The dual-release insulin preparation Overview of published studies

The dual-release insulin preparation

Overview of published studies

2

Contents

NovoMix® 30 – the dual release insulin

Contents Slides

Insulin aspart 34

Dual-release kinetics 512

Postprandial glycaemic control 1336

Hypoglycaemia 3750

Combination with oral medications 5176

Convenience & flexibility 7794

Use in adolescents 9596

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

Insulin aspart: preclinical proof-of-concept

Adapted from Brange J et al. Nature 1988;333:679–682

02

3

4

5

5 hours4321

Injection

0

1.5

3.0

4.5

Pla

sma

glu

cose

(m

M)

IRI (

10-1

0 M

)Insulin aspartHuman insulin

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


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

• 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

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 HbA1c in combination with oral medications

4. Simplifies dosing

– Option of postprandial dosing

9

Comparison

PK and PD profiles of NovoMix® 30 vs. BHI 30

Design

1. Randomised, double-blind, two-way single dose crossover1

2. Randomised, double-blind, crossover single dose euglycaemic clamp2

NovoMix® 30:PK/PD studies in healthy volunteers

1. Jacobsen L et al. Eur J Clin Pharm 2000;56:399–403 2. Weyer C et al. Diabetes Care 1997;10:1612–1614

10

Proof of concept: rapid absorption and higher peak concentration

Jacobsen L et al. Eur J Clin Pharm 2000;56:399–403

***p < 0.0001n = 24

Time of day

Ser

um

insu

lin (

mU

/l)

25

20

15

10

5

0

8:00 11:00 14:00 17:00 20:00 23:00 2:00 5:00 8:00

*** BHI 30NovoMix® 30

11

Proof of concept:faster onset and more effective

Weyer C et al. Diabetes Care 1997;10:1612–1614

Glu

cose

infu

sio

n r

ate

(mg

/kg

/min

) 12

8

6

4

2

0

10

Time (min)

0 240 480 720 960 1200 1400

NovoMix® 30

BHI 30 (Actraphane)

n = 24, dose = 0.3 U/kg

12

PK/PD conclusions: NovoMix® 30 vs. BHI 30

• Faster absorption1,2

• Higher peak concentrations1,2

• More rapid and pronounced glucose-lowering effect1,2

• Similar duration of action of basal component1,2

Faster onset and greater glucose-lowering effect of insulin aspart are retained in dual-release NovoMix® 30

1. Jacobsen L et al. Eur J Clin Pharm 2000;56:399–403 2. Weyer C et al. Diabetes Care 1997;10:1612–1614

13

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):445-452

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 2patients


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

420

NovoMix® 30 NovoMix® 30

BHI 30 BHI 30

Screening visit (n = 13) Follow-up

+3 to 7 days

15

NovoMix® 30 is rapidly absorbed


To

tal s

eru

m in

sulin

(m

U/l)

120

80

60

40

20

0

100

Time

18:00 22:00 08:00 13:00 18:00

NovoMix® 30

Biphasic human insulin

n = 13

* p < 0.05 in favour of NovoMix® 30 for mean serum insulin level and insulin Cmax after dinner and breakfast

* *

16

Improved postprandial glucose control with NovoMix® 30

Blo

od

glu

cose

(m

mo

l/l)

20

10

5

0

15

Time

18:00 22:00 08:00 13:00 18:00


Biphasic human insulin

NovoMix® 30

n = 13* *

* p < 0.05 in favour of NovoMix® 30 for lower PPG levels after dinner and breakfast

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


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


19

Type 1 diabetes: single dose crossover

NovoMix® 30 at meal

7–14 days3–21 days 5–21 days 5–21 days

BHI 30 at –30 minutes

(n = 50)

BHI 30 at meal


Study day 1 Study day 2 Study day 3

Screening Follow-up

20

Reduced glucose exposure intype 1 patients after a meal

5

10

15

20

0

Blo

od

glu

cose

(m

mo

l/l)

30 120 150 210

Nominal time (min)

–30 180 24090

NovoMix® 30 ( t = 0)BHI 30 (t = 0)BHI 30 (t = –30)

0 60

Max glucose concn

15% lower at t = 0

*

23% lower glucose exposure

than BHI at t = 0*Max glucose concn

20 min earlier

*

* p < 0.001n = 50


21

Reduced glucose excursion irrespective of timing of BHI 30 injection

BHI 30

NovoMix® 30

Blo

od

glu

cose

exc

urs

ion

4 h

aft

er

inje

ctio

n (

mm

ol.m

in.l-1

)

