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The dual-release insulin preparation. Overview of published studies. Contents. NovoMix ® 30 – the dual release insulin Contents Slides Insulin aspart 3  4 Dual-release kinetics 5  12 Postprandial glycaemic control 13 36 Hypoglycaemia 37 50

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The dual-release insulin preparation


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    1. The dual-release insulin preparation Overview of published studies

    2. Contents NovoMix® 30 –the dual release insulin Contents Slides Insulin aspart34 Dual-release kinetics512 Postprandial glycaemic control1336 Hypoglycaemia3750 Combination with oral medications5176 Convenience & flexibility7794 Use in adolescents9596

    3. Return to contents slide Insulin aspart – a rapid acting analogue

    4. Insulin aspart: preclinical proof-of-concept 4.5 Insulin aspart IRI (10-10 M) 3.0 Human insulin 1.5 0 5 4 Plasma glucose (mM) 3 Injection 2 0 1 4 2 3 5 hours Adapted from Brange J et al. Nature 1988;333:679–682

    5. Return to contents slide Dual-release kinetics

    6. Physiological insulin profile: • basal component • meal-related peaks Physiological insulin profile BHI 30 Soluble human insulin NPH • Soluble insulin fails to match normal insulin peak • Intermediate-acting insulin provides basal insulin replacement but… • …together these fail to re-create the physiological insulin profile The dual-release insulin concept – BHI 30

    7. Physiological insulin profile: • basal component • meal-related peaks • Analogue premixes such as NovoMix® 30 replace both meal-related and basal insulin The dual-release insulin concept Physiological insulin profile Soluble insulin aspart Protamine crystallised insulin aspart • Rapid-acting insulin analogues together with a basal insulin provide physiological insulin replacement NovoMix® 30

    8. Benefits of dual-release insulin replacement • Mimics physiological insulin release • Early release of rapid-acting insulin targets postprandial glucose • Delayed release of intermediate-acting insulin fulfils basal insulin requirement • Reduces hypoglycaemic risk • < Conventional premix • Improves HbA1c in combination with oral medications • Simplifies dosing • Option of postprandial dosing

    9. NovoMix® 30:PK/PD studies in healthy volunteers Comparison PK and PD profiles of NovoMix® 30 vs. BHI 30 Design • Randomised, double-blind, two-way single dose crossover1 • Randomised, double-blind, crossover single dose euglycaemic clamp2 1. Jacobsen L et al. Eur J Clin Pharm 2000;56:399–403 2. Weyer C et al. Diabetes Care 1997;10:1612–1614

    10. NovoMix® 30 BHI 30 Proof of concept: rapid absorption and higher peak concentration 25 *** 20 ***p < 0.0001n = 24 15 Serum insulin (mU/l) 10 5 0 8:00 11:00 14:00 17:00 20:00 23:00 2:00 5:00 8:00 Time of day Jacobsen L et al. Eur J Clin Pharm 2000;56:399–403

    11. Proof of concept:faster onset and more effective n = 24, dose = 0.3 U/kg 12 NovoMix®30 10 BHI 30 (Actraphane) 8 Glucose infusion rate (mg/kg/min) 6 4 2 0 0 240 480 720 960 1200 1400 Time (min) Weyer C et al. Diabetes Care 1997;10:1612–1614

    12. PK/PD conclusions: NovoMix® 30 vs. BHI 30 • Faster absorption1,2 • Higher peak concentrations1,2 • More rapid and pronounced glucose-lowering effect1,2 • Similar duration of action of basal component1,2 Faster onset and greater glucose-lowering effect of insulin aspart are retained in dual-release NovoMix® 30 1. Jacobsen L et al. Eur J Clin Pharm 2000;56:399–403 2. Weyer C et al. Diabetes Care 1997;10:1612–1614

    13. Return to contents slide Improved postprandial glycaemic control

    14. Screening visit (n = 13) NovoMix®30 NovoMix® 30 BHI 30 BHI 30 Twice-daily NovoMix® 30 in patients with type 2 diabetes Follow-up +3 to 7 days –3 to14 days 4 0 2 Weeks McSorley PT et al. Clin Ther 2002;24(4):530–539

