Insulin initiation and

intensification in
outpatient

Ketut Suastika
Universitas Udayana Denpasar

Outlines

Presentation structure
Diabetes is a progressive disease and is increasing
in prevalence
The mapping of insulin treatment based recent guidelines
Insulin Initiaton and Intensification from latest update study (A1chieve)
Conclusion

Diabetes is a global disease

Estimated global prevalence of diabetes

171 million1
2000
1.
2.

366 million2
2011
2010

Wild. Diabetes Care. 2004. 27:1047-1053.

International Diabetes Federation. IDF Diabetes Atlas. Fifth Edition. 2011

552 million2
2030

T2DM: Progressive loss of insulin

secretion with increasing insulin resistance1
Impaired
glucose tolerance

Undiagnosed
diabetes

Known
diabetes

Insulin resistance

Insulin secretion
Postprandial glucose
Fasting glucose

Microvascular complications
Macrovascular complications
1.

Adapted from: Ramlo-Halsted BA, Edelman SV. Clincial Diabetes 2000;18(2): http://journal.diabetes.org/clinicaldiabetes/v18n22000/pg80.htm

Diabetes is a progressive disease

Type 2 diabetes (T2DM) progression is characterised by decline in beta-cell function
and worsening insulin resistance1
Getting to, or maintaining, target HbA1c levels in T2DM requires intensified treatment
over time2

1.
2.

Fonseca VA. Br J Diab Vasc Dis 2008;8:S3

Nathan DM, et al. Diabetes Care 2009;32:193-203

Diabetes being a progressive disease that is increasing

in prevalence
T2DM results in a progressive loss of insulin secretion with increasing insulin
resistance1
By 2030, IDF predicts 552 million people worldwide will have diabetes2
Diabetes is the fourth most common diagnosed chronic condition3
Many people with diabetes do not have good glycaemic control3

1.
2.
3.

Ramlo-Halsted BA, Edelman SV. Clincial Diabetes 2000;18(2): http://journal.diabetes.org/clinicaldiabetes/v18n22000/pg80.htm

International Diabetes Federation. IDF Diabetes Atlas. Fifth Edition. 2011
Brunton. Curr Med Res Opin 2011;2765-72

Outlines

Presentation structure
Diabetes is a progressive disease and is increasing
in prevalence
The mapping of insulin treatment based recent guidelines
Insulin Initiaton and Intensification from latest update study (A1chieve)
Conclusion

New position statement of the ADA and EASD on

management of hyperglycemia in type 2 diabetes

Inzucci SE, et al. Diabetologia. 2012

New ADA/EASD Position on Sequential Insulin

Strategy in Type 2 Diabetes
Non-Insulin
Non-Insulin
Regimes
Regimes

Number of
Injections

Regimen
Complexity

Basal
Basal Insulin
Insulin Only
Only
Usually
Usually with
with OAD
OAD

Low

Mod.

+3

High

Basal
Basal Insulin
Insulin +
+1
1 mealtime
mealtime
rapid-acting
injection
rapid-acting injection

Pre-mixed Insulin twice-daily

Basal
Basal Insulin
Insulin +
+
2
2 mealtime
mealtime
rapid-acting
injection
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*

Patient Centered Approach

What is the optimal target HbA1c level?

EASD/ADA1

HbA1c
<7.0%

IDF2

HbA1c
<7.0%

EMA3

HbA1c
<7.0%

Goals of optimum HbA1c levels:

Good glycaemic control
Minimise development and progression of microvascular
and macrovascular complications
1.
2.
3.

Inzucchi et al. Diabetes care. Published online 19Apr2012.

IDF Treatment Algorithm. International Diabetes Federation 2011. http://www.idf.org/treatment-algorithm-people-type-2-diabetes
EMA Draft guidance on clinical investigation in DM Jan 2010

Treat T2DM early for long-term benefits1

Long-term benefits in reducing cardiovascular risk can be achieved with good
control from diagnosis1
50% of patients with T2DM with complications
already have them at diagnosis2
Each HbA1c
percentage
point
reduction
counts3

HbA1c
-1%
1.
2.
3.

