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Sulfonylureas and meglitinides in the treatment of diabetes mellitus

David K McCulloch, MD
Section Editor
David M Nathan, MD
Deputy Editor
Jean E Mulder, MD


Two classes of oral hypoglycemic drugs directly stimulate release of insulin from pancreatic beta cells: the sulfonylureas and meglitinides. The pharmacology, efficacy, indications, and side effects of these drugs will be discussed here. A general discussion of initial and subsequent treatment of type 2 diabetes is reviewed separately.

(See "Initial management of blood glucose in adults with type 2 diabetes mellitus".)

(See "Management of persistent hyperglycemia in type 2 diabetes mellitus".)


Mechanism of action — Sulfonylureas are among the most widely used drugs for the treatment of patients with type 2 diabetes [1]. They work by stimulating insulin secretion so are useful only in patients with some beta cell function.

The sulfonylurea receptor is a component of the adenosine triphosphate (ATP)-sensitive potassium channel (K-ATP channel) in the pancreatic beta cells [2]. The K-ATP channel regulates the release of insulin from pancreatic beta cells. Sulfonylurea binding leads to inhibition of these channels, which alters the resting potential of the cell, leading to calcium influx and stimulation of insulin secretion. The net effect is increased responsiveness of beta cells to both glucose and non-glucose secretagogues (such as amino acids), resulting in more insulin being released at all blood glucose concentrations. Sulfonylureas may also have extrapancreatic effects, one of which is to increase tissue sensitivity to insulin, but the clinical importance of these effects is minimal [1].

