Premix Analogue VS.

Premix Human Insulin In

Clinical Practice

Dr Ravi Kant

Agenda
Objectives
The pharmacological differences between premixed insulin
analogue and premixed human insulin BHI 30
Efficacy and safety with BIAsp 30 and BHI 30: evidence
from RCT and meta-analysis
Switching from BHI 30 to BIAsp 30
Cost- effectiveness
Case Study

BHI, biphasic human insulin; BIAsp, biphasic insulin aspart

Objectives
To explore the rationale for treating with premix insulin
analogues with focus on:
The difference between premixed insulin analogue and BHI
30
Evidence from clinical practice for BIAsp 30 as a switch
option for individuals on BHI 30

The dual-release insulin concept

Physiological insulin profile
Soluble insulin aspart

Physiological
insulin profile:
Basal component
Meal-related peaks

Rapid-acting
insulin
analogues
together with a
basal insulin
provide
physiological
insulin
replacement

Protamine crystallised
insulin aspart

Analogue mix
insulins such as
BIAsp 30 replace
both
meal-related and
basal insulin

BIAsp 30

Schematic presentation

Garber et al. Diabetes Obes Metab 2007;9:6309

How is BIAsp 30 different from BHI 30?

BIAsp 30
A premixed
suspension of:

BHI 30
A premixed
suspension of:

Soluble insulin aspart

30%

30%

Regular
human insulin

Protamine-crystallised
insulin aspart

70%

70%

NPH insulin

BIAsp 30

BHI 30

BIAsp, biphasic insulin aspart; BHI, biphasic human insulin; NPH, neutral protamine Hagedorn
Novo Nordisk. BIAsp 30 SPC. http://ec.europa.eu/health/documents/community-register/2000/200008013730/anx_3730_en.pdf

Proof of concept: rapid absorption and higher

peak concentration
25

BIAsp 30

***

Serum insulin (mU/L)

BHI 30
20
15
10
5
0
8:00

11:00 14:00 17:00 20:00 23:00

Time
***p<0.0001; n=24
Adapted from Jacobson et al. Eur J Clin Pharm 2000;56:399403

2:00

5:00

8:00

Faster absorption of BIAsp 30 is reflected in

the earlier onset of serum glucose lowering
5.5

BIAsp 30

Serum glucose (mmol/L)

BHI 30
5.0

4.5

4.0

3.5

3.0
08:00 11:00 14:00 17:00 20:00 23:00 02:00 05:00 08:00

Time
Adapted from Jacobson et al. Eur J Clin Pharm 2000;56:399403

Twice-daily BIAsp 30 in patients with

type 2 diabetes: improved PPG control
BIAsp 30

Blood glucose (mmol/L)

20

BHI 30

15

10

0
18:00

22:00

*p<0.05 in favour of BIAsp 30 for lower PPG levels after dinner and breakfast; n=13
PPG, postprandial plasma glucose
Adapted from McSorley et al. Clin Ther 2002;24:5309

Time

08:00

13:00

18:00

Pharmacological profile

Compared with BHI, BIAsp 30 has:

Faster
absorption

Jacobson et al. Eur J Clin Pharm 2000;56:399403

Higher peak
concentration

More rapid
and
pronounced
glucoselowering
effect

Similar
duration of
action of
basal
component

Efficacy and safety with BIAsp 30

and BHI 30: evidence from RCTs and
meta-analysis

RCT, randomised controlled trial.

Long-term comparison of efficacy and safety of

BIAsp 30 vs. BHI 30
BIAsp 30 (n=140)
Insulin-using patients with
type 1 and type 2 diabetes
(n=294)
One screening visit;
patients already using a
twice-daily insulin regimen

BHI 30 (n=151)
Initial period
3 months

Extension period
21 months

BHI, biphasic human insulin; BIAsp, biphasic insulin aspart

Adapted from Boehm et al. Diabet Med 2002;19:39399; Boehm et al. Eur J Intern Med. 2004;15:496-502.

Long-term comparison of efficacy of BIAsp 30

vs. BHI 30
BIAsp 30

BHI 30

8.35

8.13

HbA1c at 24 months (%)

8
7
6
5
4
3
2
1
0

BHI, biphasic human insulin; BIAsp, biphasic insulin aspart; NS, not significant
Boehm et al. Eur J Intern Med. 2004;15:496-502.

