Risk of Hypoglycaemia with Oral Antidiabetic Agents in Patients with Type 2 Diabetes

Abstract

In patients with Type 2 diabetes, the appropriate intensity of glucose control is determined by age, life expectancy, and the presence of concomitant disease. Geriatric patients are especially susceptible to hypoglycaemia and therefore particular care should be taken in this group characterized by polypharmacy, renal or hepatic dysfunction, cardiovascular multimorbidity and malnutrition. As hypoglycaemia is a significant cause of morbidity and mortality, treatment regimens for diabetes should minimize the occurrence of hypoglycaemic episodes and be tailored to the patient's individual needs. The pharmacological options for treating Type 2 diabetes have increased considerably and the risk of hypoglycaemia of the currently available drugs varies considerably. Metformin, thiazolidinediones, and acarbose, oral antidiabetic drugs that decrease insulin resistance or postprandial glucose absorption, are associated with a low risk of hypoglycaemia. These drugs can also be used effectively in various combination regimens; however, by improving insulin sensitivity, combinations of metformin and thiolidinediones with sulphonylureas or meglitinides may considerably increase the risk of hypoglycaemia. On account of its complex pharmacoprofile glibenclamide is a problematic substance carrying a high risk of hypoglycaemia. There are limited preliminary data indicating that, under routine conditions, glimepiride may be associated with a lower risk of hypoglycaemia than glibenclamide and is no more likely to cause hypoglycaemia than other shorter-acting agents such as gliclazide and glipizide. Nateglinide and repaglinide as short-acting insulin secretagogues may be associated with a reduced risk of hypoglycaemia compared with glibenclamide, in particular when dosed flexibly. Repaglinide might be beneficial in individuals with renal impairment.

Key words

Hypoglycaemia - Type 2 diabetes - sulphonylureas - glibenclamide - glimepiride - meglitinides - thiazolidinediones - metformin - acarbose

References

• 1 Aronoff S, Rosenblatt S, Braithwaite S, Egan J, Mathisen A L, Schneider R L. Pioglitazone hydrochloride monotherapy improves glycemic control in the treatment of patients with Type 2 diabetes.  Diabetes Care. 2000;  23 1605-1611
• 2 Asplund K, Wiholm B E, Lithner F. Glibenclamide-associated hypoglycaemia: a report on 57 cases.  Diabetologia. 1983;  24 412-417
• 3 Bachmann W, Löbe A, Lacher F. Medikamentös bedingte Hypoglykämien bei Typ-II-Diabetes.  Diabetes und Stoffwechsel. 1995;  4 83-89
• 4 Badian M, Korn A, Lehr K-H, Malerczyk V, Waldhausl W. Pharmacokinetics and pharmacodynamics of the hydroxymetabolite of glimepiride (Amaryl) after intravenous administration.  Drug Metab Drug Interact. 1996;  13 69-85
• 5 Balant L, Zahnd G, Gorgia A, Schwarz R, Fabre J. Pharmacokinetics of glipizide in man: influence of renal insufficiency.  Diabetologia. 1973;  9 (Suppl) 331-338
• 6 Balant L, Zahnd G R, Weber F, Fabre J. Behaviour of glibenclamide on repeated administration to diabetic patients.  Eur J Clin Pharmacol. 1977;  11 19-25
• 7 Ben-Ami H, Nagachandran P, Mendelson A, Edoute Y. Glibenclamide-induced hypoglycemic coma in 51 older patients with type 2 diabetes mellitus.  JAGS. 1999;  47 631-633