0

2000

2200

2400

2600

2800

3000

t = 0 t = –30

Injection time in relation to meal

p < 0.0001

23%

p = 0.013


9%

t = 0

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


23

Comparison of NovoMix® 30, Humalog® Mix25TM 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® Mix25TM immediately before meal, BHI 30 15 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® Mix25TM at meal


24

Reduced glucose excursions vs. Humalog® Mix25TM and BHI 30


p < 0.05

–10%

p < 0.001

–17%

0

13

14

15

16

17

18

19

20

21

Humalog® Mix 25TM NovoMix® 30 BHI 30

Blo

od

glu

cose

exc

urs

ion

0– 5

h (m

mo

l/l h

)

25

Improved postprandial control vs. Humalog® Mix25TM and BHI 30


a NovoMix® 30 significantly less than Humalog® Mix25TM (p < 0.05)

b NovoMix® 30 significantly less than BHI (p < 0.001)

c NovoMix® 30 significantly earlier than BHI (p < 0.05)

d NovoMix® 30 significantly earlier than Humalog® Mix25TM (p < 0.01)

Glucose parameter

EXC0–5h

(mmol/l h)

Cmax

(mmol/l h)

tmax

(min)

NovoMix® 30 16.6 4.4a,b 15.9 2.7c 75.1 22.2c,d

Humalog® Mix25TM

18.9 6.1 16.4 3.2 86.5 26.9

BHI 30 20.1 4.9 16.7 2.6 88.0 26.4

26

Larger and more rapid increasein serum insulin with NovoMix® 30

Insulin parameter

AUC (ins0–5h)

(pmol/l h)

Cmax(ins)

(pmol/l h)

Tmax(ins)

(min)

NovoMix® 30 1079 535a 415 244a 115 59a

Humalog® Mix25TM

1031 621 360 211 100 41

BHI 30 741 426 237 156 169 71

a Values for NovoMix® 30 are significantly different from BHI 30 (p < 0.001)


27

Improved postprandial glucose vs. BHI 30 and Humalog® Mix25TM

• Superior postprandial glucose control to BHI 30 and Humalog® Mix25TM in type 2 patients

• Higher maximum serum insulin with BHI and Humalog® Mix25TM

• Well tolerated with no serious adverse events occurring related to treatment


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


One screening visit; patients already using a twice-daily insulin regimen

29

Improved postprandial glucose after 3 months

*

Blo

od

glu

cose

(m

mo

l/l)

*

0Pre-

10

12

Post-

8

6

NovoMix® 30

BHI 30* p < 0.05*

*

Lunch

Pre- Post-

Breakfast

Pre- Post-

Dinner

Bedtime 0200 h


30

Significantly lower prandial glucose increment with NovoMix® 30

0

0.5

1

1.5

2

2.5

3

NovoMix® 30 BHI 30

Mea

n p

ran

dia

l glu

cose

in

crem

ent

(mm

ol/

l)


p < 0.02 between treatment groups

(n = 128) (n = 141)

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


32

NovoMix® 30 vs. NPHin 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


• NPH monotherapy

33

NovoMix® 30 vs. NPH: lower prandial glucose increment

-0.69

**

-1.33

**

*0.56

-1.26

**-2

-1.5

-1

-0.5

0

0.5

1

Dif

fere

nce

in p

ran

dia

l glu

cose

incr

emen

t b

etw

een

tre

atm

ent

gro

up

s (m

mo

l/l)

Breakfast Lunch Dinner

* p < 0.005

** p < 0.0001Favours NPH

Favours NovoMix® 30

Mean prandial glucose increment


34

Greater HbA1c reduction with NovoMix® 30 vs. NPH

NovoMix® 30(n = 66)

NPH(n = 66)

Ch

ang

e in

Hb

A1c

(%)

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

p = 0.03


35

• Mean prandial glucose increment lower in NovoMix® 30 group (p < 0.0001)

• Patients receiving NPH monotherapy benefit from switching to NovoMix® 30 (bid)

