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The dual-release insulin preparation Overview of published studies.

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1 The dual-release insulin preparation Overview of published studies

2 2 Contents NovoMix ® 30 – the dual release insulin ContentsSlides Insulin aspart3  43  4 Dual-release kinetics5  125  12 Postprandial glycaemic control13  3613  36 Hypoglycaemia37  5037  50 Combination with oral medications51  7651  76 Convenience & flexibility77  9477  94 Use in adolescents95  9695  96

3 3 Insulin aspart – a rapid acting analogue Brange J et al. Nature 1988;333:679–682 Clinical proof of concept study for insulin aspart Return to contents slide

4 4 Insulin aspart: preclinical proof- of-concept Adapted from Brange J et al. Nature 1988;333:679– hours Injection Plasma glucose (mM) IRI ( M) Insulin aspart Human insulin

5 5 Dual-release kinetics Jacobsen L et al. Eur J Clin Pharm 2000;56: 399–403 Weyer C et al. Diabetes Care 1997;10:1612–1614 PK studies in healthy volunteers PD studies in healthy volunteers Return to contents slide

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

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

8 8 Benefits of dual-release insulin replacement 1.Mimics physiological insulin release –Early release of rapid-acting insulin targets postprandial glucose –Delayed release of intermediate-acting insulin fulfils basal insulin requirement 2.Reduces hypoglycaemic risk –< Conventional premix 3.Improves HbA 1c in combination with oral medications 4.Simplifies dosing –Option of postprandial dosing

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

10 10 Proof of concept: rapid absorption and higher peak concentration Jacobsen L et al. Eur J Clin Pharm 2000;56:399–403 ***p < n = 24 Time of day Serum insulin (mU/l) :0011:0014:0017:0020:0023:002:005:008:00 *** BHI 30 NovoMix ® 30

11 11 Proof of concept: faster onset and more effective Weyer C et al. Diabetes Care 1997;10:1612–1614 Glucose infusion rate (mg/kg/min) Time (min) NovoMix ® 30 BHI 30 (Actraphane) n = 24, dose = 0.3 U/kg

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

13 13 Improved postprandial glycaemic control McSorley PT et al. ClinTher 2002;24(4):530–539 Hermansen K et al. Metabolism 2002;51(7):896–900 Hermansen K et al. Diabetes Care 2002;25:883–888 Boehm B et al. Diabet Med 2002;19(5):393–399 Christiansen JS et al. Diabetes, Obesity & Metabolism 2003;5(6): Meal study in type 2 patients vs. BHI 30 Comparison vs. BHI 30 in type 1 patients Comparison vs. BHI 30 and lispro mix 25 in type 2 patients Comparison vs. BHI 30 in type 1 and type 2 patients Comparison vs. NPH in type 2 patients Return to contents slide

14 14 Twice-daily NovoMix ® 30 in patients with type 2 diabetes McSorley PT et al. Clin Ther 2002;24(4):530–539 Weeks –3 to14 days 4 20 NovoMix ® 30 BHI 30 Screening visit (n = 13) Follow-up +3 to 7 days

15 15 NovoMix ® 30 is rapidly absorbed McSorley PT et al. Clin Ther 2002;24(4):530–539 Total serum insulin (mU/l) Time 18:0022:0008:0013:0018:00 NovoMix ® 30 Biphasic human insulin n = 13 * p < 0.05 in favour of NovoMix ® 30 for mean serum insulin level and insulin C max after dinner and breakfast * *

16 16 Improved postprandial glucose control with NovoMix ® 30 Blood glucose (mmol/l) Time 18:0022:0008:0013:0018:00 McSorley PT et al. Clin Ther 2002;24(4):530–539 Biphasic human insulin NovoMix ® 30 n = 13 * * * p < 0.05 in favour of NovoMix ® 30 for lower PPG levels after dinner and breakfast

17 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 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 19 Type 1 diabetes: single dose crossover NovoMix ® 30 at meal 7 – 14 days 3 – 21 days 5 – 21 days BHI 30 at –30 minutes (n = 50) BHI 30 at meal Hermansen K et al. Metabolism 2002;51(7):896–900 Study day 1 Study day 2 Study day 3 Screening Follow-up

