RTD LEVEMIR

Outlines

• Prevalence
• Current management
• Rationale for early initiation
• Insulin guideline
• Insulin detemir profile
• Glycaemic control, weight benefit, hypoglycaemia using insulin
detemir
• Insulin detemir in special population
• Summary
 Indonesia is One of The Largest Diabetes Population

Top 10 Countries/Territories of number

Of people with diabetes (20-79 years), 2014

China 96,2

India 66,8

USA 25,7

Brazil 11,6

Indonesia 9,1 5
Mexico 9

7 Egypt 7,5

German 7,2
7
Turkey 7,2

Japan 7,2

Prevalence: 5,55% (adult pop.) Prevalence: 5,55% (adult pop.)

Sources :
1. IDF Diabetes Atlas, 6th ed
2. IDF Diabetes Atlas 6th ed UPDATE
3. IDF Diabetes Atlas, 7th ed
Top ten countries/territories for the number of the people with
impaired glucose tolerance (PRE-DIABETES) (20-79 y.o), 2015 and
2024

IDF Atlas 7th edition, 2015

Outlines

• Prevalence
• Current management
• Rationale for early initiation
• Insulin guideline
• Insulin detemir profile
• Glycaemic control, weight benefit, hypoglycaemia using insulin
detemir
• Insulin detemir in special population
• Summary
Pharmacological interventions in T2D
Plasma glucose
α-Glucosidase Glitazones
Carbohydrate Glucose Glucose
inhibitors
absorption production uptake (+)
(–)

(–)
Metformin Insulin (+)
secretion

Insulin
(+)
Sulphonylureas
Meglitinides
GLP-1 analogues
DPP-4 inhibitors
 Insulin remains the most efficacious glucose
lowering agent
Decrease in HbA1c: Potency of monotherapy
HbA1c %

CHOOSING INSULIN EARLIER

FOR BETTER EFFICACY

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

Outlines

• Prevalence
• Current management
• Rationale for early initiation
• Insulin guideline
• Insulin detemir profile
• Glycaemic control, weight benefit, hypoglycaemia using insulin
detemir
• Insulin detemir in special population
• Summary
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)
SOLVE: HbA1c at time of insulin initiation
Baseline HbA1c at time of
insulin initiation
10.0 9,8 9,8 • The average HbA1c was 8.9%
9.5 9,4 • Prior to insulin initiation, patients
9,2 9,1 had received OAD therapy for
8,9 8,9 8.7±6.7 years
HbA1c (%)

9.0
8,5 8,4 • Patients remain poorly controlled
8.5 8,3 on OAD treatment for prolonged
periods of time
8.0

7.5

Khunti et al. Diabetes Obes Metab 2012;14(7):654–61

Reduction in HbA1c with OADs and insulin
−1.3%*

10.0 +0.2%
−0.5%*
−1.0%*

9.0 Pre-treatment
Mean HbA1c (%)

Post-treatment

8.0

7.0

6.0
Two OADs Three OADs Four OADs Insulin

*p<0.001
Calvert et al. Br J Gen Pract 2007;57:455–60
Outlines

• Prevalence
• Current management
• Rationale for early initiation
• Insulin guideline
• Insulin detemir profile
• Glycaemic control, weight benefit, hypoglycaemia using insulin
detemir
• Insulin detemir in special population
• Summary
Outlines

• Prevalence
• Current management
• Rationale for early initiation
• Insulin guideline
• Insulin detemir profile
• Glycaemic control, weight benefit, hypoglycaemia using insulin
detemir
• Insulin detemir in special population
• Summary
 Levemir®
LysB29(N-tetradecanoyl)des(B30) human insulin

Phe Phe Gly Arg

Albumin- Pro
Thr
Tyr Glu
Gly
Cys
binding moeity Thr
Lys
Lys
B29 A21 Asn Cys
Val
Tyr Leu
A1 Gly Asn Tyr
Ile Glu Leu
Val Leu Ala
Glu Gln Glu
Gln Tyr Val
Cys Leu
Cys Ser Leu
Thr Ser Ile Cys
His
Ser
Gly
Cys
Gln His Leu
B1 Phe Val Asn

Whittingham et al. Biochemistry 1997;36:2826

 Insulin detemir molecule: dimer and hexamer
The protracted action of insulin detemir is mediated by a combination of
self-association of insulin detemir molecules at the injection site and albumin
binding via the myristic acid side-chain

Monomer Dimer Hexamer Di-hexamer

A-chain B-chain Myristic acid residue Zn2+
Hamilton-Wessler et al. Diabetologia 1999;42:1254–63
 Insulin detemir molecule: sites of protraction