NovoMix® 30 offers better glycaemic control than NPH


36

Superior postprandial control

• Higher plasma insulin levels with NovoMix® 30 vs. BHI 30

• Improved postprandial control vs. BHI 30

• Superior postprandial control vs. Humalog® Mix25TM

• Lower postprandial increment and HbA1c vs. NPH

• No safety concerns

37

Superior hypoglycaemia profile


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


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


One screening visit; patients already using a twice-daily insulin regimen

39

Improved postprandial glucose after 3 months


*

Blo

od

glu

cose

(m

mo

l/l)

*

0Pre-

10

12

Post-

8

6

NovoMix® 30

BHI 30* p < 0.05*

*

Lunch

Pre- Post-

Breakfast

Pre- Post-

Dinner

Bedtime 0200 h

40

Significantly lower prandial glucose increment with NovoMix® 30

0

0.5

1

1.5

2

2.5

3

NovoMix® 30 BHI 30

Mea

n p

ran

dia

l glu

cose

in

crem

ent

(mm

ol/

l)


p < 0.02 between treatment groups

(n = 128) (n = 141)

41

Reduced major hypoglycaemia after 3 months

Nu

mb

er o

f h

ypo

gly

caem

ic e

pis

od

es

0

5

10

15

20

25

30

35

40

45

NovoMix® 30 BHI 30

42 events

20 events

50% relative risk reduction


(n = 138) (n = 153)

42

Trend towards reduced minor nocturnal hypoglycaemic episodes

NovoMix® 30 BHI 30

p = 0.06N

um

ber

of

hyp

og

lyca

emic

ep

iso

des

0

5

10

15

20

25

30

35

40

45

58 events

39 events

55

50

60


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


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 Months0


BiAsp-1069

Reduced major hypoglycaemia after 2 years


0

2

4

6

8

10

12

1st year 2nd year

Year of study

Pa

tie

nts

wit

h a

t le

as

t o

ne

ma

jor

ep

iso

de

(%

)

p = NS

p = 0.04

NovoMix® 30

BHI 30

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


47

NovoMix® 30 vs. BHI 30: 4-year safety in type 2 diabetes


Insulin-using type 2 patients (n = 73)


BHI 30 bid (n = 41)

Months0 24 42 48

48

Twice-daily NovoMix® 30 and BHI 30 gives stable metabolic control


0

7.0

7.5

8.0

8.5

9.0

0 3 6 12 18 24 30 36 42

NovoMix® 30

BHI 30

Hb

A1c

(%

)

Months

49

Hypoglycaemic episodes in patients completing the 4-year trial


NovoMix® 30

(n = 32)

BHI 30

(n = 41)

p-value

People with major episodes

First 2 years 1 7 0.04

Entire period 4 11 0.08

People with nocturnal episodes

Entire period 0 6 0.02

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

Superior HbA1c control with oral medication

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

Kilo C et al. J Diabetes Complications 2003;17(6):30713

Raz I et al. Submitted to Diabetes, Obesity and Metabolism

Raz I et al. Clin Ther 2003;25:31093123

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


52

NovoMix® 30 in combination withmetformin

Weeks

160

NovoMix® 30 bid + metformin (n = 108)


Metformin failures

glibenclamide + metformin (n = 114)

(n = 329)

(HbA1c 7.5–13.0%)


53

Demographic characteristics (total population) NovoMix® 30 NovoMix® 30

+ met

Met

+ SU

No of patients 107 108 114

Mean age (yrs ± SD) 55.2 ± 10.3 56.4 ± 9.0 58.1 ± 8.8

Male/Female 50/57 53/55 52/62

BMI (kg/m2 ± SD) 30.9 ± 4.5 30.4 ± 4.0 30.5 ± 4.4

NovoMix® 30 plus metformin intype 2 diabetes


54

Improved HbA1c with NovoMix® 30 combination in total population


7

7.5

8

8.5

NM NM+met Met+su

Treatment group

Hb

A1c

(%

) fo

llow

ing

16

we

eks'

tr

eam

en

t

p = 0.004

HbA1c difference of 0.6%

0

55

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

p = 0.037 p = 0.033


7

7.5

8

8.5

NM NM+met Met+SU

Treatment group

Hb

A1c

(%

)

0

56

Lower insulin dose when used with metformin

0

1

2

3

4

5

6

7

0 1 2 3 4

0

0.2

0.4

0.6

0 1 2 3 4

Time (months)

No

voM

ix®

30

do

se (

IU/m

g/d

ay) NovoMix® 30 NovoMix® + met

Time (months)