20 20 Reduced glucose exposure in type 1 patients after a meal Blood glucose (mmol/l) Nominal time (min) – NovoMix ® 30 ( t = 0) BHI 30 (t = 0) BHI 30 (t = –30) 060 Max glucose conc n 15% lower at t = 0 * 23% lower glucose exposure than BHI at t = 0 * Max glucose conc n 20 min earlier * * p < n = 50 Hermansen K et al. Metabolism 2002;51(7):896–900

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

22 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 23 Comparison of NovoMix ® 30, Humalog ® Mix25 TM and BHI 30 Objective To compare the postprandial blood glucose excursion between treatment groups Design Randomised, open-labelled, three-period crossover trial Method Single dose meal test, NovoMix ® 30 and Humalog ® Mix25 TM immediately before meal, BHI min before meal Population 45 type 2 patients Primary test EXC (glucose 0–5h) NovoMix ® 30 at meal BHI 30 at –15 min (n = 45) Humalog® Mix25 TM at meal Hermansen K et al. Diabetes Care 2002;25:883–888

24 24 Reduced glucose excursions vs. Humalog ® Mix25 TM and BHI 30 Hermansen K et al. Diabetes Care 2002;25:883–888 p < 0.05 –10% p < –17% Humalog ® Mix 25 TM NovoMix ® 30BHI 30 Blood glucose excursion 0– 5h (mmol/l h)

25 25 Improved postprandial control vs. Humalog ® Mix25 TM and BHI 30 Hermansen K et al. Diabetes Care 2002;25:883–888 a NovoMix ® 30 significantly less than Humalog ® Mix25 TM (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 ® Mix25 TM (p < 0.01) Glucose parameter EXC 0–5h (mmol/l h) C max (mmol/l h) t max (min) NovoMix ®  4.4 a,b 15.9  2.7 c 75.1  22.2 c,d Humalog ® Mix25 TM 18.9    26.9 BHI    26.4

26 26 Larger and more rapid increase in serum insulin with NovoMix ® 30 Insulin parameter AUC (ins 0–5h) (pmol/l h) C max(ins) (pmol/l h) T max(ins) (min) NovoMix ®  535 a 415  244 a 115  59 a Humalog ® Mix25 TM 1031    41 BHI    71 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 27 Improved postprandial glucose vs. BHI 30 and Humalog ® Mix25 TM Superior postprandial glucose control to BHI 30 and Humalog ® Mix25 TM in type 2 patients Higher maximum serum insulin with BHI and Humalog ® Mix25 TM Well tolerated with no serious adverse events occurring related to treatment Hermansen K et al. Diabetes Care 2002;25:883–888

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

29 29 Improved postprandial glucose after 3 months * Blood glucose (mmol/l) * 0 Pre Post- 8 6 NovoMix ® 30 BHI 30 * p < 0.05 * * Lunch Pre-Post- Breakfast Pre-Post- Dinner Bedtime0200 h Boehm B et al. Diabet Med 2002;19(5):393–399

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

31 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 32 NovoMix ® 30 vs. NPH in type 2 patients NPH + OHA OHA only No treatment Screening 7–14 days 16 weeks 2 weeks Twice-daily NovoMix ® 30 (n = 201) Twice-daily NPH insulin (n = 202) Original treatment Randomisation Christiansen JS et al. Diabetes, Obesity & Metabolism 2003;5(6): NPH monotherapy

33 33 NovoMix ® 30 vs. NPH: lower prandial glucose increment ** ** * ** Difference in prandial glucose increment between treatment groups (mmol/l) Breakfast Lunch Dinner * p < ** p < Favours NPH Favours NovoMix ® 30 Mean prandial glucose increment Christiansen JS et al. Diabetes, Obesity & Metabolism 2003;5(6):

34 34 Greater HbA 1c reduction with NovoMix ® 30 vs. NPH NovoMix ® 30 (n = 66) NPH (n = 66) Change in HbA 1c (%) p = 0.03 Christiansen JS et al. Diabetes, Obesity & Metabolism 2003;5(6):

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

36 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 ® Mix25 TM Lower postprandial increment and HbA 1c vs. NPH No safety concerns

