The dual release insulin preparation
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The dual-release insulin preparation. Overview of published studies. Contents. NovoMix ® 30 – the dual release insulin ContentsSlides 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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The dual-release insulin preparation

Overview of published studies


Contents

NovoMix® 30 –the dual release insulin

ContentsSlides

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


Return to contents slide

Insulin aspart – a rapid acting analogue


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


Return to contents slide

Dual-release kinetics


  • 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


  • 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


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


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


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


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


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


Return to contents slide

Improved postprandial glycaemic control


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


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


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


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


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


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


*

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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


Return to contents slide

Superior hypoglycaemia profile


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


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


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


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


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


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


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


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


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


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


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


Hypoglycaemic episodes in patients completing the 4-year trial

Boehm B et al.Diabetologia 2003;46(Suppl 2):A269


Superior hypoglycaemic profile vs. BHI 30

  • No major hypoglycaemic episodes during second year of treatment

  • No nocturnal hypoglycaemic events during 4 years’ treatment


Return to contents slide

Superior HbA1c control with oral medication


NovoMix® 30 in combination withmetformin

NovoMix® 30 bid + metformin (n = 108)

(n = 329)

NovoMix® 30 bid (n = 107)

Metformin failures

(HbA1c 7.5–13.0%)

glibenclamide + metformin (n = 114)

0

16

Weeks

Kvapil M et al. Diabetes 2002;51(Suppl 2):A104


Demographic characteristics (total population)

NovoMix® 30 plus metformin intype 2 diabetes

Kvapil M et al. Diabetes 2002;51(Suppl 2):A104


p = 0.004

Improved HbA1c with NovoMix® 30 combination in total population

8.5

HbA1c difference of 0.6%

8

(%) following 16 weeks'

treament

7.5

1c

0

HbA

7

NM

NM+met

Met+su

Treatment group

Kvapil M et al. Diabetes 2002;51(Suppl 2):A104


p = 0.037

Superior glycaemic control with NovoMix® 30 + metformin in poorly controlled patients (HbA1c > 9%)

p = 0.033

8.5

8

(%)

1c

HbA

7.5

0

7

NM

NM+met

Met+SU

Treatment group

Kvapil M et al. Diabetes 2002;51(Suppl 2):A104


7

6

5

4

3

2

1

0

0

1

2

3

4

Lower insulin dose when used with metformin

NovoMix® +met

NovoMix® 30

Met + SU

0.6

0.4

NovoMix® 30 dose (IU/mg/day)

SU dose (mg/day)

0.2

0

0

1

2

3

4

Time (months)

Time (months)

Kvapil M et al. Diabetes 2002;51(Suppl 2):A104


p = 0.05

Significantly lower body weight* for NovoMix® 30 + met vs. NovoMix® 30

p = 0.0004

120

100

80

weight (kg)

60

End of trial mean body

40

* Mean body weights adjusted for baseline

20

0

NovoMix® 30

NovoMix® 30 + met

Met + SU

Kvapil M et al.Diabetologia 2002;45(Suppl 2):A18


NovoMix® 30 plus metformin is well tolerated

  • 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

  • Kvapil M et al. Diabetes 2002;51(Suppl 2):A104


    Improved glycaemic control with NovoMix® 30 combination

    • 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

    Kvapil M et al. Diabetes 2002;51(Suppl 2):A104


    Once-daily (dinnertime) NovoMix® 30 with metformin

    Metformin + NovoMix® 30 od (n = 46)

    Run-in period – metformin (up to 2550 mg/day)

    Metformin + human insulin NPH od (n = 47) Follow-up

    Metformin + BHI 30 od (n = 47)

    Eligible patients: FPG  126 mg/dl

    –4 0 12 14Weeks

    Kilo C et al. J Diabetes Complications 2003;17(6):307-13


    Addition of insulin to metformin improves glycaemic control

    Treatment group (+metformin)

    NovoMix® 30

    NPH

    BHI 30

    -1

    (%)

    1c

    -1.2

    Reduction in HbA

    -1.4

    Kilo C et al. J Diabetes Complications 2003;17(6):307-13


    Benefits of reaching fastingglycaemic targets

    Treatment (+ metformin)

    NovoMix® 30

    NPH

    BHI30

    0

    -0.5

    -1

    (%)

    Change in HbA1c from baseline

    -1.5

    -2

    FPG <7 mmol/l (n = 26)

    -2.5

    Kilo C et al. J Diabetes Complications 2003;17(6):307-13


    No major hypoglycaemic events during the study

    Kilo C et al. J Diabetes Complications 2003;17(6):307-13


    Addition of second therapy when glibenclamide fails (I)

