9. [QxMD MEDLINE Link].
Gummin DD, Mowry JB, Beuhler MC, Spyker DA, Rivers LJ, Feldman R, et al. 2021 Annual Report of the National Poison Data System(©) (NPDS) from America's Poison Centers: 39th Annual Report. Clin Toxicol (Phila). 2022 Dec. 60 (12):1381-1643. [QxMD MEDLINE Link]. [Full Text].

Media Gallery

Normal hypoglycemic counterregulation.

of 1

Table. Sulfonylurea exposures reported to the American Association of Poison Control Centers' National Data Collection System from 2012-2022

Table. Sulfonylurea exposures reported to the American Association of Poison Control Centers' National Data Collection System from 2012-2022

Year	Exposures	< 6 Years	≥6 Years	Unintentional Exposures	Overall Mortality*	Pediatric Mortality
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
2016	1582	677	905	1295	2†	-
2017	1471	693	778	1240	2†	-
2018	1512	613	899	1199	1†
2019	1370	570	800	1113	0
2020	1189	482	707	957	1†
2021	1084	409	640	844	2†
2022	1098	416	649	840	2†
*Overall mortality includes adult and pediatric cases † Patient age not noted

Back to List

Author

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.

Specialty Editor Board

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.

Chief Editor

Stephen L Thornton, MD Associate Clinical Professor, Department of Emergency Medicine (Medical Toxicology), University of Kansas Hospital; Medical Director, University of Kansas Hospital Poison Control Center; Staff Medical Toxicologist, Children’s Mercy Hospital

Stephen L Thornton, MD is a member of the following medical societies: American Academy of Clinical Toxicology, American College of Emergency Physicians, American College of Medical Toxicology

Disclosure: Nothing to disclose.

Additional Contributors

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.

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.

Acknowledgements

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.