37 37 Superior hypoglycaemia profile Boehm B et al. Diabet Med 2002;19(5):393–399 Boehm et al. Submitted to Eur J Int Med Boehm B et al. Diabetologia 2003;46(Suppl 2):A269 Safety comparison vs. BHI 30 in type 1 and type 2 patients 2-year safety data in type 2 patients vs. BHI 30 4-year safety data in type 2 patients vs. BHI 30 Return to contents slide

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

39 39 Improved postprandial glucose after 3 months Boehm B et al. Diabet Med 2002;19(5):393–399 * Blood glucose (mmol/l) * 0 Pre Post- 8 6 NovoMix ® 30 BHI 30 * p < 0.05 * * Lunch Pre-Post- Breakfast Pre-Post- Dinner Bedtime0200 h

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

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

42 42 Trend towards reduced minor nocturnal hypoglycaemic episodes NovoMix ® 30 BHI 30 p = 0.06 Number of hypoglycaemic episodes events 39 events Boehm B et al. Diabet Med 2002;19(5):393–399

43 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 44 NovoMix ® 30 vs. BHI 30: 2-year safety in type 2 diabetes Insulin-using type 2 diabetic patients (n = 125) NovoMix ® 30 bid (n = 58) BHI 30 bid (n = 67) 24 Months 0 Boehm et al. Submitted to Eur J Int Med

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

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

48 48 Twice-daily NovoMix ® 30 and BHI 30 gives stable metabolic control Boehm B et al. Diabetologia 2003;46(Suppl 2):A NovoMix ® 30 BHI 30 HbA 1c (%) Months

49 49 Hypoglycaemic episodes in patients completing the 4-year trial Boehm B et al. Diabetologia 2003;46(Suppl 2):A269 NovoMix ® 30 (n = 32) BHI 30 (n = 41) p-value People with major episodes First 2 years Entire period People with nocturnal episodes Entire period060.02

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

51 51 Superior HbA 1c control with oral medication Kvapil M et al. Diabetes 2002;51(Suppl 2):A104 Kilo C et al. J Diabetes Complications 2003;17(6):307  13 Raz I et al. Submitted to Diabetes, Obesity and Metabolism Raz I et al. Clin Ther 2003;25:3109  3123 Raz I et al. Manuscript in preparation Raz I et al. Diabetologia 2003;46(Suppl 2):A8 Addition of twice-daily NovoMix ® 30 to metformin vs. addition of SU Addition of once-daily NovoMix ® 30 to metformin Addition of twice-daily NovoMix ® 30 or metformin to glibenclamide Addition of rosiglitazone to glibenclamide vs. switch to NovoMix ® 30 plus rosiglitazone Addition of NovoMix ® 30, NovoMix ® 30 plus repaglinide or glibenclamide to metformin Comparison of NovoMix ® 30, NovoMix ® 30 plus pioglitazone and glibenclamide plus pioglitazone in SU failures Return to contents slide

52 52 NovoMix ® 30 in combination with metformin Weeks 160 NovoMix ® 30 bid + metformin (n = 108) NovoMix ® 30 bid (n = 107) Metformin failures glibenclamide + metformin (n = 114) (n = 329) (HbA 1c 7.5–13.0%) Kvapil M et al. Diabetes 2002;51(Suppl 2):A104

53 53 Demographic characteristics (total population) NovoMix ® 30 + met Met + SU No of patients Mean age (yrs ± SD)55.2 ± ± ± 8.8 Male/Female50/5753/5552/62 BMI (kg/m 2 ± SD)30.9 ± ± ± 4.4 NovoMix ® 30 plus metformin in type 2 diabetes Kvapil M et al. Diabetes 2002;51(Suppl 2):A104

54 54 Improved HbA 1c with NovoMix ® 30 combination in total population Kvapil M et al. Diabetes 2002;51(Suppl 2):A NMNM+metMet+su Treatment group HbA 1c (%) following 16 weeks' treament p = HbA 1c difference of 0.6% 0

55 55 Superior glycaemic control with NovoMix ® 30 + metformin in poorly controlled patients (HbA 1c > 9%) p = p = Kvapil M et al. Diabetes 2002;51(Suppl 2):A NMNM+metMet+SU Treatment group HbA 1c (%) 0