• 8 Burge M R, Zeise T M, Sohby T A, Rassam A G, Schade D S. Low-dose ethanol predisposes elderly fasted patients with type 2 diabetes to sulfonylurea-induced low blood glucose.  Diabetes Care. 1999;  22 2037-2043
• 9 Campbell D, Gordon B, Ings R, Beaufils M, Meyrier A, Jones R. The effects of renal disease on the pharmacokinetics of gliclazide in diabetic patients.  Br J Clin Pharmacol. 1985;  21 P572-573
• 10 Clark C M, Goldberg R B. Postgraduate medicine special report: therapeutic strategies for managing NIDDM. Whitehouse F, Gavin J Therapeutic Strategies for Managing NIDDM. McGraw-Hill Healthcare Information Group 1997: 45-56
• 11 Corsonello A, Pedone C, Corica F, Malara A, Carosella L, Sgadari A, Mauro V N, Ceruso D, Pahor M, Carbonin P. Antihypertensive drug therapy and hypoglycemia in elderly diabetic patients treated with insulin and/or sulfonylureas. Gruppo Italiano di Farmacovigilanza nell'Anziano (GIFA).  Eur J Epidemiol. 1999;  15 893-901
• 12 Cryer P E. Hypoglycaemia: The limiting factor in the glycaemic management of type I and type II diabetes.  Diabetologia. 2002;  45 937-948
• 13 Damsbo P, Clauson P, Marbury T C, Windfeld K. A double-blind randomized comparison of meal-related glycemic control by repaglinide and glyburide in well-controlled type 2 diabetic patients.  Diabetes Care. 1999;  22 789-794
• 14 Davidson M B, Peters A L. An overview of metformin in the treatment of type 2 diabetes mellitus.  Am J Med. 1997;  102 99-110
• 15 DCCT . Epidemiology of severe hypoglycemia in the Diabetes Control and Complications Trial: Diabetes Control and Complications Trial Research Group.  Am J Med. 1991;  90 450-459
• 16 DCCT . The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus.  New Eng J Med. 1993;  329 977-986
• 17 Di Cicco R A, Allen A, Carr A, Fowles S, Jorkasky D K, Freed M I. Rosiglitazone does not alter the pharmacokinetics of metformin.  J Clin Pharmacol. 2000;  40 1280-1285
• 18 Dills D, Schneider J. Clinical evaluation of glimepiride versus glyburide in NIDDM in a double-blind comparative study. Glimepiride/Glyburide Research Group.  Horm Metab Res. 1996;  28 426-429
• 19 Dreary I J. Symptoms of hypoglycaemia and effects on mental performance and emotions. Frier B, Fisher B Hypoglycaemia in Clinical Diabetes. Chichester; Wiley 1999: 29-54
• 20 Einhorn D, Rendell M, Rosenzweig J, Egan J, Mathisen A, Schneider R. Pioglitazone hydrochloride in combination with metformin in the treatment of type 2 diabetes mellitus: a randomized, placebo-controled study.  Clinical Therapeutics. 2000 a;  22 1395-1409
• 21 Einhorn D, Rendell M, Rosenzweig J, Egan J W, Mathisen A L, Schneider R L. Pioglitazone hydrochloride in combination with metformin in the treatment of type 2 diabetes mellitus: a randomized, placebo-controlled study. The Pioglitazone 027 Study Group.  Clin Ther. 2000 b;  22 1395-1409
• 22 Fisher B M, Heller S. Mortality, cardiovascular morbidity, and possible effects of hypoglycaemia on diabetic complications. Frier BM, Fisher BM Hypoglycaemia in Clinical Diabetes. Chichester; Wiley 1999: 77-82
• 23 Fonseca V, Rosenstock J, Patwardhan R, Salzman A. Effect of metformin and rosiglitazone combination therapy in patients with type 2 diabetes mellitus.  JAMA. 2000;  283 1695-1702
• 24 Frier B M, Fisher M. Impaired hypoglycaemia awareness. Frier BM, Fisher BM Hypoglycaemia in Clinical Diabetes. Chichester; Wiley 1999: 111-146
