Acta Diabetologica

, 45:253

The role of new basal insulin analogues in the initiation and optimisation of insulin therapy in type 2 diabetes

Original Article


Intensive insulin therapy aimed at achieving normoglycaemia is becoming increasingly accepted in the treatment of type 2 diabetes (T2DM) to reduce the risk of diabetes-related complications. Insulin therapy is increasingly combined with oral antidiabetic drugs (OADs) to moderate insulin dosage, reduce weight gain and confer cardiovascular protection. However, traditional insulins are associated with limitations that may act as barriers to initiation, and intensive use of insulin therapy. The advent of newer, longer-acting, basal insulin analogues, such as insulin glargine (glargine) and insulin detemir (detemir), offer improved pharmacokinetic and pharmacodynamic profiles compared with neutral protamine Hagedorn insulin (NPH). This potentially provides concomitant improvements in safety, efficacy and variability of glycaemic control. This paper reviews the properties of these new long-acting, basal insulin analogues and their potential roles in facilitating the initiation and optimisation of insulin therapy. Studies that reported the use of insulin and insulin analogues for the treatment of T2DM were identified using Medline. Key search terms included: ‘insulin glargine’, ‘insulin detemir’, ‘NPH insulin’, ‘basal insulin’, ‘long-acting insulin’, ‘insulin analogue’, ‘pharmacokinetics’, ‘pharmacodynamics’, ‘dose titration’, ‘algorithms’ and ‘type 2 diabetes’. Abstracts presented at the American Diabetes Association and the European Association for the Study of Diabetes annual congresses were also searched. The data show that the long-acting insulin analogues glargine and detemir both offer a low risk of hypoglycaemia and improved glycaemic control. Aggressive dose titration with glargine and detemir facilitates attainment of glycaemic control targets. The goal of achieving good glycaemic control with a low risk of hypoglycaemia may be more feasible with newer insulin therapies as part of a simple basal insulin regimen with continued OADs.


Insulin glargine Insulin detemir NPH insulin Basal insulin Type 2 diabetes 


  1. 1.
    United Kingdom Prospective Diabetes Study Group (1998) Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352:854–865CrossRefGoogle Scholar
  2. 2.
    United Kingdom Prospective Diabetes Study Group (1998) 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 352:837–853CrossRefGoogle Scholar
  3. 3.
    Ohkubo Y, Kishikawa H, Araki E et al (1995) 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. Diabetes Res Clin Pract 28:103–117PubMedCrossRefGoogle Scholar
  4. 4.
    Stratton IM, Adler AI, Neil HA et al (2000) Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 321:405–412PubMedCrossRefGoogle Scholar
  5. 5.
    Gaede P, Vedel P, Larsen N et al (2003) Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 348:383–393PubMedCrossRefGoogle Scholar
  6. 6.
    Genuth S, Eastman R, Kahn R et al (2003) Implications of the United kingdom prospective diabetes study. Diabetes Care 26:S28–S32PubMedCrossRefGoogle Scholar
  7. 7.
    Chiasson JL (2006) Acarbose for the prevention of diabetes, hypertension, and cardiovascular disease in subjects with impaired glucose tolerance: the Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM) Trial. Endocr Pract 12:25–30PubMedGoogle Scholar
  8. 8.
    Selvin E, Wattanakit K, Steffes MW, Coresh J, Sharrett AR (2006) HbA1c and peripheral arterial disease in diabetes: the atherosclerosis risk in communities study. Diabetes Care 29:877–882PubMedCrossRefGoogle Scholar
  9. 9.
    Kirkman MS, McCarren M, Shah J, Duckworth W, Abraira C (2006) The association between metabolic control and prevalent macrovascular disease in Type 2 diabetes: the VA Cooperative Study in diabetes. J Diabetes Complications 20:75–80PubMedCrossRefGoogle Scholar
  10. 10.
    Martin S, Schneider B, Heinemann L et al (2006) Self-monitoring of blood glucose in type 2 diabetes and long-term outcome: an epidemiological cohort study. Diabetologia 49:271–278PubMedCrossRefGoogle Scholar
  11. 11.
    American Diabetes Association (2003) Standards of medical care for patients with diabetes mellitus. Diabetes Care 26:S33–S50CrossRefGoogle Scholar
  12. 12.
    European Diabetes Policy Group (1999) A desktop guide to Type 2 diabetes mellitus. Diabet Med 16:716–730CrossRefGoogle Scholar
  13. 13.