56 56 Lower insulin dose when used with metformin Time (months) NovoMix ® 30 dose (IU/mg/day) NovoMix ® 30 NovoMix ® + met Time (months) Met + SU Kvapil M et al. Diabetes 2002;51(Suppl 2):A104 SU dose (mg/day)

57 57 Significantly lower body weight* for NovoMix ® 30 + met vs. NovoMix ® 30 p = 0.05 p = NovoMix ® 30NovoMix ® 30 + metMet + SU End of trial mean body weight (kg) * Mean body weights adjusted for baseline Kvapil M et al. Diabetologia 2002;45(Suppl 2):A18

58 58 There were no reports of major hypoglycaemia during the trial The total number of minor hypoglycaemic episodes was similar between groups: NovoMix ® 30 + met23 NovoMix ® 30 alone20 Met + SU 28 No other safety concerns were raised NovoMix ® 30 plus metformin is well tolerated Kvapil M et al. Diabetes 2002;51(Suppl 2):A104

59 59 In poorly controlled patients: NovoMix ® 30 plus metformin achieved better glycaemic control than NovoMix ® 30 alone or sulphonylurea plus metformin The end of trial mean weight was not different between the NovoMix ® 30 plus metformin group and SU plus metformin group NovoMix ® 30 plus metformin is well tolerated There was no difference in hypoglycaemia between the two groups Improved glycaemic control with NovoMix ® 30 combination Kvapil M et al. Diabetes 2002;51(Suppl 2):A104

60 60 Once-daily (dinnertime) NovoMix ® 30 with metformin Metformin + human insulin NPH od (n = 47) Follow-up – Weeks Metformin + NovoMix ® 30 od (n = 45) Run-in period – metformin (up to 2550 mg/day) Metformin + BHI 30 od (n = 46) Kilo C et al. J Diabetes Complications 2003;17(6): Eligible patients: FPG  126 mg/dl

61 61 Addition of insulin to metformin improves glycaemic control NovoMix ® 30NPHBHI 30 Treatment group (+metformin) Reduction in HbA 1c (%) Kilo C et al. J Diabetes Complications 2003;17(6):307-13

62 62 Benefits of reaching fasting glycaemic targets with NovoMix ® 30 Change in HbA 1c from baseline (%) FPG (mmol/l) 5 – 8 (n = 54) Treatment (+metformin) NovoMix ® 30NPHBHI 30 Kilo C et al. J Diabetes Complications 2003;17(6):307-13

63 63 Fewer nocturnal hypoglycaemic events with NovoMix ® 30 combination NovoMix ® 30NPHBHI 30 Patients (n) Major events000 Symptomatic nocturnal events Minor nocturnal events 169 There were no major hypoglycaemic events reported during the study. There were numerically fewer nocturnal hypoglycaemic events in the NovoMix ® 30 group Kilo C et al. J Diabetes Complications 2003;17(6):307-13

64 64 Once-daily (dinnertime) NovoMix ® 30 with metformin is effective and well tolerated With metformin non-responders, starting NovoMix ® 30 once-daily and continuing metformin is effective and well tolerated. Reaching FPG target with NovoMix ® 30 plus metformin achieves greater benefits than NPH or BHI 30 groups Less nocturnal hypoglycaemic events occurred in the NovoMix ® 30 combination group compared to NPH or BHI 30 groups Kilo C et al. J Diabetes Complications 2003;17(6):307-13

65 65 Addition of second therapy when glibenclamide fails (I) Raz I et al. Submitted to Diabetes, Obesity and Metabolism NovoMix ® 30 (BID) + glibenclamide (n = 22) Metformin (850 mg OD) + glibenclamide (n = 24) Glibenclamide (7.5–15 mg/day) Type 2 patients, HbA 1c 8  13% Weeks 0 6

66 66 Improved glycaemic control with addition of NovoMix ® 30 vs. metformin –1.5 –1.2 GLI+MET GLI+ NovoMix ® 30 –0.9 –0.6 – GLI+MET GLI+ NovoMix ® 30 *p < 0.05 –4.0 –3.5 –3.0 –2.5 –2.0 –1.5 –1.0 – Mean glucose reduction (mmol/l) HbA 1c reduction (%) Raz I et al. Submitted to Diabetes, Obesity and Metabolism

