Presentation title Date 1

Insulin Initiation :
When We should Start with Basal Insulin?

Dr Ali Santosa SPPD


AGENDA
Diabetes is a progressive disease and is increasing
in prevalence
The mapping of insulin treatment based recent guidelines
Insulin Initiation, when we should start with basal insulin
Conclusion


2010
2000
171 million
1
2030
552 million
2
2011
366 million
2
Diabetes is a global disease
Estimated global prevalence of diabetes
1. Wild. Diabetes Care. 2004. 27:1047-1053.
2. International Diabetes Federation. IDF Diabetes Atlas. Fifth Edition. 2011
Indonesia, No. 7 largest diabetes population in
the world
7
2035
Prediction
Prevalence: 5,55% (adult pop.)
14,1 mill people with
diabetes

No. 6 largest diabetes
population in the world

6,67% diabetes
prevalence (adult pop.)
Source: International Diabetes Federation. IDF Diabetes Atlas, 6th edn. Brussels, Belgium: International Diabetes
Federation, 2013. http://www.idf.org/diabetesatlas


Normal
The progressive nature of
type 2 diabetes
Impaired
glucose
tolerance
Type 2
diabetes
Fasting plasma glucose
Insulin sensitivity
Insulin secretion
Insulin
sensitive
Normal insulin
secretion
Normoglycaemia
Hyperglycaemia
-cell
exhaustion
Insulin
resistance
Late type 2
diabetes
complications
Adapted from Bailey CJ et al. Int J Clin Pract 2004;58:867876.
Groop LC. Diabetes Obes Metab 1999;1 (Suppl. 1):S1S7.
Insulin resistance
Insulin and Glucagon Response to a Large
Carbohydrate Meal in Type 2 Diabetes
6
I
n
s
u
l
i
n

(

U
/
m
l
)

G
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a
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(

g
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)

G
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u
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o
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(
m
g
/
1
0
0

m
l
)

*Insulin measured in five patients
Adapted from Mller WA et al N Engl J Med 1970;283:109115.
Type 2 diabetes mellitus (n=12)*
Nondiabetic controls (n=11)
150
0
140
90
360
80
240
60
Time (minutes)
30
60
90
120
110
270
300
330
100
110
120
130
Meal
Nonsuppressed glucagon
0 60 120 180 240
Depressed/delayed insulin response
Adapted from Stumvoll M et al. Lancet 2005;365:13331346.
Model of underlying factors in type 2 diabetes:
insulin resistance and -cell dysfunction
-CELL
DYSFUNCTION
INSULIN
RESISTANCE
Glucose uptake
Blood glucose
Free fatty acids
Glucose production

Diabetes genes
Adipokines
Inflammation
Hyperglycaemia
Free fatty acids
Other factors
Insulin secretion
Lipolysis
8
8
100


75


50


25


0
UKPDS : Progressive Deterioration of -Cell Function
Years from Diagnosis
Adapted fromLebovitz H. Diabetes Review 1999;7: 139-53
B
e
t
a

C
e
l
l

F
u
n
c
t
i
o
n

(
%
)

-12 10 -6 -2 0 2 6 10 14
Th/Expectation with
intensive treatment
Facts
Why ?
ETIOLOGY OF BETA CELL FAILURE IN T2DM
Age
5. Incretin
Effect
Genetic
(TCF 7L2)
4. Amyloid
Deposition
1. Glucose
toxicity
2. Lipotoxicity
FFA
3. Insulin
Resistance
Beta-cell
Failure
De Fronzo Banting Lecture (submitted ADA Meeting 2008 /Claude Bernard Award Winner EASD 2008)
Diabetes is a progressive disease
Type 2 diabetes (T2DM) progression is characterised by decline in beta-cell function and
worsening insulin resistance
1
Getting to, or maintaining, target HbA
1c
levels in T2DM requires intensified treatment
over time
2


1. Fonseca VA. Br J Diab Vasc Dis 2008;8:S3
2. Nathan DM, et al. Diabetes Care 2009;32:193-203
10
-Cell Function Continues to Decline
Regardless of Intervention in T2DM
T2DM = type 2 diabetes mellitus
*-cell function measured by homeostasis model assessment (HOMA)
Adapted from UKPDS Group. Diabetes. 1995;44:12491258.
0
20
40
60
80
100
5 4 3 2 1 0 1 2 3 4 5 6
Years Since Diagnosis

-
C
e
l
l

F
u
n
c
t
i
o
n

(
%
)
*

Progressive loss of -cell function
occurs prior to diagnosis
Metformin (n = 159)
Diet (n = 110)
Sulfonylurea (n = 511)
AGENDA
Diabetes is a progressive disease and is increasing
in prevalence
The mapping of insulin treatment based recent guidelines
Insulin Initiation, when we should start with basal insulin
Conclusion