    NovoMix®30 (BID) +

    glibenclamide (n = 22)

    Glibenclamide

    (7.5–15 mg/day)

    Type 2 patients, HbA1c 813%

    Metformin (850 mg OD) +

    glibenclamide (n = 24)

    Weeks

    0 6

    Raz I et al. Diabetologia 2002;45(Suppl. 2): A263


    Improved glycaemic control with addition of NovoMix® 30 vs. metformin

    GLI+NovoMix® 30

    GLI+NovoMix® 30

    GLI+MET

    GLI+MET

    0.0

    0.0

    –0.5

    –0.3

    –1.0

    –1.5

    –0.6

    Mean glucose reduction

    (mmol/l)

    –2.0

    HbA1c reduction (%)

    –0.9

    –2.5

    –3.0

    –1.2

    –3.5

    *

    p < 0.05

    –4.0

    –1.5

    Raz I et al. Diabetologia 2002;45(Suppl. 2): A263


    Addition of second therapy when glibenclamide fails (II)

    NovoMix®30 (BID) +

    rosiglitazone (4 mg OD) (n = 26)

    Glibenclamide

    (7–15 mg)

    Type 2 patients, HbA1c (813%)

    Glibenclamide +

    rosiglitazone (4mg OD) (n = 23)

    Weeks

    0 6

    Raz I et al. Clin Ther 2003;25:3109-3123


    Improved glycaemic control with NovoMix® 30 combination

    ROS+NovoMix® 30

    ROS+NovoMix® 30

    ROS+GLI

    ROS+GLI

    0.0

    0.0

    –0.5

    –0.3

    –1.0

    –1.5

    –0.6

    Mean glucose reduction

    (mmol/l)

    –2.0

    HbA1c reduction (%)

    –2.5

    –0.9

    –3.0

    –1.2

    –3.5

    –4.0

    –1.5

    *

    p < 0.05

    Raz I et al. Clin Ther 2003;25:3109-3123


    Treatment options when metformin fails

    NovoMix®30 (BID) + metformin (OD) (n = 23)

    Metformin

    (1700–2550 mg)

    NovoMix® 30 (BID) + repaglinide 1 mg (OD) + metformin (OD) (n = 24)

    Glibenclamide 5 mg (OD) + metformin (OD) (n = 23)

    Weeks

    0 6

    Raz I et al. Manuscript in preparation


    Reduction in HbA1c after 6 weeks’ treatment

    MET+

    REP+

    NovoMix® 30

    MET+

    REP+NovoMix® 30

    MET+NovoMix® 30

    MET+

    GLI

    MET+NovoMix® 30

    MET+

    GLI

    0.0

    0.0

    –0.5

    –0.3

    –1.0

    –1.5

    Mean glucose reduction

    (mmol/l)

    –0.6

    HbA1c reduction (%)

    –2.0

    –0.9

    –2.5

    –3.0

    –1.2

    –3.5

    –1.5

    –4.0

    Raz I et al. Manuscript in preparation


    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 HbA1c

    • All treatment therapies showed improvements in HbA1c

    Raz I et al. Diabetologia 2002;45(Suppl 2):A263


    Treatment options with NovoMix® 30 when SU therapy fails

    NovoMix® 30 (BID) + pioglitazone (30 mg OD)

    SU mono or combination therapy

    (HbA1c 7.513.0%)

    NovoMix® (BID)

    Glibenclamide (515 mg, OD) +

    pioglitazone (30 mg OD)

    0 1 2 4 8 12 18

    Time (weeks)

    Screening

    Randomisation

    (SU therapy discontinued)

    Discontinuation of trial product

    Raz I et al.Diabetologia 2003;46(Suppl 2):A8


    Lower HbA1c with NovoMix® 30 combination treatment

    11.0

    NovoMix® 30

    10.5

    NovoMix® 30 + pioglitazone

    Glibenclamide + pioglitazone

    10.0

    9.5

    HbA1c (%)

    *

    *

    9.0

    8.5

    8.0

    7.5

    *p < 0.01

    7.0

    Week 18

    Screening

    Week 8

    Raz I et al.Diabetologia 2003;46(Suppl 2):A8


    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


    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


    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


    Return to contents slide

    Convenience and flexibility


    Patient preference for NovoMix® 30 compared with BHI 30

    • Patients with type 2 diabetes received either NovoMix® 30 or BHI 30; both treatments were administered twice daily during the 12-week trial

    • Patients continued on their respective treatment for 6 months

    • An analysis of preference-weighted treatment satisfaction (diabetes-specific Quality of Life scale combined for type 1 and type 2 diabetes) was performed at the 6-month follow-up visit