67 67 Addition of second therapy when glibenclamide fails (II) Type 2 patients, HbA1c (8  13%) NovoMix ® 30 (BID) + rosiglitazone (4 mg OD) (n = 26) Glibenclamide + rosiglitazone (4mg OD) (n = 23) Glibenclamide (7–15 mg) Raz I et al. Clin Ther 2003;25: Weeks 0 6

68 68 Improved glycaemic control with NovoMix ® 30 combination *p < 0.05 ROS+GLI ROS+ NovoMix ® 30 –4.0 –3.5 –3.0 –2.5 –2.0 –1.5 –1.0 – Mean glucose reduction (mmol/l) –1.5 –1.2 ROS+GLI ROS+ NovoMix ® 30 –0.9 –0.6 – HbA 1c reduction (%) Raz I et al. Clin Ther 2003;25:

69 69 Treatment options when metformin fails NovoMix ® 30 (BID) + metformin (OD) (n = 23) Glibenclamide 5 mg (OD) + metformin (OD) (n = 23) Metformin (1700–2550 mg) Raz I et al. Manuscript in preparation NovoMix® 30 (BID) + repaglinide 1 mg (OD) + metformin (OD) (n = 24) Weeks 0 6

70 70 Reduction in HbA 1c after 6 weeks’ treatment –4.0 –3.5 –3.0 –2.5 –2.0 –1.5 –1.0 – MET+ GLI MET+ NovoMix ® 30 MET+ REP+ NovoMix ® 30 Mean glucose reduction (mmol/l) –1.5 –1.2 –0.9 –0.6 – MET+ GLI MET+ NovoMix ® 30 MET+ REP+ NovoMix ® 30 HbA 1c reduction (%) Raz I et al. Manuscript in preparation

71 71 NovoMix ® 30 + oral agent is preferable to a second oral agent The addition of NovoMix ® 30 to an oral agent was more effective in lowering average glucose than when a second oral agent was added Addition of NovoMix ® 30 also showed a trend to decrease HbA 1c All treatment therapies showed improvements in HbA 1c Raz I et al. Diabetologia 2002;45(Suppl 2):A263

72 72 SU mono or combination therapy (HbA 1c 7.5  13.0%) Treatment options with NovoMix ® 30 when SU therapy fails Raz I et al. Diabetologia 2003;46(Suppl 2):A Time (weeks) Randomisation (SU therapy discontinued) Discontinuation of trial product Screening NovoMix ® (BID) Glibenclamide (5  15 mg, OD) + pioglitazone (30 mg OD) NovoMix ® 30 (BID) + pioglitazone (30 mg OD)

73 73 Lower HbA 1c with NovoMix ® 30 combination treatment Raz I et al. Diabetologia 2003;46(Suppl 2):A8 HbA 1c (%) ScreeningVisit 6End of Trial NovoMix ® 30 NovoMix ® 30 + pioglitazone Glibenclamide + pioglitazone * * *p < 0.01

74 74 Superior glycaemic control with NovoMix ® 30 combination therapy At end of trial, NovoMix ® 30 + pioglitazone was superior to glibenclamide + pioglitazone on almost all measures of blood glucose (p < 0.05–p < 0.001) Significantly lower prandial BG increment for NovoMix ® 30 + pioglitazone versus glibenclamide + pioglitazone (p < 0.05) NovoMix ® + pioglitazone superior to NovoMix ® 30 in reducing dinner-related glucose Raz I et al. Diabetologia 2003;46(Suppl 2):A8

75 75 NovoMix ® 30 + pioglitazone is effective in type 2 diabetes NovoMix ® 30 and pioglitazone is an effective treatment combination in type 2 diabetic patients The combination of NovoMix ® 30 and pioglitazone offers better glycaemic control than the combination of glibenclamide and pioglitazone and NovoMix ® 30 only The combination of NovoMix ® 30 and pioglitazone is well tolerated and associated with a low incidence of nocturnal hypoglycaemia Raz I et al. Diabetologia 2003;46(Suppl 2):A8

