The American Journal of Medicine
Volume 121, Issue 6, Supplement , Pages S9-S19 , June 2008

Pharmacokinetic and Pharmacodynamic Advantages of Insulin Analogues and Premixed Insulin Analogues Over Human Insulins: Impact on Efficacy and Safety

  • Arturo Rolla, MD

      Affiliations

    • Corresponding Author InformationRequests for reprints should be addressed to Arturo Rolla, MD, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215.

References 

  1. Polonsky KS, Given BD, Hirsch LJ, et al. Abnormal patterns of insulin secretion in non-insulin-dependent diabetes mellitus. N Engl J Med. 1988;318:1231–1239
  2. Gough SC. A review of human and analogue insulin trials. Diabetes Res Clin Pract. 2007;77:1–15
  3. Peterson G. Intermediate and long-acting insulins: a review of NPH insulin, insulin glargine and insulin detemir. Curr Med Res Opin. 2006;22:2613–2619
  4. Wang F, Carabino JM, Vergara CM. Insulin glargine: a systematic review of a long-acting insulin analogue. Clin Ther. 2003;25:1541–1577discussion 1539–1540
  5. Havelund S, Plum A, Ribel U, et al. The mechanism of protraction of insulin detemir, a long-acting, acylated analog of human insulin. Pharm Res. 2004;21:1498–1504
  6. Kurtzhals P. Engineering predictability and protraction in a basal insulin analogue: the pharmacology of insulin detemir. Int J Obes Relat Metab Disord. 2004;28(suppl 2):S23–S28
  7. Heinemann L, Linkeschova R, Rave K, et al. Time-action profile of the long-acting insulin analog insulin glargine (HOE901) in comparison with those of NPH insulin and placebo. Diabetes Care. 2000;23:644–649
  8. Lepore M, Pampanelli S, Fanelli C, et al. Pharmacokinetics and pharmacodynamics of subcutaneous injection of long-acting human insulin analog glargine, NPH insulin, and ultralente human insulin and continuous subcutaneous infusion of insulin lispro. Diabetes. 2000;49:2142–2148
  9. Luzio S, Dunseath G, Peter R, et al. Comparison of the pharmacokinetics and pharmacodynamics of biphasic insulin aspart and insulin glargine in patients with type 2 diabetes. Diabetologia. 2006;49:1163–1168
  10. Heinemann L, Sinha K, Weyer C, et al. Time-action profile of the soluble, fatty acid acylated, long-acting insulin analogue NN304. Diabet Med. 1999;16:332–338
  11. Brunner GA, Sendhofer G, Wutte A, et al. Pharmacokinetic and pharmacodynamic properties of long-acting insulin analogue NN304 in comparison to NPH insulin in humans. Exp Clin Endocrinol Diabetes. 2000;108:100–105
  12. Plank J, Bodenlenz M, Sinner F, et al. A double-blind, randomized, dose-response study investigating the pharmacodynamic and pharmacokinetic properties of the long-acting insulin analog detemir. Diabetes Care. 2005;28:1107–1112
  13. Klein O, Lynge J, Endahl L, et al. Albumin-bound basal insulin analogues (insulin detemir and NN344): comparable time–action profiles but less variability than insulin glargine in type 2 diabetes. Diabetes Obes Metab. 2007;9:290–299
  14. Klein O, Lynge J, Endahl L, et al. Insulin detemir and insulin glargine: similar time-action profiles in subjects with type 2 diabetes [abstract]. Diabetes. 2006;55(suppl 1):325-OR
  15. Heise T, Nosek L, Ronn BB, et al. Lower within-subject variability of insulin detemir in comparison to NPH insulin and insulin glargine in people with type 1 diabetes. Diabetes. 2004;53:1614–1620
  16. Scholtz HE, Pretorius SG, Wessels DH, Becker RH. Pharmacokinetic and glucodynamic variability: assessment of insulin glargine, NPH insulin and insulin ultralente in healthy volunteers using a euglycaemic clamp technique. Diabetologia. 2005;48:1988–1995