24 months

Improved postprandial blood glucose with BIAsp 30 vs. BHI 30

Blood glucose (mmol/L)

12

BIAsp 30

BHI 30

10
*

0
Pre- PostBreakfast

*p<0.05

Pre- PostLunch

Bedtime

02.00 h

After 12 weeks of treatment, levels of HbA1c did not differ

between the two treatment groups
Mean difference: 0.01 (90% CI: 0.14;0.12)

BHI, biphasic human insulin; BIAsp, biphasic insulin aspart; CI, confidence interval
Boehm et al. Diabet Med 2002;19:39399

Pre- PostDinner

Reduced major hypoglycaemia with BIAsp 30

vs. BHI 30
BIAsp 30

p=0.04

BHI 30

Patients with at least one major

hypoglycaemic episode (%)

12

p=NS

10
8
events

8
11
events

6
4
2

3
events

0
events

1st year

BHI, biphasic human insulin; BIAsp, biphasic insulin aspart; NS, not significant
Boehm et al. Eur J Intern Med. 2004;15:496-502.

2nd year

Similar change in HbA1c with premixed human

insulin vs. BIAsp 30
Superior with premix insulin analogues vs. long-acting insulin analogues or non-insulin therapy
Comparison
Long-acting insulin analogue vs.:
All premixed insulin analogues
Insulin aspart 70/30
Insulin lispro 75/25
Insulin lispro 50/50

Studies
Mean difference of change
in HbA1c level (95% CI), % (participants), n
-0.39
-0.48
-0.33
-0.40

(-0.50;-0.28)
(-0.61;-0.34)
(-0.48;-0.17)
(-0.65;-0.15)

11
4
5
3

(3108)
(976)
(1720)
(530)

Premixed human insulin vs.:

All premixed insulin analogues
Insulin aspart 70/30
Insulin lispro 75/25
Insulin lispro 50/50

-0.05
0.06
-0.06
-0.06

(-0.15;-0.04)
(-0.04;0.16)
(-0.26;0.14)
(-0.35;0.23)

9
4
3
3

(2717)
(708)
(1499)
(226)

Noninsulin antidiabetic agents vs.:

All premixed insulin analogues
All premixed insulin analogues
Insulin aspart 70/30
Insulin aspart 70/30
Insulin lispro 75/25
Insulin lispro 50/50

-0.49 (-0.86;-0.12)
-0.55 (-0.94;-0.16)
-0.52 (-1.00;-0.04)
-0.61 (-1.13;-0.10)
-0.42 (-1.00;0.16)
No data

10
9
7
6
3

(2422)
(1921)
(1510)
(1009)
(912)

-1.2 -1 -0.8 -0.6 -0.4 -0.2 0

Favours premixed
analogue

0.2 0.4

Favours
comparator

Pooled results include those of a study that administered insulin lispro 50/50 in the morning and insulin lispro 75/25 in the evening. CI, confidence interval

Adapted from Qayyum et al. Ann Intern Med 2008;149:54959

BIAsp 30 associated with a significantly lower rate

of major hypoglycaemia compared with BHI 30
Trial

Rate ratio (95% CI)

Boehm et al. 2002 (n=187)

0.50 (0.12;1.98), p=0.32

Kilo et al. 2003 (n=93)

0.34 (0.01;8.28), p=0.50

Iwamoto 2003 (n=428)

0.57 (0.16;2.00), p=0.38

1394 (n=292)

0.53 (0.03;8.63), p=0.66

McNally et al. 2007 (n=160)

0.31 (0.06;1.54), p=0.15

3002 bioequivalence trial (n=36)

0.25 (0.01;6.62), p=0.41

Overall

0.45 (0.22;0.93), p<0.05

I2=32%

0.01

0.1
Favours
BIAsp 30

Davidson et al. Clin Ther 2009;31:164151

10

100

Favours
BHI 30

Version June 2014

BIAsp 30 associated with a significantly lower rate

of nocturnal hypoglycaemia compared with BHI 30
Trial

Rate ratio (95% CI)

Boehm et al. 2002 (n=187)

0.57 [0.20;1.58], p=0.28

Kilo et al. 2003 (n=93)

0.89 [0.25;3.16], p=0.86

1234 (n=180)

0.44 [0.22;0.89], p=0.02

Iwamoto 2003 (n=428)

1.03 [0.42;2.53], p=0.95

1394 (n=292)

1.03 [0.38;2.76], p=0.96

McNally et al. 2007 (n=160)

0.33 [0.21;0.51], p<0.01

1536 (n=195)

0.44 [0.11;1.47], p=0.17

Bioequivalence trial (n=36)

1.05 [0.11;10.09], p=0.97

3006 (n=103)

2.43 [0.31;18.90], p=0.39

Overall
I2=32%

0.50 [0.38;0.67], p<0.01

0.1 0.2
Favours
BIAsp 30

Davidson et al. Clin Ther 2009;31:164151

10 20
Favours
BHI 30

Version June 2014

Switching from BHI 30 to BIAsp 30

BHI, biphasic human insulin; BIAsp, biphasic insulin aspart

Real-life switching from BHI 30 to BIAsp 30:

HbA1c
IMPROVE2

0.0
-0.5

-2.21*

-2.13*

-2.24*

HbA1c change after

6 months (%)

HbA1c change after

6 months (%)

PRESENT1
Overall population
-2.27*

-1.6

-1.0
-1.5
-2.0

Baseline value 9.3%

0.0
-0.5

-1.8***

-1.8***

-1.6***

-1.0
-1.5
-2.0

Baseline value 9.2%

HbA1c change after

6 months (%)

A1chieve3
0.0
-0.5

-1.9**
-1.7**

-1.0
-1.5
-2.0

Baseline value 9.1%

*p<0.05 for all comparisons vs. baseline; **p<0.001; ***p<0.0001. BIAsp, biphasic insulin aspart; BHI, biphasic human insulin
1. Shestakova et al. Curr Med Res Opin 2007;23:320914; 2. Shah et al. Int J Clin Pract 2009;63:57482; 3. El Naggar et al. Diabetes Res Clin Pract 2012;98:40813

Real-life switching from BHI 30 to BIAsp 30:

FPG
IMPROVE2

0.0
-0.5
-1.0
-1.5
-2.0
-2.5
-3.0
-3.5

-2.21*

-2.13*

-2.24*

FPG change after

6 months (mmol/L)

FPG change after

6 months (mmol/L)

PRESENT1
Overall population
-2.27*

-2.92

Baseline value 11.0 (mmol/L)

0.0
-1.0

-1.8***
-3.48**

-1.6***

-2.0
-3.0
-4.0

Baseline value 10.3 (mmol/L)

FPG change after

6 months (mmol/L)

A1chieve3
0.0
-0.5
-1.0
-1.5
-2.0
-2.5
-3.0
-3.5

-1.9**
-3.0**

Baseline value 10.2 (mmol/L)

**p<0.001; BIAsp, biphasic insulin aspart; BHI, biphasic human insulin

1. Shestakova et al. Curr Med Res Opin 2007;23:320914; 2. Shah et al. Int J Clin Pract 2009;63:57482; 3. El Naggar et al. Diabetes Res Clin Pract 2012;98:40813

Real-life switching from BHI 30 to BIAsp 30:

PPG
IMPROVE2
PPG change after
6 months (mmol/L)

PPG change after

6 months (mmol/L)

PRESENT1
Overall population
0.0
-1.0

-2.21*

-2.13*

-2.24*

-2.27*

-4.75

-2.0
-3.0
-4.0
-5.0

Baseline value 15.3 (mmol/L)

0.0
-1.0
-2.0

-1.8***
-5.48**

-1.6***

-3.0
-4.0
-5.0
-6.0

Baseline value 14.9 (mmol/L)

PPG change after

6 months (mmol/L)

A1chieve3
0.0
-1.0

-1.9**
-4.3**

-2.0
-3.0
-4.0
-5.0

Baseline value 14.2 (mmol/L)

**p<0.001; BIAsp, biphasic insulin aspart; BHI, biphasic human insulin

1. Shestakova et al. Curr Med Res Opin 2007;23:320914; 2. Shah et al. Int J Clin Pract 2009;63:57482; 3. El Naggar et al. Diabetes Res Clin Pract 2012;98:40813

Real-life switching from BHI 30 to BIAsp 30:

Minor hypoglycaemia rates
IMPROVE2

-2.21*

-2.13*

-2.24*

Hypoglycaemia rate
change after
6 months
(events/patient/year)

0.0
-1.0
-2.0
-3.0
-4.0
-5.0
-6.0
-7.0

-2.27*

-6.0

Baseline value 8.2

(events/patient/year)

Hypoglycaemia rate
change after
6 months
(events/patient/year)

Hypoglycaemia rate
change after
6 months
(events/patient/year)

PRESENT1
Overall population

0.0
-1.0
-2.0

-1.8***
-5.7

-1.6***

-3.0
-4.0
-5.0
-6.0
Baseline value 7.7
(events/patient/year)

A1chieve3
0.0
-0.5
-1.0
-1.5
-2.0
-2.5
-3.0
-3.5

-1.9**
-3.1

Baseline value 5.3

(events/patient/year)

BIAsp, biphasic insulin aspart; BHI, biphasic human insulin

1. Shestakova et al. Curr Med Res Opin 2007;23:320914; 2. Shah et al. Int J Clin Pract 2009;63:57482; 3. El Naggar et al. Diabetes Res Clin Pract 2012;98:40813

A1chieve: quality of life following switch from

BHI 30 to BIAsp 30
Improvement
12.5 points
Week 24
76.5
(SD 11.9)