    British Cardiac Society, British Hypertension Society, Diabetes UK, et al. (2005) JBS 2: Joint British Societies’ guidelines on prevention of cardiovascular disease in clinical practice. Heart 91:v1–v52Google Scholar
  14. 14.
    De Backer G, Ambrosioni E, Borch-Johnsen K et al (2003) European guidelines on cardiovascular disease prevention in clinical practice. Third Joint Task Force of European and Other Societies on Cardiovascular Disease Prevention in Clinical Practice. Eur Heart J 24:1601–1610PubMedCrossRefGoogle Scholar
  15. 15.
    Ryden L, Standl E, Bartnik M et al (2007) Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary. The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD). Eur Heart J 28:88–136PubMedCrossRefGoogle Scholar
  16. 16.
    Fox KM, Gerber RA, Bolinder B, Chen J, Kumar S (2006) Prevalence of inadequate glycemic control among patients with type 2 diabetes in the United Kingdom general practice research database: a series of retrospective analyses of data from 1998 through 2002. Clin Ther 28:388–395PubMedCrossRefGoogle Scholar
  17. 17.
    United Kingdom Prospective Diabetes Study Group (1995) Overview of 6 years’ therapy of type II diabetes: a progressive disease. (UKPDS 16). Diabetes 44:1249–1258CrossRefGoogle Scholar
  18. 18.
    Wright A, Burden AC, Paisey RB, Cull CA, Holman RR (2002) Sulfonylurea inadequacy: efficacy of addition of insulin over 6 years in patients with type 2 diabetes in the U.K. Prospective Diabetes Study (UKPDS 57). Diabetes Care 25:330–336PubMedCrossRefGoogle Scholar
  19. 19.
    Riddle MC (2002) Timely addition of insulin to oral therapy for type 2 diabetes. Diabetes Care 25:395–396PubMedCrossRefGoogle Scholar
  20. 20.
    Chan JL, Abrahamson MJ (2003) Pharmacological management of type 2 diabetes mellitus: rationale for rational use of insulin. Mayo Clin Proc 78:459–467PubMedCrossRefGoogle Scholar
  21. 21.
    Riddle MC (2004) Timely initiation of basal insulin. Am J Med 116:3S–9SPubMedCrossRefGoogle Scholar
  22. 22.
    Boyne MS, Saudek CD (1999) Effect of insulin therapy on macrovascular risk factors in type 2 diabetes. Diabetes Care 22:C45–C53PubMedCrossRefGoogle Scholar
  23. 23.
    Cerveny JD, Leder RD, Weart CW (1998) Issues surrounding tight glycemic control in people with type 2 diabetes mellitus. Ann Pharmacother 32:896–905PubMedCrossRefGoogle Scholar
  24. 24.
    Nathan DM, Buse JB, Davidson MB et al (2006) Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 29:1963–1972PubMedCrossRefGoogle Scholar
  25. 25.
    Riddle MC, Rosenstock J, Gerich J (2003) The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care 26:3080–3086PubMedCrossRefGoogle Scholar
  26. 26.
    Cryer PE (2002) Hypoglycaemia: the limiting factor in the glycaemic management of Type I and Type II diabetes. Diabetologia 45:937–948PubMedCrossRefGoogle Scholar
  27. 27.
    Korytkowski M (2002) When oral agents fail: practical barriers to starting insulin. Int J Obes Relat Metab Disord 26:S18–S24PubMedCrossRefGoogle Scholar
  28. 28.
    Rubin RR (2005) Adherence to pharmacologic therapy in patients with type 2 diabetes mellitus. Am J Med 118:27S–34SPubMedCrossRefGoogle Scholar
  29. 29.
    Monnier L, Lapinski H, Colette C (2003) Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA(1c). Diabetes Care 26:881–885PubMedCrossRefGoogle Scholar
  30. 30.
    Goudswaard AN, Furlong NJ, Rutten GE, Stolk RP, Valk GD (2004) Insulin monotherapy versus combinations of insulin with oral hypoglycaemic agents in patients with type 2 diabetes mellitus. Cochrane Database Syst Rev 4:CD003418Google Scholar
  31. 31.
    Yki-Jarvinen H, Dressler A, Ziemen M (2000) 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. HOE 901/3002 Study Group. Diabetes Care 23:1130–1136PubMedCrossRefGoogle Scholar
  32. 32.
    Lepore M, Pampanelli S, Fanelli C et al (2000) 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 49:2142–2148PubMedCrossRefGoogle Scholar
  33. 33.