Holman, et al. NEJM 2008;359:157789

UKPDS 6. Diabetes Res 1990;13(1):1-11
Stratton, et al. BMJ 2000;321(7258):405-12

-14%
-37%
-21%

Myocardial infarction
Microvascular complications
Death related to diabetes

Insulin remains the most efficacious glucose

lowering agent

HbA1c %

Decrease in HbA1c: Potency of monotherapy

CHOOSING INSULIN EARLIER

FOR BETTER EFFICACY
Nathan et al., Diabetes Care 2009;32:193-203.

Insulin can be initiated at any time

Traditionally, insulin has been reserved as the last line of therapy

However, considering the benefits of normal glycemic status, Insulin

can be initiated earlier and as soon as possible

Inadequate
Lifestyle

+ 1 OAD

+ 2 OAD

INITIATE INSULIN

+ 3 OAD

Outlines

Presentation structure
Diabetes is a progressive disease and is increasing
in prevalence
The mapping of insulin treatment based recent guidelines
Insulin Initiaton and Intensification from latest update study (A1chieve)
Conclusion

How to start Basal Insulin

Start with basal insulin (Insulin Detemir) 10 U or 0,1-0,2 U per Kg BB
Once daily injection, anytime injection but in same time per each day

Levemir Dose Titration Guidelines:

3-0-3 Algorithm
Start with Levemir 10 U or 0,1-0,2 U per Kg BB
Simple Dose titration with Levemir
Mean 3-day FPG (mg/dL)
Increase
FPG>90 mg/dl (5.0 mm/L)
FPG target range
70-90 mg/dL

FPG <70 mg/dL (3.8 mmol/L)

3units
units
Maintain
dose
Decrease
3 units

FPG>110 mg/dL (6.1 mmol/L)

FPG target range
80-110 mg/dL

FPG <80 mg/dL (4.4 mmol/L)

Patients who experienced hypoglycemia reduced their daily dose by 3 units

Blonde L et al. Diabetes Obes Metab. 2009; 11(6):623-631.

Levemir/Glargine Head-to-Head:
Similar Profiles in Type 2 Diabetes
Insulin detemir

2.5
(mg/kg/min)

Glucose infusion rate

3.0

0.4 U/kg

0.8 U/kg

Insulin glargine

2.0
1.5
1.0
0.5
0
0

10 12 14 16 18 20 22
Time (h)

Klein O et al. Diab Obes Metab 2007; 9:290-299

24

Levemir reduces nocturnal hypoglycaemia by up to

65% compared to NPH
NPH vs. glargine
-44%

-53%

-65%

Relative Risk

-29%

NPH vs. detemir

Insulin Determir
Insulin NPH
Insulin glargine

Riddle et al., 2003

Phillis-Tsimikas et al., 2006

Phillis-Tsimikas. Clin Ther 2006;28(10):156981; Riddle et al 2003. Diabetes Care; 26 (11): 30806; Asakura T et al, 2008. Expert Opin Pharmacother; 10 (9): 1-5; Hanel H et al 2008. J Diabetes

How to Intensify

Treatment therapies for Type 2 diabetes

Premixed
Insulin

Lifestyle +
Metformin

+-other
OAD or
GLP-1
agonists

Basal
Insulin

(Once-daily
treat-totarget)

HbA1c
7.0%
1c

(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
1c

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

% contribution to HbA1c

To normalise blood glucose both FPG and PPG

must be reduced
Most insulin is
initiated when
HbA1c >8.5%

100
80
60

70%

50%

45%

40%

30%

50%

55%

60%

70%

40
20
0

30%
<7.3

7.38.4
8.59.2 9.310.2
HbA1c range (%)

Adapted from Monnier L et al. Diabetes Care 2003;26:8815

>10.2

PPG
FPG

Step up with BIAsp 30 (NovoMix) from basal analogue

insulin significantly reduced HbA1c after 6 months
Mean HbA1c reduction from baseline on basal analogue insulin

Jang HC et al. Int J Clin Pract 2008;62(7);1013-1018; Gumprecht J et al., Int J Clin Pract, June 2009; 63, 6, 966-972

Insulin Treatment Optimization

How to Optimize Treatment after Basal Initiation

Start with Basal Insulin
10u / daily with meal or
before bedtime. Same
injection time every day

Basal
Basal Insulin
Insulin Only
Only
Usually
with
OAD
Usually with OAD
If glycemic target is not reached titrate
according to Basal Titration Scheme
Basal
Basal Insulin
Insulin Only
Only
Usually
Usually with
with OAD
OAD
If glycemic target is not reached within
2-3 months the intensify Insulin
treatment

Premix Insulin
Usually keep OAD

Basal
Basal with
with Prandial
Prandial
Usually
keep
Usually keep OAD
OAD

Basal
Basal Bolus
Bolus
Usually
keep
Usually keep OAD
OAD

Switch to Premix twice-daily.