Subcutaneous Major protraction

depot
Self-association + albumin binding

Minor protraction
Circulation
Albumin binding

Interstitial fluid No further significant protraction

Hamilton-Wessler et al. Diabetologia 1999;42:1254–63

 PK/PD: dose response in type 2 diabetes
Dose-proportional glucose-lowering effect and duration of action

Insulin detemir
0.4 U/kg 0.8 U/kg 1.4 U/kg
Insulin glargine
3.0
No
Glucose infusion

(mg/kg/min)

2.5 significant
2.0 between-
rate

1.5 treatment
difference at
1.0
each dose
0.5 level
0
0 2 4 6 8 10 12 14 16 18 20 22 24
Time from insulin injection (hours)

PD, pharmacodynamics; PK, pharmacokinetics

Klein et al. Diabetes Obes Metab 2007;9:290–9
 PK/PD: duration of action in type 2 diabetes
CGM shows similar blood glucose levels for once-daily insulin detemir and insulin
glargine
Insulin injection Insulin detemir once daily
Insulin glargine once daily

12

Blood glucose (mmol/L)

9

Time of day

24-h glucose profiles. Each point represents the treatment groups’ mean glucose for each hour and standard error of 29 subjects treated with
once-daily insulin detemir or glargine starting at 20:00 hours. The basal period is from 24:00 hours to 06:00 hours.

CGM, continuous glucose monitoring system; PD, pharmacodynamics; PK, pharmacokinetics

King et al. Diabetes Obes Metab 2009;11:69–71

Insulin Detemir demonstrate less intra-individual day-
to-day variability
NPH NPH NPH

Glargine Glargine Glargine

Detemir Detemir Detemir

20
Adapted from Heise T et al. Diabetes. 2004;53:1614-20.
Outlines

• Prevalence
• Current management
• Rationale for early initiation
• Insulin guideline
• Insulin detemir profile
• Glycaemic control, weight benefit, hypoglycaemia using
insulin detemir
• Insulin detemir in special population
• Summary
 Type 2 diabetes: basal–oral – HbA1c
Similar or less change in HbA1c with IDet compared with IGlar and NPH insulin
NS NS NS p<0.05
9.5
OD BID
9.0 Insulin detemir
NPH insulin
8.5
HbA1c (%)

Insulin glargine
8.0

7.5

7.0

6.5

Philis-Tsimikas Hermansen Rosenstock Meneghini

2006 2006 2008 2013
BID, twice daily; IDet, insulin detemir; IGlar, insulin glargine; NPH, neutral protamine Hagedorn;
NS, not significant; OD, once daily
 Type 2 diabetes: basal–oral – FPG
Similar FPG with IDet compared with IGlar and NPH insulin
NS NS NS NS
12.0
OD BID
11.5
11.0 Insulin detemir
10.5 NPH insulin
FPG (mmol/L)

10.0
9.5 Insulin glargine
9.0
8.5
8.0
7.5
7.0
6.5
6.0

Philis-Tsimikas Hermansen Rosenstock Meneghini

2006 2006 2008 2013
BID, twice daily; FPG, fasting plasma glucose; IDet, insulin detemir; IGlar, insulin glargine;
NPH, neutral protamine Hagedorn; NS, not significant; OD, once daily
 Type 2 diabetes: basal–oral – hypoglycaemia
Significantly less hypoglycaemia compared with NPH insulin

1.3 NS
1.2 Insulin detemir
p<0.02 p=0.031 p<0.001 p<0.001 NS NS p<0.05
1.1
1.0
NPH insulin
0.9
Insulin glargine
Relative risk

0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Overall Nocturnal Overall Nocturnal Overall Nocturnal Overall Nocturnal
Philis-Tsimikas 2006 Hermansen 2006 Rosenstock 2008 Meneghini 2013

Based on biochemically confirmed events: plasma glucose <3.1 mmol/L

NPH, neutral protamine Hagedorn; NS, not significant
 Type 2 diabetes: basal–oral – weight
Less weight gain with IDet compared with NPH insulin and IGlar across all trials
p<0.001

p<0.05
Insulin detemir
p<0.005 p<0.001 NS p<0.001
4.0
NPH insulin
3.5
Weight change (kg)

3.0 Insulin glargine

2.5
2.0
1.5
1.0
0.5
BID OD
0
-0.5

Philis-Tsimikas Hermansen Rosenstock Meneghini

2006 2006 2008 2013
BID, twice daily; IDet, insulin detemir; IGlar, insulin glargine; OD, once daily; NPH, neutral protamine
Hagedorn; NS, not significant
 Type 2 diabetes: basal–oral – overview

FPG Risk of hypoglycaemia (all)