    15. NovoMix® 30 is rapidly absorbed * * NovoMix®30 120 Biphasic human insulin 100 n = 13 * p < 0.05 in favour of NovoMix® 30 for mean serum insulin level and insulin Cmax after dinner and breakfast 80 Total serum insulin (mU/l) 60 40 20 0 18:00 22:00 08:00 13:00 18:00 Time McSorley PT et al. Clin Ther 2002;24(4):530–539

    16. Improved postprandial glucose control with NovoMix® 30 NovoMix®30 Biphasic human insulin 20 * * n = 13 15 Blood glucose (mmol/l) 10 5 * p < 0.05 in favour of NovoMix® 30 for lower PPG levels after dinner and breakfast 0 18:00 22:00 08:00 13:00 18:00 Time McSorley PT et al. Clin Ther 2002;24(4):530–539

    17. NovoMix® 30 is well tolerated • Both insulins were well tolerated • Both insulins had comparable adverse-event profiles • No major hypoglycaemic episodes or serious adverse events were reported • No other safety concerns McSorley PT et al. Clin Ther 2002;24(4):530–539

    18. NovoMix® 30 twice daily improves postprandial glucose control Compared with BHI 30, NovoMix® 30 given immediately before a meal (twice daily) in type 2 diabetic patients resulted in: • Significantly faster absorption • Significantly higher peak concentrations 2 hours after injection • Smaller postprandial glucose excursions • No safety concerns McSorley PT et al. Clin Ther 2002;24(4):530–539

    19. 3–21 days 5–21 days 5–21 days Type 1 diabetes: single dose crossover NovoMix® 30 at meal Screening Follow-up BHI 30 at meal (n = 50) BHI 30 at –30 minutes Study day 1 Study day 2 Study day 3 7–14 days Hermansen K et al. Metabolism 2002;51(7):896–900

    20. * Max glucose concn 15% lower at t = 0 * p < 0.001n = 50 * 23% lower glucose exposure than BHI at t = 0 * Max glucose concn 20 min earlier Reduced glucose exposure in type 1 patients after a meal NovoMix® 30 (t = 0) BHI 30 (t = 0) 20 BHI 30 (t = –30) 15 Blood glucose (mmol/l) 10 5 0 –30 30 90 120 150 180 210 240 0 60 Nominal time (min) Hermansen K et al. Metabolism 2002;51(7):896–900

    21. p < 0.0001 p = 0.013 23% 9% Reduced glucose excursion irrespective of timing of BHI 30 injection 3000 BHI 30 2800 NovoMix® 30 2600 Blood glucose excursion 4 h after injection (mmol.min.l-1) 2400 2200 2000 0 t = 0 t = –30 t = 0 Injection time in relation to meal Hermansen K et al. Metabolism 2002;51(7):896–900

    22. NovoMix® 30 is more effective than BHI 30 • Superior efficacy in controlling postprandial glucose levels • Higher reduction in blood glucose concentrations when injected immediately before meals • Significantly larger insulin concentrations achieved regardless of the time of BHI 30 administration Hermansen K et al. Metabolism 2002;51(7):896–900

    23. Comparison of NovoMix® 30, Humalog® Mix25TM and BHI 30 NovoMix® 30 at meal • ObjectiveTo compare the postprandial blood glucose excursion between treatment groups • DesignRandomised, open-labelled, three-period crossover trial • Method Single dose meal test, NovoMix® 30 and Humalog®Mix25TM immediately before meal, BHI 30 15 min before meal • Population 45 type 2 patients • Primary test EXC (glucose 0–5h) Humalog® Mix25TM at meal (n = 45) BHI 30 at –15 min Hermansen K et al. Diabetes Care 2002;25:883–888

    24. p < 0.001 p < 0.05 Reduced glucose excursions vs. Humalog®Mix25TM and BHI 30 21 –17% (mmol/l h) 20 –10% 19 0– 5h 18 17 16 Blood glucose excursion 15 14 13 0 Humalog® Mix 25TM NovoMix® 30 BHI 30 Hermansen K et al. Diabetes Care 2002;25:883–888

