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Meglitinide Analogues in the Treatment of Type 2 Diabetes Mellitus

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Abstract

Type 2 diabetes mellitus is a complex heterogenous metabolic disorder in which peripheral insulin resistance and impaired insulin release are the main pathogenetic factors. The rapid response of the pancreatic β-cells to glucose is already markedly disturbed in the early stages of type 2 diabetes mellitus. The consequence is often postprandial hyperglycaemia, which seems to be extremely important in the development of secondary complications, especially macro-vascular disease. Therefore one of the main aims of treatment is to minimise blood glucose oscillations and attain near-normal glycosylated haemoglobin levels.

Meglitinide analogues belong to a new family of insulin secretagogues which stimulate insulin release by inhibiting ATP-sensitive potassium channels of the β-cell membrane via binding to a receptor distinct from that of sulphonylureas (SUR1/KIR 6.2). The pharmacokinetic and pharmacodynamic properties of repaglinide, the first drug of these new antihyperglycaemic agents on the market, and of nateglinide, which will be available soon, differ markedly from the currently used sulphonylureas [mainly glibenclamide (glyburide) and glimepiride]. Repaglinide and nateglinide are absorbed rapidly, stimulate insulin release within a few minutes, are rapidly metabolised in the liver and are mainly excreted in the bile. Therefore, following preprandial administration of these drugs, insulin is more readily available during and just after the meal. This leads to a significant reduction in postprandial hyperglycaemia without the danger of hypoglycaemia between meals.

The short action of these compounds and biliary elimination makes repaglinide and nateglinide especially suitable for patients with type 2 diabetes mellitus who would like to have a more flexible lifestyle, need more flexibility because of unplanned eating behaviour (e.g. geriatric patients) or in whom one of the other first-line antidiabetic drugs, i.e. metformin, is strictly contraindicated (e.g. nephropathy with creatinine clearance ≤50 ml/min). Meglitinide analogues act synergistically with metformin and thiazolidinediones (pioglitazone and rosiglitazone) and can be also combined with long-acting insulin (NPH insulin at bedtime).

Therefore, these drugs enrich the palette of antidiabetic drugs and make the treatment more flexible and better tolerated, which both add to better metabolic control and support the empowerment and compliance of the patient. However, this will only be the case if the patient and the diabetes care team are trained for this new therapeutic schedule and the healthcare system is able to pay for these rather expensive drugs.

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References

  1. Diabetes Control and Complication Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329: 977–86

    Article  Google Scholar 

  2. Reichard P, Nilsson BY, Rosenquist U. The effect of long-term intensified insulin treatment on the development of microvascular complications of diabetes mellitus. N Engl J Med 1993; 329: 304–9

    Article  PubMed  CAS  Google Scholar 

  3. Ohkubo Y, Kishikawa H, Araki E, et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabet Res Clin Pract 1995; 28: 103–17

    Article  CAS  Google Scholar 

  4. UK Prospective Diabetes Study Group. Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837–53

    Article  Google Scholar 

  5. UK Prospective Diabetes Study Group. Effect of intensive blood glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998; 352: 854–65

    Article  Google Scholar 

  6. Polonsky KS, Given BD, Hirsch LJ, et al. Abnormal patterns of insulin secretion in non-insulin-dependent diabetes mellitus. N Engl J Med 1988; 318: 1231–9

    Article  PubMed  CAS  Google Scholar 

  7. Ceriello A. The emerging role of postprandial hyperglycemic spikes in the pathogenesis of diabetic complications. Diabet Med 1998; 15: 188–93

    Article  PubMed  CAS  Google Scholar 

  8. Landgraf R. Approaches in the management of postprandial hyperglycemia. Exp Clin Endocrinol Diabetes 1999 Suppl. 4; 107: 128–32

    Article  Google Scholar 

  9. Mooradian AD, Thurman JE. Drug therapy of postprandial hyperglycemia. Drugs 1999; 57: 19–29

    Article  PubMed  CAS  Google Scholar 

  10. Evans AJ, Krentz AJ. Recent developments and emerging therapies for type 2 diabetes mellitus. Drugs R & D 1999; 2(2): 75–94

    Article  CAS  Google Scholar 

  11. Malaisse WJ. Stimulation of insulin release by non-sulfonylurea hypoglycemic agents: the meglitinide family. Horm Metab Res 1995; 27(6): 263–6