76 76 NovoMix ® 30 is an effective add-on therapy Superior glycaemic improvements when NovoMix ® 30 added to metformin vs. addition of SU Adding NovoMix ® 30 (once-daily) to metformin is more effective for controlling blood glucose levels compared with adding NPH or BHI 30 Overall, adding NovoMix ® 30 to a failing oral agent provides superior glycaemic control than adding another oral therapy

77 77 Convenience and flexibility Return to contents slide Kapitza C et al. In press Diabet Med Postprandial dosing vs. BHI 30 Warren et al. Submitted to Diabet Res Clin Prac Postprandial dosing vs. BHI 30 in the elderly Vora JP et al. Diabetologia 2002;45(Suppl 2):A255 NovoMix ® 30 FlexPen ® vs. Humalog ® Mix25 TM Pen Asakura T & Seino H Diabetes Metab 2003;29:4S236 NovoRapid ® FlexPen ® vs. Humalog ® Kit TM Pen Korytkowski M et al. Clin Ther 2003;25(11): in press FlexPen ® vs. vial/syringe with NovoMix ® 30

78 78 Postprandial dosing with NovoMix ® 30 Kapitza C et al. In press Diabet Med NovoMix ® 30, +15 min BHI 30, –15 min 5–21 3–21 3–21 3–21 1–14 Days between visits Visit (Screening) (Randomisation) (Follow-up) NovoMix ® 30, 0 min BHI 30, 0 min

79 79 Postprandial dosing efficacy with NovoMix ® 30 Blood glucose (mmol/l) –2 –4 4 Time (min) NovoMix ® 30 ( t= +15 min) NovoMix ® 30 (t = 0 min) BHI 30 (t = 0 min) BHI 30 (t = –15 min) Kapitza C et al. In press Diabet Med

80 80 Postprandial dosing with NovoMix ® 30 Kapitza C et al. In press Diabet Med NovoMix ® 30 (t = 0 min) NovoMix ® 30 (t = +15 min) BHI 30 (t = – 15 min) BHI 30 (t = 0 min) *AUC (0–240mins) (mM/min) 2563 a *C max (mM) b T max (median, min) * Values are expressed as geometric means a AUC for NovoMix ® 30 significantly smaller than both BHI treatments (p = and p = for t = – 15 min and t = 0 min, respectively) b C max is smaller for NovoMix ® 30 (t = 0 min) compared with both BHI treatments, but only significantly smaller than BHI (t = 0 min) (p = 0.007)

81 81 NovoMix ® 30 allows flexible dosing Superior postprandial blood glucose control compared with either of BHI 30 injection regimens Comparable postprandial blood glucose control when injected after meal to BHI 30 (either injection regimen) Gives advantage of increased flexibility in injection timing Opportunity to alter insulin dose according to meal size and composition Kapitza C et al. In press Diabet Med

82 82 Postprandial NovoMix ® 30 dosing in elderly patients Warren et al. Submitted to Diabet Res Clin Prac Preprandial dosing Run-in (n = 91) Weeks Preprandial dosing Postprandial dosing NovoMix ® 30, bid, preprandial

83 83 Blood glucose levels did not differ between treatment groups Warren et al. Submitted to Diabet Res Clin Prac Preprandial dosing (NovoMix ® 30, bid) Postprandial dosing (NovoMix ® 30, bid) Before breakfast Before dinner 2 hrs after breakfast 2 hrs after dinner Blood glucose levels (mg/dl) n = 91 p = NS in all cases

84 84 Postprandial NovoMix ® 30 is effective in elderly type 2 patients Postprandial NovoMix ® 30 offers acceptable alternative to standard preprandial injections No significant difference in hypoglycaemic episodes between treatment groups Postprandial injections appear to be well tolerated Warren et al. Submitted to Diabet Res Clin Prac

85 85 Comparison of NovoMix ® 30 FlexPen ® with Humalog ® Mix25 TM Pen Weeks – NovoMix ® 30 FlexPen ® Humalog ® Mix25 TM Pen Run-in (n = 133) Vora JP et al. Submitted to Diabetes, Obesity and Metabolism

