- An observational study in Indonesia examined the use of premixed insulin aspart 30 (BiAsp 30) in addition to oral antidiabetic drugs for the treatment of type 2 diabetes in real-world clinical practice. The study found that treatment with BiAsp 30 significantly reduced HbA1c, fasting plasma glucose, and postprandial glucose levels over 24 weeks with a low rate of hypoglycemia. The results demonstrate the effectiveness and safety of BiAsp 30 intensification in routine care of type 2 diabetes patients in Indonesia.

1. Slide no 1
Riwayat Hidup :
•
•
•
•
•
Nama
: Dr Eddy Supriadi, Sp.PD, FINASIM
Tempat/ Tgl. Lahir : Jakarta, 19 Feb 1968
Pendidikan
: Dokter, FKUI 1993, Penyakit Dalam FKUI 2006
Tempat Kerja
: RS Dr H. MARZOEKI MAHDI KOTA BOGOR
Pengalaman
:
- Inspire Diabetes Program. PERKENI Indonesia-STENO Denmark.
Jakarta 2013.
- Workshop and Symposium on the Diabetic Foot. Noordwijkerhout,
The Netherlands, 2011
- dll.

2. Insulin intensification : the usage of premixed insulin after basal fails
EDDY SUPRIADI, MD.
MARZOEKI MAHDI , MD. HOSPITAL.
BOGOR

3. Outlines
Presentation structure
• What recent guideline say
• Addresing post prandial glucose excursion
• Minimising hypoglycaemia
• A1chieve observational study: real life experience including Indonesia
• Insulin Intensification : how simple ?
• Conclusion

4. Background
•
Type 2 diabetes progression is characterised by a decline in ß-cell
function and worsening insulin resistance1
•
Within 1 year, the majority of basal insulin patients will need another
insulin to reach target2
The ADA/EASD have found that basal plus two or more
bolus injections is a highly complex regimen3
•
Premix Insulin offer a simple intensification of one insulin in one device4
1. Fonseca. Br J Diab Vasc Dis 2008;8(Suppl 2):S3; 2. Holman et al. N Engl J Med 2007;357:1716–30; 3. Inzucchi et al. Diabetologia 2012;55:1577–96.. 4. Garber AJ, et al. Diabetes, Obesity and Metabolism, 8, 2006, 58–66
4

5. Slide 5
Type 2 diabetes is a progressive disease
HOMA: homeostasis model assessment
Lebovitz. Diabetes Reviews 1999;7:139–53 (data are from the UKPDS population: UKPDS 16. Diabetes 1995;44:1249–58)

6. ADA/EASD Position on Sequential Insulin Strategy in Type 2 Diabetes
Non-Insulin
Regimes
Number of
Injections
Regimen
Complexity
Basal Insulin Only
Usually with OAD
1
Low
2
Mod.
+3
High
Basal Insulin + 1 mealtime
rapid-acting injection
Pre-mixed Insulin
twice-daily
Basal Insulin + >2 mealtime
rapid-acting injection
More Flexible
Less Flexible
Less Convenient
More Convenient
Inzucci SE, et al. Diabetologia. 2012. * Gumprecht et al. Intensification to to biphasic insulin
aspart 30/70. Int J Clin Pract 2009
Flexibility
Convenience*

7. 7
IDF recommends premix or basal insulin at start
and intensification
Lifestyle measures
If not at target (generally HbA1c <7%)
First line
Second line
Third line:
insulin start
Fourth line:
insulin intensification
• Metformin
• Sulphonylurea
• Premix insulin
• Premix insulin
•
•
•
•
Standard
approach
Alternative
approach
• Sulphonylurea
• a-glucosidase
inhibitor
• Metformin
• a-glucosidase
inhibitor
• DPP-4 inhibitor
• Thiazolidinedione
Basal insulin
• Basal insulin
a-glucosidase inhibitor • Basal-bolus insulin
DPP-4 inhibitor
Thiazolidinedione
• GLP-1 agonist
1. Adapted from the IDF Treatment algorithm for people with type 2 diabetes. Accessed at: http://www.idf.org/treatment-algorithm-people-type-2-diabetes (accessed May 2012)
APROM ID# 5069 approval date: May 2013
treatments that can
help to address PPG
are included at every
stage of the IDF
treatment algorithm1