    • Patients receiving NovoMix® 30 scored significantly higher than BHI 30-treated patients (p<0.05)

    Home P et al, Diab Res Clin Pract 2000;50(Suppl 1):S37


    Postprandial dosing with NovoMix® 30

    NovoMix® 30, 0 min

    NovoMix® 30, +15 min

    BHI 30, –15 min

    BHI 30, 0 min

    Visit 1 2 3 4 5 6

    (Screening) (Randomisation) (Follow-up)

    Days

    between

    visits

    5–21 3–21 3–21 3–21 1–14

    Kapitza C et al. Diabet Med 2004;21(5):500-1


    Postprandial dosing efficacy with NovoMix® 30

    BHI 30(t = –15 min)

    6

    BHI 30(t = 0 min)

    NovoMix®30(t = 0 min)

    4

    NovoMix®30( t= +15 min)

    2

    Blood glucose (mmol/l)

    0

    –2

    –4

    0

    60

    120

    180

    240

    300

    Time (min)

    Kapitza C et al. Diabet Med 2004;21(5):500-1


    Postprandial dosing with NovoMix® 30

    * Values are expressed as geometric means

    a AUC for NovoMix® 30 significantly smaller than both BHI treatments (p = 0.0057 and p = 0.0006 for t = – 15 min and t = 0 min, respectively)

    b Cmax 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)

    Kapitza C et al. Diabet Med 2004;21(5):500-1


    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 15 min after start of meal to BHI 30 injected 0 or 15 min before meal

    • Gives advantage of increased flexibility in injection timing

    • Opportunity to alter insulin dose according to meal size and composition

    Kapitza C et al. Diabet Med 2004;21(5):500-1


    Postprandial NovoMix® 30 dosing in elderly patients

    Run-in (n = 91)

    Preprandial dosing

    Preprandial dosing

    Postprandial dosing

    Postprandial dosing

    NovoMix® 30, bid, preprandial

    0 4 8 12 Weeks

    Warren et al.Diab Res Clin Pract, in press 2004


    Blood glucose levels did not differ between treatment groups

    200

    Preprandial dosing(NovoMix® 30, bid)

    180

    Postprandial dosing(NovoMix® 30, bid)

    160

    140

    n = 91

    p = NS in all cases

    120

    Blood glucose levels (mg/dl)

    100

    80

    60

    40

    20

    0

    Before

    breakfast

    Before

    dinner

    2 hrs after

    breakfast

    2 hrs after

    dinner

    Warren et al.Diab Res Clin Pract, in press 2004


    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.Diab Res Clin Pract, in press 2004


    Run-in (n = 133)

    NovoMix® 30 FlexPen®

    NovoMix® 30 FlexPen®

    Humalog® Mix25TM Pen

    Humalog® Mix25TM Pen

    –3

    0

    12

    24

    Weeks

    Comparison of NovoMix® 30 FlexPen® with Humalog® Mix25TM Pen

    Niskanen et al. Clin Ther 2004;26(4):531-540


    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

    Niskanen et al. Clin Ther 2004;26(4):531-540


    NovoMix® 30 FlexPen® is preferred over Humalog® Mix25TM Pen

    Equally easy/

    either

    NovoMix® 30

    FlexPen®

    Humalog®

    Mix25TM

    Equally difficult/

    neither

    100

    90

    *

    *

    80

    70

    60

    50

    % of patients

    40

    30

    20

    10

    0

    Overall, which pen device do

    Overall, which pen device would

    you find easiest to use?

    you prefer to continue to use

    after this trial?

    * p < 0.001 compared with Humalog® Mix25TM Pen

    Niskanen et al. Clin Ther 2004;26(4):531-540


    Comparable efficacy and safety vs. Humalog® Mix25TM

    • A similar reduction in HbA1c was seen in the NovoMix® 30 and Humalog® Mix25TM 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

    Niskanen et al. Clin Ther 2004;26(4):531-540


    Higher patient satisfaction with NovoMix® 30 FlexPen®

    • Patients were more satisfied and experienced fewer problems than with the Humalog® Mix25TM 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® Mix25TM Pen users would

    • Efficacy and safety of NovoMix® 30 and Humalog® Mix25TM were comparable

    Niskanen et al. Clin Ther 2004;26(4):531-540


    Comparison of FlexPen® with Humalog® KitTM

    ”Device-naïve” patients

    Run-in (n = 58)

    FlexPen®

    FlexPen®

    Humalog® KitTM

    Humalog® KitTM

    0

    2

    4

    Days

    Both pens contained rapid-acting analogues, however, no insulin was injected during the testing procedure