    25. Improved postprandial control vs. Humalog®Mix25TM and BHI 30 a NovoMix® 30 significantly less than Humalog® Mix25TM (p < 0.05) b NovoMix® 30 significantly less than BHI (p < 0.001) c NovoMix® 30 significantly earlier than BHI (p < 0.05) d NovoMix® 30 significantly earlier than Humalog® Mix25TM (p < 0.01) Hermansen K et al. Diabetes Care 2002;25:883–888

    26. Larger and more rapid increasein serum insulin with NovoMix® 30 a Values for NovoMix® 30 are significantly different from BHI 30 (p < 0.001) Hermansen K et al. Diabetes Care 2002;25:883–888

    27. Improved postprandial glucose vs. BHI 30 and Humalog® Mix25TM • Superior postprandial glucose control to BHI 30 and Humalog® Mix25TM in type 2 patients • Higher maximum serum insulin with BHI and Humalog® Mix25TM • Well tolerated with no serious adverse events occurring related to treatment Hermansen K et al. Diabetes Care 2002;25:883–888

    28. Comparison of efficacy and safety of NovoMix® 30 vs. BHI 30: study design NovoMix® 30 (n = 140) Insulin-using type 1 and type 2 diabetic patients (n = 294) One screening visit; patients already using a twice-daily insulin regimen BHI 30 (n = 151) 12 weeks Boehm B et al. Diabet Med 2002;19(5):393–399

    29. Improved postprandial glucose after 3 months NovoMix® 30 * p < 0.05 * 12 BHI 30 * * 10 * 8 Blood glucose (mmol/l) 6 0 Pre- Post- Pre- Post- Pre- Post- Bedtime 0200 h Breakfast Lunch Dinner Boehm B et al. Diabet Med 2002;19(5):393–399

    30. 3 2.5 2 1.5 1 0.5 0 Significantly lower prandial glucose increment with NovoMix® 30 p < 0.02 between treatment groups (mmol/l) Mean prandial glucose increment NovoMix® 30 BHI 30 (n = 141) (n = 128) Boehm B et al. Diabet Med 2002;19(5):393–399

    31. Improved postprandial control with NovoMix® 30 • Superior postprandial glycaemic control achieved compared with BHI 30 • No increased risk of hypoglycaemia with NovoMix® 30 • Trend for reduction in nocturnal hypoglycaemic episodes with NovoMix® 30 Boehm B et al. Diabet Med 2002;19(5):393–399

    32. NovoMix® 30 vs. NPHin type 2 patients • OHA only Twice-daily NovoMix® 30 (n = 201) • NPH + OHA • NPH monotherapy • No treatment Original treatment Twice-daily NPH insulin (n = 202) 16 weeks 7–14 days 2 weeks Screening Randomisation Christiansen JS et al.Diabetes, Obesity & Metabolism 2003;5(6):445-452

    33. Favours NPH Favours NovoMix® 30 NovoMix® 30 vs. NPH: lower prandial glucose increment * 1 • *p < 0.005 • ** p < 0.0001 0.56 0.5 0 Difference in prandial glucose increment between treatment groups (mmol/l) -0.5 -0.69 -1 ** -1.5 Mean prandial glucose increment -1.26 -1.33 ** ** -2 Breakfast Lunch Dinner Christiansen JS et al.Diabetes, Obesity & Metabolism 2003;5(6):445-452

    34. Greater HbA1c reduction with NovoMix® 30 vs. NPH NovoMix® 30 (n = 66) NPH (n = 66) 0.0 -0.2 -0.4 Change in HbA1c (%) -0.6 -0.8 p = 0.03 -1.0 Christiansen JS et al.Diabetes, Obesity & Metabolism 2003;5(6):445-452

    35. NovoMix® 30 offers better glycaemic control than NPH • Mean prandial glucose increment lower in NovoMix® 30 group (p < 0.0001) • Patients receiving NPH monotherapy benefit from switching to NovoMix® 30 (bid) Christiansen JS et al.Diabetes, Obesity & Metabolism 2003;5(6):445-452

    36. Superior postprandial control • Higher plasma insulin levels with NovoMix® 30 vs. BHI 30 • Improved postprandial control vs. BHI 30 • Superior postprandial control vs. Humalog® Mix25TM • Lower postprandial increment and HbA1c vs. NPH • No safety concerns