• 25 Gudat U, Heinemann L. The effect of physical exercise on glycemia on healthy subjects following administration of glimepiride.  Arzneimittelforsch. 1996;  46 606-609
• 26 Hanefeld M, Bouter K P, Dickinson S, Guitard C. Rapid and short-acting mealtime insulin secretion with nateglinide controls both prandial and mean glycemia.  Diabetes Care. 2000;  23 202-207
• 27 Hansen A M, Christensen I T, Hansen J B, Carr R D, Ashcroft F M, Wahl P. Differential interactions of nateglinide and repaglinide on the human beta-cell sulphonylurea receptor 1.  Diabetes. 2002;  51 2789-2795
• 28 Harrigan R A, Nathan M S, Beattie P. Oral agents for the treatment of type 2 diabetes mellitus: pharmacology, toxicity, and treatment.  Ann Emerg Med. 2001;  38 68-78
• 29 Harrower A D. Comparison of efficacy, secondary failure rate, and complications of sulfonylureas.  J Diabetes Complicat. 1994;  8 201-203
• 30 Harrower A D. Pharmacokinetics of oral antihyperglycaemic agents in patients with renal insufficiency.  Clin Pharmacokinet. 1996;  31 111-119
• 31 Hart S, Frier B. Causes, management, and morbidity of acute hypoglycaemia in adults requiring hospital admission.  QJM. 1998;  91 505-510
• 32 Hasslacher C, Koselj M, Gall M, Sieber J, Leyck Dieken M. Safety and efficacy of repaglinide in 281 type 2 diabetic patients with or without renal impairment.  Diabetes. 2001;  50 (Suppl 2) A116
• 33 Hatorp V, Walther K H, Christensen M S, Haug-Pihale G. Single-dose pharmacokinetics of repaglinide in subjects with chronic liver disease.  J Clin Pharmacol. 2000;  40 142-152
• 34 Hellman B, Sehlin J, Taljedal I B. Glibenclamide is exceptional among hypoglycaemic sulphonylureas in accumulating progressively in beta-cell-rich pancreatic islets.  Acta Endocrinol (Copenh). 1984;  105 385-390
• 35 Hollander P A, Schwartz S L, Gatlin M R, Haas S J, Zheng H, Foley J E, Dunning B E. Importance of early insulin secretion: comparison of nateglinide and glyburide in previously diet-treated patients with type 2 diabetes.  Diabetes Care. 2001;  24 983-988
• 36 Holman R R, Cull C A, Turner R C. A randomized double-blind trial of acarbose in type 2 diabetes shows improved glycemic control over 3 years (UKPDS 44).  Diabetes Care. 1999;  22 960-964
• 37 Holstein A, Plaschke A, Egberts E-H. Lower incidence of severe hypoglycaemia in patients with type 2 diabetes treated with glimepiride versus glibenclamide.  Diabetes Metab Res Rev. 2001;  17 467-473
• 38 Holstein A, Plaschke A, Egberts E-H. Incidence and costs of severe hypoglycemia.  Diabetes Care. 2002;  25 2109-2110
• 39 Holstein A, Plaschke A, Egberts E-H. Risk factors for prolonged and non-prolonged hypoglycemia in sulfonylurea-treated patients.  Diabetes. 2002 a;  51 (Suppl 2) A491-492
• 40 Horton E S, Clinkingbeard C, Gatlin M, Foley J, Mallows S, Shen S. Nateglinide alone and in combination with metformin improves glycemic control by reducing mealtime glucose levels in type 2 diabetes.  Diabetes Care. 2000;  23 1660-1665
• 41 Jaap A J, Jones G C, Mc Crimmon R J, Deary I J, Frier B M. Perceived symptoms of hypoglycaemia in elderly type 2 diabetic patients treated with insulin.  Diabet Med. 1998;  15 398-401
• 42 Jonsson A, Rydberg T, Sterner G, Melander A. Pharmacokinetics of glibenclamide and ist metabolites in diabetic patients with impaired renal function.  Eur J Clin Pharmacol. 1998;  53 429-435
• 43 Karam J H, Sanz N, Salamon E, Nolte M S. Selective unresponsiveness of pancreatic B cells to acute sulfonylurea stimulation during sulfonylurea therapy in NIDDM.  Diabetes. 1986;  35 1314-1320
