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TERAPI INSULIN ANALOG PADA

DIABETES DENGAN KEHAMILAN

Oleh Bowo Pramono, Suharnadi Fx

C V BOWO PRAMONO

Lahir Tegal 27 jan 1959

Dokter Umum dari FK UGM 1985

Dokter SpPD dari FK UGM 1997

KEMD dari Kolegium Penyakit Dalam 2008

Puskesmas Kedung Waringin Bekasi 1985-92

RSU selong Lombok Timur 1998-2004

RSUP DR Sardjito 2004-sekarang

Jabatan sekarang:

Ketua KSM Peny Dalam RSUP DR Sardjito Ketua PAPDI cabang Yogyakarta

PENDAHULUAN

Pedersen (1954) hiperglikemia pada ibu hamil

menyebabkan makrosomia

Frienkel: asam amino rantai cabang dan asam

lemak bebas meningkatkan sekresi insulin pada janin

Casson (UK) : DM tipe 1 yang hamil

malformasi janin (10x), lahir mati (5x), kematian perinatal (3x)

PENDAHULUAN

Intensifikasi insulin pada ibu hamil

menurunkan kejadian malformasi janin

(DCCT) pada 680 wanita hamil dengan DM

Patogenesis hiperglikemia malformasi janin multifaktorial : defisiensi myoinositol,

defisiensi asam arakhidonat dan peningkatan

radikal bebas

PENDAHULUAN

Komplikasi hiperglikemia pada neonatus :

Hipokalsemia

Hipoglikemia

Hiperbilirubinemia

Makrosomia Intra uterine growth retardation

Respiratory distress syndrome

Policitemia Hipertropic cardiomyopati

METABOLISME PADA IBU HAMIL

Trimester pertama : sensitivitas insulin masih

normal

Trimester kedua dan ketiga : menurun sampai

akhir kehamilan (50%)

Resistensi insulin disebabkan oleh hormon-

hormon fetoplacenta : hormon placental

lactogen, estrogen, progesteron, hormon chorionic somatropin

METABOLISME PADA IBU HAMIL

Resistensi insulin pada ibu hamil lebih

dominan pada otot skeletal dibandingkan

jaringan adiposa

Sekresi insulin akan meningkat disertai hipertrofi dan hiperplasi sel beta pankreas

untuk mengatasi resistensi insulin

Sensitifitas insulin menurun glukosa post prandial meningkat janin

METABOLISME PADA IBU HAMIL

Sintesis asam lemak meningkat cadangan

makanan janin facilitated anabolism

Difusi glukosa dan transport aktif asam amino

melalui placenta akan menimbulkan

hipoglikemia dan hipoalaninemia pada ibu accelerated starvation

Bila sekresi insulin tidak cukup untuk

mengatasi resistensi insulin gestational diabetes (5% dari kehamilan normal)

KEBUTUHAN INSULIN MENINGKAT PADA IBU HAMIL

KEBUTUHAN INSULIN MENINGKAT PADA IBU HAMIL

KADAR GLUKOSA DARAH PADA IBU HAMIL YANG MEMERLUKAN INSULIN

Tabel 2.

KADAR GLUKOSA DARAH PADA IBU HAMIL YANG MEMERLUKAN INSULIN • Tabel 2.

UPAYA MENCEGAH MALFORMASI KONGENITAL

Perencanaan makan

Pemantauan gula darah mandiri

Pengaturan dosis insulin mandiri

Penanganan terhadap hipoglikemia

Aktifitas fisik yang benar

Pengelolaan stres

PENINGKATAN KEBUTUHAN DOSIS INSULIN

Tabel 3. Suggested Starting Total Daily Insulin During Pregnancy

PENINGKATAN KEBUTUHAN DOSIS INSULIN Tabel 3. Suggested Starting Total Daily Insulin During Pregnancy

TARGET GLUKOSA DARAH PADA IBU HAMIL

Tabel 4. Self Monitored Blood Glucose (SMBG) Plasma Goals

TARGET GLUKOSA DARAH PADA IBU HAMIL Tabel 4. Self Monitored Blood Glucose (SMBG) Plasma Goals