8. Outlines
Presentation structure
• What recent guideline say
• Addresing post prandial glucose excursion
• Minimising hypoglycaemia
• A1chieve observational study: real life experience including Indonesia
• Insulin Intensification : how simple ?
• Conclusion

9. Treatment therapies for Type 2 diabetes:
Achieving HbA1c < 7%
Premixed
Insulin
Lifestyle +
Metformin
+-other OAD
or GLP-1
agonists
Basal
Insulin
(Once-daily
treat-totarget)
HbA1c ≥7.0%
(Twice daily
Treat to
target)
Basal
Insulin
(Basal + 3
prandial)
Basal
Insulin
(Basal + 1 or
2 prandial)
HbA1c ≥7.0%, FPG on target, PPG ≥160 mg/dl
Adapted from Raccah et al. Diabetes Metab Res Rev 2007;23:257.

10. 10
Every 1% drop in HbA1c can reduce long-term diabetes
complications1
14%
37%
21%
Myocardial
infarction*
Microvascular
complications*
*p<0.0001. 1. Adapted from Stratton et al. BMJ 2000;321:405–12 (UKPDS 35)
Deaths related
to diabetes*

11. Slide 11
The benefits of good blood glucose control are
clear
Myocardial
infarction
Good control is ≤ 7.0%
HbA1c
HbA1c measures the
average
blood glucose level
over the
last three months
-14%
HbA1c
-1%
Microvascular
complications
-37%
Deaths related
to diabetes
-21%
Source: UKPDS = United Kingdom Prospective Diabetes Study. Stratton IM et al. BMJ.
2000;321(7258):405-412.

12. Yet good glycaemic control is not achieved
HbA1c (%)
10.0
12.4% have HbA1c>10.0 %
9.5
9.0
20.2% have HbA1c>9.0 %
8.5
8.0
64.2% of patients
with type 2 diabetes
have HbA1c≥7.0 %
37.2% have HbA1c>8.0 %
7.5
7.0
6.5
6.0
5.5
Adapted from Unger et al. Am J Med 2008;121:S3–S8.

13. 13
Relative contribution to
overall hyperglycaemia
(%)
PPG control is vital to achieving HbA1c targets1
100
80
PPG has an
60
40
20
0
<7.3
7.3–8.4
8.5–9.2
9.3–10.2
HbA1c quintiles
FPG
PPG
1. Adapted from Monnier et al. Diabetes Care 2003;26:881–5
APROM ID# 5069 approval date: May 2013
>10.2
to overall
hyperglycaemia
as patients
approach HbA1c
targets1

14. 14
Patients spend 50% of their day in the postprandial state1
MIDNIGHT
Evening meal
4h
Fasting state
6 PM
6 AM
Postprandial state
4h
Breakfast
Lunch
MID-DAY
1. Adapted from Monnier. Eur J Clin Invest 2000;30(Suppl. 2):3–11
4h

15. Is postprandial hyperglycaemia harmful?
IDF Recommendation:
Postprandial hyperglycaemia is harmful, and should be addressed
• Postprandial hyperglycaemia are independent risk factors for
macrovascular disease
• Postprandial hyperglycaemia is associated with:
• Increased risk of retinopathy, increased CIMT, decreased
myocardial blood volume/blood flow, increased risk of cancer,
impaired cognitive function in the elderly
• Postprandial hyperglycaemia causes oxidative stress,
inflammation and endothelial dysfunction