• 44 Kemmer F W, Tacken M, Berger M. Mechanism of exercise-induced hypoglycemia during sulfonylurea treatment.  Diabetes. 1987;  36 1178-1182
• 45 Kerr D, Macdonald I A, Heller S R, Tattersall R B. Alcohol causes hypoglycaemic unawareness in healthy volunteers and patients with type I (insulin-dependent) diabetes.  Diabetologia. 1990;  33 216-221
• 46 Kipnes M, Krosnick A, Rendell M S, Egan J W, Mathisen A L, Schneider R L. Pioglitazone hydrochloride in combination with sulfonylurea therapy improves glycemic control in patients with type 2 diabetes mellitus: a randomized, placebo-controlled study.  Am J Med. 2001;  111 10-17
• 47 Kramer W, Muller G, Geisen K. Characterization of the molecular mode of action of the sulfonylurea, glimepiride, at adipocytes.  Horm Metab Res. 1996;  28 469-487
• 48 Krepinsky J, Ingram A J, Clase C M. Prolonged sulfonylurea-induced hypoglycemia in diabetic patients with end-stage renal disease.  Am J Kidney Dis. 2000;  35 500-505
• 49 Landgraf R, Bilo H J, Muller P G. A comparison of repaglinide and glibenclamide in the treatment of type 2 diabetic patients previously treated with sulphonylureas.  Eur J Clin Pharmacol. 1999;  55 165-171
• 50 Landstedt-Hallin L, Adamson U, Lins P E. Oral glibenclamide suppresses glucagon secretion during insulin-induced hypoglycemia in patients with type 2 diabetes.  J Clin Endocrinol Metab. 1999;  84 3140-3145
• 51 Lebovitz H E, Melander A. Sulfonylureas basic aspects and clinical uses. Alberti KGMM, DeFronzo RA, Keen H, Zimmet P International Textbook of Diabetes Mellitus. Vol. 1. Chichester; Wiley 1992: 745-772
• 52 Levy C J, Kinsley B T, Bjaj M, Simonson D C. Effect of glycemic control on glucose counterregulation during hypoglycemia in NIDDM.  Diabetes Care. 1998;  21 1330-1338
• 53 Lindblad U, Melander A. Sulphonylurea dose-response relationships: relation to clinical practice.  Diabetes Obes Metab. 2000;  2 25-31
• 54 Madsbad S, Kilhovd B, Lager I, Mustajoki P, Dejgaard A. Comparison between repaglinide and glipizide in type 2 diabetes mellitus: a 1-year multicentre study.  Diabet Med. 2001;  18 395-401
• 55 Mafauzy M. Repaglinide versus glibenclamide treatment of Type 2 diabetes during Ramadan fasting.  Diabetes Res Clin Pract. 2002;  58 45-53
• 56 Marbury T, Huang W C, Strange P, Lebovitz H. Repaglinide versus glyburide: a one-year comparison trial.  Diab Res Clin Pract. 1999;  43 155-166
• 57 Marbury T, Ruckle J L, Hartop V, Andersen M P, Kramer Nielsen K, Huang W C, Strange P. Pharmocokinetics of repaglinide in subjects with renal impairment.  Clin Pharmacol Therap. 2000;  67 7-15
• 58 Massi-Benedetti M, Herz M, Pfeiffer C. The effects of acute exercise on metabolic control in type 2 diabetic patients treated with glimepiride orglibenclamide.  Horm Metab Res. 1996;  28 451-455
• 59 Miller C D, Phillips L S, Ziemer D C, Gallina D L, Cook C B, El-Kebbi I M. Hypoglycemia in patients with type 2 diabetes mellitus.  Arch Intern Med. 2001;  161 1653-1659
• 60 Mooradian A D, Kalis J, Nugent C A. The nutritional status of ambulatory elderly type 2 diabetic patients.  Age. 1990;  13 87-89
• 61 Morley J E. The elderly type 2 diabetic patient: special considerations.  Diabet Med. 1998;  15 (Suppl 4) S41-46
