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Clinical presentation

Clinical presentation . Insulin detemir: Agenda. Rationale: The need for a new basal insulin Pharmacology Clinical efficacy in type 1 and type 2 diabetes Variability Hypoglycaemia Body weight Summary. Rationale: The need for a new basal insulin. The physiological insulin profile.

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Clinical presentation

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  1. Clinical presentation

  2. Insulin detemir: Agenda • Rationale: The need for a new basal insulin • Pharmacology • Clinical efficacy in type 1 and type 2 diabetes • Variability • Hypoglycaemia • Body weight • Summary

  3. Rationale: The need for a new basal insulin

  4. The physiological insulin profile Adapted from Polonsky et al. 1988

  5. Basal-bolus therapy attempts torecreate the physiological insulin profile

  6. Insulin analogues: desired properties • Meal-related analogues (e.g. insulin aspart) designed to give: • Rapid absorption • Peak action coinciding with peak carbohydrate absorption • Basal insulin analogue should provide: • Slow and steady rate of absorption • Protracted action • Low within-subject variability in action

  7. Therapeutic potential of intensive analogue-based insulin therapy Achievement and maintenance of glycaemic targets: • HbA1c • Postprandial plasma glucose • Fasting plasma glucose • Low within-subject variability • Reduced risk of hypoglycaemia • Minimal weight gain • Enhanced convenience and improved quality of life

  8. Pharmacokinetic limitations of subcutaneous exogenous basal insulin NPH insulin Improved basal insulin

  9. Variability in glucose infusion rate (GIR) profiles for 3 patients with type 1 diabetes following NPH injection Data from study1450 (T. Heise et al. Diabetes 2003;52 (Suppl.1): A121)

  10. Variability in GIR profiles for 3 patients with type 1 diabetes following insulin glargine injection Data from study1450 (T. Heise et al. Diabetes 2003;52 (Suppl.1): A121)

  11. The balance between control and tolerability: data from DCCT New Engl J Med 1993;328:977

  12. Factors influencing insulin absorption • Insulin preparation • Dose, concentration and volume • Physical status (solution or suspension) • Mechanism of protraction • Self association • Precipitation • Albumin binding • Injection site factors • Region of injection • Depth of injection • Lipodystrophy • Blood flow changes e.g. temperature, exercise, hypoglycaemia, ketoacidosis

  13. Receptor binding, metabolic and mitogenic potency of insulin analogues Adapted from P. Kurtzhals et al. Diabetes 2000;49:999

  14. Pharmacology Return to Agenda

  15. Strategies for engineering basal insulins Modification of isoelectric point: precipitation at pH 7.4 • NovoSol Basal • Insulin glargine Strengthening of hexamer association, e.g. • Co(III)-hexamer Acylation with hydrophobic residues, e.g. • Insulin detemir

  16. Structure of insulin detemir

  17. 3-Dimensional structure of hexameric insulin Human insulin Insulin detemir

  18. Subcutaneous depot Plasma compartment Interstitial compartment Potential sites of protraction In the subcutaneous depot In the circulation In the interstitial space

  19. Insulin detemir Mode of protraction • Self association (hexameric) • Fatty acid side chains bind to albumin in injection depot • Albumin binding in circulation Protracted absorption ‘Buffering’ effect and minor contribution to protraction

  20. Absorption rate from subcutaneous depot 225 200 Interstitial human insulin (muscle/fat) 175 Absorption and relative change in periphery (%) 150 Interstitial detemir (muscle/fat) 125 100 75 0 300 0 60 120 180 240 360 Duration Calculated effect of a 60-minute doubling of absorption rate on the interstitial concentrations of NPH insulin and insulin detemir Albumin binding buffers against changes in absorption rate Data on file: Novo Nordisk

  21. Safety of albumin binding (1) • Plasma concentration of HSA ~600 x 10-6 M • FFA binding sites/HSA molecule at least 8 • Plasma concentration of FFA ~300 x 10-6 M • Insulin detemir conc. at therapeutic dose <0.01 x 10-6 M • Therefore, insulin detemir occupies only a minute fraction of available albumin binding sites HSA: human serum albumin FFA: free fatty acid

  22. Safety of albumin binding (2) No drug–drug interactions observed in in vitro studies with drugs at clinically relevant concentrations. Compounds investigated: • FFA (C8 FA, C12 FA, C16 FA) • phenylbutazone, warfarin • ibuprofen, diazepam • Sulphonylureas (tolbutamide, glibenclamide) • aspirin, valproate P. Kurtzhals et al. Journal of Pharmaceutical Sciences 1997;86(12)

  23. Insulin detemir 0.2 U/kg Insulin detemir 0.3 U/kg Insulin detemir 0.4 U/kg Pharmacodynamic profile of insulin detemir - subjects with type 1 diabetes Adapted from T. Pieber et al. Diabetes 2002;51(Suppl. 2):A53