Baseline
64.0
(SD 16.3)

10

20

30

Worst

40

50

60

70

90

100

Best
Visual analogue scale
0 = worst imaginable health state
100 = best imaginable health state

BIAsp, biphasic insulin aspart; BHI, biphasic human insulin; SD, standard deviation
El Naggar et al. Diabetes Res Clin Pract 2012;98:40813

80

Cost-effectiveness of switching from

BHI 30 to BIAsp 30

BHI, biphasic human insulin; BIAsp, biphasic insulin aspart

Switching from therapy with BHI 30 or insulin glargine

OADs to BIAsp 30 OADs improves life expectancy
Increase in life
expectancy (years)

Change in life expectancy following change from

therapy with BHI 30 or insulin glargine OADs to
BIAsp 30 OADs

1.5
1.0
0.5
0

0.7

0.9

1.2

0.9
Saudi Arabia

Decrease in life
expectancy (years)

India

Indonesia

Saudi Arabia

India

0.5
1.0

1.7

1.5
BHI 30 OADs to BIAsp 30 OADs

Simulated over 30 years

OAD, oral antidiabetic drug

Gupta et al. J Med Econ 2015;18:26372

Insulin glargine OADs

to BIAsp 30 OADs

Reduction in incidence
(% people)

Switching from BHI 30 to BIAsp 30: incidence of

complications (CORE Diabetes Model simulation)
0.0

Severe vision loss

-2.6

End-stage renal disease

Myocardial infarction

-1.4

-1.9

-5.0

-4.4

-7.5

-3.8
-5.1

-5.7

-6.2

-7.8

-10.0
India (n=866)

Indonesia (n=175)

BHI, biphasic human insulin; BIAsp, biphasic insulin aspart; CORE, The Centre of Outcomes Research
Gupta et al. J Med Econ 2015;18(4):26372

Ulcer

Saudi Arabia (n=401)

-0.8 -0.6

Switching from BHI 30 to BIAsp 30 results in a

projected delay in onset of complications
44.6

56.3

Any
complication

44.6

56.1

65.1

Myocardial
infarction

64.2

Age at diagnosis

BHI, biphasic human insulin; BIAsp, biphasic insulin aspart;

Gupta et al. J Med Econ 2015;18(4):26372

66.8

66.9

Ulcer

66.2

Severe vision
loss

65.9

Macrovascular complications

67.2

67.3

End-stage
renal disease

66.4

Death

66.6

Microvascular complications

General
population
74.9

Switching from BHI 30 to BIAsp 30: sensitivity

analyses show cost-effectiveness to be robust
1-year analyses

0.44

Base effect

2.92

0.17

30-year analyses

0.26

Base effect

1.25

0.01
0.28

Median treatment effect (HbA1c)

1.29

0.03
0.28

No HbA1c deterioration

1.24

0.02
0.27

50-year time horizon

1.23

0.01
0

0.5

1.5

Saudi Arabia

2
Indonesia

BHI, biphasic human insulin; BIAsp, biphasic insulin aspart; CORE, The Centre of Outcomes Research
Gupta et al. J Med Econ 2015;18(4):26372

2.5
India

3.5

Case Study

Case Study
Mr Omkar

Age: 52
Diagnosis: type 2 diabetes since 2008
Current employment: Shopkeeper
HbA1c: 7.9%

Weight: 77 kg
Height: 1.61 m
BMI: 29.7 kg/m2
Diabetes treatment: human premix insulin 25 for 2 years (9 kg weight gain since start of insulin
treatment), metformin, sitagliptin
Medical history: asthma (inhaled steroids), symptomatic hypoglycaemia nearly every day during his
morning work
Lifestyle: occasional alcohol intake; stressful job; early morning starts

Case Study

Mr Omkar
Blood glucose profile 1
Human premix insulin 30, 28-0-16 IU
JanuMet 50/1000 bid

bid, twice daily

Case Study
Interactive question

Case Study
Mr Omkar
Blood glucose profile 2

Switched to:
Prandial insulin 188-10
Basal insulin 0-0-012
Still experiencing
minor hypoglycaemic
events before noon;
Has to snack every day

In the evening (4 weeks later) he consumes alcohol, and his wife has to call the emergency ambulance
during the night due to severe hypoglycaemia. It is totally unclear what insulin he had injected and
when.

What is the cause of the severe hypoglycaemia?

NPH, neutral protamine Hagedorn; RHI, regular human insulin

Case Study
Mr Omkar
Blood glucose profile 3

We change the regimen to insulin BIAsp 30 14-0-14 IU. In the following weeks the dose is
titrated to 16-0-18 IU

Case Study
How did Mr Omkar fare?

Thanks for patient hearing