Start with equal basal dose, but
give 50% per injection and
titrate accordingly

Add Prandial starting with

4u / day either once or
twice-daily and titrate
accordingly

Switch to Basal Bolus (3

daily prandial) start with 4u
/ day and titrate
accordingly)

Source: PERKENI Insulin Guidelines 2011

Practical guideline on intensification of insulin therapy

with BIAsp 30 (NovoMix)
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

HbA1c >8%
FPG: 73-110 mg/dl

Titrate basal insulin to achieve

FPG <110 mg/dl

Switch to BIAsp 30
BID

Practical guideline for swiching from basal insulin OD or BID to BIAsp 30 BID
1:1 Total dose transfer to BIAsp 30
Split the dose 50:50 prebreakfast and predinner
Titrate the dose preferably once a week
Discontinue sulfonylureas (SUs)
Continue metformin
Consider discontinuing TZDs as per local guideline and practice
Administer BIAsp 30 just before meals

Practical guideline on intensification of insulin therapy

with BIAsp 30 (NovoMix)
Preprandial blood glucose value
<80 mg/dl
80-110 mg/dl
110-140 mg/dl
141-180 mg/dl
>180 mg/dl

Unnikrishnan AG et al.Int J Clin Pract 2009; 63 (11) : 1571-7

Dose change
-2U
0
+2 U
+4 U
+6 U

A1chieve study overview and design

Observational study of people with T2DM in
routine clinical practice
Start
Start aa study
study
insulin
insulin
Biphasic
Biphasic insulin
insulin
aspart
aspart 30
30
Insulin
Insulin detemir
detemir
Insulin
Insulin aspart
aspart

BASELINE
BASELINE
Week
Week 0
0

INTERIM
INTERIM
Week
Week 12
12

FINAL
FINAL
Week
Week 24
24

Study objectives

Primary: number of attributed adverse drug

reactions (includes major hypoglycaemia)

Secondary: other safety and effectiveness

measures

Levemir OGLD:

Indonesia efficacy
results
HbA (%)
1c

Insulin nave
FPG (mg/dl)

PPG (mg/dl)

Baseline values

9.5

219

263

147

317

295

-80

Changefrombaselineto
week24

0.0

-1.0

-100
-101*
-2.0
-2.2*

-115*
-3.0

-120

*p<0.001

NovoMix OAD:

Indonesia efficacy
results
HbA (%)
1c

Insulin users
FPG (mg/dl)

Baseline values

10.0

9.4

232

204

385

92

769

383

PPG (mg/dl)
303
752

278
328

0.0

Changefrombaselineto
week24

-10
-30
-1.0

-50
-70
-72*
-90

-2.0
-2.1*

-110
-110*
-130

-3.0

-150

*p<0.001

A1chieve: Self-rated health in insulin users

(NovoMix)
Best imaginable
health

Baseline

Patients on
NovoMix
100
90
80
70
60

24 weeks

50
40

Worst imaginable
health

30
20
10
0
Baseline

24 weeks

Physiologic insulin secretion

Analogue insulin mechanisme of action

-------

Breakfast

Lunch

Dinner

Insulin endogen
Levemir
NovoRapid
NovoMix

Bed time

Outlines

Presentation structure
Diabetes is a progressive disease and is increasing
in prevalence
The mapping of insulin treatment based recent guidelines
Insulin Initiaton and Intensification from latest update study (A1chieve)
Conclusion

Conclusion
Diabetes is a progressive disease that is increasing in prevalence in the world
Starting with basal insulin after metformin to reach better glycemic control
In Indonesia, in real life clinical practice (A1chieve study) Levemir show significant
improvements in overall glycaemic control in terms of HbA1c, FPG and PPG.
Premixed insulin NovoMix is one option for insulin intensification, provide simple and
convenient for patients
Basal bolus treatment is an ideal option but has limitation with 4 times injection per
day

Thank You