Met + SU


SU

do

se (

mg

/day

)

57

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

p = 0.05

p = 0.0004

0

20

40

60

80

100

120

NovoMix® 30 NovoMix® 30 + met Met + SU

En

d o

f tr

ial

me

an

bo

dy

we

igh

t (

kg

)

* Mean body weights adjusted for baseline

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

58

• 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

NovoMix® 30 plus metformin is well tolerated


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


60

Once-daily (dinnertime) NovoMix® 30 with metformin

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

–4 0 12 14Weeks

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):307-13

Eligible patients: FPG 126 mg/dl

61

Addition of insulin to metformin improves glycaemic control

-1.4

-1.2

-1

NovoMix® 30 NPH BHI 30

Treatment group (+metformin)

Red

uct

ion

in H

bA

1c (

%)


62

Benefits of reaching fasting glycaemic targets with NovoMix® 30

Ch

ang

e in

Hb

A1c f

rom

bas

elin

e (%

)

FPG (mmol/l) 5–8 (n = 54)

Treatment (+metformin)

-3

-2.5

-2

-1.5

-1

-0.5

0NovoMix® 30 NPH BHI 30


63

Fewer nocturnal hypoglycaemic events with NovoMix® 30 combination

NovoMix® 30 NPH BHI 30

Patients (n) 45 46 47

Major events 0 0 0

Symptomatic nocturnal events

9 18 14

Minor nocturnal events

1 6 9

There were no major hypoglycaemic events reported during the study.There were numerically fewer nocturnal hypoglycaemic events in the NovoMix® 30 group


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


65

Addition of second therapy when glibenclamide fails (I)


NovoMix® 30 (BID) + glibenclamide (n = 22)

Metformin (850 mg OD) + glibenclamide (n = 24)

Glibenclamide (7.5–15 mg/day)

Type 2 patients, HbA1c 813%

Weeks0 6

66

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

–1.5

–1.2

GLI+MET GLI+NovoMix® 30

–0.9

–0.6

–0.3

0.0GLI+MET

GLI+NovoMix® 30

* p < 0.05–4.0

–3.5

–3.0

–2.5

–2.0

–1.5

–1.0

–0.5

0.0

Mea

n g

luco

se r

edu

ctio

n (

mm

ol/l

)

Hb

A1c

red

uct

ion

(%

)


67

Addition of second therapy when glibenclamide fails (II)

Type 2 patients, HbA1c (813%)

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;25:3109-3123

Weeks0 6

68

Improved glycaemic control with NovoMix® 30 combination

* p < 0.05

ROS+GLIROS+

NovoMix® 30

–4.0

–3.5

–3.0

–2.5

–2.0

–1.5

–1.0

–0.5

0.0

Mea

n g

luco

se r

edu

ctio

n

(mm

ol/l

)

–1.5

–1.2

ROS+GLIROS+

NovoMix® 30

–0.9

–0.6

–0.3

0.0

Hb

A1c

red

uct

ion

(%

)

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

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)


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

Weeks0 6

70

Reduction in HbA1c after 6 weeks’ treatment

–4.0–3.5–3.0–2.5–2.0–1.5–1.0–0.50.0

MET+GLI

MET+NovoMix® 30

MET+REP+NovoMix® 30

Mea

n g

luco

se r

edu

ctio

n (

mm

ol/l

)

–1.5

–1.2

–0.9

–0.6

–0.3

0.0

MET+GLI

MET+NovoMix® 30

MET+REP+NovoMix® 30

Hb

A1c

red

uct

ion

(%

)


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 HbA1c

• All treatment therapies showed improvements in HbA1c


72

SU mono or combination therapy

(HbA1c 7.513.0%)

Treatment options with NovoMix® 30 when SU therapy fails


0 1 2 4 8 12 18 Time (weeks)

Randomisation(SU therapy discontinued)

Discontinuation of trial product

Screening

NovoMix® (BID)

Glibenclamide (515 mg, OD) +pioglitazone (30 mg OD)

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

73

Lower HbA1c with NovoMix® 30 combination treatment


Hb

A1c

(%

)

