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.

Slide no 1

Insulin intensification : the usage of premixed insulin after basal fails

EDDY SUPRIADI, MD.MARZOEKI MAHDI , MD. HOSPITAL.BOGOR

OutlinesPresentation 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

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

The ADA/EASD have found that basal plus two or more

bolus injections is a highly complex regimen3

4

• 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

• Premix Insulin offer a simple intensification of one insulin in one device4

Background

Slide 5

Type 2 diabetes is a progressive disease

Lebovitz. Diabetes Reviews 1999;7:139–53 (data are from the UKPDS population: UKPDS 16. Diabetes 1995;44:1249–58)

HOMA: homeostasis model assessment

ADA/EASD Position on Sequential Insulin Strategy in Type 2 Diabetes

Non-Insulin Regimes

Basal Insulin OnlyUsually with OAD

Basal Insulin + 1 mealtime rapid-acting injection

Pre-mixed Insulin twice-daily

Basal Insulin + >2 mealtime rapid-acting injection

1

2

+3

Low

Mod.

High

Number of Injections

Regimen Complexity

FlexibilityLess FlexibleMore Flexible

Convenience*More ConvenientLess Convenient

Inzucci SE, et al. Diabetologia. 2012. * Gumprecht et al. Intensification to to biphasic insulin aspart 30/70. Int J Clin Pract 2009

Lifestyle measuresIf not at target (generally HbA1c <7%)

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)

treatments that can help to address PPG are included at every stage of the IDF treatment algorithm1

• Sulphonylurea

Second line

• Metformin• a-glucosidase

inhibitor• DPP-4 inhibitor• Thiazolidinedione

• Premix insulin• Basal insulin• Basal-bolus insulin

Fourth line:insulin intensification

• Premix insulin• Basal insulin• a-glucosidase inhibitor• DPP-4 inhibitor• Thiazolidinedione

Third line:insulin start

• GLP-1 agonist

First line

• Metformin

• Sulphonylurea• a-glucosidase

inhibitor

IDF recommends premix or basal insulin at start

and intensification

Standard approach

Alternative approach

7

APROM ID# 5069 approval date: May 2013

OutlinesPresentation 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

Treatment therapies for Type 2 diabetes: Achieving HbA1c < 7%

Adapted from Raccah et al. Diabetes Metab Res Rev 2007;23:257.

Lifestyle + Metformin

+-other OAD or GLP-1 agonists

Basal Insulin

(Once-daily treat-to-target)

PremixedInsulin

(Twice dailyTreat to target)

Basal Insulin

(Basal + 1 or 2 prandial)

Basal Insulin

(Basal + 3 prandial)

HbA1c ≥7.0% HbA1c ≥7.0%, FPG on target, PPG ≥160 mg/dl

Every 1% drop in HbA1c can reduce long-term diabetes

complications1

37%

Microvascular complications*

21%

Deaths relatedto diabetes*

14%

Myocardialinfarction*

*p<0.0001. 1. Adapted from Stratton et al. BMJ 2000;321:405–12 (UKPDS 35)

10

Slide 11

The benefits of good blood glucose control are clear

Good control is ≤ 7.0% HbA1c

HbA1c measures the average blood glucose level over thelast three months

Source: UKPDS = United Kingdom Prospective Diabetes Study. Stratton IM et al. BMJ. 2000;321(7258):405-412.

Deaths related to diabetes

Microvascular complications

Myocardial infarction

-14%

-37%

-21%

HbA1c

-1%

Yet good glycaemic control is not achieved

Adapted from Unger et al. Am J Med 2008;121:S3–S8.

12.4% have HbA1c>10.0 %

20.2% have HbA1c>9.0 %

37.2% have HbA1c>8.0 %

HbA1c (%)

10.0

9.5

9.0

8.5

8.0

7.5

7.0

6.5

6.0

5.5

64.2% of patients with type 2 diabetes have HbA1c≥7.0 %

PPG control is vital to achieving HbA1c targets1

1. Adapted from Monnier et al. Diabetes Care 2003;26:881–5

Rela

tive c

on

trib

uti

on

to

o

verall h

yp

erg

lycaem

ia(%

)

HbA1c quintiles

0

20

40

60

80

100

<7.3 7.3–8.4 8.5–9.2 9.3–10.2 >10.2

to overall hyperglycaemia as patients approach HbA1c

targets1

PPG has an

FPG PPG

APROM ID# 5069 approval date: May 2013

13

Patients spend 50% of their day in the postprandial state1

1. Adapted from Monnier. Eur J Clin Invest 2000;30(Suppl. 2):3–11

4 h4 h

4 h

MIDNIGHT

6 PM

Breakfast

Evening meal

Lunch

6 AM

MID-DAY

Fasting state

Postprandial state

14

Is postprandial hyperglycaemia harmful?