  24. Variability in time-action profile of basal insulins GIR profiles following four non-consecutive injections of identical doses (0.4U/kg, thigh) in three patients Data from study1450 (T. Heise et al. Diabetes 2003;52 (Suppl.1): A121)

  25. Clinical efficacy in type 1 and type 2 diabetes Return to Agenda D. Russell-Jones et al. Diabetologia 2002;45(Suppl. 2):A51

  26. 9-point blood glucose profiles after 6 months’ therapy with once-daily insulin detemir or NPH insulin Type 1 diabetes * D. Russell-Jones et al. Diabetologia 2002;45(Suppl. 2):A51

  27. FPG at baseline and after 16 weeksin subjects with type 1 diabetes p = 0.004 Data from 1448 study (P. Home et al. Diabetes 2003;52(Suppl. 1):A122)

  28. Glycaemia results Baseline HbA1c = 8.60%

  29. Insulin detemir consistently achieves lower FPG values than NPH insulin *Study in type 2 diabetes † Meta-analysis of trials 1181, 1205, 1335, 1447, 1448

  30. HbA1c: Meta-analysis of phase 3 trials in type 1 diabetes Endpoint data from three trials (1335, 1447, 1448) comparing insulin detemir with NPH insulin in basal-bolus therapy

  31. Variability Return to Agenda

  32. Variability in time-action profile of basal insulins Glucose infusion rate profiles following four non-consecutive injections of identical doses (0.4U/kg, thigh) in three patients Data from study1450 (T. Heise et al. Diabetes 2003;52 (Suppl.1): A121)

  33. Reproducibility: Probability ranges for blood glucose lowering effect of repeated injections 95% probability ranges for individual pharmacodynamic responses relative to the mean Average GIR over 24 hours T. Heise et al. Diabetes 2003;52(Suppl.1):A121

  34. Implications of within-subject pharmacodynamic variability Data from study1450 (T. Heise et al. Diabetes 2003;52 (Suppl.1): A121)

  35. Mean fluctuation from average blood glucose level across the day in monitored type 1 patients Daytime Nocturnal Insulin detemir 3 NPH insulin 2 1 Mean fluctuation from individual average blood glucose (mmol/L) 0 –1 –2 6 10 14 18 22 2 6 Time (hours) D. Russell-Jones et al. Diabetologia 2002;45(Suppl. 2):A51

  36. Within-subject variability of self-monitored pre-breakfast glucose concentrations Insulin detemir NPH insulin Trial Mean (mmol/l) SD Mean (mmol/l) SD p (SD) 1335 7.6 2.8 8.4 3.6 < 0.001 1447 7.9 2.6 8.2 3.1 < 0.001 1448 8.2 2.9 9.0 3.5 < 0.001 1336* 7.5 1.3 7.6 1.4 < 0.05 1374** 7.8 2.6 8.3 3.0 < 0.0001 *Type 2 diabetes **Analogue vs. HI

  37. Hypoglycaemia Return to Agenda

  38. 12 months 12 months 6 months 6 months Overall hypoglycaemic event rate by study

  39. Nocturnal hypoglycaemic event rate by study in type 1 diabetes 12 months 12 months 6 months

  40. Monthly rate of hypoglycaemic events in type 1 diabetes P. Vague et al. Diabetes Care 2003;26(3):590-596

  41. Risk of all nocturnal hypoglycaemic events in type 1 diabetes I. De Leeuw et al. Diabetologia 2002;45(Suppl. 2):A257

  42. Relative risk for all hypoglycaemic events: Insulin detemir vs. NPH insulin *Meta-analyses of trials comparing insulin detemir with NPH insulin in type 1 diabetes Data on file: Novo Nordisk

  43. Body weight Return to Agenda

  44. Weight gain with insulin therapy • Seen in both type 1 and type 2 diabetes • May worsen underlying defect in type 2 diabetes • Barrier to starting insulin therapy in type 2 diabetes • May decrease compliance with insulin regimens • May lower self-esteem

  45. Weight gain in type 1 diabetes: DCCT data Quartile of weight gain at mean follow up, 6.1 years Initial 12 months DCCT. Diabetes Care 1988;11:567-73 and Purnell et al. JAMA 1998;280:140-46

  46. Weight change in comparative trials in type 1 diabetes

  47. Weight gain in type 2 diabetes: UKPDS data 10.0 7.5 Intensive (Insulin) 5.0 Change in weight (kg) 2.5 Conventional 0 0 3 6 9 12 15 Years from randomisation UKPDS Group (33). Lancet 1998;352:837-853

  48. Weight change over 6 months in type 2 diabetes Data from study 1336. (T. Haak et al. Diabetes 2003;52( Suppl.1):A120

  49. Mean body weight (kg) and between- group difference at end of trials

  50. Analogue versus human insulin-based basal-bolus therapy: 8-point blood glucose profiles K. Hermansen et al. ADS/ADEA Annual Scientific Meeting: Abstract 510

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