• 62 Morris A D, Boyle D I, McMahon A D, Pearce H, Evans J M, Newton R W, Jung R T, MacDonald T M. ACE inhibitor use is associated with hospitalization for severe hypoglycemia in patients with diabetes. DARTS/MEMO Collaboration. Diabetes Audit and Research in Tayside, Scotland. Medicines Monitoring Unit.  Diabetes Care. 1997;  20 1363-1367
• 63 Mueller G, Geisen K. Characterization of the molecular mode of action of the sulfonylurea, glimepiride, at adipocytes.  Horm Metab Res. 1996;  28 469-487
• 64 Mueller G, Hartz D, Punter J, Okonomopolos R, Kramer W. Differential interaction of glimepiride and glibenclamide with the beta cell sulphonylurea receptor. I. Binding characteristics.  Biochim Biophys Acta. 1994;  1191 267-277
• 65 Niemi M, Brackman J T, Neuvonen M, Laitila J, Neuvonen P J, Kivisto K T. Effects of fluconazole and fluvoxamine on the pharmacokinetics and pharmacodynamics of glimepiride.  Clin Pharmacol Ther. 2001;  69 194-200
• 66 Niemi M, Neuvonen P J, Kivisto K T. Effects of gemfibrozil on the pharmacokinetics and pharmacodynamics of glimepiride.  Clin Pharmacol Ther. 2001 a;  70 439-445
• 67 Niemi M, Cascorbi I, Timm R, Kroemer H K, Neuvonen P J, Kivisto K T. Glyburide and glimepiride pharmacokinetics in subjects with different CYP2C9 genotypes.  Clin Pharmacol Ther. 2002;  72 326-332
• 68 Nolan J J, Jones N P, Patwardhan R, Deacon L F. Rosiglitazone taken once daily provides effective glycaemic control in patients with type 2 diabetes mellitus.  Diabet Med. 2000;  17 287-294
• 69 Pearson J G, Antal E J, Raehl C L, Gorsch H K, Craig W A, Albert K S, Welling P G. Pharmacokinetic disposition of 14 C - glyburide in patients with varying renal function.  Clin Pharmacol Ther. 1986;  39 318-324
• 70 Roberge R J, Kaplan R, Frank R, Fore C. Glyburide-ciprofloxacin interaction with resistant hypoglycemia.  Ann Emerg Med. 2000;  36 160-163
• 71 Rosenblatt S, Miskin B, Glazer N B, Prince M J, Robertson K E. The impact of pioglitazone on glycemic control and atherogenic dyslipidemia in patients with type 2 diabetes mellitus.  Coron Artery Dis. 2001;  12 413-423
• 72 Rosenkranz B. Pharmacokinetic basis for the safety of glimepiride in risk groups of NIDDM patients.  Horm Metab Res. 1996;  28 434-439
• 73 Rosenkranz B, Profozic V, Metelko Z, Mrzljak V, Lange C, Malerczyk V. Pharmacokinetics and safety of glimepiride at clinically effective doses in diabetic patients with renal impairment.  Diabetologia. 1996;  39 1617-1624
• 74 Rosenstock J, Shen S G, Gatlin M R, Foley J E. Combination therapy with nateglinide and a thiazolidinedione improves glycemic control in type 2 diabetes.  Diabetes Care. 2002;  25 1529-1533
• 75 Rydberg T, Wahlin-Boll E, Melander A. Determination of glibenclamide and its two major metabolites in human serum and urine by column liquid chromatography.  J Chromatogr. 1991;  564 223-233
• 76 Rydberg T, Jonsson A, Roder M, Melander A. Hypoglycemic activity of glyburide (glibenclamide) metabolites in humans.  Diabetes Care. 1994;  17 1026-1030
• 77 Sawicki P, Düwel P, Berger M. Struktur der Notfallversorgung schwerer Hypoglykämien.  Diabetes und Stoffwechsel. 1994;  3 176
• 78 Segel S A, Paramore D S, Cryer P E. Hypoglycemia-associated autonomic failure in advanced type 2 diabetes.  Diabetes. 2002;  51 724-733
• 79 Shichiri M, Kishikawa H, Ohkubo Y, Wake N. Long-term results of the Kumamoto Study on optimal diabetes control in type 2 diabetic patients.  Diabetes Care. 2000;  23 (Suppl 2) B21-29