  17. Lantus [package insert]. Kansas City, MO: Aventis Pharmaceuticals Inc; 2004;http://www.fda.gov/cder/foi/label/2005/21081s017lbl.pdfAccessed May 1, 2007
  18. Levemir [package insert]. Bagsvaerd, Denmark: Novo Nordisk; 2002;http://www.fda.gov/cder/foi/label/2005/021536lbl.pdfAccessed May 1, 2007
  19. Tibaldi J. Initiating and intensifying insulin therapy in type 2 diabetes mellitus. Am J Med. 2008;121(suppl 6A):S20–S29
  20. Riddle MC, Rosenstock J, Gerich J Insulin Glargine 4002 Study Investigators. The Treat-to-Target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care. 2003;26:3080–3086
  21. Yki-Jarvinen H, Dressler A, Ziemen M HOE 901/300s Study Group. Less nocturnal hypoglycemia and better post-dinner glucose control with bedtime insulin glargine compared with bedtime NPH insulin during insulin combination therapy in type 2 diabetes. Diabetes Care. 2000;23:1130–1136
  22. Rosenstock J, Schwartz SL, Clark CM, et al. Basal insulin therapy in type 2 diabetes: 28-week comparison of insulin glargine (HOE 901) and NPH insulin. Diabetes Care. 2001;24:631–636
  23. Fritsche A, Schweitzer MA, Haring HU 4001 Study Group. Glimepiride combined with morning insulin glargine, bedtime neutral protamine Hagedorn insulin, or bedtime insulin glargine in patients with type 2 diabetes: a randomized, controlled trial. Ann Intern Med. 2003;138:952–959
  24. Hermansen K, Davies M, Derezinski T, et al. A 26-week, randomized, parallel, treat-to-target trial comparing insulin detemir with NPH insulin as add-on therapy to oral glucose-lowering drugs in insulin-naive people with type 2 diabetes. Diabetes Care. 2006;29:1269–1274
  25. Philis-Tsimikas A, Charpentier G, Clauson P, et al. Comparison of once-daily insulin detemir with NPH insulin added to a regimen of oral antidiabetic drugs in poorly controlled type 2 diabetes. Clin Ther. 2006;28:1569–1581
  26. Raslova K, Bogoev M, Raz I, et al. Insulin detemir and insulin aspart: a promising basal-bolus regimen for type 2 diabetes. Diabetes Res Clin Pract. 2004;66:193–201
  27. Massi Benedetti M, Humburg E, Dressler A, Ziemen M. A one-year, randomised, multicentre trial comparing insulin glargine with NPH insulin in combination with oral agents in patients with type 2 diabetes. Horm Metab Res. 2003;35:189–196
  28. Fonseca V, Bell DS, Berger S, Thomson S, Mecca TE. A comparison of bedtime insulin glargine with bedtime neutral protamine Hagedorn insulin in patients with type 2 diabetes: subgroup analysis of patients taking once-daily insulin in a multicenter, randomized, parallel group study. Am J Med Sci. 2004;328:274–280
  29. Haak T, Tiengo A, Draeger E, Suntum M, Waldhausl W. Lower within-subject variability of fasting blood glucose and reduced weight gain with insulin detemir compared to NPH insulin in patients with type 2 diabetes. Diabetes Obes Metab. 2005;7:56–64
  30. Dornhorst A, Luddeke H-J, Sreenan S, et al. PREDICTIVE Study Group Safety and efficacy of insulin detemir in clinical practice: 14-week follow-up data from type 1 and type 2 diabetes patients in the PREDICTIVE European cohort. Int J Clin Pract. 2007;61:523–528
  31. Luddeke H-J, Philotheou A, Horn-Rosenberg K, et al. PREDICTIVE™: a global, prospective, observational study to evaluate insulin detemir treatment in type 1 and type 2 diabetes — 3 month follow-up data. Diabet Med. 2006;23(suppl 4):139;Abstract P380