PENGGUNAAN INSULIN ANALOG

Insulin lispro digunakan pertama kali pada th

1996

Bentuk heksamer yang cepat terdisosiasi

menjadi monomer

Masa kerja cepat 2-4 jam, kadar puncak 1 jam

Dibandingkan insulin reguler : penurunan gula

darah dan HBA1C lebih baik dan resiko hipoglikemia lebih rendah

PENGGUNAAN INSULIN ANALOG

Insulin aspart digunakan pertama kali th 1999

Bentuk heksamer

Masa kerja 2-4 jam

Kadar puncak 30-70 mnt

Dibandingkan dengan insulin reguler:

penurunan gula darah dan HBA1C lebih

rendah dengan episode hipoglikemia yang

50% lebih rendah

Insulin glargine digunakan pertama kali th

2000

Perubahan pH:5,4 6,7 : lebih stabil

Masa kerja 24 jam, mulai beraksi dalam 90 mnt

Tidak memiliki masa puncak peakless

Resiko hipoglikemia jauh lebih kecil

INSULIN ANALOG DAN KEHAMILAN

Rapid acting insulin analog bermanfaat pada

ibu hamil dengan diabetes

Cepat menurunkan glukosa pstprandial

Mengurangi resiko hipoglikemia karena masa kerjanya yang singkat

Insulin glargine bermanfaat pada pasien DM

tipe 1 yang hamil mengurangi nokturnal hipoglikemia

IMUNOGENESITAS

Insulin akan masuk placenta bila terbentuk

komplek antigen-antibodi

Tidak terdapat kadar insulin lispro dalam

darah tali pusat (sejak umur 26 minggu kehamilan)

Kadar antibodi anti insulin hampir sama

antara insulin lispro dan insulin reguler

TERATOGENESITAS DAN EMBRIOTOKSISITAS

Tidak ada bukti adanya teratogenesitas dan

embriotoksisitas baik pada inslin lispro, aspart

maupun reguler

Penelitian retrospektif pada 867 wanita hamil dengan insulin, malformasi kongenital : 4,8%

(lispro) dan 6,8% (reguler) meskipun tidak

berbeda bermakna (Lapolla, 2005)

MITOGENESITAS

Mitogenesitas dikaitkan dengan keterikatan

insulin dengan reseptor IGF-1

Tidak ada perbedaan yang bermakna antara

insulin lispro, aspart dan reguler dalam ikatannya dengan reseptor IGF-1

Keterikatan insulin dengan reseptor IGF-1

lebih berhubungan dengan kejadian retinopati diabetika

MITOGENESITAS

Tidak ada perbedaan yang bermakna antara

insulin lispro, aspart maupun reguler terhadap

kemungkinan menimbulkan retinopati

diabetik, atau memperburuk kondisi retinopati yang sudah ada

The usage of Basal Insulin Therapy

in Special Population (Focus on Pregnancy)

23

Insulin Usage in Pregnancy

Background: diabetes and pregnancy

Pre-existing diabetes in pregnancy is associated with high rates of fetal, neonatal and maternal complications 1

Recommended glycaemic control targets for pregnant women are more strict than for regular patients with diabetes 2

Many women use long-acting insulin analogues and would like to know that they are safe to continue doing so during pregnancy 3

Data on the use of insulin detemir in pregnant women with type

1 diabetes are now available; studies in women with type 2 diabetes are ongoing

available; studies in women with type 2 diabetes are ongoing 1. Dunne et al. Diabetes Care

1. Dunne et al. Diabetes Care 2009;32:12056. 2. Kitzmiller et al. Diabetes Care 2008;31:106079. 3. Mathiesen et al. Diabetes Care

2012;35:20127

– 6. 2. Kitzmiller et al. Diabetes Care 2008;31:1060 – 79. 3. Mathiesen et al. Diabetes