    Article  PubMed  CAS  Google Scholar 

  12. 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(3): 345–51

    Article  PubMed  CAS  Google Scholar 

  13. Ashcroft FM, Gribble FM. ATP-sensitive K+ channels and insulin secretion. Diabetologia 1999; 42: 903–19

    Article  PubMed  CAS  Google Scholar 

  14. Akiyoshi M, Kakei M, Nakazaki M, et al. A new hypoglycemic agent, A-4166, inhibits ATP-sensitive potassium channels in rat pancreatic β-cells. Am J Physiol 1995; 268: E185–93

    PubMed  CAS  Google Scholar 

  15. Dorschner H, Brekardin E, Uhde I, et al. Stoichiometry of sulfonylurea-induced ATP-sensitive potassium channel closure. Mol Pharmacol 1999; 55(6): 1060–6

    PubMed  CAS  Google Scholar 

  16. Gribble FM, Ashfield R, Ammala C, et al. Properties of cloned ATP-sensitive K+ currents expressed in Xenopus oocytes. J Physiol (Lond) 1997; 498(Pt 1): 87–98

    CAS  Google Scholar 

  17. Gromada J, Dissing S, Kofod H, et al. Effects of the hypoglycaemic drugs repaglinide and glibenclamide on ATP-sensitive potassium-channels and cytosolic calcium levels in beta TC3 cells and rat pancreatic beta cells. Diabetologia 1995; 38(9): 1025–32

    Article  PubMed  CAS  Google Scholar 

  18. Tian YA, Johnson G, Ashcroft SJ. Sulfonylureas enhance exocytosis from pancreatic beta-cells by a mechanism that does not involve direct activation of protein kinase C. Diabetes1998; 47(11): 1722–6

    Article  PubMed  CAS  Google Scholar 

  19. Malaisse WJ. Repaglinide, a new oral antidiabetic agent: a review of recent preclinical studies. Eur J Clin Invest 1999; 2: 21–9

    Article  Google Scholar 

  20. Dunning BE. New non-sulfonylurea insulin secretagogues. Exp Opin Invest Drugs 1997; 6: 1041–8

    Article  CAS  Google Scholar 

  21. Dunnig BE. Nateglinide: a glucose-sensitive insulinotropic agent that is chemically and pharmacologically distinct from the sulfonylureas. Curr Opin Endocrinol Diabetes 1999; 6Suppl. 1: S29–31

    Google Scholar 

  22. Leclercq-Meyer V, Ladriere L, Fuhlendorff J, et al. Stimulation of insulin and somatostatin release by two meglitinide analogs. Endocrine 1997; 7(3): 311–7

    Article  PubMed  CAS  Google Scholar 

  23. Kofod H, Fuhlendorff J. Repaglinide compared to glibenclamide in isolated mouse islets by perifusion. Diabetologia 1995; 38Suppl. 1: A195

    Google Scholar 

  24. Fujitani S, Ikenoue T, Akiyoshi M, et al. Somatostatin and insulin secretion due to common mechanisms by a new hypoglycemic agent, A-4166, in perfused rat pancreas. Metabolism 1996; 45: 184–9

    Article  PubMed  CAS  Google Scholar 

  25. Malaisse WJ. The beta cell in NIDDM: giving light to the blind. Diabetologia 1994; 37Suppl. 2: S36–42

    Article  PubMed  Google Scholar 

  26. Mark M, Grell W. Hypoglycaemic effects of the novel antidiabetic agent repaglinide in rats and dogs. Br J Pharmacol 1997; 121(8): 1597–604

    Article  PubMed  CAS  Google Scholar 

  27. Laghmich A, Ladriere L, Malaisse-Lagae F, et al. Pancreatic islet responsiveness to D-glucose after repeated administration of repaglinide. Eur J Pharmacol 1998; 348(2–3): 265–70

    Article  PubMed  CAS  Google Scholar 

  28. Ladriere L, Malaisse-Lagae F, Fuhlendorff J, et al. Effect of antidiabetic agents on the increase in glycemia and insulinemia caused by refeeding in hereditarily diabetic rats. Res Commun Mol Pathol Pharmacol 1997; 97(1): 53–9