  32. Meneghini LF, Rosenberg KH, Koenen C, et al. Insulin detemir improves glycemic control with less hypoglycemia and no weight gain in patients with type 2 diabetes who were insulin naïve or treated with NPH or insulin glargine: clinical practice experience from a German subgroup of the PREDICTIVE study. Diabetes Obes Metab. 2007;9:418–427
  33. Schreiber SA, Haak T. Insulin glargine benefits patients with type 2 diabetes inadequately controlled on oral antidiabetic treatment: an observational study of everyday practice in 12,216 patients. Diabetes Obes Metab. 2007;9:31–38
  34. Tremble JM, Donaldson D. Is continued weight gain inevitable in type 2 diabetes mellitus?. J R Soc Health. 1999;119:235–239
  35. Home P, Kurtzhals P. Insulin detemir: from concept to clinical experience. Expert Opin Pharmacother. 2006;7:325–343
  36. Brange J, Volund A. Insulin analogs with improved pharmacokinetic profiles. Adv Drug Deliv Rev. 1999;35:307–335
  37. Galloway JA. New directions in drug development: mixtures, analogues, and modeling. Diabetes Care. 1993;16(suppl 3):S16–S23
  38. Robinson DM, Wellington K. Insulin glulisine. Drugs. 2006;66:861–869
  39. Rosenfalck AM, Thorsby P, Kjems L, et al. Improved postprandial glycaemic control with insulin Aspart in type 2 diabetic patients treated with insulin. Acta Diabetol. 2000;37:41–46
  40. Humalog [package insert]. Indianapolis, IN: Eli Lilly and Company; 2004;http://www.fda.gov/cder/foi/label/2005/020563s054lbl.pdfAccessed May 1, 2007
  41. DECODE Study group on behalf of the European Diabetes Epidemiology Group. Glucose tolerance and mortality: comparison of WHO and American Diabetes Association diagnostic criteria. Lancet. 1999;354:617–621
  42. Bonora E, Muggeo M. Postprandial blood glucose as a risk factor for cardiovascular disease in type II diabetes: the epidemiological evidence. Diabetologia. 2001;44:2107–2114
  43. Monnier L, Lapinski H, Colette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA1c. Diabetes Care. 2003;26:881–885
  44. NovoLog [package insert]. Bagsvaerd, Denmark: Norvo Nordisk A/S; 2005;http://www.fda.gov/cder/foi/label/2005/20986s032lbl.pdfAccessed May 1, 2007
  45. Apidra [package insert]. Kansas City, MO: Aventis Pharmaceuticals Inc; 2005;http://www.fda.gov/cder/foi/label/2005/021629s001,002lbl.pdfAccessed May 1, 2007
  46. Home PD, Lindholm A, Riis A European Insulin Aspart Study Group. Insulin aspart vs. human insulin in the management of long-term blood glucose control in Type 1 diabetes mellitus: a randomized controlled trial. Diabet Med. 2000;17:762–770
  47. Home PD, Barriocanal L, Lindholm A. Comparative pharmacokinetics and pharmacodynamics of the novel rapid-acting insulin analogue, insulin aspart, in healthy volunteers. Eur J Clin Pharmacol. 1999;55:199–203
  48. Frick A, Becker RHA, Wessels D, et al. Pharmacokinetic and glucodynamic profiles of insulin glulisine following subcutaneous administration at various injection sites [abstract]. Diabetes. 2003;52(suppl 1):A119
  49. AndersonJH Jr, Brunelle RL, Koivisto VA, et al. Multicenter Insulin Lispro Study Group Reduction of postprandial hyperglycemia and frequency of hypoglycemia in IDDM patients on insulin-analog treatment. Diabetes. 1997;46:265–270
  50. Lindholm A, McEwen J, Riis AP. Improved postprandial glycaemic control with insulin aspart: a randomized double-blind cross-over trial in type 1 diabetes. Diabetes Care. 1999;22:801–805
