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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

The dual-release insulin preparation

Overview of published studies

contents
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

slide3

Return to contents slide

Insulin aspart – a rapid acting analogue

insulin aspart preclinical proof of concept
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

slide5

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Dual-release kinetics

the dual release insulin concept bhi 30

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
the dual release insulin concept

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
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
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

proof of concept rapid absorption and higher peak concentration

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
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
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

slide13

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Improved postprandial glycaemic control

twice daily novomix 30 in patients with type 2 diabetes

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 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
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
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
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

type 1 diabetes single dose crossover

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

slide20

*

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

reduced glucose excursion irrespective of timing of bhi 30 injection

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
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 mix25 tm and bhi 30
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

reduced glucose excursions vs humalog mix25 tm and bhi 30

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 mix25 tm and bhi 30
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 increase in serum insulin with novomix 30
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 mix25 tm
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
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
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

significantly lower prandial glucose increment with novomix 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

improved postprandial control with novomix 30
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 nph in type 2 patients
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

novomix 30 vs nph lower prandial glucose increment

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 hba 1c reduction with novomix 30 vs nph
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
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
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
slide37

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Superior hypoglycaemia profile

comparison of efficacy and safety of novomix 30 vs bhi 30 study design1
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 months1
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

significantly lower prandial glucose increment with novomix 301

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
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
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
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 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
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
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
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
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
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
Superior hypoglycaemic profile vs. BHI 30
  • No major hypoglycaemic episodes during second year of treatment
  • No nocturnal hypoglycaemic events during 4 years’ treatment
slide51

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Superior HbA1c control with oral medication

novomix 30 in combination with metformin
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
Demographic characteristics (total population)

NovoMix® 30 plus metformin intype 2 diabetes

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

improved hba 1c with novomix 30 combination in total population

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

superior glycaemic control with novomix 30 metformin in poorly controlled patients hba 1c 9

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

lower insulin dose when used with metformin

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

significantly lower body weight for novomix 30 met vs novomix 30

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
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 + met 23
      • NovoMix® 30 alone 20
      • 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
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
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 14 Weeks

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

addition of insulin to metformin improves glycaemic control
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 fasting glycaemic targets
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
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
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
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
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 combination1
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
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 hba 1c after 6 weeks treatment
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
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
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 hba 1c with novomix 30 combination treatment
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
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 + 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
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
slide76

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Convenience and flexibility

patient preference for novomix 30 compared with bhi 30
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
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
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 301
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
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
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
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 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

comparison of novomix 30 flexpen with humalog mix25 tm pen

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
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 mix25 tm pen
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 mix25 tm
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
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 kit tm
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
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
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
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
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
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
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

reduction in hba 1c with novomix 30

* 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
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
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
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
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
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:
  • 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
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):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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