    PubMed  CAS  Google Scholar 

  29. Ikenoue T, Okazaki K, Fujitani S, et al. Effect of a new hypoglycemic agent, A-4166 ((−)−N-(trans-4-isopropyl-cyclo-hexanecarbonyl)-D-phenylalanine), on postprandial blood glucose excursion: comparison with voglibose and glibenclamide. Biol Pharm Bull 1997; 20(4): 354–9

    Article  PubMed  CAS  Google Scholar 

  30. Dunning B, Gutierrez C. Pharmacodynamics of nateglinide and repaglinide in Cynomolgus monkeys [abstract no. A0446]. Diabetes 1999; 48Suppl. 1: 104

    Google Scholar 

  31. Dunning B, Paladini S. Mimicking cephalic insulin release with the rapid-onset/short-duration insulinotropic agent, nateglinide, reduces prandial glucose excursions without increasing total exposure in IGT monkeys [abstract no. A1233]. Diabetes 1999; 48Suppl. 1: 282

    Google Scholar 

  32. Senaglinide. Drugs R & D 1999; 2(2): 123–6

    Google Scholar 

  33. Van Heiningen PNM, Hatorp V, Kramer-Nilesen K, et al. Absorption, metabolism and excretion of a single oral dose of 14C-repaglinide during repaglinide multiple dosing. Eur J Clin Pharmacol 1999; 55: 521–5

    Article  PubMed  Google Scholar 

  34. Bauer E, Beschke K, Ebner T, et al. Biotransformation of (14C) rapaglinide in human, cynomolgus monkey, dog, rabbit, rat and mouse [abstract]. Diabetologia 1997; 40Suppl. 1: 1282

    Google Scholar 

  35. Plum A, Muller LK, Jansen JA. The effects of selected drugs on the in vitro protein binding of repaglinide in human plasma. Meth Find Exper Clin Pharmacol 2000; 22: 139–43

    CAS  Google Scholar 

  36. Hatorp V, Huang WC, Strange P. Repaglinide pharmacokinetics in healthy young adult and elderly subjects. Clin Ther 1999; 21(4): 702–10

    Article  PubMed  CAS  Google Scholar 

  37. Hatorp V, Huang WC, Strange P. Pharmacokinetic profiles of repaglinide in elderly subjects with type 2 diabetes. J Clin Endocrinol Metab 1999; 84(4): 1475–8

    Article  PubMed  CAS  Google Scholar 

  38. Hatorp V, Haugh-Pihale G. A comparison of the pharmacokinetics of repaglinide in healthy subjects with that in subjects with chronic liver disease [abstract]. Diabetologia 1998; 41Suppl. 1: A236

    Google Scholar 

  39. Marbury TC, Ruckle JL, Hatorp V, et al. Pharmacokinetics of repaglinide in subjects with renal impairment. Clin Pharmacol Ther 2000; 67: 7–15

    Article  PubMed  CAS  Google Scholar 

  40. Luzio S, Mukherjee S, Anderson D, et al. The hypoglycemic properties of a novel phenylalanine derivative in healthy subjects-timing of adminstration and meal effect on absorption [abstract]. Diabetes 1996; 45Suppl. 2: 72

    Google Scholar 

  41. Karara AH, Dunning BE, McLeod JF. The effect of food on the bioavailability and the pharmacodynamic actions of the insulinotropic agent nateglinide in healthy subjects. J Clin Pharmacol 1999; 39: 172–9

    Article  PubMed  CAS  Google Scholar 

  42. Juhl CB, Porksen N, Hollingdal M, et al. Repaglinide acutely amplifies pulsatile insulin secretion by augmentation of burst mass with no effect on burst frequency. Diabet Care 2000; 23: 675–81

    Article  CAS  Google Scholar 

  43. Owens DR, Luzio SD, Ismail I, et al. Increased prandial insulin secretion after administration of a single preprandial oral dose of repaglinide in patients with type 2 diabetes. Diabet Care 2000; 23: 518–23

    Article  CAS  Google Scholar 

  44. Goldberg RB, Einhorn D, Lucas CP, et al. A randomized placebo-controlled trial of repaglinide in the treatment of type 2 diabetes. Diabet Care 1998; 21(11): 1897–903