Study vs. HbA1c change Weight change
change
Overall Nocturnal

No significant No significant Insulin detemir Insulin detemir significantly Insulin detemir significantly
Philis-Tsimikas 2006 NPH difference difference significantly better better than comparator better than comparator
than comparator
No significant No significant Insulin detemir Insulin detemir significantly Insulin detemir significantly
Hermansen 2006 NPH difference difference significantly better better than comparator better than comparator
than comparator
No significant No significant Insulin detemir No significant difference No significant difference
difference difference significantly better
Rosenstock 2008 IGlar than comparator

Comparator No significant Insulin detemir Insulin detemir significantly No significant difference

significantly better difference significantly better better than comparator
Meneghini 2013 IGlar than insulin detemir than comparator

FPG, fasting plasma glucose; IGlar, insulin glargine; NPH, neutral protamine Hagedorn
A1chieve study overview and design

• Observational study of people with T2DM in routine clinical practice

Start a study BASELINE INTERIM FINAL

insulin Week 0 Week 12 Week 24
• Biphasic insulin
aspart 30
• Insulin detemir • Study objectives
• Insulin aspart
• Primary: number of attributed adverse drug
reactions (includes major hypoglycaemia)
• Secondary: other safety and effectiveness
measures
 Starting Insulin Detemir from insulin naive patients
A1chieve Indonesia: efficacy results Insulin naïve

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

Baseline values 9.5 219 263

n 147 317 295

0.0 -80
Change from baseline to

-1.0
week 24

-100
-101*
-2.0
-2.2*

-115*
-3.0 -120

*p<0.001
Soewondo P, et al. Clinical experience with insulin detemir: Results from the Indonesian cohort of the international A1chieve study.
Diabetes Research and Clinical Practice 2013; 100(S1): S47–S53
 Starting Insulin Detemir from insulin naive patients
A1chieve Indonesia: hypoglycaemia results

Overall Major Nocturnal

Insulin naïve Insulin naïve Insulin naïve

6.0
Percent with at least one event

5.10
5.0 4.80

4.0

3.0

2.0

1.0
0.30
0.00 0.00 0.00
0.0
Baseline Week 24 Baseline Week 24 Baseline Week 24

Soewondo P, et al. Clinical experience with insulin detemir: Results from the Indonesian cohort of the international A1chieve study.
Diabetes Research and Clinical Practice 2013; 100(S1): S47–S53
 A1chieve: Self-rated health in Insulin naïve participants
initiated on IDet
Patients on
Best imaginable Levemir®
health 100
90
80
24 weeks
70 Baseline
60
50
40
30 Baseline 24 weeks
20
Worst imaginable
health 10
0
Soewondo P, et al. Clinical experience with insulin detemir: Results from the Indonesian cohort of the international A1chieve study.
Diabetes Research and Clinical Practice 2013; 100(S1): S47–S53
 Summary of A1chieve study in Indonesia
Insulin naïve participants initiated on IDet (Indonesia)

Efficacy Safety Other

Baseline
HbA1c Δ HbA1c Δ FPG Δ PPG Hypoglycaemia Weight

IDet 9.5% ↓2.2% ↓101

mg/dL
↓115
mg/dL
1.0*

Significant improvement
(p<0.001)

*p<0.001

Soewondo P, et al. Clinical experience with insulin detemir: Results from the Indonesian cohort of the international A1chieve study.
Diabetes Research and Clinical Practice 2013; 100(S1): S47–S53
How to Titrate Basal Insulin
Levemir® Dose Titration Guidelines:
3-0-3 Algorithm

Simple Dose titration with Levemir ®

Mean 3-day FPG (mg/dL)

Start with Levemir® 10 U or 0.1-0.2 U per Kg body weight

FPG>110 mg/dL +3U

FPG 80-110 mg/dL 0

FPG <80 mg/dL -3U

Patients who experienced hypoglycemia reduced their daily dose by 3 units

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

Levemir Indonesia Prescribing Information 2017
Outlines

• Prevalence
• Current management
• Rationale for early initiation
• Insulin guideline
• Glycaemic control, weight benefit, hypoglycaemia using insulin
detemir
• Insulin detemir in special population
• Summary
Levemir® is approved in special population

• Levemir® can be used in pregnant women and children ≥ 2 years

Levemir® Indonesia Prescribing Information 2017

Outlines

• Prevalence
• Current management
• Rationale for early initiation
• Insulin guideline
• Insulin detemir profile
• Glycaemic control, weight benefit, hypoglycaemia using insulin
detemir
• Insulin detemir in special population
• Summary
Summary

Indonesia is one of the largest diabetes population

Diabetes is a progressive disease which will lead to the need of insulin

therapy

Insulin therapy is the most efficacious therapy and can reduce HbA1c up to
2,5%

Starting with basal insulin detemir 10 U once daily and titrate based on
patient condition to reach glycemic control

In Indonesia, in real life clinical practice (A1chieve study), Levemir® show

significant improvements in overall glycemic control in terms of HbA1c, FPG,
PPG and patient quality of life