RCT comparing insulin detemir with NPH

insulin in 310 pregnant women with type

1 diabetes

Overall aims To compare the efficacy and safety of insulin detemir with NPH insulin in
Overall aims
To compare the efficacy and safety
of insulin detemir with NPH insulin in
pregnant women with type 1
diabetes
Maternal
endpoints:
Neonatal
endpoints:
glycaemic control,
hypoglycaemia and
safety 1
perinatal and obstetric
pregnancy outcomes 2
Main inclusion criteria Main exclusion criteria • Treatment with insulin for ≥12 months • Impaired
Main inclusion
criteria
Main exclusion
criteria
• Treatment with
insulin for ≥12
months
• Impaired
hepatic or renal
function
• Planning to
• Uncontrolled
become pregnant
hypertension
and HbA 1c ≤9.0%
• Pregnant with a
singleton
pregnancy of 8–
12 gestational
weeks
• Use of in vitro
fertilisation or
other medical
infertility
treatment
• At confirmation of
pregnancy,
HbA 1c ≤8.0%
• Previous
randomisation
in this trial
HbA 1c ≤8.0% • Previous randomisation in this trial 1. Mathiesen et al. Diabetes Care 2012;35:2012

1. Mathiesen et al. Diabetes Care 2012;35:20127; 2. Hod et al. J Matern Fetal Neonatal Med

2014;27:713

trial 1. Mathiesen et al. Diabetes Care 2012;35:2012 – 7; 2. Hod et al. J Matern

Study withdrawal criteria and participant disposition

313 randomly assigned

313 randomly assigned
152 insulin detemir 161 NPH insulin 3 participants did not receive study drug Full analysis
152 insulin detemir
161 NPH insulin
3 participants did not
receive study drug
Full analysis set: 152
79 pregnant at randomisation
Full analysis set: 158
83 pregnant at randomisation
73 randomised before pregnancy
75 randomised before pregnancy
25 withdrawals
22 further
withdrawals

152 pregnancies

25 withdrawals 22 further withdrawals 152 pregnancies 160 pregnancies* 145 (91%) pregnancy outcome Main withdrawal

160 pregnancies*

22 further withdrawals 152 pregnancies 160 pregnancies* 145 (91%) pregnancy outcome Main withdrawal criteria: •

145 (91%) pregnancy outcome

Main withdrawal criteria:

HbA 1c >8.0% at conception

Remaining not pregnant 12 months after randomisation

Multiple pregnancies

Insufficient glycaemic control

Of 470 initial participants,

313 were pregnant during the study

142 (93%) pregnancy outcome

were pregnant during the study 142 (93%) pregnancy outcome 127 (84%) completed per protocol 137 (87%)
were pregnant during the study 142 (93%) pregnancy outcome 127 (84%) completed per protocol 137 (87%)

127 (84%) completed per protocol 137 (87%) completed per protocol

completed per protocol 137 (87%) completed per protocol *2 women became pregnant again after a miscarriage

*2 women became pregnant again after a miscarriage

1. Mathiesen et al. Diabetes Care 2012;35:20127 (and supplementary material)

Adapted from 1

after a miscarriage 1. Mathiesen et al. Diabetes Care 2012;35:2012 – 7 (and supplementary material) Adapted

HbA 1c (%)

Results: HbA 1c levels, insulin detemir vs. NPH insulin

Randomised before pregnancy

7.00 6.75 6.50 6.25 6.00 5.75 0 HbA 1c (%)
7.00
6.75
6.50
6.25
6.00
5.75
0
HbA 1c (%)

Randomised during pregnancy

7.00 6.75 6.50 6.25 6.00 5.75 0
7.00
6.75
6.50
6.25
6.00
5.75
0
8 12 16 20 24 28 32 36 GA (weeks) 44 8 12 16 20
8
12 16 20 24 28 32 36
GA (weeks)
44
8 12 16 20 24 28 32 36
44
1 GA (weeks)
Adapted from
Adapted from
1
Insulin detemir was non-inferior to NPH insulin in terms of HbA 1c
Total pregnant
population
Insulin
NPH
Difference
detemir
insulin
[95% CI]
Mean HbA 1c (%), GW 36
6.27
6.33 –0.06 [–0.21;0.08]
CI, confidence interval; GW, gestational week