Treat T2DM early for long-term benefits
1

Long-term benefits in reducing cardiovascular risk can be achieved with
good control from diagnosis
1
-14%
-37%
-21%
Myocardial infarction
Microvascular complications
Death related to diabetes
Each HbA
1c
percentage
point
reduction
counts
3
HbA
1c

-1%
1. Holman, et al. NEJM 2008;359:157789
2. UKPDS 6. Diabetes Res 1990;13(1):1-11
3. Stratton, et al. BMJ 2000;321(7258):405-12
50% of patients with T2DM with complications
already have them at diagnosis
2
What is the optimal target HbA
1c
level?
Goals of optimum HbA
1c
levels:
Good glycaemic control
Minimise development and progression of microvascular
and macrovascular complications
HbA
1c
<7.0%
HbA
1c
<7.0%
1. Inzucchi et al. Diabetes care. Published online 19Apr2012.
2. IDF Treatment Algorithm. International Diabetes Federation 2011. http://www.idf.org/treatment-algorithm-people-type-2-diabetes
3. EMA Draft guidance on clinical investigation in DM Jan 2010
HbA
1c
<7.0%
EMA
3
EASD/ADA
1

IDF
2

AGENDA
Diabetes is a progressive disease and is increasing
in prevalence
The mapping of insulin treatment based recent guidelines
Insulin Initiation, when we should start with basal insulin
Conclusion


Gaya hidup +
Metformin +
Pioglitazon
Gaya hidup +
Metformin +
GLP-1 agonis
Gaya hidup +
Metformin +
Pioglitazon +
sulfonilurea
Gaya hidup +
Metformin +
Insulin Basal
Less well validated
therapies
Saat diagnosis:
Gaya hidup
+
Metformin
Gaya hidup +
Metformin +
Insulin Basal
Gaya hidup +
Metformin +
Sulfonilurea
Well validated
therapies
Tahap 1 Tahap 2 Tahap 3
Gaya hidup +
Metformin +
Insulin Intensif
Nathan DM et al, Diabetes Care 32:193203, 2009
ADA-EASD 2009
Insulin remains the most efficacious glucose
lowering agent
Decrease in HbA
1c
: Potency of monotherapy
H
b
A
1
c

%

Nathan et al., Diabetes Care 2009;32:193-203.
CHOOSING INSULIN EARLIER
FOR BETTER EFFICACY
Choosing Insulin
for your Patient?
Insulin can be initiated anytime
Inadequate
Lifestyle
+
1 OAD
+
2 OAD
+
3 OAD
Initiate Insulin
Traditionally, insulin had been reserved as the last line of therapy
Considering the benefits of normal glycemic status,
insulin can be initiated earlier, as soon as is required.
1. Fasting BG > 250 mg/dL
2. Random BG > 300 mg/dL
3. Hb A1c > 10 %
4. Weight loss ++
5. Ketonuria
Indication:
19
Time of day (hours)
400
300
200
100
0
06.00 06.00 10.00 14.00 18.00 22.00 02.00
P
l
a
s
m
a

g
l
u
c
o
s
e

(
m
g
/
d
l
)

Normal
Meal Meal Meal
20
15
10
5
0
P
l
a
s
m
a

g
l
u
c
o
s
e

(
m
m
o
l
/
l
)

Suntikkan 10 iu Levemir sekali sebelum tidur. Atur
dosisnya (+3 atau -3) setiap 3 hari sd. GDP mencapai
target GDP 80-110 mg/dL (Perkeni 2006)
Hyperglycaemia due to an increase in fasting glucose
T2DM
Tambahkan Injeksi NovoRapid di setiap makan (2-6 iu)
untuk mengendalikan Gula darah 2 jam PP mencapai target
< 180 mg/dL (Perkeni 2006)
Basal Bolus Concept dengan Levemir -
NovoRapid
Profile T2DM
Once daily injection, anytime injection but in same time per each day

How to start basal insulin
Titrate the dose every
3 days, if FPG >
110mg/dl increased 3
units and if FPG < 80
mg/dl decrease 3
units
Start with basal
insulin (Insulin
Detemir) 10 U or 0,1-
0,2 U per Kg BB
Titrate Start
Meneghini L et al. Diabetes Obes Metab, 9, 2007, 902-913
How to titrate basal insulin
Levemir

Dose Titration Guidelines:
3-0-3 Algorithm
FPG>110 mg/dL + 3 U
80-110 mg/dL 0
FPG <80 mg/dL - 3 U
Simple Dose titration with Levemir


