Annals of Emergency Medicine
Volume 38, Issue 1 , Pages 68-78 , July 2001

Oral agents for the treatment of type 2 diabetes mellitus: Pharmacology, toxicity, and treatment

Received 9 December 1999 ,Revised 15 December 2000 ,Accepted 2 January 2001.

References 

  1. Harris MI, Flegal KM, Cowie CC, et al.  Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in U.S. adults. The Third National Health and Nutrition Examination Survey, 1988-1994. Diabetes Care. 1998;21:518–526
  2. Henry RR. Glucose control and insulin resistance in non-insulin-dependent diabetes mellitus. Ann Intern Med. 1996;124:97–103
  3. Bressler R, Johnson DG. Pharmacological regulation of blood glucose levels in non-insulin-dependent diabetes mellitus. Arch Intern Med. 1997;157:836–848
  4. Henry RR, Wallace P, Olefsky JM. Effects of weight loss on mechanisms of hyperglycemia in non-insulin-dependent diabetes mellitus. Diabetes. 1986;35:990–998
  5. American Diabetes Association . The pharmacological treatment of hyperglycemia in NIDDM [consensus statement]. Diabetes Care. 1995;18:1510–1518
  6. DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med. 1999;131:281–303
  7. Melander A. Clinical pharmacology of sulfonylureas. Metabolism. 1987;36:12–16
  8. Campbell RK. Glimepiride: role of new sulfonylureas in the treatment of type 2 diabetes mellitus. Ann Pharmacother. 1998;32:1044–1052
  9. Hellman B, Taljedal IB. Effects of sulfonylurea derivatives on pancreatic B cells. In: 1st ed.  Hasselblatt A,  Brucchausen F editor. Handbook of Experimental Pharmacology. Vol. 32:Berlin: : Springer-Verlag; 1975;p. 174–194 Insulin, part 2
  10. Abrahamsson H. Direct measurement of increased free cytoplasmic Ca2+ in mouse pancreatic B-cells following stimulation by hypoglycemic sulfonylureas. FEBS Lett. 1985;190:21–24
  11. Goldfine ID. Effects of biguanides and sulfonylureas on insulin receptors in cultured cells. Diabetes Care. 1984;7(Suppl 1):54–58
  12. Marshall A, Gingereich RL, Wright PH. Hepatic effect of sulfonylurea. Metabolism. 1970;19:1046–1052
  13. Groop L, Groop PH, Stenman S, et al.  Do sulfonylureas influence hepatic insulin clearance?. Diabetes Care. 1988;11:689–690
  14. Kolterman OG, Gray RS, Shapiro G, et al.  The acute and chronic effects of sulfonylurea therapy in type II diabetic subjects. Diabetes. 1984;33:345–346
  15. Groop LC. Sulfonylureas in NIDDM. Diabetes Care. 1992;15:737–754
  16. Harrower ADB. Comparative tolerability of sulphonylureas in diabetes mellitus. Drug Saf. 2000;22:313–320
  17. Spiller HA. Management of antidiabetic agents in overdose. Drug Saf. 1998;19:411–424
  18. Taylor JA. Pharmacokinetics and biotransformation of chlorpropamide in man. Clin Pharmacol Ther. 1972;13:710–718
  19. Scott J, Pfoffenbarger PL. Pharmacokinetics of tolbutamide metabolism in humans. Diabetes. 1979;28:1–51
  20. Feldman JM, Lebovitz HE. Biological activities of tolbutamide and its metabolites. Diabetes. 1969;18:529–537
  21. Moses AM, Howanitz J, Miller M, et al.  Diuretic action of three sulfonylurea drugs. Ann Intern Med. 1973;78:541–544
  22. Shumack SL, Coernblum B, Steiner G. Recurrent hypoglycemia secondary to drug dispensing error. Arch Intern Med. 1991;151:1877–1878