16. 16
The dual-release insulin concept: Premix Insulin
targets both FPG and PPG1
Physiological insulin
profile:
Basal component
Basal insulin
Meal-related peaks
BiAsp 30
Plasma insulin level
•
•
Physiological insulin profile
Time
Adapted from Garber2
1. Garber et al. Diabetes Obes Metab 2006;8:58–66; 2. Garber et al. Diabetes Obes Metab 2007;9:630–9
APROM ID# 5069 approval date: May 2013

17. 17
The IMPROVE™ study - reduced FPG and PPG with BiAsp 301
1
Blood glucose
(mmol/L)
1
14
12
10
8
6
4
2
0
12.6
10.9
7.9
6.6
Pre-breakfast FPG
Post-dinner PPG
Baseline
Week 26
*p<0.001
1. Adapted from Valensi et al. Int J Clin Pract 2009;63:522–31
APROM ID# 5069 approval date: May 2013
FPG and PPG
from baseline
at Week 26
following
initiation or
switch to BiAsp
301

18. INITiation of Insulin to reach A1c TargEt
(INITIATE): BIAsp 30 (BID) vs. glargine (OD)
Insulin glargine OD (12 U, bedtime) + metformin ± pioglitazone
n=233
Type 2 diabetes
BMI <40 kg/m2
Body weight <125 kg
HbA1c >8%
on metformin ± TZD
BIAsp 30, pre-breakfast (6 U) and pre-dinner (6 U) + metformin ± pioglitazone
4-week run-in:
Stop insulin secretagogues (SUs, nateglinide, repaglinide)
and -glucosidase inhibitors (acarbose)
Optimise metformin to ≥1500 mg/day
Switch rosiglitazone for 30 mg pioglitazone
–4
0
28
Time (weeks)
Raskin et al. Diabetes Care 2005;28(2):260–5
SUs, sulphonylureas

19. INITIATE: significantly more patients met HbA1c targets
with BIAsp 30
BIAsp 30 (n=100)
Insulin glargine (n=109)
Patients reaching target
at Week 28 (%)
p=0.0002
70
60
50
40
30
20
10
0
p=0.0356
66%
42%
40%
28%
HbA1c <7.0%
(ADA goal)
HbA1c ≤6.5%
(ACE and IDF goal)
HbA1c target
Raskin et al. Diabetes Care 2005;28(2):260–5

20. Difference in prandial glucose
increment between treatments
(mmol/L)
INITIATE: improved control of PPG with BIAsp 30
ns
0.66
1.0
*p<0.05
**p<0.01
Favours glargine
0.5
0.0
–0.5
–1.0
–1.5
–2.0
–2.5
–1.17
**
–1.25
*
Breakfast
Lunch
Dinner
Raskin et al. Diabetes Care 2005;28(2):260–5
–0.59
*
Favours
BIAsp 30
Total mean
prandial glucose
increment
ns, not significant

21. Outlines
Presentation structure
• What recent guideline say
• Addresing post prandial glucose excursion
• Minimising hypoglycaemia
• A1chieve observational study: real life experience including Indonesia
• Insulin Intensification : how simple ?
• Conclusion

22. 22
A well-documented tolerability profile
2002–2012
In at least
68 BiAsp 30
RCTs*
2007–10
PRESENT
observational
study1–3
>22,000
patients
2008–2012
IMPROVE™
observational
study4–6
>51,000
patients
2010–2012
A1chieve®
observational
study7,8
>66,000
patients
BiAsp 30
tolerability profile
demonstrated over
of clinical
experience*1–8
* PubMed search using term ‘biphasic insulin aspart’ and the limit ‘randomised controlled trial’. 1. Sharma et al. Curr Med Res Opin 2008;24:645–52; 2. Almustafa et al. Diabetes Res Clin Pract 2008;81(Suppl. 1):S10–5; 3. Güler et al. Arch
Drug Inf 2009;2:23–33; 4. Valensi et al. Int J Clin Pract 2009;63:522–31; 5. Wenying et al. Curr Med Res Opin 2009;25:2643–54;
6. Gumprecht et al. Int J Clin Pract 2009;63:966–72; 7. Home et al. Diabetes Res Clin Pract 2011;94:352–63; 8. El Naggar et al. Diabetes Res Clin Pract 2012;98:408–13