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

IDF Recommendation:

Physiological insulin

profile:

• Basal component

• Meal-related peaks

The dual-release insulin concept: Premix Insulin

targets both FPG and PPG1

1. Garber et al. Diabetes Obes Metab 2006;8:58–66; 2. Garber et al. Diabetes Obes Metab 2007;9:630–9

Basal insulin

BiAsp 30

Physiological insulin profile

Time

Pla

sm

a insulin level

APROM ID# 5069 approval date: May 2013

Adapted from Garber2

16

The IMPROVE™ study - reduced FPG and PPG with BiAsp 301

*p<0.001

1. Adapted from Valensi et al. Int J Clin Pract 2009;63:522–31

Pre-breakfast FPG Post-dinner PPG

Baseline Week 26

FPG and PPG from baseline at Week 26 following initiation or switch to BiAsp301

14

12

10

8

6

4

2

0

10.9

6.6

12.6

7.9

Blo

od

glu

co

se

(mm

ol/

L)

APROM ID# 5069 approval date: May 2013

1 1

17

INITiation of Insulin to reach A1c TargEt (INITIATE): BIAsp 30 (BID) vs. glargine (OD)

n=233Type 2 diabetesBMI <40 kg/m2

Body weight <125 kgHbA1c >8%on metformin ± TZD

Insulin glargine OD (12 U, bedtime) + metformin ± pioglitazone

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/daySwitch rosiglitazone for 30 mg pioglitazone

–4 0 28Time (weeks)

SUs, sulphonylureasRaskin et al. Diabetes Care 2005;28(2):260–5

BIAsp 30 (n=100)Insulin glargine (n=109)

66%

42%40%

28%

0

10

20

30

40

50

60

70

HbA1c <7.0% (ADA goal)

HbA1c ≤6.5% (ACE and IDF goal)

HbA1c target

Pati

ents

rea

chin

g ta

rget

at W

eek

28

(%

)p=0.0002

p=0.0356

INITIATE: significantly more patients met HbA1c targets with BIAsp 30

Raskin et al. Diabetes Care 2005;28(2):260–5

Dif

fere

nce

in p

ran

dia

l glu

cose

in

crem

ent

bet

wee

n t

reat

men

ts

(mm

ol/

L)

Total meanprandial glucose

increment

Favours glargine

Favours BIAsp 30

Breakfast

–1.17

0.66

–1.25

–0.59

**

ns

*

*

*p<0.05**p<0.01

–2.5

–2.0

–1.5

–1.0

–0.5

0.0

0.5

1.0

INITIATE: improved control of PPG with BIAsp 30

ns, not significant

Lunch Dinner

Raskin et al. Diabetes Care 2005;28(2):260–5

OutlinesPresentation 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

A well-documented tolerability profile

* 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

2002–2012In at least 68 BiAsp 30 RCTs*

2007–10 PRESENT observational study1–3

>22,000 patients

2008–2012 IMPROVE™ observational study4–6

>51,000 patients

2010–2012A1chieve®

observational study7,8

>66,000 patients

of clinical experience*1–8

BiAsp 30 tolerability profile demonstrated over

22

Hypoglycaemia following intensification from basal

insulin analogue to BiAsp 301

1. Adapted from Gumprecht et al. Int J Clin Pract 2009;62:1809–19

Baseline Final visit

in the rate of hypoglycaemia following intensification to BiAsp 301Hypoglycaemia

8

6

4

2

0Even

ts/

pati

en

t year

0.197

Major

0.016

7.8

6.1

Minor

APROM ID# 5069 approval date: May 2013

23

10

OutlinesPresentation 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

Presentation title Slide no 26Date

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

Presentation title Slide no 27Date

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

• Observational study of people with T2DM in routine clinical practice

• Study objectives• Primary: number of attributed adverse drug reactions

(includes major hypoglycaemia)