7.0

7.5

8.0

8.5

9.0

9.5

10.0

10.5

11.0

Screening Visit 6 End of Trial

NovoMix® 30

NovoMix® 30 + pioglitazone

Glibenclamide + pioglitazone

* *

*p < 0.01

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


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


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

Convenience and flexibility


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® Mix25TM Pen

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

NovoRapid® FlexPen® vs. Humalog® KitTM Pen

Korytkowski M et al. Clin Ther 2003;25(11): in press

FlexPen® vs. vial/syringe with NovoMix® 30

78

Postprandial dosing with NovoMix® 30


NovoMix® 30, +15 min

BHI 30, –15 min

5–21 3–21 3–21 3–21 1–14

Days between visits

Visit 1 2 3 4 5 6 (Screening) (Randomisation) (Follow-up)

NovoMix® 30, 0 min

BHI 30, 0 min

79

Postprandial dosing efficacy with NovoMix® 30

Blo

od

glu

cose

(m

mo

l/l)

6

2

0

–2

–4

4

Time (min)

0 60 120 180 240 300

NovoMix® 30( t= +15 min)

NovoMix® 30(t = 0 min)

BHI 30(t = 0 min)

BHI 30(t = –15 min)


80

Postprandial dosing with NovoMix® 30


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)

2563a 2864 2958 2777

*Cmax (mM)

13.47b 15.28 15.08 14.42

Tmax (median,

min)

75 75 90 90* 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)

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


82

Postprandial NovoMix® 30 dosing in elderly patients


Preprandial dosing

Run-in (n = 91)

0 4 8 12 Weeks

Preprandial dosing

Postprandial dosing

Postprandial dosingNovoMix® 30,

bid, preprandial

83

Blood glucose levels did not differ between treatment groups


Preprandial dosing(NovoMix® 30, bid)

Postprandial dosing(NovoMix® 30, bid)

0

20

40

60

80

100

120

140

160

180

200

Before breakfast

Before dinner

2 hrs after breakfast

2 hrs afterdinner

Blo

od

glu

cose

leve

ls (

mg

/dl)

n = 91

p = NS in all cases

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


85

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

Weeks

–3 24120

NovoMix® 30 FlexPen®


Humalog® Mix25TM Pen

Humalog®

Mix25TM Pen

Run-in (n = 133)

Vora JP et al. Submitted to Diabetes, Obesity and Metabolism

86


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


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

0102030405060708090

100

Overall, which pen device do

you find easiest to use?

Overall, which pen device would

you prefer to continue to use

after this trial?

% o

f p

atie

nts

Equally easy/either


Humalog®

Mix25TM

Equally difficult/neither

* *

* p < 0.001 compared with Humalog® Mix25TM Pen

88

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


89

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


90


Comparison of FlexPen® with Humalog® KitTM

Days

420

FlexPen® FlexPen®

Humalog® KitTM Humalog® KitTM

Run-in (n = 58)

”Device-naïve” patients

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

91

FlexPen® is more user-friendly than Humalog® Kit

Pen feature

** ** * * *

0

50

100

150

200

250

Numberlegibility

Ease of dose setting

Ease of pressingrelease button

Simplicity Injection confirmation

To

tal

sc

ore

FlexPen®

Humalog® Kit


* p < 0.01

** p < 0.001

92

More patients prefer FlexPen® to Humalog® Kit

0102030405060708090

FlexPen® Humalog® Kit No preference

Device preference

Pat

ien

ts (

%)

* p < 0.01


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


94

Comparison of FlexPen® vs vial/syringe

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

Run-in

Type 1 and type 2 patients

(using vial/syringe)

0 4 8 12

Weeks

Randomisation (n = 108)

FlexPen® FlexPen®

Vial/syringe Vial/syringe

95

Patients prefer FlexPen® to vial/syringe

74%*

20%

6% FlexPenVial/syringeNo differenceQ: Overall, which

device would you prefer to continue using?

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


96

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

FlexPen®

Vial/syringe

No preference

0 10 20 30 40 50 60 70 80 90 100

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):2836-48

97

Reduction in HbA1c with NovoMix® 30

* p<0.05

0

6.5

7

7.5

8

8.5

9

9.5

Baseline (week 0) End of trial (week 12)

Time point

Ab

so

lute

Hb

A1

c (

%)


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


99

82% of healthcare professionals preferred FlexPen®

compared with two other prefilled pens

0

20

40

60

80

100

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

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® Mix25TM

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

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, 10-17 yrs

0 2 weeks 16 weeks (Time)

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 : 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

103

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

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):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. 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):2836-48

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

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

Documents

The dual-release insulin preparation Overview of published studies