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
Combination with oral medications 5176
Convenience & flexibility 7794
Use in adolescents 9596
Insulin aspart – a rapid acting analogue

Brange J et al. Nature Clinical proof of concept

1988;333:679–682 study for insulin aspart

Return to contents slide

Insulin aspart: preclinical proof-
of-concept
4.5

IRI (10-10 M)
Insulin aspart
3.0 Human insulin

1.5

0
Plasma glucose (mM)

Injection
2
0 1 2 3 4 5 hours

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

Dual-release kinetics

Jacobsen L et al. Eur J PK studies in healthy

Clin Pharm 2000;56: volunteers
399–403
Weyer C et al. Diabetes PD studies in healthy
Care 1997;10:1612–1614 volunteers

Return to contents slide

The dual-release insulin concept
• Physiological insulin profile:
basal component
meal-related peaks

• 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
• Physiological insulin profile:
basal component
meal-related peaks

• Rapid-acting insulin analogues

together with a basal insulin provide
physiological insulin replacement

• Analogue premixes such as

NovoMix® 30 replace both meal-
related and basal insulin
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
 NovoMix® 30:
PK/PD studies in healthy volunteers

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

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
25 *** BHI 30

20 ***p < 0.0001

Serum insulin (mU/l)

n = 24

15

10

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
Glucose infusion rate (mg/kg/min)

NovoMix® 30
10 BHI 30 (Actraphane)

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
Improved postprandial glycaemic control

McSorley PT et al. ClinTher Meal study in type 2 patients vs.

2002;24(4):530–539
Hermansen K et al. Metabolism
2002;51(7):896–900
Hermansen K et al. Diabetes Care Comparison vs. BHI 30 and lispro
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
BHI 30
Comparison vs. BHI 30 in type 1
patients
mix 25 in type 2 patients
Comparison vs. BHI 30 in type 1
and type 2 patients
Comparison vs. NPH in type 2
patients

Return to contents slide

 Twice-daily NovoMix® 30 in
patients with type 2 diabetes

Screening
visit (n = 13) NovoMix® 30 ®
Follow-up
NovoMix 30

BHI 30 BHI 30

–3 to14 +3 to 7
days days

0 2 4
Weeks

McSorley PT et al. Clin Ther 2002;24(4):530–539

 NovoMix® 30 is rapidly absorbed

* * NovoMix® 30
120
Biphasic human insulin
Total serum insulin (mU/l)

100 n = 13
* p < 0.05 in favour of NovoMix® 30 for
80 mean serum insulin level and insulin
Cmax after dinner and breakfast

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
20 Biphasic human insulin

* * n = 13
Blood glucose (mmol/l)

15

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

Type 1 diabetes:
single dose crossover

NovoMix® 30 at meal

Screening BHI 30 at meal Follow-up

(n = 50)

BHI 30 at –30 minutes

Study day 1 Study day 2 Study day 3

3–21 days 5–21 days 5–21 days 7–14 days

Hermansen K et al. Metabolism 2002;51(7):896–900

Reduced glucose exposure in
type 1 patients after a meal

NovoMix® 30 ( t = 0)
BHI 30 (t = 0)
20
Max glucose concn
* BHI 30 (t = –30)
15% lower at t = 0
Blood glucose (mmol/l)

15 * p < 0.001
n = 50

10

5 * 23% lower glucose

Max glucose conc n
exposure *
20 min earlier than BHI at t = 0
0
–30 0 30 60 90 120 150 180 210 240
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

Blood glucose excursion 4 h after

3000
BHI 30
2800
injection (mmol.min.l-1)

23% 9% NovoMix® 30
2600

2400

2200

2000

0
t=0 t=0 t = –30

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

Humalog®
Mix25TM at meal
(n = 45)

BHI 30 at –15 min

• 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)

Hermansen K et al. Diabetes Care 2002;25:883–888

 Reduced glucose excursions vs.
Humalog® Mix25TM and BHI 30

p < 0.001
Blood glucose excursion0– 5h(mmol/l h)

21
p < 0.05 –17%
20
19 –10%

18
17
16
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

Glucose parameter
EXC0–5h Cmax tmax
(mmol/l h) (mmol/l h) (min)
NovoMix® 30 16.6  4.4a,b 15.9  2.7c 75.1  22.2c,d