• Secondary: other safety and effectiveness measures

BASELINEWeek 0

INTERIMWeek 12

FINALWeek 24

Start a study insulin

• Biphasic insulin aspart 30

• Insulin detemir• Insulin aspart

A1chieve study overview and design

BiAsp 30± OAD: Indonesia efficacy results Insulin users

HbA1c (%) FPG (mg/dl) PPG (mg/dl)

Baseline values 10.0 9.4 232 204 303 278

n 385 92 769 383 752 328

*p<0.001

-2.1*

-3,0

-2,0

-1,0

0,0

Cha

nge

from

bas

elin

e to

w

eek

24

-72*

-110*

-150

-130

-110

-90

-70

-50

-30

-10

BiAsp 30± OAD: Indonesia hypoglycaemia results

1.64

0.00

0.51

0.03 0.00 0.00 0.0

1.0

2.0

3.0

Overall Major Nocturnal

Insulin users Insulin users Insulin users

No. of pt w/hypo 29 1 0 0 16 0

Events

/patient-

year

Baseline

24 weeks

A1chieve: Self-rated health in insulin users (BiAsp 30)

24 weeks

Baseline

Best imaginable health

Worst imaginable health0

10

20

30

40

50

60

70

80

90

100

Baseline 24 weeks

Patients on BiAsp 30

BiAsp 30: real world

improvement in patients

quality of life

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

OutlinesPresentation 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

How do we define insulin intensification?

Modification of the insulin regimen, e.g. adding to or changing the therapy in order to maintain glycaemic control

INTENSIFY

Starting insulin therapy

Dose titration to ensure that the patient receives the maximum benefit from the prescribed treatment

OPTIMISE

INITIATE

Slide 35

Basic Insulin Start Recommendation

If Fasting Blood Glucose is elevated • Start with Basal Insulin

If both Fasting and Prandial Blood Glucose are elevated

• Start with Premix Insulin• OR add Basal Insulin to OAD

• OR Start Basal/Bolus Therapy

Source: ADA Guidelines

Insulin Treatment OptimizationHow to Optimize Treatment with Pre-mix

Basal Once-DailyUsually with OAD

Start with basal 10u / day and titrate accordingly if glycemic target is not reached.

Pre-mix Twice-DailyUsually with OAD

Source: PERKENI Insulin Guidelines 2011

Pre-mix Thrice-DailyUsually with OAD

Switch to Pre-mix twice-daily ifglycemic target is not reached.Initially keep the dose equalfrom basal but split it in halfand inject at morning anddinner time. If high bloodglucose before evening mealincrease morning dose of pre-mix and if high fasting Bloodglucose increase evening dosepre-mix.

Switch to Pre-mix thrice-daily if glycemic target isnot reached. Add 2-6 unit or10% of daily dose to thetotal dose and inject atlunch. Reduce morning dosewith 2-4 units after staringlunch time injections

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

Switch to BIAsp 30 BID

HbA1c 7-8%

Titrate basal insulin to achieveFPG <110 mg/dl

FPG >110 mg/dl FPG: 73-110 mg/dl

HbA1c >8%

1. Adapted from Unnikrishnan et al. Int J Clin Pract 2009;63:1571–7

Intensifying basal insulin patients to Premix

is simple

• 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 three-times-daily dosing3

• BIAsp 30 TID: alternative to basal-bolus (fewer daily injection and only one device need)

*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

Adapted from Unnikrishan1

Breakfast Dinner

Split total daily dose 50% 50%

In basal insulin patients: start with the same total daily dose1

unitbasal insulin

Intensify to

unitBiAsp 30

38

Twice daily BiAsp 30

Adjusting the dose of BiAsp 30

1. Novo Nordisk. NovoMix® 30 summary of product characteristics. May 2012

Adapted from NovoMix® 30 SmPC1

Pre-meal bloodglucose level

mg/dL

BiAsp 30dose adjustment

Units

<80 -2

80–110 0

111–140 +2

>180 +6

141–180 +4

Recommended dose adjustments

39

OutlinesPresentation 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

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

Thank You