  23. Kristensen M, Hansen JM. Accumulation of chlorpropamide caused by dicoumarol. Acta Med Scand. 1968;183:83–86
  24. Christensen LK, Skovsted L. Inhibition of drug metabolism by chloramphenicol. Lancet. 1969;2:1397–1399
  25. Petitpierre B. Behaviour of chlorpropamide in renal insufficiency and under the effect of associated drug therapy. Int J Clin Pharm Ther Toxicol. 1972;6:120–124
  26. Syvalahti EKG, Pihlajamaki KK, Ilsalo EJ. Rifampicin and drug metabolism. Lancet. 1974;1:232–233
  27. Pogatsa MZ, Koltai I, Balkany I, et al.  Effects of various hypoglycaemic sulphonylureas on the cardiotoxicity of glycosides. Eur J Clin Pharmacol. 1985;28:367–370
  28. Kristensen M, Hansen JM. Potentiation of the tolbutamide effect by dicoumarol. Diabetes. 1967;16:211–214
  29. Christensen LK, Hansen JM, Kristensen M. Sulphaphenazole-induced hypoglycaemic attacks in tolbutamide-treated diabetics. Lancet. 1963;2:1298–1300
  30. Scheen AJ, Lefebvre PJ. Antihyperglycemic agents: drug interactions of clinical importance. Drug Saf. 1995;12:32–45
  31. Marchetti P, Navalesi R. Pharmacokinetic-pharmacodynamic relationships of oral hypoglycemic agents: an update. Clin Pharmacokinet. 1989;16:100–128
  32. Roberge RJ, Kaplan R, Frank R, et al.  Glyburide-ciprofloxacin interaction with resistant hypoglycemia. Ann Emerg Med. 2000;36:160–163
  33. Self TH, Tsiu SJ, Fowler JW. Interaction of rifampicin and glyburide. Chest. 1989;96:1443–1444
  34. Melander A. Oral antidiabetic drugs: an overview. Diabetic Med. 1996;13:143–147
  35. Spiller HA, Villalobos D, Krenzelok EP, et al.  Prospective multicenter study of sulfonylurea ingestion in children. J Pediatr. 1997;131:143–148
  36. Quadrani DA, Spiller HA, Widder P. Five year retrospective evaluation of sulfonylurea ingestion in children. J Toxicol Clin Toxicol. 1996;34:267–270
  37. Robertson WO. Sulfonylurea ingestions: hospitalization not mandatory. J Toxicol Clin Toxicol. 1997;35:115–116
  38. Mullins ME, Warden CR, Horowitz BZ. Delayed hypoglycemia after ingestion of a single glipizide tablet. [letter] Ann Emerg Med. 1999;33:129–130
  39. Litovitz TL, Klein-Schwartz W, White S, et al.  1999 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med. 2000;18:517–574
  40. Jeffrys DB, Volans GN. Self poisoning in diabetic patients. Hum Toxicol. 1983;2:345–348
  41. Stahl M, Berger W. Higher incidence of severe hypoglycemia leading to hospital admission in type 2 diabetic patients treated with long-acting versus short-acting sulphonylureas. Diabetes Med. 1999;16:586–590
  42. Shorr RI, Ray WA, Daugherty JR, et al.  Incidence and risk factors for serious hypoglycemia in older persons using insulin or sulfonylureas. Arch Intern Med. 1997;157:1681–1686
  43. Burge MR, Schmitz-Fiorentino K, Fischette C, et al.  A prospective trial of risk factors for sulfonylurea-induced hypoglycemia in type 2 diabetes mellitus. JAMA. 1998;279:137–143
  44. Krepinsky J, Ingram AJ, Clase CM. Prolonged sulfonylurea-induced hypoglycemia in diabetic patients with end-stage renal disease. Am J Kidney Dis. 2000;35:500–505
  45. Ciechanowski K, Borowiak KS, Potocka BA, et al.  Chlorpropamide toxicity with survival despite 27-day hypoglycemia. J Toxicol Clin Toxicol. 1999;37:869–871