Humalog® 18.9  6.1 16.4  3.2 86.5  26.9

Mix25TM
BHI 30 20.1  4.9 16.7  2.6 88.0  26.4

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

Insulin parameter

AUC (ins0–5h) Cmax(ins) Tmax(ins)

(pmol/l h) (pmol/l h) (min)
NovoMix® 30 1079  535a 415  244a 115  59a

Humalog® 1031  621 360  211 100  41

Mix25TM
BHI 30 741  426 237  156 169  71

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

Hermansen K et al. Diabetes Care 2002;25:883–888

 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
*
Blood glucose (mmol/l)

10 *

8
*

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
p < 0.02 between treatment groups
Mean prandial glucose increment

2.5

2
(mmol/l)

1.5

0.5

0
NovoMix® 30 BHI 30
(n = 128) (n = 141)

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. NPH
in type 2 patients

• OHA only Twice-daily NovoMix® 30

• NPH + OHA (n = 201)
• NPH monotherapy
• No treatment Original treatment

Twice-daily NPH insulin

(n = 202)

7–14 days 16 weeks 2 weeks

Screening Randomisation

Christiansen JS et al. Diabetes, Obesity & Metabolism 2003;5(6):445-452

 NovoMix® 30 vs. NPH: lower
prandial glucose increment
*
Difference in prandial glucose increment

1
0.56 *
between treatment groups (mmol/l)

p < 0.005
0.5 ** p < 0.0001
Favours NPH

-0.5
Favours
NovoMix® 30
-1 -0.69
**
-1.5
-1.26 -1.33 Mean prandial
** ** glucose increment
-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 NPH
(n = 66) (n = 66)
0.0

-0.2
Change in HbA1c (%)

-0.4

-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
Superior hypoglycaemia profile

Boehm B et al. Diabet Med Safety comparison vs. BHI 30 in

2002;19(5):393–399 type 1 and type 2 patients

2-year safety data in type 2 patients

Boehm et al. Submitted to Eur
vs. BHI 30
J Int Med

4-year safety data in type 2 patients

Boehm B et al. Diabetologia
vs. BHI 30
2003;46(Suppl 2):A269

Return to contents slide

 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
*
Blood glucose (mmol/l)

10 *

8
*

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
p < 0.02 between treatment groups
Mean prandial glucose increment

2.5

2
(mmol/l)

1.5

0.5

0
NovoMix® 30 BHI 30
(n = 128) (n = 141)

Boehm B et al. Diabet Med 2002;19(5):393–399

 Reduced major hypoglycaemia
after 3 months

50% relative
45 risk reduction
40
hypoglycaemic episodes

35
30
Number of

25 42
20 events
15
20
10
events
5
0
NovoMix® 30 BHI 30
(n = 138) (n = 153)
Boehm B et al. Diabet Med 2002;19(5):393–399
Trend towards reduced minor
nocturnal hypoglycaemic episodes
p = 0.06
60
55
50
hypoglycaemic episodes

45
40
Number of

35
30
58
25 events
20 39
15 events
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
12 p = 0.04
Patients with at least one major

p = NS NovoMix® 30
10
BHI 30
8
episode (%)

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

9.0 BHI 30

8.5
HbA1c (%)

8.0

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

NovoMix® 30 BHI 30 p-value

(n = 32) (n = 41)
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

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
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):30713
Raz I et al. Submitted to Diabetes, Obesity
and Metabolism
Raz I et al. Clin Ther 2003;25:31093123
Raz I et al. Manuscript in preparation
Raz I et al. Diabetologia 2003;46(Suppl
2):A8
Return to contents slide
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
 NovoMix® 30 in combination with
metformin
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
NovoMix® 30 plus metformin in
type 2 diabetes
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

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

 Improved HbA1c with NovoMix®
30 combination in total
population
8.5 p = 0.004
HbA 1c (%) following 16 weeks'

HbA1c difference
8
of 0.6%
treament

7.5

0
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 (HbA1c > 9%)
8.5
p = 0.037 p = 0.033

8
HbA 1c (%)

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
NovoMix® 30 NovoMix® + met
NovoMix® 30 dose (IU/mg/day)