1. Mathiesen et al. Diabetes Care 2012;35:20127

Insulin detemirweek 1. Mathiesen et al. Diabetes Care 2012;35:2012 – 7 NPH insulin HbA 1 c levels

NPH insulinet al. Diabetes Care 2012;35:2012 – 7 Insulin detemir HbA 1 c levels were similar between

HbA 1c levels were similar between

treatments

Overall, the treatment target of HbA 1c ≤6.0% at GWs 24 and 36 was obtained
Overall, the treatment
target of HbA 1c ≤6.0%
at GWs 24 and 36 was
obtained in 41% of
women treated with
insulin detemir vs. 32%
those treated with NPH
insulin (p=0.280)
24 and 36 was obtained in 41% of women treated with insulin detemir vs. 32% those

HbA 1c (%)

Results: maternal FPG, insulin detemir vs.

NPH insulin

Randomised before pregnancy

Randomised during pregnancy

7.00 7.00 6.50 6.50 6.00 6.00 5.50 5.50 5.00 5.00 4.50 4.50 0 0 8
7.00
7.00
6.50
6.50
6.00
6.00
5.50
5.50
5.00
5.00
4.50
4.50
0
0
8
12 16 20 24 28 32 36
GA (weeks)
8 12 16 20 24 28 32 36
1 GA (weeks)
Adapted from
Adapted from
1
Mean FPG,
Insulin
NPH
total pregnant
95% CI
P -value
detemir
insulin
population
At GW 36,
mmol/L
4.8
5.4
−1.2;−0.1
0.017
At GW 24,
mmol/L
5.4
6.3
−1.7;−0.2
0.012
HbA 1c (%)

1. Mathiesen et al. Diabetes Care 2012;35:20127

Insulin detemir1c (%) 1. Mathiesen et al. Diabetes Care 2012;35:2012 – 7 NPH insulin Maternal FPG was

NPH insulinet al. Diabetes Care 2012;35:2012 – 7 Insulin detemir Maternal FPG was significantly lower with insulin

Maternal FPG was significantly lower with insulin detemir compared with NPH insulin The difference was
Maternal FPG was
significantly lower
with insulin
detemir compared
with NPH insulin
The difference was
most pronounced in
those randomised
before pregnancy
insulin detemir compared with NPH insulin The difference was most pronounced in those randomised before pregnancy

Results: maternal hypoglycaemia, insulin

detemir vs. NPH insulin

Major hypoglycaemia rate

Minor hypoglycaemia rate
Minor hypoglycaemia rate
2,0 16 vs. 21% of patients 1,6 11 vs. 19% of patients 1,2 0,8 9
2,0
16 vs. 21%
of patients
1,6
11 vs. 19%
of patients
1,2
0,8
9 vs. 6%
of patients
0,4
0,0
Overall
Daytime
Nocturnal
per yearEpisodes
Episodes per year

100,0

80,0

60,0

40,0

20,0

0,0

95 vs. 92%

of patients

Insulin detemir NPH insulin
NPH insulinInsulin detemir

76 vs. 80% of patients
76 vs. 80%
of patients

95 vs. 92% of patients

Overall

Daytime Nocturnal

Based on 1 Based on 1 Maternal hypoglycaemia rates were similar with insulin detemir and
Based on 1
Based on 1
Maternal hypoglycaemia rates were similar with insulin detemir
and NPH insulin
p=NS for all rates

Based on: 1. Mathiesen et al. Diabetes Care 2012;35:20127

Summary (Levemir)

Insulin detemir is non-inferior to NPH insulin for HbA 1c at 36 GW when given as a treatment for type 1 diabetes 1

FPG was significantly lower in patients receiving insulin detemir compared with NPH insulin at 24 and 36 GW 1

Rates of major hypoglycaemia were low and similar between groups 1

Studies in pregnant women with type 2 diabetes are

ongoing

Studies in pregnant women with type 2 diabetes are ongoing 1. Mathiesen et al. Diabetes Metab