23. 23
Events/patient year
Hypoglycaemia following intensification from basal
insulin analogue to BiAsp 301
10
7.8
8
6.1
6
4
2
0
0.197
0.016
Major
Minor
Hypoglycaemia
Baseline
Final visit
1. Adapted from Gumprecht et al. Int J Clin Pract 2009;62:1809–19
APROM ID# 5069 approval date: May 2013
in the rate of
hypoglycaemia
following
intensification to
BiAsp 301

24. Outlines
Presentation structure
• What recent guideline say
• Addresing post prandial glucose excursion
• Minimising hypoglycaemia
• A1chieve observational study: real life experience including Indonesia
• Insulin Intensification : how simple ?
• Conclusion

26. Presentation title
Role of observational studies and RCTs
Observational studies . . .
" . . . complement (the data) from RCTs by
providing an insight into how treatments perform
in day-to-day practice in more clinically
representative patient populations ”
Home, Diabetes Res Clin Pract, 2010
Date
Slide no 26

27. Presentation title
Date
Strengths of observational studies





1. Yang et al Diabetes Res Clin Pract, 2010 2. Home Diabetes Res Clin Pract, 2010 3. Dreyer et al Health Affairs 2010
Slide no 27

28. A1chieve study overview and design
• Observational study of people with T2DM in
routine clinical practice
Start a study
insulin
• Biphasic insulin
aspart 30
• Insulin detemir
• Insulin aspart
BASELINE
Week 0
•
INTERIM
Week 12
FINAL
Week 24
Study objectives
•
Primary: number of attributed adverse drug reactions
(includes major hypoglycaemia)
•
Secondary: other safety and effectiveness measures

29. BiAsp 30± OAD:
Indonesia efficacy results
Insulin users
HbA1c (%)
FPG (mg/dl)
Baseline values
10.0
9.4
232
204
n
385
92
769
383
Change from baseline to
week 24
0,0
PPG (mg/dl)
303
752
278
328
-10
-30
-1,0
-50
-70
-90
-2,0
-2.1*
-110
-130
-3,0
-150
*p<0.001
-72*
-110*

30. BiAsp 30± OAD:
Baseline
24 weeks
Indonesia hypoglycaemia results
Overall
Insulin users
No. of pt w/hypo
29
Major
Nocturnal
Insulin users
1
0
Insulin users
0
16
0
Events/patientyear
3.0
2.0
1.64
1.0
0.51
0.0
0.03
0.00
0.00
0.00

31. A1chieve: Self-rated health in insulin users (BiAsp 30)
Best imaginable health
Patients on
BiAsp 30
100
Baseline
90
80
70
60
24 weeks
BiAsp 30: real
world
improvement
in patients
quality of life
50
40
30
20
Worst imaginable health
10
0
Baseline
24 weeks

32. A1chieve study overall summary
• Significant HbA1c, FPG and PPG reductions for BiAsp
• 2.1% HbA1c reduction in insulin users
• Indonesian patients reported a reduction in hypoglycaemia during treatment with
BiAsp at 24 weeks in term of:
• Minor
• Major
• Nocturnal
• Patient quality of life increased significantly with BiAsp following 24 weeks of
treatment

33. Outlines
Presentation structure
• What recent guideline say
• Addresing post prandial glucose excursion
• Minimising hypoglycaemia
• A1chieve observational study: real life experience including Indonesia
• Insulin Intensification : how simple?
• Conclusion

34. How do we define insulin intensification?
INITIATE
OPTIMISE
INTENSIFY
Starting insulin therapy
Dose titration to ensure that the patient
receives the maximum benefit from the
prescribed treatment
Modification of the insulin regimen, e.g.
adding to or changing the therapy in order
to maintain glycaemic control