    Asakura T & Seino H Diabetes Metab 2003;29:4S236


    FlexPen® is more user-friendly than Humalog® Kit

    **

    **

    *

    *

    *

    250

    FlexPen®

    Humalog® Kit

    200

    * p < 0.01

    ** p < 0.001

    150

    100

    Total score

    50

    0

    Ease of

    pressing

    release

    button

    Ease of

    dose setting

    Number

    legibility

    Injection

    confirmation

    Simplicity

    Pen feature

    Asakura T & Seino H Diabetes Metab 2003;29:4S236


    More patients prefer FlexPen® to Humalog® Kit

    * p < 0.01

    90

    80

    70

    60

    50

    Patients (%)

    40

    30

    20

    10

    0

    FlexPen®

    Humalog® Kit

    No preference

    Device preference

    Asakura T & Seino H Diabetes Metab 2003;29:4S236


    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


    Comparison of FlexPen® vs vial/syringe

    Run-in

    Type 1 and type 2 patients

    (using vial/syringe)

    FlexPen® FlexPen®

    Vial/syringe Vial/syringe

    Randomisation (n = 108)

    0 4 8 12

    Weeks

    Korytkowski M et al. Clinical Therapeutics 2003;25(11):2836-48


    Patients prefer FlexPen® to vial/syringe

    6%

    FlexPen

    20%

    Vial/syringe

    Q: Overall, which device would you prefer to continue using?

    No difference

    * Significantly more patients (p<0.05) preferred to continue using FlexPen®vs. vial/syringe

    74%*

    Korytkowski M et al. Clinical Therapeutics 2003;25(11):2836-48


    FlexPen® is preferred to vial/syringe in a number of injection parameters

    Easier to read dose

    FlexPen®

    Vial/syringe

    No preference

    Confidence in setting dose

    Confidence in injecting correct dose

    Injection parameters

    More discreet in public

    More stable

    Easier to handle

    Confidence in glycaemic control

    Easier to use

    0

    10

    20

    30

    40

    50

    60

    70

    80

    90

    100

    Patients expressing preference (%)

    Korytkowski M et al. Clinical Therapeutics 2003;25(11):2836-48


    * p<0.05

    Reduction in HbA1cwith NovoMix® 30

    9.5

    9

    (%)

    8.5

    1c

    8

    7.5

    Absolute HbA

    7

    6.5

    0

    Baseline (week 0)

    End of trial (week 12)

    Time point

    Korytkowski M et al. Clinical Therapeutics 2003;25(11):2836-48


    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):2836-48


    Health care professionals’ opinion

    82% of healthcare professionals preferred FlexPen®

    compared with two other prefilled pens

    100

    * p<0.01 vs. Humalog® pen and OptiSet® (n=102)

    82%*

    80

    Proportion of patients (%)

    60

    40

    14%

    20

    3%

    0

    FlexPen®

    Humalog® Pen**

    OptiSet®

    ** Same device as Humalog® Mix 25 pen

    Lawton S et al. Diabetes 2001;50 (Suppl 2):A440


    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® toHumalog® Mix25TM

    • Patients with impaired manual dexterity and vision prefer FlexPen® to Humalog® Kit


    Efficacy and safety of NovoMix® 30 in type 1 adolescents

    NovoMix®30 (TID) + NPH (bedtime)

    Snack insulin (IAsp) was administered when required (n = male/female 37/49)

    Type 1 patients, 10-17 yrs

    HI + BHI + NPH (bedtime)

    Snack insulin (HI) was administered when required (n = male/female 43/38)

    0 2 weeks 16 weeks (Time)

    Mortensen H et al.Diabetes Metab 2003;29:4S227


    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 : HbA1c 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


    NovoMix® 30:

    • NovoMix® 30 provides improved postprandial glycaemic control compared to biphasic human insulin and Humalog® Mix25TM

    • NovoMix® 30 provides a superior hypoglycaemic profile to biphasic human insulin

    • NovoMix® 30 improves HbA1c 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


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    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):445-452

    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):307-13

    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. Diabet Med 2004;21(5):500-1

    Warren et al.Diabetes Res Clin Pract, in press 2004

    Niskanen et al. Clin Ther 2004;26(4):531-540

    Asakura T & Seino H Diabetes Metab 2003;29:4S236

    Korytkowski M et al. Clinical Therapeutics 2003;25(11):2836-48

    Lawton S et al. Diabetes 2001;50 (Suppl 2):A440

    Mortensen H et al.Diabetes Metab 2003;29:4S227

    Publications/abstracts used in this slide kit


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