    Article  CAS  Google Scholar 

  45. Damsbo P, Clauson P, Marbury TC, et al. 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(5): 789–94

    Article  PubMed  CAS  Google Scholar 

  46. Wolffenbuttel BH, Nijst L, Sels JP, et al. Effects of a new oral hypoglycaemic agent, repaglinide, on metabolic control in sulphonylurea-treated patients with NIDDM. Eur J Clin Pharmacol 1993; 45(2): 113–6

    Article  PubMed  CAS  Google Scholar 

  47. Landgraf R, Bilo HJ, Muller PG. A comparison of repaglinide and glibenclamide in the treatment of type 2 diabetic patients previously treated with sulphonylureas. Eur J Clin Pharmacol 1999; 55(3): 165–71

    Article  PubMed  CAS  Google Scholar 

  48. 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. Diabet Care 1999; 22(3): 463–7

    Article  CAS  Google Scholar 

  49. Marbury T, Huang WC, Strange P, et al. Repaglinide versus glyburide: a one-year comparison trial. Diabet Res Clin Pract 1999; 43(3): 155–66

    Article  CAS  Google Scholar 

  50. Van Gaal L, Drouin P, Navalesi R. One-year multicenter, randomized and double-blind comparison of repaglinide and gliclazide for the treatment of type 2 diabetes mellitus. Copenhagen, Novo Norddisk study AGEE/DCD/047/B/F/I, 1996. (Data on file)

    Google Scholar 

  51. Madsbad S, Kilhovd B, Lager I, et al. Superior glycemic control with repaglinide compared with glipizide in type 2 diabetics [abstract]. Diabetes 2000; 49Suppl. 1: A1514

    Google Scholar 

  52. Moses R, Slobodniuk R, Boyages S, et al. Effect of repaglinide addition to metformin monotherapy on glycemic control in patients with type 2 diabetes. Diabet Care 1999; 22(1): 119–24

    Article  CAS  Google Scholar 

  53. Landin-Olsson M, Brogard JM, Eriksson J, et al. The efficacy of repaglinide administered in combination with bedtime NPH-insulin in patients with type 2 diabetes [abstract]. Diabetes 1999; 48Suppl. 1: A117

    Google Scholar 

  54. Raskin P, Jovanovic L, Berger S, et al. Repaglinide/troglitazone combination therapy: improved glycemic control in type 2 diabetes. Diabet Care 2000; 23: 979–83

    Article  CAS  Google Scholar 

  55. Hanefeld M, Bouter KP, Dickinson S, et al. Rapid and shortacting mealtime insulin secretion with nateglinide controls both prandial and mean glycemia. Diabet Care 2000; 23: 202–7

    Article  CAS  Google Scholar 

  56. Hirschberg Y, Karara AH, Pietri AO, et al. Improved control of mealtime glucose excursions with coadministration of nateglinide and metformin. Diabet Care 2000; 23: 349–53

    Article  CAS  Google Scholar 

  57. Viertel B, Güttner J. Effects of the oral antidiabetic repaglinide on the reproduction of rats. Drug Res 2000; 50: 425–40

    Article  CAS  Google Scholar 

  58. Asplund K, Wiholm BE, Lithner F. Glibenclamide-associated hypoglycemia: a report on 57 cases. Diabetologia 1983; 24: 412–417

    Article  PubMed  CAS  Google Scholar 

  59. Berger W, Caduff F, Pasquel M, et al. The relatively frequent incidence of severe sulpfonylurea-induced hypoglycemia in the last 25 years in Switzerland: results of 2 surveys in Switzerland in 1969 and 1984. Schweiz Med Wochenschr 1986; 116: 145–51

    PubMed  CAS  Google Scholar 

  60. Asplund K, Wiholm BE, Lundman B. Severe hypoglycemia during treatment with glipizide. Diabet Med 1991; 8: 726–31

    Article  PubMed  CAS  Google Scholar 

  61. European Diabetes Policy Group. A desktop guide to type 2 diabetes mellitus. Diabet Med 1999; 16: 716–30

    Article  Google Scholar 

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Correspondence to Rüdiger Landgraf.

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Landgraf, R. Meglitinide Analogues in the Treatment of Type 2 Diabetes Mellitus. Drugs & Aging 17, 411–425 (2000). https://doi.org/10.2165/00002512-200017050-00007

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