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INITIATING BASAL INSULIN

dr. Miftahurachman, SpPD-KEMD, M.Kes, FINASIM


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

GLP-1 analogue
Pramlintide

Metformin
DPPIV inh

Exenatide

SU/GLIN

Insulin
AGIs

TZD
0

-0,5
HbA1c %

-1

-1,5

-2

-2,5

-3
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
Insulin Detemir
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
B1 Asn Gln His Leu
Phe Val

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 Initiate and Titrate Basal Insulin
Insulin Detemir Dose Titration Guidelines:
3-0-3 Algorithm

Simple Dose titration with Insulin Detemir


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


Paediatric: Background

In 2015, there were 542,000


children and adolescents with type 1
diabetes…

…around 86,000 children


develop type 1 diabetes each year

…and the annual increase in incidence


of type 1 diabetes in children was

3%
IDF Atlas, 7th edition 2015. http://www.idf.org/diabetesatlas
Paediatric: insulin detemir pharmacokinetics
Consistent pharmacokinetic profile across all age groups in T1D

Children (6–12 years)


5000 700
Adolescents (13–17 years)
600 Adults (18–65 years)
4000
Insulin detemir

Human insulin
500
(pmol/L)

(pmol/L)
3000 400

2000 300
200
1000
100
0
0 3 6 9 12 15 18 21 24 0 3 6 9 12 15 18 21 24
Elapsed time (h) Elapsed time (h)

• Open-label, randomised, crossover trial


• All age groups were treated with 0.5 U/kg of
insulin detemir and human insulin
T1D, type 1 diabetes

Danne et al. Diabetes Care 2003;26:3087–92


Paediatric: insulin detemir pharmacokinetics
Less within-subject variability with insulin detemir than insulin glargine in T1D

Children Adolescents Children &


adolescents
CV (%) CV (%)
0 20 40 60 0 20 40 60 CV (%)
Cmax Cmax Cmax 0 20 40** 60
* **
13 9
38 34 12
35
AUC(0–16 h)Ins 10 AUC(0–16 h)Ins 9 AUC(0–16 h)Ins **
* **
25 36 10
31

15 AUC(0–5 h)Ins 20 AUC(0–5 h)Ins 18 **


AUC(0–5 h)Ins
37 * 50 * 45

*p<0.003
Insulin detemir
**p<0.0001
Insulin glargine

AUC, area under the curve; Cmax, maximum concentration; CV, coefficient of variance; Ins, insulin; T1D, type 1 diabetes

Danne et al. Pediatr Diabetes 2008:9:554–60


Paediatric: 2–16 years
Study design – IDet vs. NPH insulin in children with T1D

• In spite of the importance of optimising diabetes care in children, few comparative


randomised clinical trials have been conducted in this age group
• 52-week, randomised 1:1, multinational, open-label, parallel-group, non-inferiority
trial in 347 children and adolescents with type 1 diabetes
• 82 subjects were 2–5 years old

n=177 Insulin detemir once/twice daily


+ mealtime insulin aspart
Main inclusion criteria:
• Type 1 diabetes
for ≥12 months Screening
and consent
• Aged 2–16 years NPH insulin once/twice daily
+ mealtime insulin aspart
• HbA1c ≤11%
• BMI <20 kg/m2 n=171
Week
0 26 52
BMI, body mass index; IDet, insulin detemir; NPH, neutral protamine Hagedorn; T1D, type 1 diabetes

Thalange et al. Diabet Med 2013;30:216–25


Paediatric: 2–16 years
Similar HbA1c and FPG in children with IDet vs. NPH insulin
Insulin detemir
9,0
NPH insulin
9,0

8,5

Mean FPG (mmol/L)


8,5
Mean HbA1c (%)

8,0

7,5
8,0
7,0

6,5
Difference: 0.12 CI [–0.12; 0.36] Difference: –0.63 CI [–1.56; 0.31]
7,5 6,0

Time (weeks) Time (weeks)


CI, confidence interval; FPG, fasting plasma glucose; IDet, insulin detemir; NPH, neutral protamine Hagedorn

Thalange et al. Diabet Med 2013;30:216–25


Paediatric: 2–16 years
Significantly less hypoglycaemia and less inappropriate weight gain vs. NPH insulin

Estimated mean BMI


RR=0.76 (0.60–0.97) Insulin detemir 0.60 Z-score difference:
80 p=0.028 –0.15 CI [–0.23; –
NPH insulin
0.07]; p<0.001
70 0.50