  46. Weissman PN, Shenkman P, Gregerman RI. Chlorpropamide hyponatremia: drug-induced inappropriate antidiuretic hormone activity. N Engl J Med. 1971;284:65–71
  47. Kadowaki T, Hagura R, Kajinuma H, et al.  Chlorpropamide-induced hyponatremia: incidence and risk factors. Diabetes Care. 1983;6:468–471
  48. Jackson JE, Bressler R. Clinical pharmacology of sulfonylurea hypoglycemic agents: part 1. Drugs. 1981;22:211–245
  49. Jackson JE, Bressler R. Clinical pharmacology of sulfonylurea hypoglycemic agents: part 2. Drugs. 1981;22:295–320
  50. Cartron G. Glimepiride-induced thrombocytopenic purpura. [letter] Ann Pharmacother. 2000;34:120
  51. Gan SC, Barr J, Arieff AI, et al.  Biguanide-associated lactic acidosis: Case report and review of the literature. Arch Intern Med. 1992;152:2333–2336
  52. Pearlman BL, Fenves AZ, Emmett M. Metformin-associated lactic acidosis. Am J Med. 1996;101:109–110
  53. Kwong SC, Brubacher J. Phenformin and lactic acidosis: a case report and review. J Emerg Med. 1998;16:881–886
  54. Bailey CJ, Turner RC. Metformin. N Engl J Med. 1996;334:574–579
  55. Yki-Jarvinen H, Ryysy L, Nikkila K, et al.  Bedtime insulin plus metformin prevents weight gain and reduces frequency of hypoglycemia in type 2 diabetes. Ann Intern Med. 1999;130:389–396
  56. Guthrie R. Treatment of non-insulin-dependent diabetes mellitus with metformin. J Am Board Fam Pract. 1997;10:213–221
  57. Brown JB, Pedula K, Barzilay J, et al.  Lactic acidosis rates in type 2 diabetes. Diabetes Care. 1998;21:1659–1663
  58. Hanefeld M. The role of acarbose in the treatment of non-insulin-dependent diabetes mellitus. J Diabetes Complications. 1998;12:228–237
  59. Coniff R, Krol A. Acarbose: a review of US clinical experience. Clin Ther. 1997;19:16–26
  60. Yee HS, Fong NT. A review of the safety and efficacy of acarbose in diabetes mellitus. Pharmacotherapy. 1996;16:792–805
  61. Reuser AJJ, Wisselaar HA. An evaluation of the potential side-effects of α-glucosidase inhibitors used for the management of diabetes mellitus. Eur J Clin Invest. 1994;24(Suppl 3):19–24
  62. Avandia [package insert]. Philadelphia, PA: : SmithKline Beecham Pharmaceuticals; 1999;
  63. Actos [package insert]. Osaka, Japan: : Takeda/Eli Lilly Pharmaceuticals; 1999;
  64. Guay DRP. Repaglinide, a novel, short-acting hypoglycemic agent for type 2 diabetes mellitus. Pharmacotherapy. 1998;18:1195–1204
  65. Wolffenbuttel BHR, Nijst L, Sels JPJE, et al.  Effects of a new oral hypoglycemic agent, repaglinide, on metabolic control in sulphonylurea-treated patients with NIDDM. J Clin Pharmacol. 1993;45:113–116
  66. Bergman U, Boman G, Wiholm B. Epidemiology of adverse drug reactions to phenformin and metformin. BMJ. 1978;2:464–466
  67. Pepper GM, Schwartz M. Lactic acidosis associated with Glucophage in a man with normal renal and hepatic function. Diabetes Care. 1997;20:232–233
  68. Nawaz S, Cleveland T, Gaines PA, et al.  Clinical risk associated with contrast angiography in metformin treated patients: a clinical review. Clin Radiol. 1998;53:342–344