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Literature review current through: Sep 2017. | This topic last updated: Feb 22, 2017.
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  1. Bressler R, Johnson DG. Pharmacological regulation of blood glucose levels in non-insulin-dependent diabetes mellitus. Arch Intern Med 1997; 157:836.
  2. Aguilar-Bryan L, Nichols CG, Wechsler SW, et al. Cloning of the beta cell high-affinity sulfonylurea receptor: a regulator of insulin secretion. Science 1995; 268:423.
  3. Gloyn AL, Pearson ER, Antcliff JF, et al. Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med 2004; 350:1838.
  4. Babenko AP, Polak M, Cavé H, et al. Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. N Engl J Med 2006; 355:456.
  5. Pearson ER, Flechtner I, Njølstad PR, et al. Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. N Engl J Med 2006; 355:467.
  6. Jönsson A, Rydberg T, Ekberg G, et al. Slow elimination of glyburide in NIDDM subjects. Diabetes Care 1994; 17:142.
  7. Rydberg T, Jönsson A, Røder M, Melander A. Hypoglycemic activity of glyburide (glibenclamide) metabolites in humans. Diabetes Care 1994; 17:1026.
  8. Shorr RI, Ray WA, Daugherty JR, Griffin MR. Individual sulfonylureas and serious hypoglycemia in older people. J Am Geriatr Soc 1996; 44:751.
  9. Hermann LS, Scherstén B, Bitzén PO, et al. Therapeutic comparison of metformin and sulfonylurea, alone and in various combinations. A double-blind controlled study. Diabetes Care 1994; 17:1100.
  10. Hirst JA, Farmer AJ, Dyar A, et al. Estimating the effect of sulfonylurea on HbA1c in diabetes: a systematic review and meta-analysis. Diabetologia 2013; 56:973.
  11. Maruthur NM, Tseng E, Hutfless S, et al. Diabetes Medications as Monotherapy or Metformin-Based Combination Therapy for Type 2 Diabetes: A Systematic Review and Meta-analysis. Ann Intern Med 2016; 164:740.
  12. Genuth S. Should sulfonylureas remain an acceptable first-line add-on to metformin therapy in patients with type 2 diabetes? No, it's time to move on! Diabetes Care 2015; 38:170.
  13. Abrahamson MJ. Should sulfonylureas remain an acceptable first-line add-on to metformin therapy in patients with type 2 diabetes? Yes, they continue to serve us well! Diabetes Care 2015; 38:166.
  14. Monami M, Genovese S, Mannucci E. Cardiovascular safety of sulfonylureas: a meta-analysis of randomized clinical trials. Diabetes Obes Metab 2013; 15:938.
  15. Varvaki Rados D, Catani Pinto L, Reck Remonti L, et al. The Association between Sulfonylurea Use and All-Cause and Cardiovascular Mortality: A Meta-Analysis with Trial Sequential Analysis of Randomized Clinical Trials. PLoS Med 2016; 13:e1001992.
  16. Hong J, Zhang Y, Lai S, et al. Effects of metformin versus glipizide on cardiovascular outcomes in patients with type 2 diabetes and coronary artery disease. Diabetes Care 2013; 36:1304.
  17. Simpson SH, Majumdar SR, Tsuyuki RT, et al. Dose-response relation between sulfonylurea drugs and mortality in type 2 diabetes mellitus: a population-based cohort study. CMAJ 2006; 174:169.
  18. Roumie CL, Hung AM, Greevy RA, et al. Comparative effectiveness of sulfonylurea and metformin monotherapy on cardiovascular events in type 2 diabetes mellitus: a cohort study. Ann Intern Med 2012; 157:601.
  19. Schramm TK, Gislason GH, Vaag A, et al. Mortality and cardiovascular risk associated with different insulin secretagogues compared with metformin in type 2 diabetes, with or without a previous myocardial infarction: a nationwide study. Eur Heart J 2011; 32:1900.
  20. A study of the effects of hypoglycemia agents on vascular complications in patients with adult-onset diabetes. VI. Supplementary report on nonfatal events in patients treated with tolbutamide. Diabetes 1976; 25:1129.
  21. Stevens RJ, Coleman RL, Adler AI, et al. Risk factors for myocardial infarction case fatality and stroke case fatality in type 2 diabetes: UKPDS 66. Diabetes Care 2004; 27:201.
  22. Garratt KN, Brady PA, Hassinger NL, et al. Sulfonylurea drugs increase early mortality in patients with diabetes mellitus after direct angioplasty for acute myocardial infarction. J Am Coll Cardiol 1999; 33:119.
  23. Malmberg K. Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus. DIGAMI (Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction) Study Group. BMJ 1997; 314:1512.
  24. Zeller M, Danchin N, Simon D, et al. Impact of type of preadmission sulfonylureas on mortality and cardiovascular outcomes in diabetic patients with acute myocardial infarction. J Clin Endocrinol Metab 2010; 95:4993.