60
(events/patient/year)
Hypoglycaemia rate

BMI Z-score*
0.40
50
40 0.30

30 0.20
RR=0.62 (0.47–0.84)
20 p=0.002
0.10
10
0 0
Overall Nocturnal Baseline 12 24 36
Time (weeks)
*A BMI Z-score indicates how many units a child’s BMI is above or below the average BMI value for their age group and sex.
BMI, body mass index; CI, confidence interval; NPH, neutral protamine Hagedorn; RR, relative risk

Thalange et al. Diabet Med 2013;30:216–25


Paediatric: 6–17 years
Study design – IDet vs. NPH insulin in children with T1D

• First study to investigate the efficacy and safety of insulin detemir compared with
NPH insulin in children with type 1 diabetes
• 26-week, randomised 2:1 (insulin detemir:NPH), multinational, open-label, parallel-
group trial in 347 children and adolescents, aged 6–17 years

Insulin detemir once/twice daily


Main inclusion criteria
+ mealtime insulin aspart
• Children with type 1
diabetes (6–17 years n=232
of age) 140 pre-pubertal and
207 pubertal children
• Treated with insulin and adolescents
≥12 months (total NPH insulin once/twice daily
insulin dose n=115 + mealtime insulin aspart
≤2 U/kg/day )
20 weeks’
6 weeks’
• HbA1c ≤12% maintenance period
titration period

NPH, neutral protamine Hagedorn; T1D, type 1 diabetes

Robertson et al. Diabet Med 2007;24:27–34


Paediatric: 6–17 years
Similar HbA1c, lower FPG and less within-subject variation with IDet

Insulin detemir NPH insulin p-value

HbA1c, %* 8.0 (0.1) 7.9 (0.1) NS

FPG, mmol/L 8.4 (0.3) 9.6 (0.4) 0.022

Within-subject SD (CV [%]), FPG 3.3 (40.4) 4.3 (46.0) <0.001

*Baseline-adjusted
Data for HbA1c and FPG are mean (SD)
CV, coefficient of variance; FPG, fasting plasma glucose; IDet, insulin detemir; NS, not significant; SD, standard deviation

Robertson et al. Diabet Med 2007;24:27–34


Paediatric: 6–17 years
Lower risk of hypoglycaemia and lower inappropriate weight gain with IDet

p<0.001
26% reduction Treatment difference:
Relative risk‡ of event with

−0.18
insulin detemir vs. NPH

NS p=0.041 NS NS
1,0 0,3 CI [−0.26;−0.1]

BMI Z-score*
0,8
0,6 0,2
0,4 Insulin detemir

0,2 0,1 NPH insulin

0,0
Overall Nocturnal Major Confirmed
Type of hypoglycaemic event 0

Lower risk of nocturnal hypoglycaemia Lower BMI Z-score with insulin detemir
with insulin detemir than NPH insulin than NPH insulin after 26 weeks
‡Relative risk is based on hypoglycaemic episodes during last 20 weeks of treatment (maintenance period)
*A BMI Z-score indicates how many units a child’s BMI is above or below the average BMI value for their age group and sex.
BMI, body mass index; CI, confidence interval; IDet, insulin detemir; NPH, neutral protamine Hagedorn; NS, not significant

Robertson et al. Diabet Med 2007;24:27–34


Paediatric: summary
• The pharmacokinetic profile of insulin detemir shows a consistent
pharmacokinetic profile across age ranges and less variability than NPH
insulin and insulin glargine

• A study in children aged 2–16 years with type 1 diabetes showed that
insulin detemir vs. NPH insulin resulted in similar glycaemic control with
fewer overall and nocturnal cases of hypoglycaemia and less inappropriate
weight gain

• A study in children aged 6–17 years with type 1 diabetes also showed
similar HbA1c with insulin detemir vs. NPH insulin, but with significantly
lower FPG and lower within-subject variability
• Lower nocturnal hypoglycaemia and less weight gain was also demonstrated
FPG, fasting plasma glucose; NPH, neutral protamine Hagedorn
Pregnancy: background
The risk of adverse pregnancy outcomes increases continuously with glucose levels1
30 35
Frequency (%) Birth weight >90th percentile Primary C-section FPG
25 30
25 1-h glucose
20 2-h glucose
20
15
15
10 10
5 5
0 0
1 2 3 4 5 6 7 1 2 3 4 5 6 7

5 Clinical neonatal hypoglycaemia Cord blood serum C-peptide >90th


35
Frequency (%)

30
percentile
4
25
3 20
2 15
10
1
5
0 0
1 2 3 4 5 6 7 1 2 3 4 5 6 7
Glucose category Glucose category