• 80 Shorr R I, Ray W A, Daugherty J R, Griffin M R. Individual sulfonylureas and serious hypoglycemia in older people.  JAGS. 1997;  44 751-755
• 81 Sills M N, Ogu C C, Maxa J. Prolonged hypoglycemic crisis associated with glyburide.  Pharmacotherapy. 1997;  17 1338-1340
• 82 Song D K, Ashcroft F M. Glimepiride block of cloned beta-cell, cardiac, and smooth muscle K(ATP) channels.  Br J Pharmacol. 2001;  133 193-199
• 83 Sonnenberg G, Garg D C, Weidler D, Dixon R, Jaber L, Bowen A, DeCherney G, Mullican W, Stonesifer L. Short-term comparison of once- versus twice-daily administration of glimepiride in patients with non-insulin dependent diabetes mellitus.  Ann Pharmacother. 1997;  31 671-676
• 84 Sonnenblick M, Shilo S. Glibenclamide induced prolonged hypoglycaemia.  Age Ageing. 1986;  15 185-189
• 85 Spranger R, Bachmann W. Hypoglykämische Stoffwechselentgleisungen bei medikamentös behandelten Typ-II-Diabetikern.  Diabetes und Stoffwechsel. 1999;  8 (Suppl 1) 89
• 86 Stahl M, Berger W. Higher incidence of severe hypoglycaemia leading to hospital admission in type 2 diabetic patients treated with long-acting versus short-acting sulphonylureas.  Diabet Med. 1999;  16 586-590
• 87 Stumvoll M, Häring H U. Glitazones. Clinical effects and molecular mechanisms.  Ann Med. 2002;  34 217-224
• 88 Sugarman J R. Hypoglycemia-associated hospitalizations in a population with a high prevalence of non-insulin-dependent diabetes mellitus.  Diabetes Res Clin Pract. 1991;  14 139-147
• 89 Tatterhall R B. Frequency, causes, and treatment of hypoglycaemia. Frier B, Fisher B Hypoglycaemia in Clinical Diabetes. Chichester; Wiley 1999: 55-89
• 90 Tessier D, Dawson K, Tetrault J P, Bravo G, Meneilly G S. Glibenclamide vs. gliclazide in type 2 diabetes of the elderly.  Diabet Med. 1994;  11 974-980
• 91 ter Braak E W, Appelmann A M, van Der Tweel I, Erkelens D W, van Haeften T W. The sulfonylurea glyburide induces impairment of glucagon and growth hormone responses during mild insulin-induced hypoglycemia.  Diabetes Care. 2002;  25 107-112
• 92 UKPDS28 . A randomized trial of efficacy of early addition of metformin in sulfonylurea-treated type 2 diabetes. U. K. Prospective Diabetes Study Group.  Diabetes Care. 1998;  21 87-92
• 93 UKPDS33 . Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS33).  Lancet. 1998;  352 837-853
• 94 van Staa T, Abenhaim L, Monette J. Rates of hypoglycemia in users of sulfonylureas.  J Clin Epidemiol. 1997;  50 735-741
• 95 Veneman T, Mitrakou A, McKan M, Cryer P, Gerich J. Induction of hypoglycaemia unawareness by asymptomatic nocturnal hypoglycaemia.  Diabetes. 1993;  42 1233-1237
• 96 Veneman T F, Erkelens D W. Clinical review 88: Hypoglycemia unawareness in noninsulin-dependent diabetes mellitus.  J Clin Endocrinol Metab. 1997;  82 1682 -1684
• 97 Werner A L, Travaglini M T. A review of rosiglitazone in type 2 diabetes mellitus.  Pharmacotherapy. 2001;  21 1082-1099
• 98 Whipple A O. The surgical therapy of hyperinsulinism.  J Int Chir. 1938;  3 237-276
• 99 Wolffenbuttel B H, 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;  22 463-467
• 100 Wolffenbuttel B H, Gomist R, Squatrito S, Jones N P, Patwardhan R N. Addition of low-dose rosiglitazone to sulphonylurea therapy improves glycaemic control in type 2 diabetic patients.  Diabet Med. 2000;  17 40-47
• 101 Yee H S, Fong N T. A review of the safety and efficacy of acarbose in diabetes mellitus.  Pharmacotherapy. 1996;  16 792-805