Mean 3-day FPG (mg/dL)
Blonde L et al. Diabetes Obes Metab. 2009; 11(6):623-631.
Patients who experienced hypoglycemia reduced their daily dose by 3 units
Start with Levemir 10 U or 0,1-0,2 U per Kg BB
Levemir

provide optimal HbA1c reduction

Reference: 1. Soewondo P et al. Clinical experience with insulin detemir: Result from the Indonesian cohort of the international A1chieve study. Diabetes Res Clin Pract;suppl.S192013) S47-S53.
Basal insulin analogue profile
Levemir

/Glargine

Time (h)
Klein O et al. Diab Obes Metab 2007; 9:290-299
G
l
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i
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f
u
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n

r
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(
m
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/
k
g
/
m
i
n
)

0 2 4 6 8 10 12 14 16 18 20 22 24
0
0.5
1.0
1.5
2.0
2.5
3.0
0.4 U/kg
Insulin detemir
Insulin glargine
Levemir reduces nocturnal hypoglycaemia by up to
65% compared to NPH
Phillis-Tsimikas. Clin Ther 2006;28(10):156981; Riddle et al 2003. Diabetes Care; 26 (11): 3080-
6; Asakura T et al, 2008. Expert Opin Pharmacother; 10 (9): 1-5; Hanel H et al 2008. J Diabetes
Sci Technol; 2 (3): 478-81
Insulin NPH
Insulin Determir
Insulin glargine
R
e
l
a
t
i
v
e

R
i
s
k

Riddle et al., 2003 Phillis-Tsimikas et al., 2006
-29% -44% -53% -65%
NPH vs. glargine NPH vs. detemir
Levemir

Demonstrated More Consistent Insulin Action

54 Type 1 Diabetic Subjects Randomly Assigned to receive one type of Insulin, single
dose 0.4 u/kg, 4 Different Times
25
Adapted from Heise T et al. Diabetes. 2004;53:1614-20.
NPH NPH NPH
Glargine Glargine Glargine
Detemir

Detemir

Detemir

Levemir

is approved in pregnancy and children 2
years
EMEA, FDA and BPOM has been approved Levemir

in diabetes gestational
(B category)and children 2 years

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
BASELINE
Week 0
INTERIM
Week 12
FINAL
Week 24
Start a study
insulin
Biphasic insulin
aspart 30
Insulin detemir
Insulin aspart
A
1
chieve study overview and design

HbA
1c
(%) FPG (mg/dl) PPG (mg/dl)
Baseline values 9.5 219 263
n 147 317 295
Levemir

OAD:
Indonesia efficacy results
-101*
-115*
-120
-100
-80
-2.2*
-3.0
-2.0
-1.0
0.0
C
h
a
n
g
e

f
r
o
m

b
a
s
e
l
i
n
e

t
o


w
e
e
k

2
4

Insulin nave
*p<0.001
Levemir

OAD:
Indonesia hypoglycaemia results
5,10
0,30
4,80
0,00 0,00 0,00
0,0
1,0
2,0
3,0
4,0
5,0
6,0
Overall Major Nocturnal
Insulin nave Insulin nave Insulin nave
No. of pt w/hypo 19 0 1 0 18 0
P
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w
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a
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l
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o
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e

e
v
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t

Baseline
24 weeks
AGENDA
Diabetes is a progressive disease and is increasing
in prevalence
The mapping of insulin treatment based recent guidelines
Insulin Initiation, when we should start with basal insulin
Conclusion


32
How to Intensify
Premixed insulin, simple and effective
33
Postprandial hyperglycaemia: Role
in diabetic complications
Postprandial hyperglycaemia: An independent risk
factor for macrovascular complications
Postprandial hyperglycaemia is associated with
increased risk of retinopathy
Postprandial hyperglycaemia causes oxidative
stress, inflammation and endothelial dysfunction
Postprandial hyperglycaemia is associated with
decreased myocardial blood volume and
myocardial blood flow
Guideline for Management of Postmeal Glucose (IDF, 2007).
34
The association between post-challenge
glycaemia and mortality
Adjusted for age, centre, sex, cholesterol, BMI, SBP, smoking
2.5
0
H
a
z
a
r
d