Met + SU
0.6 7
6

SU dose (mg/day)
5
0.4
4
3
0.2
2
1
0 0
0 1 2 3 4 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 = 0.0004

120 p = 0.05

100
End of trial mean body

80
weight (kg)

60

40
* Mean body
20 weights
adjusted for
0 baseline
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 + 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
• 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 = 45)

Run-in period –
metformin (up to
2550 mg/day)
Metformin + human insulin NPH od (n = 47) Follow-up

Metformin + BHI 30 od (n = 46)

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

Treatment group (+metformin)

NovoMix® 30 NPH BHI 30
-1
(%) 1c
Reduction in HbA

-1.2

-1.4

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

 Benefits of reaching fasting
glycaemic targets with NovoMix® 30

FPG (mmol/l) 5–8 (n = 54)

Treatment (+metformin)
Change in HbA1c from baseline (%)

NovoMix® 30 NPH BHI 30

0

-0.5
-1

-1.5
-2

-2.5
-3

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

 Fewer nocturnal hypoglycaemic
events with NovoMix® 30 combination

NovoMix® 30 NPH BHI 30

Patients (n) 45 46 47

Major events 0 0 0

Symptomatic
9 18 14
nocturnal events
Minor nocturnal
1 6 9
events

There were no major hypoglycaemic events reported during the study.

There were numerically fewer nocturnal hypoglycaemic events in the
NovoMix® 30 group

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

 Once-daily (dinnertime)
NovoMix® 30 with metformin is
effective and well tolerated
• With metformin non-responders, starting NovoMix® 30
once-daily and continuing metformin is effective and well
tolerated.
• Reaching FPG target with NovoMix® 30 plus metformin
achieves greater benefits than NPH or BHI 30 groups
• Less nocturnal hypoglycaemic events occurred in the
NovoMix® 30 combination group compared to NPH or BHI
30 groups

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

 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)

0 Weeks 6

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

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

GLI+ GLI+
GLI+MET NovoMix® 30 GLI+MET
NovoMix® 30
0.0 0.0
Mean glucose reduction

–0.5

HbA1c reduction (%)

–0.3
–1.0
(mmol/l)

–1.5 –0.6
–2.0
–2.5 –0.9
–3.0
–1.2
–3.5 * p < 0.05
–4.0 –1.5

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

 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+ ROS+
ROS+GLI NovoMix® 30 ROS+GLI
0.0 NovoMix® 30
0.0
Mean glucose reduction

–0.5

HbA1c reduction (%)

–0.3
–1.0
(mmol/l)

–1.5
–0.6
–2.0
–2.5 –0.9
–3.0
–3.5 –1.2
–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 NovoMix® 30 (BID) + repaglinide 1 mg (OD)

(1700–2550 mg) + 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+ MET+
MET+ MET+ REP+ MET+
MET+ REP+
GLI NovoMix 30 NovoMix® 30
®
NovoMix ®
30
Mean glucose reduction

GLI NovoMix® 30
0.0 0.0

HbA1c reduction (%)

–0.5
–1.0 –0.3
(mmol/l)

–1.5 –0.6
–2.0
–2.5 –0.9
–3.0 –1.2
–3.5
–4.0 –1.5

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 NovoMix® (BID)

(HbA1c 7.513.0%)
Glibenclamide (515 mg, OD) +
pioglitazone (30 mg OD)

0 1 2 4 8 12 18
Time (weeks)

Screening Randomisation Discontinuation of

(SU therapy trial product
discontinued)

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

10.0 Glibenclamide + pioglitazone

HbA1c (%)

9.5

9.0 * *

8.5

8.0

7.5
*p < 0.01
7.0
Screening Visit 6 End of Trial

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
Convenience and flexibility
Kapitza C et al. In press Diabet Postprandial dosing vs. BHI 30
Med

Warren et al. Submitted to Diabet Postprandial dosing vs. BHI 30 in

Res Clin Prac the elderly

Vora JP et al. Diabetologia NovoMix® 30 FlexPen® vs.

2002;45(Suppl 2):A255 Humalog® Mix25TM Pen

Asakura T & Seino H Diabetes NovoRapid® FlexPen® vs.