  69. McCartney MM, Gilbert FJ, Murchison LE, et al.  Metformin and contrast media—a dangerous combination?. Clin Radiol. 1999;54:29–33
  70. Lalau JD, Race JM. Lactic acidosis in metformin-treated patients: prognostic value of arterial lactate levels and plasma metformin concentrations. Drug Saf. 1999;20:377–384
  71. Lin K, Lin J, Juang J. Metformin-induced hemolysis with jaundice. [letter] N Engl J Med. 1998;339:1860–1861
  72. Somogyi A, Stockley C, Keal J, et al.  Reduction of metformin renal tubular secretion by cimetidine in man. Br J Clin Pharmacol. 1987;23:544–551
  73. Chan NN, Fauvel NJ, Feher MD. Non-steroidal anti-inflammatory drugs and metformin: a cause for concern?. [letter] Lancet. 1998;352:201
  74. Brady WJ, Carter CT. Metformin overdose. [letter] Am J Emerg Med. 1997;15:107–108
  75. Teale KFH, Devine A, Stewart H, et al.  The management of metformin overdose. Anaesthesia. 1998;53:691–701
  76. Carrascosa M, Pascual F, Aresti S. Acarbose-induced severe hepatotoxicity. [letter] Lancet. 1997;349:698–699
  77. Andrade RJ, Lucena MI, Rodriguez-Mendizabel M. Hepatic injury caused by acarbose. [letter] Ann Intern Med. 1996;124:9311
  78. Fujimoto Y, Ohhira M, Miyokawa N, et al.  Acarbose-induced hepatic injury. [letter] Lancet. 1998;351:340
  79. Andrade RJ, Lucena M, Vega JL, et al.  Acarbose-associated hepatotoxicity. Diabetes Care. 1998;21:2029–2030
  80. Diaz-Gutierrez FL, Ladero JM, Diaz-Rubio M. Acarbose-induced acute hepatitis. [letter] Am J Gastroenterol. 1998;93:481
  81. Henry RR. Thiazolidinediones. Endocrinol Metab Clin North Am. 1997;26:553–573
  82. Imura H. A novel antidiabetic drug, troglitazone—reason for hope and concern. N Engl J Med. 1998;38:908–909
  83. Giotlin N, Julie NL, Spurr CL, et al.  Two cases of severe clinical and histologic hepatotoxicity associated with troglitazone. Ann Intern Med. 1998;129:36–38
  84. Watkins PB, Whitcomb RW. Hepatic dysfunction associated with troglitazone. [letter] N Engl J Med. 1998;338:916–917
  85. Neuschwander-Tetri BA, Isley WL, Oki JC, et al.  Troglitazone-induced hepatic failure leading to liver transplantation. Ann Intern Med. 1998;129:38–41
  86. Vella A, de Groen PC, Dinneen SF. Fatal hepatotoxicity associated with troglitazone. [letter] Ann Intern Med. 1998;129:1080
  87. Misbin RI. Troglitazone-associated hepatic failure. [letter] Ann Intern Med. 1999;130:330
  88. Herrine SK, Choudhary C. Severe hepatotoxicity associated with troglitazone. [letter] Ann Intern Med. 1999;130:163–164
  89. Shibuya A, Watanabe M, Fujita Y, et al.  An autopsy case of troglitazone-induced fulminant hepatitis. Diabetes Care. 1998;21:2140–2143
  90. Al-Salman J, Arjomand H, Kemp DG, et al.  Hepatocellular injury in a patient receiving rosiglitazone. Ann Intern Med. 2000;132:121–124
  91. Forman LM, Simmons DA, Diamond RH. Hepatic failure in a patient taking rosiglitazone. Ann Intern Med. 2000;132:118–121
  92. Fried J, Everitt D, Boscia J. Rosiglitazone and hepatic failure. [letter] Ann Intern Med. 2000;132:164
  93. Nattrass M. Repaglinide: a novel oral antidiabetic agent. Hosp Med. 2000;61:112–115
  94. Chyka PA, Seger D. Position statement of the American Academy of Clinical Toxicology and the European Association of Poison Centers and Clinical Toxicologists: single dose activated charcoal. J Toxicol Clin Toxicol. 1997;35:721–741