1. Mathiesen et al. Diabetes Metab Res Rev 2011;27:54351

Studies in pregnant women with type 2 diabetes are ongoing 1. Mathiesen et al. Diabetes Metab

NovoRapid ® in Gestational

Global Guideline Pregnancy and Diabetes International Diabetes Federation, 2009

and Diabetes International Diabetes Federation, 2009 • “The rapid -acting analogue, insulin aspart, has been
and Diabetes International Diabetes Federation, 2009 • “The rapid -acting analogue, insulin aspart, has been

• “The rapid-acting analogue,

insulin aspart, has been shown

to be safe and effective in pregnancy in type 1 diabetes [85,86] and GDM [87].”

• “The use of these analogues has

been the subject of a systematic

review [88].”

85. Mathiesen ERet al. Diabetes Care 2007; 30: 771-6. 86. Hod M, et al. Am J Obstet Gynecol 2008; 198 (2): 186.e1186.e7.

87. Pettitt Det al. Diabet Med 2007; 24: 1129-35. 88. Plank J, et al. Arch Intern Med 2005; 165: 1337-44.

NovoRapid in Pregnancy

APPROVED FOR USE IN PREGNANCY based on multicentric randomized clinical trials

APPROVED BY EMEA (EU)

US FDA Approved: Category B

APPROVED BY BPOM

multicentric randomized clinical trials • APPROVED BY EMEA (EU) • US FDA Approved: Category B •
multicentric randomized clinical trials • APPROVED BY EMEA (EU) • US FDA Approved: Category B •

glucose (mmol/L)Plasma

Better PPG control during Gestation

Mean prandial increments

2.0 * p < 0.01 * p < 0.05 (n = 322) 1.5 NovoRapid ®
2.0
* p < 0.01
* p < 0.05
(n = 322)
1.5
NovoRapid ®
(mean±2SEM)
1.0
HI
(mean±2SEM)
0.5
0
-0.5
-1.0
Visit
VP1*
VP2
VP3
VP4

* Only subjects pregnant after screening

Mathiesen ER et al. Diabetes Care 2007;30(4):771-6.

(episodes/year)

Rate

Lower Risk of Hypoglycemia

2.5

2.0

1.5

1.0

0.5

0

NovoRapid ® ®

HI2.5 2.0 1.5 1.0 0.5 0 NovoRapid ® p=0.362 28% lower risk p=0.660 15% lower risk

p=0.362 28% lower risk p=0.660 15% lower risk p=0.096 52% lower risk 24h Nocturnal Daytime
p=0.362
28% lower risk
p=0.660
15% lower risk
p=0.096
52% lower risk
24h
Nocturnal
Daytime

Of 322 pregnant subjects, a total of 73 subjects experienced 287 major hypoglycaemic episodes.

RR=Relative Risk.

Mathiesen ER et al. Diabetes Care 2007;30(4):771-6.

Perinatal Outcomes

NovoRapid RHI N 137 131 Birth weight (gm) 3438±71.5 3555±72.9 Preterm delivery, N (%) 28
NovoRapid
RHI
N
137
131
Birth weight (gm)
3438±71.5
3555±72.9
Preterm delivery, N (%)
28
(20%)
41
(31%)
Neonatal hypo requiring
46
(34%)
52
(40%)
treatment

Summary (Novorapid)

NovoRapid ® treatment Safe in Mother:

52% lower risk of major nocturnal hypoglycaemia

better glycaemic control

NovoRapid ® treatment Safe for Child:

Fewer preterm deliveries

Fewer neonatal hypoglycaemic episodes

RINGKASAN

Kebutuhan insulin meningkat pada ibu hamil,

karena adanya resistensi insulin dan hormon-

hormon kontra insulin dari fetoplacental

Insulin analog lebih baik dibandingkan insulin reguler meskipun tidak terdapat perbedaan

yang bermakna, karena lebih cepat

menurunkan glukosa postprandial dengan efek hipoglikemik yang lebih rendah

TERIMA KASIH

TERIMA KASIH