    Owens DR, Coates PA, Luzio SD, Tinbergen JP, Kurzhals R (2000) Pharmacokinetics of 125I-labeled insulin glargine (HOE 901) in healthy men: comparison with NPH insulin and the influence of different subcutaneous injection sites. Diabetes Care 23:813–819PubMedCrossRefGoogle Scholar
  34. 34.
    Raslova K, Bogoev M, Raz I et al (2004) Insulin detemir and insulin aspart: a promising basal-bolus regimen for type 2 diabetes. Diabetes Res Clin Pract 66:193–201PubMedCrossRefGoogle Scholar
  35. 35.
    Haak T, Tiengo A, Draeger E, Suntum M, Waldhausl W (2005) 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 7:56–64PubMedCrossRefGoogle Scholar
  36. 36.
    Gerstein HC, Yale JF, Harris SB et al (2006) A randomized trial of adding insulin glargine vs. avoidance of insulin in people with Type 2 diabetes on either no oral glucose-lowering agents or submaximal doses of metformin and/or sulphonylureas. The Canadian INSIGHT (Implementing New Strategies with Insulin Glargine for Hyperglycaemia Treatment) Study. Diabet Med 23:736–742PubMedCrossRefGoogle Scholar
  37. 37.
    Rosenstock J, Sugimoto D, Strange P et al (2006) Triple therapy in type 2 diabetes: insulin glargine or rosiglitazone added to combination therapy of sulfonylurea plus metformin in insulin-naive patients. Diabetes Care 29:554–559PubMedCrossRefGoogle Scholar
  38. 38.
    Horvath K, Jeitler K, Berghold A et al (2007) Long-acting insulin analogues versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus. Cochrane Database Syst Rev 2:CD005613Google Scholar
  39. 39.
    Dunn CJ, Plosker GL, Keating GM, McKeage K, Scott LJ (2003) Insulin glargine: an updated review of its use in the management of diabetes mellitus. Drugs 63:1743–1778PubMedCrossRefGoogle Scholar
  40. 40.
    Luzio SD, Beck P, Owens DR (2003) Comparison of the subcutaneous absorption of insulin glargine (Lantus) and NPH insulin in patients with Type 2 diabetes. Horm Metab Res 35:434–438PubMedCrossRefGoogle Scholar
  41. 41.
    Rosenstock J, Dailey G, Massi-Benedetti M et al (2005) Reduced hypoglycemia risk with insulin glargine: a meta-analysis comparing insulin glargine with human NPH insulin in type 2 diabetes. Diabetes Care 28:950–955PubMedCrossRefGoogle Scholar
  42. 42.
    Barlocco D (2003) Insulin detemir. Novo Nordisk. Curr Opin Investig Drugs 4:449–454PubMedGoogle Scholar
  43. 43.
    Havelund S, Plum A, Ribel U et al (2004) The mechanism of protraction of insulin detemir, a long-acting, acylated analog of human insulin. Pharm Res 21:1498–1504PubMedCrossRefGoogle Scholar
  44. 44.
    Heise T, Nosek L, Ronn BB et al (2004) Lower within-subject variability of insulin detemir in comparison to NPH insulin and insulin glargine in people with type 1 diabetes. Diabetes 53:1614–1620PubMedCrossRefGoogle Scholar
  45. 45.
    Plank J, Bodenlenz M, Sinner F et al (2005) A double-blind, randomized, dose-response study investigating the pharmacodynamic and pharmacokinetic properties of the long-acting insulin analog detemir. Diabetes Care 28:1107–1112PubMedCrossRefGoogle Scholar
  46. 46.
    Porcellati F, Rossetti P, Busciantella NR et al (2007) Comparison of pharmacokinetics and dynamics of the long-acting insulin analogs glargine and detemir at steady state in type 1 diabetes: a double-blind, randomized, crossover study. Diabetes Care 30:2447–2452PubMedCrossRefGoogle Scholar
  47. 47.
    Klein O, Lynge J, Endahl L et al (2007) 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 9:290–299PubMedCrossRefGoogle Scholar
  48. 48.
    Paes AH, Bakker A, Soe-Agnie CJ (1997) Impact of dosage frequency on patient compliance. Diabetes Care 20:1512–1517PubMedCrossRefGoogle Scholar
  49. 49.
    Claxton AJ, Cramer J, Pierce C (2001) A systematic review of the associations between dose regimens and medication compliance. Clin Ther 23:1296–1310PubMedCrossRefGoogle Scholar
  50. 50.
    Holman RR, Thorne KI, Farmer AJ et al (2007) Addition of biphasic, prandial, or basal insulin to oral therapy in type 2 diabetes. N Engl J Med 357:1716–1730PubMedCrossRefGoogle Scholar
  51. 51.