86 86 Vora JP et al. Submitted to Diabetes, Obesity and Metabolism NovoMix ® 30 FlexPen ® is simple to use Device specific, and comparative questionnaires assessed patients’ opinion about attributes of the devices Features included: –confidence in setting and injecting the correct dose –readability of the dose scale –confidence in managing daily insulin injections using the pen device For all 16 device features assessed NovoMix ® 30 FlexPen ® was statistically superior to Humalog ® Mix25™ Pen, p < 0.001

87 87 Vora JP et al. Submitted to Diabetes, Obesity and Metabolism NovoMix ® 30 FlexPen ® is preferred over Humalog ® Mix25 TM Pen Overall, which pen device do you find easiest to use? Overall, which pen device would you prefer to continue to use after this trial? % of patients Equally easy/ either NovoMix ® 30 FlexPen ® Humalog ® Mix25 TM Equally difficult/ neither * * * p < compared with Humalog ® Mix25 TM Pen

88 88 Comparable efficacy and safety vs. Humalog ® Mix25 TM A similar reduction in HbA 1c was seen in the NovoMix ® 30 and Humalog ® Mix25 TM treatment groups Both treatments lowered postprandial glucose to a similar extent The number of hypoglycaemic events did not differ significantly between treatment groups Both treatment groups experienced few adverse events Vora JP et al. Submitted to Diabetes, Obesity and Metabolism

89 89 Higher patient satisfaction with NovoMix ® 30 FlexPen ® Patients were more satisfied and experienced fewer problems than with the Humalog ® Mix25 TM Pen More patients found the NovoMix ® 30 FlexPen ® the easiest device to use More patients (75%) would continue to use the NovoMix ® 30 FlexPen ® while only 14% of Humalog ® Mix25 TM Pen users would Efficacy and safety of NovoMix ® 30 and Humalog ® Mix25 TM were comparable Vora JP et al. Submitted to Diabetes, Obesity and Metabolism

90 90 Asakura T & Seino H Diabetes Metab 2003;29:4S236 Comparison of FlexPen ® with Humalog ® Kit TM Days 420 FlexPen ® Humalog ® Kit TM Run-in (n = 58) ”Device-naïve” patients Both pens contained rapid-acting analogues, however, no insulin was injected during the testing procedure

91 91 FlexPen ® is more user-friendly than Humalog ® Kit Pen feature ** * ** Number legibility Ease of dose setting Ease of pressing release button Simplicity Injection confirmation Total score FlexPen ® Humalog ® Kit Asakura T & Seino H Diabetes Metab 2003;29:4S236 * p < 0.01 ** p < 0.001

92 92 More patients prefer FlexPen ® to Humalog ® Kit FlexPen ® Humalog ® KitNo preference Device preference Patients (%) * p < 0.01 Asakura T & Seino H Diabetes Metab 2003;29:4S236

93 93 FlexPen ® is simple to use Patients preferred FlexPen ® to Humalog ® Kit for: Readability of the dosing scale Ease of dose setting Ease of pressing the release button Stability during injection Simplicity Confirmation of injection No difference between the devices regarding grip and portability Asakura T & Seino H Diabetes Metab 2003;29:4S236

94 94 Comparison of FlexPen ® vs vial/syringe Korytkowski M et al. Clinical Therapeutics 2003;25(11): Run-in Type 1 and type 2 patients (using vial/syringe) Weeks Randomisation (n = 108) FlexPen ® Vial/syringe

95 95 Patients prefer FlexPen ® to vial/syringe 74%* 20 % 6% FlexPen Vial/syringe No difference Q: Overall, which device would you prefer to continue using? * Significantly more patients (p<0.05) preferred to continue using FlexPen ® vs. vial/syringe Korytkowski M et al. Clinical Therapeutics 2003;25(11):

96 96 FlexPen ® is preferred to vial/syringe in a number of injection parameters FlexPen ® Vial/syringe No preference Easier to use Confidence in glycaemic control Easier to handle More stable More discreet in public Confidence in injecting correct dose Confidence in setting dose Easier to read dose Injection parameters Patients expressing preference (%) Korytkowski M et al. Clinical Therapeutics 2003;25(11):