r
a
t
i
o


f
o
r

m
o
r
t
a
l
i
t
y

2.0
1.5
1.0
0.5
2.5
0
2.0
1.5
1.0
0.5
H
a
z
a
r
d

r
a
t
i
o


f
o
r

m
o
r
t
a
l
i
t
y

>7.8
7-7.7
6.1-6.9
<6.1
<7.8
7.8-11.0
>11.0
The DECODE Study Group. Lancet 1999;354(9179):617-21.
35
ADA/EASD algorithm for the
management of T2DM
At diagnosis:
Lifestyle + Metformin
Lifestyle + Metformin
+ Basal insulin
Lifestyle + Metformin
+ Sulfonylureas
Lifestyle + Metformin
+ Intensive insulin
Tier 1: well-validated therapies
STEP 1 STEP 2
STEP 3
Tier 2: Less well validated therapies
Lifestyle + metformin
+ Pioglitazone
+ Sulfonylurea
Lifestyle + metformin
+ Basal insulin
Lifestyle + metformin
+ GLP-1 agonist
No hypoglycaemia
Weight loss
Nausea/vomiting
Lifestyle + Metformin
+ Pioglitazone
No hypoglycaemia
Oedema/CHF
Bone loss
Nathan D, et al. Diabetes Care 2009;32:193203.
36
Plasma Insulin
Normal 24 Hr Insulin Profiles & Bd premix
Bd premix Bd premix
37
NovoMix 30 provides better
HbA1c reduction than Mixtard 30
65%
35%
30%
13.3%
0%
10%
20%
30%
40%
50%
60%
70%
ADA target (HbA1c < 7.0%) AACE target (HbA1c > 6.5%)
P
r
o
p
o
r
t
i
o
n
s

a
c
h
i
e
v
i
n
g

H
b
A
1
c

t
a
r
g
e
t
s
NovoMix 30
Mixtard 30
p<0.05
p<0.05
Velojic-Golubovic M et al. J Endocrinol Invest. 2009;32(1):23-7.
38

Low risk of major hypoglycemia

Boehm et al. Eur J Internal Med 2004;15:496-502

0
2
4
6
8
10
12
1st year 2nd year
Year of study
P
a
t
i
e
n
t
s

w
i
t
h

a
t

l
e
a
s
t

o
n
e

m
a
j
o
r


e
p
i
s
o
d
e

(
%
)

p = NS
p = 0.04
BIAsp 30
Human Premix 30
5%
8%
0%
10%
Two Year
Long-term Safety
39
Basal-Bolus Strategy as Ideal
Concept
Levemir-Novorapid
Date Presentation title 40

10
The Basal/Basal Plus strategy for T2DM
Stepwise intensification of treatment for continuity of control
Progressive deterioration of -cell function
Lifestyle changes
Oral agents
Basal
Add basal insulin and titrate
Basal Plus
Add prandial insulin at main meal
HbA
1c
above target
FBG above target
HbA
1c
above target
Basal bolus
Additional prandial
doses as needed
FBG at target
HbA
1c
above target
Adapted from Raccah D, et al. Diabetes Metab Res Rev 2007 (in press).
Date Presentation title 41
Starting Basal-Bolus Program
In general
Calculate Total Daily Dose by using 0.5 times
to Patient Body Weight (kg)
Example :
Patients Body weight : 60 kg
Total daily dose is : 0.5 x 60 kg : 30 iu

Use 60% of Total Daily Dose as Prandial dose
(divided by 3) and 40% of TDD as Basal dose
PERKENI, Petunjuk praktis terapi insulin pada pasien DM, 2007
Date Presentation title 42
Petunjuk Praktis Basal Bolus

Regimen Basal Bolus
Date Presentation title 43
Makan
Pagi
Makan
Siang
Makan
Malam
Sebelum tidur
Levemir
NovoRapid
Insulin endogen
----
----
Regimen Basal Bolus



44
Time of day (hours)
400
300
200
100
0
06.00 06.00 10.00 14.00 18.00 22.00 02.00
P
l
a
s
m
a

g
l
u
c
o
s
e

(
m
g
/
d
l
)

Normal
Meal Meal Meal
20
15
10
5
0
P
l
a
s
m
a

g
l
u
c
o
s
e

(
m
m
o
l
/
l
)

Suntikkan 10 iu Levemir sekali sebelum tidur. Atur
dosisnya (+3 atau -3) setiap 3 hari sd. GDP mencapai
target GDP 80-110 mg/dL (Perkeni 2006)
Hyperglycaemia due to an increase in fasting glucose
T2DM
Tambahkan Injeksi NovoRapid di setiap makan (2-6 iu)
untuk mengendalikan Gula darah 2 jam PP mencapai target
< 180 mg/dL (Perkeni 2006)
Basal Bolus Concept dengan Levemir -
NovoRapid
Profile T2DM
Conclusion

Diabetes is a progressive disease that is increasing in prevalence in the
world
Starting with basal insulin detemir is easy way 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.

46