    Rosenstock J, Davies M, Home PD et al (2008) A randomised, 52-week, treat-to-target trial comparing insulin detemir with insulin glargine when administered as add-on to glucose-lowering drugs in insulin-naive people with type 2 diabetes. Diabetologia 51:408–416PubMedCrossRefGoogle Scholar
  52. 52.
    Eliaschewitz FG, Calvo C, Valbuena H et al (2006) Therapy in type 2 diabetes: insulin glargine vs. NPH insulin both in combination with glimepiride. Arch Med Res 37:495–501PubMedCrossRefGoogle Scholar
  53. 53.
    Yki-Jarvinen H, Kauppinen-Makelin R, Tiikkainen M et al (2006) Insulin glargine or NPH combined with metformin in type 2 diabetes: the LANMET study. Diabetologia 49:442–451PubMedCrossRefGoogle Scholar
  54. 54.
    Rosenstock J, Schwartz SL, Clark CM Jr et al (2001) Basal insulin therapy in type 2 diabetes: 28-week comparison of insulin glargine (HOE 901) and NPH insulin. Diabetes Care 24:631–636PubMedCrossRefGoogle Scholar
  55. 55.
    HOE901/2004 Study Investigators Group (2003) Safety and efficacy of insulin glargine (HOE 901) versus NPH insulin in combination with oral treatment in Type 2 diabetic patients. Diabet Med 20:545–551CrossRefGoogle Scholar
  56. 56.
    Hermansen K, Davies M, Derezinski T et al (2006) 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 29:1269–1274PubMedCrossRefGoogle Scholar
  57. 57.
    Davies M, Storms F, Shutler S, Bianchi-Biscay M, Gomis R (2005) Improvement of glycemic control in subjects with poorly controlled type 2 diabetes: comparison of two treatment algorithms using insulin glargine. Diabetes Care 28:1282–1288PubMedCrossRefGoogle Scholar
  58. 58.
    Meneghini L, Koenen C, Weng W, Selam JL (2007) The usage of a simplified self-titration dosing guideline (303 Algorithm) for insulin detemir in patients with type 2 diabetes—results of the randomized, controlled PREDICTIVE 303 study. Diabetes Obes Metab 9:902–913PubMedCrossRefGoogle Scholar
  59. 59.
    Janka HU, Plewe G, Riddle MC et al (2005) Comparison of basal insulin added to oral agents versus twice-daily premixed insulin as initial insulin therapy for type 2 diabetes. Diabetes Care 28:254–259PubMedCrossRefGoogle Scholar
  60. 60.
    Fritsche A, Schweitzer MA, Haring HU (2003) 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 138:952–959PubMedGoogle Scholar
  61. 61.
    Massi-Benedetti M, Humburg E, Dressler A, Ziemen M (2003) 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 35:189–196PubMedCrossRefGoogle Scholar
  62. 62.
    Bretzel RG, Nuber U, Landgraf W et al (2008) Once-daily basal insulin glargine versus thrice-daily prandial insulin lispro in people with type 2 diabetes on oral hypoglycaemic agents (APOLLO): an open randomised controlled trial. Lancet 371:1073–1084PubMedCrossRefGoogle Scholar
  63. 63.
    Gossain VV, Carella MJ, Rovner DR (1994) Management of diabetes in the elderly: a clinical perspective. J Assoc Acad Minor Phys 5:22–31PubMedGoogle Scholar
  64. 64.
    Gerich JE (2000) Physiology of glucose homeostasis. Diabetes Obes Metab 2:345–350PubMedCrossRefGoogle Scholar
  65. 65.
    Cryer PE (2004) Diverse causes of hypoglycemia-associated autonomic failure in diabetes. N Engl J Med 350:2272–2279PubMedCrossRefGoogle Scholar
  66. 66.
    Cryer PE (1999) Hypoglycemia is the limiting factor in the management of diabetes. Diabetes Metab Res Rev 15:42–46PubMedCrossRefGoogle Scholar
  67. 67.
    McCrimmon RJ, Frier BM (1994) Hypoglycaemia, the most feared complication of insulin therapy. Diabete Metab 20:503–512PubMedGoogle Scholar
  68. 68.
    Home PD, Barriocanal L, Lindholm A (1999) Comparative pharmacokinetics and pharmacodynamics of the novel rapid-acting insulin analogue, insulin aspart, in healthy volunteers. Eur J Clin Pharmacol 55:199–203PubMedCrossRefGoogle Scholar
  69. 69.