    37. Return to contents slide Superior hypoglycaemia profile

    38. Comparison of efficacy and safety of NovoMix® 30 vs. BHI 30: study design NovoMix® 30 (n = 140, 39% type 1) Insulin-using type 1 and type 2 diabetic patients (n = 294) One screening visit; patients already using a twice-daily insulin regimen BHI 30 (n = 151, 32% type 1) 12 weeks Boehm B et al. Diabet Med 2002;19(5):393–399

    39. Improved postprandial glucose after 3 months NovoMix® 30 * p < 0.05 * 12 BHI 30 * * 10 * 8 Blood glucose (mmol/l) 6 0 Pre- Post- Pre- Post- Pre- Post- Bedtime 0200 h Breakfast Lunch Dinner Boehm B et al. Diabet Med 2002;19(5):393–399

    40. 3 2.5 2 1.5 1 0.5 0 Significantly lower prandial glucose increment with NovoMix® 30 p < 0.02 between treatment groups (mmol/l) Mean prandial glucose increment NovoMix® 30 BHI 30 (n = 141) (n = 128) Boehm B et al. Diabet Med 2002;19(5):393–399

    41. Reduced major hypoglycaemia after 3 months 50% relative risk reduction 45 40 35 30 Number of hypoglycaemic episodes 42 events 25 20 15 20 events 10 5 0 NovoMix® 30 BHI 30 (n = 153) (n = 138) Boehm B et al. Diabet Med 2002;19(5):393–399

    42. Trend towards reduced minor nocturnal hypoglycaemic episodes p = 0.06 60 55 50 45 40 35 58 events Number of hypoglycaemic episodes 30 25 39 events 20 15 10 5 0 NovoMix® 30 BHI 30 Boehm B et al. Diabet Med 2002;19(5):393–399

    43. Reduced hypoglycaemic profile with NovoMix® 30 • Superior postprandial glycaemic control achieved compared with BHI 30 • No increased risk of hypoglycaemia with NovoMix® 30 • Trend for reduction in nocturnal hypoglycaemic episodes with NovoMix® 30 Boehm B et al. Diabet Med 2002;19(5):393–399

    44. NovoMix® 30 vs. BHI 30: 2-year safety in type 2 diabetes NovoMix® 30 bid (n = 58) Insulin-using type 2 diabetic patients (n = 125) BHI 30 bid (n = 67) 0 24 Months Boehm et al. Submitted to Eur J Int Med

    45. Reduced major hypoglycaemia after 2 years p = 0.04 12 NovoMix® 30 BHI 30 p = NS 10 8 Patients with at least one major episode (%) 6 4 2 0 1st year 2nd year Year of study Boehm et al. Submitted to Eur J Int Med

    46. 2-year efficacy and tolerability of NovoMix® 30 in type 2 diabetes Compared with BHI 30, NovoMix® 30 is associated with: • A reduced risk of major hypoglycaemia • An equivalent level of efficacy • More favourable balance between hypoglycaemia and hyperglycaemia in insulin-treated type 2 diabetes Boehm et al. Submitted to Eur J Int Med

    47. NovoMix® 30 vs. BHI 30: 4-year safety in type 2 diabetes Insulin-using type 2 patients (n = 73) NovoMix® 30 bid (n = 32) BHI 30 bid (n = 41) 0 24 42 48 Months Boehm B et al.Diabetologia 2003;46(Suppl 2):A269

    48. Twice-daily NovoMix® 30 and BHI 30 gives stable metabolic control NovoMix® 30 BHI 30 9.0 8.5 8.0 HbA1c (%) 7.5 7.0 0 0 3 6 12 18 24 30 36 42 Months Boehm B et al.Diabetologia 2003;46(Suppl 2):A269

    49. Hypoglycaemic episodes in patients completing the 4-year trial Boehm B et al.Diabetologia 2003;46(Suppl 2):A269

    50. Superior hypoglycaemic profile vs. BHI 30 • No major hypoglycaemic episodes during second year of treatment • No nocturnal hypoglycaemic events during 4 years’ treatment