97 97 Reduction in HbA 1c with NovoMix ® 30 * p< Baseline (week 0)End of trial (week 12) Time point Absolute HbA 1c (%) Korytkowski M et al. Clinical Therapeutics 2003;25(11):

98 98 FlexPen ® is preferred to vial/syringe Both injection devices demonstrated high acceptance by the patients according to the Diabetes Treatment Satisfaction Questionnaire (DTSQ) Efficacy and safety profiles were similar between treatment groups Given the choice, more patients expressed a preference to continue using FlexPen ® to vial/syringe Korytkowski M et al. Clinical Therapeutics 2003;25(11):

99 99 82% of healthcare professionals preferred FlexPen ® compared with two other prefilled pens FlexPen ® Humalog ® Pen** 82%* 14% 3% OptiSet ® Health care professionals’ opinion Proportion of patients (%) * p<0.01 vs. Humalog ® pen and OptiSet ® (n=102) ** Same device as Humalog ® Mix 25 pen Lawton S et al. Diabetes 2001;50 (Suppl 2):A440

100 100 Convenient and flexible dosing with NovoMix ® 30 FlexPen ® NovoMix ® 30 offers flexible dosing times while maintaining good postprandial glycaemic control Patients prefer NovoMix ® 30 FlexPen ® to Humalog ® Mix25 TM Patients with impaired manual dexterity and vision prefer FlexPen ® to Humalog ® Kit

101 101 Efficacy and safety of NovoMix ® 30 in type 1 adolescents Mortensen H et al. Diabetes Metab 2003;29:4S227 NovoMix ® 30 (TID) (n = male 37 female 49) HI + BHI (n = male 43 female 38) Type 1 patients, yrs 0 2 weeks 16 weeks (Time)

102 102 Efficacy of NovoMix ® 30 in adolescents NovoMix ® 30 significantly improved BMI in boys, but not in girls Both treatments improved glycaemic control during the 16- week period : HbA 1c decreased by ~0.2% NovoMix ® 30 tended to improve prandial glucose control more in boys than in girls There was no between-treatment difference in rate of hypoglycaemia Mortensen H et al. Diabetes Metab 2003;29:4S227

103 103 NovoMix ® 30: NovoMix ® 30 provides improved postprandial glycaemic control compared to biphasic human insulin and Humalog ® Mix25 TM NovoMix ® 30 provides a superior hypoglycaemic profile to biphasic human insulin NovoMix ® 30 improves HbA 1c when used in combination with oral medications NovoMix ® 30 is simple and convenient to use in clinical practice NovoMix ® 30 is effective and well tolerated in adolescents

104 104 Publications/abstracts used in this slide kit Brange J et al. Nature 1988;333:679–682 Jacobsen L et al. Eur J Clin Pharm 2000;56:399–403 Weyer et al. Diabetes Care 1997;20: 1612–1614 McSorley PT et al. Clin Ther 2002;24(4):530– 539 Hermansen K et al. Metabolism 2002;51(7):896–900 Hermansen K et al. Diabetes Care 2002; 25:883–888 Boehm B et al. Diabet Med 2002;19(5):393–399 Christiansen JS et al. Diabetes, Obesity & Metabolism 2003;5(6): Boehm B et al. Submitted to Eur J Int Med Boehm B et al. Diabetologia 2003;46(Suppl 2):A269 Kvapil M et al. Diabetes 2002;51(Suppl 2):A104 Kilo C et al. J Diabetes Complications 2003;17(6): Raz I et al. Submitted to Diabetes, Obesity and Metabolism Raz I et al. Clin Ther 2003;25:3109–3123 Raz I et al. Manuscript in preparation Raz I et al. Diabetologia 2002;45(Suppl 2):A263 Raz I et al. Diabetologia 2003;46(Suppl 2):A8 Kapitza C et al. In press Diabet Med Warren et al. Submitted to Diabet Res Clin Prac Vora JP et al. Submitted to Diabetes, Obesity and Metabolism Asakura T & Seino H Diabetes Metab 2003;29:4S236 Korytkowski M et al. Clinical Therapeutics 2003;25(11): Lawton S et al. Diabetes 2001;50 (Suppl 2):A440 Mortensen H et al. Diabetes Metab 2003;29:4S227


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