    Heinemann L, Linkeschova R, Rave K et al (2000) Time–action profile of the long-acting insulin analog insulin glargine (HOE901) in comparison with those of NPH insulin and placebo. Diabetes Care 23:644–649PubMedCrossRefGoogle Scholar
  70. 70.
    Lindholm A, Jacobsen LV (2001) Clinical pharmacokinetics and pharmacodynamics of insulin aspart. Clin Pharmacokinet 40:641–659PubMedCrossRefGoogle Scholar
  71. 71.
    Scholtz HE, Pretorius SG, Wessels DH, Becker RH (2005) Pharmacokinetic and glucodynamic variability: assessment of insulin glargine, NPH insulin and insulin ultralente in healthy volunteers using a euglycaemic clamp technique. Diabetologia 48:1988–1995PubMedCrossRefGoogle Scholar
  72. 72.
    de Boer H, Jansen M, Koerts J, Verschoor L (2004) Prevention of weight gain in type 2 diabetes requiring insulin treatment. Diabetes Obes Metab 6:114–119PubMedCrossRefGoogle Scholar
  73. 73.
    DeWitt DE, Hirsch IB (2003) Outpatient insulin therapy in type 1 and type 2 diabetes mellitus: scientific review. JAMA 289:2254–2264PubMedCrossRefGoogle Scholar
  74. 74.
    Lee M, Aronne LJ (2007) Weight management for type 2 diabetes mellitus: global cardiovascular risk reduction. Am J Cardiol 99:68–79CrossRefGoogle Scholar
  75. 75.
    Cusi K, Cunningham GR, Comstock JP (1995) Safety and efficacy of normalizing fasting glucose with bedtime NPH insulin alone in NIDDM. Diabetes Care 18:843–851PubMedCrossRefGoogle Scholar
  76. 76.
    Emanuele N, Azad N, Abraira C et al (1998) Effect of intensive glycemic control on fibrinogen, lipids, and lipoproteins: Veterans Affairs Cooperative Study in Type II Diabetes Mellitus. Arch Intern Med 158:2485–2490PubMedCrossRefGoogle Scholar
  77. 77.
    Heinemann L (2002) Variability of insulin absorption and insulin action. Diabetes Technol Ther 4:673–682PubMedCrossRefGoogle Scholar
  78. 78.
    Russell-Jones D (2004) Insulin detemir: improving the predictability of glycaemic control. Int J Obes Relat Metab Disord 28:S29–S34PubMedCrossRefGoogle Scholar
  79. 79.
    Heinemann L, Anderson JH Jr (2004) Measurement of insulin absorption and insulin action. Diabetes Technol Ther 6:698–718PubMedCrossRefGoogle Scholar
  80. 80.
    Hermansen K, Fontaine P, Kukolja KK et al (2004) Insulin analogues (insulin detemir and insulin aspart) versus traditional human insulins (NPH insulin and regular human insulin) in basal-bolus therapy for patients with type 1 diabetes. Diabetologia 47:622–629PubMedCrossRefGoogle Scholar
  81. 81.
    Hermansen K, Madsbad S, Perrild H, Kristensen A, Axelsen M (2001) Comparison of the soluble basal insulin analog insulin detemir with NPH insulin: a randomized open crossover trial in type 1 diabetic subjects on basal-bolus therapy. Diabetes Care 24:296–301PubMedCrossRefGoogle Scholar
  82. 82.
    Danne T, Lupke K, Walte K, Von Schuetz W, Gall MA (2003) Insulin detemir is characterized by a consistent pharmacokinetic profile across age-groups in children, adolescents, and adults with type 1 diabetes. Diabetes Care 26:3087–3092PubMedCrossRefGoogle Scholar
  83. 83.
    Vague P, Selam JL, Skeie S et al (2003) Insulin detemir is associated with more predictable glycemic control and reduced risk of hypoglycemia than NPH insulin in patients with type 1 diabetes on a basal-bolus regimen with premeal insulin aspart. Diabetes Care 26:590–596PubMedCrossRefGoogle Scholar
  84. 84.
    Kurtzhals P, Schaffer L, Sorensen A et al (2000) Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes 49:999–1005PubMedCrossRefGoogle Scholar
  85. 85.
    Johnson R, Hauber B, Bolinder B (2003) Trade-offs between glucose control and hypoglycemia in different patient types: results of a 5-country physician survey. Diabetes 52:A264 (Abstract 1134)Google Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  1. 1.DiabetologistAshford and Saint Peter’s Hospital NHS TrustChertseyUK

Personalised recommendations