Following the HAPO study1, the ADA, ACOG and IADPSG advocated universal screening for
GDM at 24–28 weeks’ gestation
ACOG, American College of Obstetricians and GynecologistsAADA, American Diabetes Association; FPG, fasting plasma glucose; GDM, gestational diabetes mellitus; HAPO,
Hyperglycemia and Adverse Pregnancy Outcome; IADPSG, International Association of the Diabetes and Pregnancy Study Groups

1. HAPO Study Cooperative Research Group. N Engl J Med 2008;358:1991–2002


Pregnancy: type 1 diabetes
Trial design: IDet vs. NPH insulin

• First randomised clinical trial with a basal insulin analogue in pregnancy


6-week
• Overall aims: to compare the efficacy and safety of insulin detemir with NPH follow-up
insulin in pregnant women with type 1 diabetes
n=73 n=79 Delivery

Inclusion criteria
Insulin aspart/insulin detemir
• Type 1 diabetes for at
least 12 months before
randomisation
• Women planning to
Insulin aspart/NPH insulin
become pregnant/
pregnant with a
singleton pregnancy n=75 n=83
• At confirmation of Women randomised Women randomised
pregnancy, all subjects before pregnancy during pregnancy 6W
with HbA1c ≤8.0%
Visit 0 12W 24W 36W 52W GW GW GW GW
8–12 14 24 36
Visit 0 = assessment/randomisation; GW 8–12 = randomisation (up to gestational age 8–12 weeks)
GW, gestational week; IDet, insulin detemir; NPH, neutral protamine Hagedorn; W, week

Mathiesen et al. Diabetes Care 2012;35:2012–7


Pregnancy: type 1 diabetes – efficacy
Similar HbA1c and lower FPG with IDet compared with NPH insulin
7,0 Insulin detemir NPH insulin
HbA1c in patients randomised Fasting plasma glucose
6,8 before pregnancy 6,5
NS
6,6 6,0
HbA1c (%)

FPG (mmol/L)
p=0.012
6,4 5,5
6,2 5,0 p=0.017

6,0 4,5
5,8 4,0
0 0 8 1012141618202224262830323436

GW
Mean HbA1c (%) Insulin NPH insulin Difference p-
detemir value
At GW 36 (all) 6.27 6.33 –0.06 [–0.21; 0.08] NS
FPG, fasting plasma glucose; GW, gestational week; IDet, insulin detemir; NPH, neutral protamine Hagedorn; NS, not significant; PP, post-partum

Mathiesen et al. Diabetes Care 2012;35:2012–7


Pregnancy: type 1 diabetes
Similar rates of hypoglycaemia with IDet vs. NPH insulin

Insulin detemir NPH insulin NS NS NS

95% vs. 92%


2,0 NS NS NS 110 of patients
95% vs. 92%
1,8 100
Major hypoglycaemia

Minor hypoglycaemia rate


rate (episodes/year)

of patients
1,6 90
16% vs. 21%

(episodes/year)
1,4 of patients 80
1,2 11% vs. 19% 70
of patients
60
1,0
50
0,8
40
0,6 9% vs. 6%
30 76% vs. 80%
of patients
0,4 20
of patients

0,2 10
0,0 0
Overall Daytime Nocturnal Overall Daytime Nocturnal

IDet, insulin detemir; NPH, neutral protamine Hagedorn; NS, not significant

Mathiesen et al. Diabetes Care 2012;35:2012–7


Pregnancy: type 1 diabetes
Similar neonatal outcomes with IDet compared with NPH insulin
Outcomes at follow-up Insulin detemir NPH insulin p-value

Pregnancy, n 142 145 -

Live births, n 128 136 0.284

Early fetal death, n (%) 11 (7.7) 9 (6.2)


Spontaneous abortion 10 (7.0) 8 (5.5) -
Ectopic pregnancy 1 (0.7) 1 (0.7)

Induced abortion, n (%) 1 (0.7) 0 (0) -

Perinatal death, n (%) 2 (1.4) 1 (0.7) -

Neonatal death, n (%) 0 (0) 0 (0) -

Pre-term delivery, <37 weeks, n (%) 26 (20.3) 36 (26.5) 0.238

Macrosomia, >4000 g, n (%) 24 (18.8) 35 (25.7) 0.180

Neonatal hypoglycaemia <24 h post-delivery, n (%) 15 (11.7) 24 (17.6) 0.223

Birth weight, g (SD) 3504 (645) 3571 (601) 0.581

Gestational age at delivery, weeks (SD) 38.2 (1.9) 37.8 (1.5) 0.012

Data are means. IDet, insulin detemir; NPH, neutral protamine Hagedorn; SD, standard deviation