  51. Nosek L, Becker RHA, Frick AD, et al. Prandial blood glucose control with pre- and post-meal insulin glulisine versus regular human insulin [abstract]. Diabetologia. 2004;47(suppl 1):A300
  52. Ross SA, Zinman B, Campos RV, Strack T Canadian Lispro Study Group. A comparative study of insulin lispro and human regular insulin in patients with type 2 diabetes mellitus and secondary failure of oral hypoglycemic agents. Clin Invest Med. 2001;24:292–298
  53. Perriello G, Pampanelli S, Porcellati F, et al. Insulin aspart improves meal time glycaemic control in patients with Type 2 diabetes: a randomized, stratified, double-blind and cross-over trial. Diabet Med. 2005;22:606–611
  54. Becker RH, Frick AD, Burger F, Scholtz H, Potgieter JH. A comparison of the steady-state pharmacokinetics and pharmacodynamics of a novel rapid-acting insulin analog, insulin glulisine, and regular human insulin in healthy volunteers using the euglycemic clamp technique. Exp Clin Endocrinol Diabetes. 2005;113:292–297
  55. von Mach MA, Brinkmann C, Hansen T, et al. Differences in pharmacokinetics and pharmacodynamics of insulin lispro and aspart in healthy volunteers. Exp Clin Endocrinol Diabetes. 2002;110:416–419
  56. Burger F, Scholtz H, Frick A, Becker R. Pharmacodynamics (PD) and pharmacokinetics (PK) of insulin glulisine (GLU) versus insulin lispro (IL) and regular human insulin (RHI) in patients with type 1 diabetes [abstract]. Diabetes. 2004;53(suppl 2):557
  57. Heinemann L, Weyer C, Rauhaus M, Heinrichs S, Heise T. Variability of the metabolic effect of soluble insulin and the rapid-acting insulin analog insulin aspart. Diabetes Care. 1998;21:1910–1904
  58. Rotella CM, Pala L, Dicembrini I, Mannucci E. Comparison between aspart and regular insulin in combination with metformin in Type 2 diabetic patients [abstract]. Diabetologia. 2004;47(suppl. 1):A266
  59. Anderson JHJr, Brunelle RL, Keohane P, et al. Multicenter Insulin Lispro Study Group Mealtime treatment with insulin analog improves postprandial hyperglycemia and hypoglycemia in patients with non-insulin-dependent diabetes mellitus. Arch Intern Med. 1997;157:1249–1255
  60. Anderson JH, Brunelle RL, Koivisto VA, et al. Multicenter Insulin Lispro Study Group Improved mealtime treatment of diabetes mellitus using an insulin analogue. Clin Ther. 1997;19:62–72
  61. Bretzel RG, Arnolds S, Medding J, Linn T. A direct efficacy and safety comparison of insulin aspart, human soluble insulin, and human premix insulin (70/30) in patients with type 2 diabetes. Diabetes Care. 2004;27:1023–1027
  62. Dailey G, Rosenstock J, Moses RG, Ways K. Insulin glulisine provides improved glycemic control in patients with type 2 diabetes. Diabetes Care. 2004;27:2363–2368
  63. Raskin P, Allen E, Hollander P, et al. INITIATE Study Group Initiating insulin therapy in type 2 diabetes: a comparison of biphasic and basal insulin analogs. Diabetes Care. 2005;28:260–265
  64. Weyer C, Heise T, Heinemann L. Insulin aspart in a 30/70 premixed formulation: pharmacodynamic properties of a rapid-acting insulin analog in stable mixture. Diabetes Care. 1997;20:1612–1614
  65. Malone JK, Woodworth JR, Arora V, et al. Improved postprandial glycemic control with Humalog Mix 75/25 after a standard test meal in patients with type 2 diabetes mellitus. Clin Ther. 2000;22:222–230
  66. Jacobsen LV, Sogaard B, Riis A. Pharmacokinetics and pharmacodynamics of a premixed formulation of soluble and protamine-retarded insulin aspart. Eur J Clin Pharmacol. 2000;56:399–403