  25. Davidson MB. Successful treatment of markedly symptomatic patients with type II diabetes mellitus using high doses of sulfonylurea agents. West J Med 1992; 157:199.
  26. Stenman S, Melander A, Groop PH, Groop LC. What is the benefit of increasing the sulfonylurea dose? Ann Intern Med 1993; 118:169.
  27. Schopman JE, Simon AC, Hoefnagel SJ, et al. The incidence of mild and severe hypoglycaemia in patients with type 2 diabetes mellitus treated with sulfonylureas: a systematic review and meta-analysis. Diabetes Metab Res Rev 2014; 30:11.
  28. Tessier D, Dawson K, Tétrault JP, et al. Glibenclamide vs gliclazide in type 2 diabetes of the elderly. Diabet Med 1994; 11:974.
  29. Holstein A, Plaschke A, Egberts EH. Lower incidence of severe hypoglycaemia in patients with type 2 diabetes treated with glimepiride versus glibenclamide. Diabetes Metab Res Rev 2001; 17:467.
  30. Gangji AS, Cukierman T, Gerstein HC, et al. A systematic review and meta-analysis of hypoglycemia and cardiovascular events: a comparison of glyburide with other secretagogues and with insulin. Diabetes Care 2007; 30:389.
  31. Shorr RI, Ray WA, Daugherty JR, Griffin MR. Incidence and risk factors for serious hypoglycemia in older persons using insulin or sulfonylureas. Arch Intern Med 1997; 157:1681.
  32. Bressler P, DeFronzo RA. Drugs and diabetes. Diabetes Reviews 1994; 2:53.
  33. Chichmanian RM, Papasseudi G, Hieronimus S, et al. [Hypersensitivity to hypoglycemic sulfonylurea compounds. Are there cross-reactions?]. Therapie 1991; 46:163.
  34. Groop L, Eriksson CJ, Huupponen R, et al. Roles of chlorpropamide, alcohol and acetaldehyde in determining the chlorpropamide-alcohol flush. Diabetologia 1984; 26:34.
  35. Kadowaki T, Hagura R, Kajinuma H, et al. Chlorpropamide-induced hyponatremia: incidence and risk factors. Diabetes Care 1983; 6:468.
  36. Fuhlendorff J, Rorsman P, Kofod H, et al. Stimulation of insulin release by repaglinide and glibenclamide involves both common and distinct processes. Diabetes 1998; 47:345.
  37. Repaglinide for type 2 diabetes mellitus. Med Lett Drugs Ther 1998; 40:55.
  38. Wolffenbuttel BH, Landgraf R. A 1-year multicenter randomized double-blind comparison of repaglinide and glyburide for the treatment of type 2 diabetes. Dutch and German Repaglinide Study Group. Diabetes Care 1999; 22:463.
  39. Moses R, Slobodniuk R, Boyages S, et al. Effect of repaglinide addition to metformin monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care 1999; 22:119.
  40. Hollander PA, Schwartz SL, Gatlin MR, et al. Importance of early insulin secretion: comparison of nateglinide and glyburide in previously diet-treated patients with type 2 diabetes. Diabetes Care 2001; 24:983.
  41. Black C, Donnelly P, McIntyre L, et al. Meglitinide analogues for type 2 diabetes mellitus. Cochrane Database Syst Rev 2007; :CD004654.
  42. Huang Y, Abdelmoneim AS, Light P, et al. Comparative cardiovascular safety of insulin secretagogues following hospitalization for ischemic heart disease among type 2 diabetes patients: a cohort study. J Diabetes Complications 2015; 29:196.
  43. NAVIGATOR Study Group, Holman RR, Haffner SM, et al. Effect of nateglinide on the incidence of diabetes and cardiovascular events. N Engl J Med 2010; 362:1463.
  44. Hasslacher C, Multinational Repaglinide Renal Study Group. Safety and efficacy of repaglinide in type 2 diabetic patients with and without impaired renal function. Diabetes Care 2003; 26:886.
  45. Gribble FM, Manley SE, Levy JC. Randomized dose ranging study of the reduction of fasting and postprandial glucose in type 2 diabetes by nateglinide (A-4166). Diabetes Care 2001; 24:1221.
  46. Guardado-Mendoza R, Prioletta A, Jiménez-Ceja LM, et al. The role of nateglinide and repaglinide, derivatives of meglitinide, in the treatment of type 2 diabetes mellitus. Arch Med Sci 2013; 9:936.
  47. Meneilly GS. Effect of repaglinide versus glyburide on postprandial glucose and insulin values in elderly patients with type 2 diabetes. Diabetes Technol Ther 2011; 13:63.
  48. Yin J, Deng H, Qin S, et al. Comparison of repaglinide and metformin versus metformin alone for type 2 diabetes: a meta-analysis of randomized controlled trials. Diabetes Res Clin Pract 2014; 105:e10.
  49. Tornio A, Filppula AM, Kailari O, et al. Glucuronidation converts clopidogrel to a strong time-dependent inhibitor of CYP2C8: a phase II metabolite as a perpetrator of drug-drug interactions. Clin Pharmacol Ther 2014; 96:498.
  50. Backman JT, Filppula AM, Niemi M, Neuvonen PJ. Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions. Pharmacol Rev 2016; 68:168.