Hod et al. J Matern Fetal Neonatal Med 2014;27:7–13


Pregnancy: type 2 diabetes + GDM
Trial design: IDet vs. NPH insulin

Open-label, non-inferiority, randomised study

Aim: to determine if insulin detemir is non-inferior to NPH insulin in the


treatment of hyperglycaemia in pregnant patients with GDM and
type 2 diabetes

Exclusion criteria:
Inclusion criteria:
• Patients aged <18 years
• Pregnant women with singleton or
• Type 1 diabetes
twin gestation
• Known allergy or prior adverse
• Pre-existing type 2 diabetes or
reaction to NPH insulin or insulin
GDM before week 34
detemir

GDM, gestational diabetes mellitus; IDet, insulin detemir; NPH, neutral protamine Hagedorn

Herrera et al. Am J Obstet Gynecol 2015;doi:10.1016/j.ajog.2015.06.010


Pregnancy: type 2 diabetes + GDM
Insulin detemir is non-inferior to NPH insulin
Treatment difference: 0.12 mmol/L (p=NS)*
Median BG
6.08 5.97 treatment
6 difference:
–0.02 mmol/L
Overall mean glucose

5 (p=NS)

4 Mean BG
(mmol/L)

(excluding type 2
3 diabetes patients)
treatment
2 difference:
0.01 mmol/L (p=NS)
1
0
Insulin detemir NPH insulin
Primary endpoint achieved

*With a one-sided upper 95% confidence limit of 0.31 (less than the maximal acceptable difference of 0.39 mmol/L)
BG, blood glucose; GDM, gestational diabetes mellitus; NPH, neutral protamine Hagedorn; NS, not significant

Herrera et al. Am J Obstet Gynecol 2015;doi:10.1016/j.ajog.2015.06.010


Pregnancy: type 2 diabetes + GDM
Significantly less hypoglycaemia with IDet compared with NPH insulin
p<0.0001 p<0.0001
Insulin detemir
Total number of events (n): 28 102 26 136
NPH insulin
p<0.0001
3,5
p=0.0245 3.02
3,0
Mean number of events

2,5 2.27
Biochemical event =
per patient

Symptomatic
event = at any
2,0 glucose <3.3 mmol/L
blood glucose regardless of the
1,5 presence or absence of
1,0 symptoms
0.67 0.62
0,5
0,0
Symptomatic events Biochemical events

GDM, gestational diabetes mellitus; IDet, insulin detemir; NPH, neutral protamine Hagedorn

Herrera et al. Am J Obstet Gynecol 2015;doi:10.1016/j.ajog.2015.06.010


Pregnancy: type 2 diabetes + GDM
No difference in perinatal and neonatal outcomes with IDet compared with NPH insulin

Insulin detemir NPH insulin p-value


(n=42) (n=45)

Median birth weight, g 3230 [2860–3530] 3235 [2670–3260] 0.87

Median gestational age at 38.9 [37.6–39.3] 38.8 [38.1–39.1] 0.72


delivery, weeks
Agpar score at 5 min <7, n 1 (3%) 0 (0%) 0.48

NICU admission, n 3 (7.5%) 6 (14%) 0.48


Neonatal hypoglycaemia 0 (0%) 2 (5%) 0.50
<2.22 mmol/L, n

Data are medians [interquartile range] or n (percent)


IDet, insulin detemir; NICU, neonatal intensive care unit; NPH, neutral protamine Hagedorn

Herrera et al. Am J Obstet Gynecol 2015;doi:10.1016/j.ajog.2015.06.010


Pregnancy: summary
• Diabetes in pregnancy confers a significant risk of maternal and neonatal
complications
• In pregnant women with type 1 diabetes
• Insulin detemir was non-inferior to NPH insulin for HbA1c at GW 36
• FPG was significantly lower with insulin detemir vs. NPH insulin throughout
pregnancy
• Rates of major hypoglycaemia were low and similar between insulin detemir and
NPH insulin
• Pregnancy outcomes were similar with insulin detemir and insulin glargine
• In pregnant women with type 2 diabetes and gestational diabetes mellitus
• Insulin detemir was non-inferior to NPH insulin in terms of glycaemic control
• NPH insulin was associated with a significantly higher risk of hypoglycaemia vs.
insulin detemir
• No difference in perinatal and neonatal outcomes between insulin detemir and
NPH insulin
FPG, fasting plasma glucose; GW, gestational week; NPH, neutral protamine Hagedorn
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
Thank You