  95. Spiller HA. Management of sulfonylurea ingestions. Pediatr Emerg Care. 1999;15:227–230
  96. Howland MA. Pharmacokinetics and toxicokinetics. In: 6th ed.  Goldfrank LR,  Flomenbaum NE,  Lewin NA, et al. editor. Goldfrank’s Toxicologic Emergencies. Stamford, CT: : Appleton & Lange; 1998;p. 173–193
  97. Burkhart KK. When does hypoglycemia develop after sulfonylurea ingestion?. Ann Emerg Med. 1998;31:771–772
  98. Borowski H, Caraccio T, Mofenson H. Sulfonylurea ingestion in children: is an 8-hour observation period sufficient?. [letter] J Pediatr. 1998;33:584
  99. Szlatenyi CS, Capes KF, Wang RY. Delayed hypoglycemia in a child after ingestion of a single glipizide tablet. Ann Emerg Med. 1998;31:773–776
  100. Robertson WO. Delayed hypoglycemia after ingestion of a single glipizide tablet. [letter] Ann Emerg Med. 1999;33:130
  101. Boyle PJ, Justice K, Krentz AJ, et al.  Octreotide reverses hyperinsulinemia and prevents hypoglycemia induced by sulfonylurea overdoses. J Clin Endocrin Metab. 1993;76:752–756
  102. Krentz AJ, Boyle PJ, Justice KM, et al.  Successful treatment of severe refractory sulfonylurea-induced hypoglycemia with octreotide. Diabetes Care. 1993;16:184–186
  103. Braatvedt GD. Octreotide for the treatment of sulfonylurea induced hypoglycemia in type 2 diabetes. N Z Med J. 1997;110:189–190
  104. Graudins A, Linden CH, Ferm RP. Diagnosis and treatment of sulfonylurea-induced hyperinsulinemic hypoglycemia. [letter] Am J Emerg Med. 1997;15:95–96
  105. Hung O, Eng J, Ho J, et al.  Octreotide as an antidote for refractory sulfonylurea hypoglycemia. [abstract] J Toxicol Clin Toxicol. 1997;35:540–541
  106. Mordel A, Sivilotti MLA, Old AC, et al.  Octreotide for pediatric sulfonylurea poisoning. [abstract] J Toxicol Clin Toxicol. 1998;36:437
  107. Bui L, Adler D, Keller KH. Prolonged octreotide infusion to treat glyburide-induced hypoglycemia. [abstract] J Toxicol Clin Toxicol. 2000;38:576
  108. McLaughlin SA, Crandall CS, McKinney PE. Octreotide: an antidote for sulfonylurea-induced hypoglycemia. Ann Emerg Med. 2000;36:133–138
  109. Palatnick W, Meatheral RC, Tenenbein M. Clinical spectrum of sulfonylurea overdose and experience with diazoxide therapy. Arch Intern Med. 1991;151:1859–1862
  110. Pollack CV. Utility of glucagon in the emergency department. J Emerg Med. 1993;11:195–205
  111. Collier A, Steedman DJ, Patrick AW, et al.  Comparison of intravenous glucagon and dextrose in treatment of severe hypoglycemia in an accident and emergency department. Diabetes Care. 1987;10:12–15
  112. Patrick AW, Collier A, Hepburn DA, et al.  Comparison of intramuscular glucagon and intravenous dextrose in the treatment of hypoglycaemic coma in an accident and emergency department. Arch Emerg Med. 1990;7:73–77
  113. Howell MA, Guly HR. A comparison of glucagon and glucose in prehospital hypoglycaemia. J Accid Emerg Med. 1997;14:30–32

 Reprints not available from the authors

PII: S0196-0644(01)38858-3

doi: 10.1067/mem.2001.114314

Annals of Emergency Medicine
Volume 38, Issue 1 , Pages 68-78 , July 2001