Metab 2003;29:4S236 Humalog® KitTM Pen

Korytkowski M et al. Clin Ther FlexPen® vs. vial/syringe with

2003;25(11): in press NovoMix® 30

Return to contents slide

 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
5–21 3–21 3–21 3–21 1–14
between
visits

Kapitza C et al. In press Diabet Med

 Postprandial dosing efficacy
with NovoMix® 30
BHI 30(t = –15 min)
6
BHI 30(t = 0 min)
NovoMix® 30(t = 0 min)
Blood glucose (mmol/l)

4
NovoMix® 30( t= +15 min)
2

–2

–4
0 60 120 180 240 300
Time (min)

Kapitza C et al. In press Diabet Med

 Postprandial dosing with
NovoMix® 30
NovoMix® 30 NovoMix® 30 BHI 30 BHI 30
(t = 0 min) (t = +15 min) (t = –15 min) (t = 0 min)

*AUC (0–240mins) 2563a 2864 2958 2777

(mM/min)
*Cmax 13.47b 15.28 15.08 14.42
(mM)
Tmax (median, 75 75 90 90
min)
* 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. In press Diabet Med

 NovoMix® 30 allows flexible
dosing

• Superior postprandial blood glucose control compared with

either of BHI 30 injection regimens
• Comparable postprandial blood glucose control when
injected after meal to BHI 30 (either injection regimen)
• Gives advantage of increased flexibility in injection timing
• Opportunity to alter insulin dose according to meal size and
composition

Kapitza C et al. In press Diabet Med

 Postprandial NovoMix® 30
dosing in elderly patients

Run-in Preprandial Preprandial

(n = 91) dosing dosing
Postprandial Postprandial
NovoMix 30,
®
dosing
dosing
bid,
preprandial

0 4 8 12 Weeks

Warren et al. Submitted to Diabet Res Clin Prac

 Blood glucose levels did not
differ between treatment groups
200
Preprandial dosing
180 (NovoMix® 30, bid)
Blood glucose levels (mg/dl)

Postprandial dosing
160 (NovoMix® 30, bid)
140

120 n = 91

100 p = NS in all cases

80

60
40

20
0
Before Before 2 hrs after 2 hrs after
breakfast dinner breakfast dinner
Warren et al. Submitted to Diabet Res Clin Prac
 Postprandial NovoMix® 30 is effective
in elderly type 2 patients

• Postprandial NovoMix® 30 offers acceptable alternative to

standard preprandial injections
• No significant difference in hypoglycaemic episodes
between treatment groups
• Postprandial injections appear to be well tolerated

Warren et al. Submitted to Diabet Res Clin Prac

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

Run-in
NovoMix® 30 NovoMix® 30
(n = 133)
FlexPen® FlexPen®
Humalog® Humalog®
Mix25TM Pen Mix25TM Pen

–3 0 12 24

Weeks

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

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

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

 NovoMix® 30 FlexPen® is preferred
over Humalog® Mix25TM Pen
Equally easy/ NovoMix® 30 Humalog® Equally difficult/
100 either FlexPen® Mix25TM neither
90
80 * *
70
% of patients

60
50
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

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

 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

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

 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

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

 Comparison of FlexPen® with
Humalog® KitTM

”Device-naïve” patients
Run-in
FlexPen® FlexPen®
(n = 58)

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®

200 Humalog® Kit

150 * p < 0.01

Total score

** p < 0.001
100

50

0
Number Ease of Ease of Simplicity Injection
legibility dose setting pressing confirmation
release
button

Pen feature

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

 More patients prefer FlexPen®
to Humalog® Kit

* p < 0.01
90
80
70
Patients (%)

60
50
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
FlexPen® FlexPen®
Type 1 and
type 2
patients
(using
vial/syringe)

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 % No difference
device would
you prefer to
continue using?

* Significantly more patients

(p<0.05) preferred to continue
74%*
using FlexPen® vs. vial/syringe

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

Confidence in FlexPen®
setting dose
Vial/syringe
Confidence in
No preference
injecting correct dose

Injection More discreet in public

parameters
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 HbA1c
with NovoMix® 30

9.5 * p<0.05

9
Absolute HbA 1c (%)

8.5

7.5

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

20 14%
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® to Humalog® 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)
(n = male 37
female 49)

Type 1 patients,
10-17 yrs
HI + BHI
(n = male 43
female 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
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