  67. McSorley PT, Bell PM, Jacobsen LV, et al. Twice-daily biphasic insulin aspart 30 versus biphasic human insulin 30: a double-blind cross-over study in adults with type 2 diabetes mellitus. Clin Ther. 2002;24:530–539
  68. Hermansen K, Colombo M, Storgaard H, et al. Improved postprandial glycemic control with biphasic insulin aspart relative to biphasic insulin lispro and biphasic human insulin in patients with type 2 diabetes. Diabetes Care. 2002;25:883–888
  69. Garber AJ, Wahlen J, Wahl T, et al. Attainment of glycaemic goals in type 2 diabetes with once-, twice-, or thrice-daily dosing with biphasic insulin aspart 70/30 (the 1-2-3 Study). Diabetes Obes Metab. 2006;8:58–66
  70. Unger J. Current strategies for evaluating, monitoring and treating type 2 diabetes. Am J Med. 2008;121(suppl 6A):S3–S8
  71. NovoLog Mix 70/30 [package insert]. Bagsvaerd, Denmark: Novo Nordisk; 2005;http://www.fda.gov/cder/foi/label/2005/021172s021lbl.pdfAccessed May 1, 2007
  72. Humalog Mix 75/25 [package insert]. Indianapolis, IN: Eli Lilly and Company; 2003;http://www.fda.gov/cder/foi/label/2003/21017scm013_humalog_lbl.pdfAccessed May 1, 2007
  73. Kapitza C, Rave K, Ostrowski K, et al. Reduced postprandial glycaemic excursion with biphasic insulin Aspart 30 injected immediately before a meal. Diabet Med. 2004;21:500–501
  74. Boehm BO, Home PD, Behrend C, et al. Premixed insulin aspart 30 vs. premixed human insulin 30/70 twice daily: a randomized trial in Type 1 and Type 2 diabetic patients [published correction appears in Diabet Med. 2002;19:797]. Diabet Med. 2002;19:393–939
  75. Boehm BO, Vaz JA, Brondsted L, Home PD. Long-term efficacy and safety of biphasic insulin aspart in patients with type 2 diabetes. Eur J Intern Med. 2004;15:496–502
  76. McNally P, Dean J, Morris A, et al. Using continuous glucose monitoring to measure the frequency of low glucose values when using biphasic insulin aspart 30 compared with biphasic human insulin 30: a double-blind crossover study in individuals with type 2 diabetes. Diabetes Care. 2007;30:1044–1048
  77. Roach P, Yue L, Arora V Humalog Mix25 Study Group. Improved postprandial glycemic control during treatment with Humalog Mix25, a novel protamine-based insulin lispro formulation. Diabetes Care. 1999;22:1258–1261
  78. Herz M, Arora V, Campaigne BN, et al. Humalog Mix25 improves 24-hour plasma glucose profiles compared with the human insulin mixture 30/70 in patients with type 2 diabetes mellitus. S Afr Med J. 2003;93:219–223
  79. Roach P, Malone JK. Comparison of insulin lispro mixture 25/75 with insulin glargine during a 24-h standardized test-meal period in patients with Type 2 diabetes. Diabet Med. 2006;23:743–749
  80. Malone JK, Kerr LF, Campaigne BN, et al. Lispro Mixture-Glargine Study Group Combined therapy with insulin lispro Mix 75/25 plus metformin or insulin glargine plus metformin: a 16-week, randomized, open-label, crossover study in patients with type 2 diabetes beginning insulin therapy. Clin Ther. 2004;26:2034–2044
  81. Malone JK, Bai S, Campaigne BN, et al. Twice-daily pre-mixed insulin rather than basal insulin therapy alone results in better overall glycaemic control in patients with Type 2 diabetes. Diabet Med. 2005;22:374–381

 Statement of author disclosure: Please see the Author Disclosures section at the end of this article.

PII: S0002-9343(08)00309-4

doi: 10.1016/j.amjmed.2008.03.022

The American Journal of Medicine
Volume 121, Issue 6, Supplement , Pages S9-S19 , June 2008

Article Tools

* Image Usage & Resolution