35. Slide 35
Basic Insulin Start Recommendation
If Fasting Blood Glucose is elevated
If both Fasting and Prandial Blood Glucose are
elevated
Source: ADA Guidelines
•
•
•
•
Start with Basal Insulin
Start with Premix Insulin
OR add Basal Insulin to OAD
OR Start Basal/Bolus Therapy

36. Insulin Treatment Optimization
How to Optimize Treatment with Pre-mix
Basal Once-Daily
Usually with OAD
Start with basal 10u /
day and titrate
accordingly if glycemic
target is not reached.
Source: PERKENI Insulin Guidelines 2011
Pre-mix Twice-Daily
Usually with OAD
Switch to Pre-mix twice-daily if
glycemic target is not reached.
Initially keep the dose equal
from basal but split it in half
and inject at morning and
dinner time. If high blood
glucose before evening meal
increase morning dose of premix and if high fasting Blood
glucose increase evening dose
pre-mix.
Pre-mix Thrice-Daily
Usually with OAD
Switch to Pre-mix thricedaily if glycemic target is
not reached. Add 2-6 unit or
10% of daily dose to the
total dose and inject at
lunch. Reduce morning dose
with 2-4 units after staring
lunch time injections

37. Practical guideline on intensification of insulin therapy
with BIAsp 30
A simple algorithm for the intensification of basal insulin OD or BiD to BIAsp 30 BID
Basal insulin OD or BID
HbA1c 7-8%
FPG >110 mg/dl
Titrate basal insulin to achieve
FPG <110 mg/dl
1. Adapted from Unnikrishnan et al. Int J Clin Pract 2009;63:1571–7
HbA1c >8%
FPG: 73-110 mg/dl
Switch to BIAsp 30
BID

38. 38
Intensifying basal insulin patients to Premix
is simple
In basal insulin patients: start with the same total daily dose1
•
BiAsp 30 can be intensified to three-times
daily* to achieve glycaemic control2
•
The morning dose can be split into
morning and lunchtime doses for threetimes-daily dosing3
•
BIAsp 30 TID: alternative to basal-bolus
(fewer daily injection and only one device
need)
Intensify to
unit
basal insulin
unit
BiAsp 30
Breakfast
Split total daily dose
50%
Dinner
50%
Twice daily BiAsp 30
Adapted from Unnikrishan1
*Guideline for the recommended dose adjustment included in the NovoMix® 30 SmPC3. 1. Unnikrishnan et al. Int J of Clin Prac 2009; 63:1571–7; 2. Garber et al. Diabetes Obes Metab
2006;8:58–66; 3. Novo Nordisk. NovoMix® 30 summary of product characteristics

39. 39
Adjusting the dose of BiAsp 30
Recommended dose adjustments
Pre-meal blood
glucose level
BiAsp 30
dose adjustment
mg/dL
Units
<80
80–110
111–140
141–180
>180
-2
0
+2
+4
+6
Adapted from NovoMix® 30 SmPC1
1. Novo Nordisk. NovoMix® 30 summary of product characteristics. May 2012

40. Outlines
Presentation structure
• What recent guideline say
• Addresing post prandial glucose excursion
• Minimising hypoglycaemia
• A1chieve observational study: real life experience including Indonesia
• Insulin Intensification : how simple?
• Conclusion

41. Conclusion
• Because of the progessiveness of diabetes, Insulin regimen and dosage
needs to be monitored and intensified
• BiAsp 30 provides effective glycaemic control with significant HbA1c
reduction, FPG and PPG reduction with additional convenience for patients
• In Indonesia, in a real life clinical practice, A1chieve study results for BiAsp
30 show significant improvements in overall glycaemic control in terms of
HbA1c, FPG and PPG, reductions in hypoglycemia and a significant
improvement in patient quality of life

42. Thank You