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
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

 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 complications1
• Recommended glycaemic control targets for pregnant women
are more strict than for regular patients with diabetes2
• Many women use long-acting insulin analogues and would like
to know that they are safe to continue doing so during
pregnancy3
• 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

1. Dunne et al. Diabetes Care 2009;32:1205–6. 2. Kitzmiller et al.

Diabetes Care 2008;31:1060–79. 3. Mathiesen et al. Diabetes Care
2012;35:2012–7
RCT comparing insulin detemir with NPH
insulin in 310 pregnant women with type
1 diabetes
Main inclusion Main exclusion
Overall aims criteria criteria
• Treatment with • Impaired
To compare the efficacy and safety insulin for ≥12 hepatic or renal
of insulin detemir with NPH insulin in months function
• Planning to
pregnant women with type 1 • Uncontrolled
become pregnant
diabetes and HbA1c ≤9.0% hypertension
• Pregnant with a • Use of in vitro
Maternal glycaemic control, singleton fertilisation or
pregnancy of 8– other medical
endpoints: hypoglycaemia and
12 gestational infertility
safety1 weeks
Neonatal perinatal and obstetric treatment
• At confirmation of
endpoints: pregnancy outcomes2 • Previous
pregnancy,
randomisation
HbA1c ≤8.0%
in this trial

1. Mathiesen et al. Diabetes Care 2012;35:2012–7; 2. Hod et al. J Matern Fetal Neonatal Med
2014;27:7–13
Study withdrawal criteria and participant
disposition
313 randomly
assigned
Main withdrawal 152 insulin detemir 161 NPH insulin
criteria:
3 participants did not
• HbA1c >8.0% at conception
receive study drug
• Remaining not pregnant
12 months after randomisation
• Multiple pregnancies Full analysis set: 152 Full analysis set: 158
• Insufficient glycaemic control 79 pregnant at randomisation 83 pregnant at randomisation
73 randomised before pregnancy 75 randomised before pregnancy

22 further
25 withdrawals
Of 470 initial participants, withdrawals
313 were pregnant during
the study 152 pregnancies 160 pregnancies*

142 (93%) pregnancy outcome 145 (91%) pregnancy outcome

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

Adapted from1

*2 women became pregnant again after a miscarriage

1. Mathiesen et al. Diabetes Care 2012;35:2012–7 (and supplementary material)
 Results: HbA1c levels, insulin detemir vs.
NPH insulin
Randomised before Randomised during Insulin detemir
pregnancy pregnancy
NPH insulin
7.00 7.00
6.75 6.75
HbA1c levels
HbA1c (%)

HbA1c (%)
6.50 6.50
were similar
6.25 6.25 between
6.00 6.00 treatments
5.75 5.75

0 0 Overall, the treatment

target of HbA1c ≤6.0%
8 12 16 20 24 28 32 36 44 8 12 16 20 24 28 32 36 44 at GWs 24 and 36 was
GA (weeks) Adapted from1 GA (weeks) obtained in 41% of
Adapted from1
women treated with
Insulin detemir was non-inferior to NPH insulin in terms of HbA1c
insulin detemir vs. 32%
those treated with NPH
insulin (p=0.280)
Total pregnant Insulin NPH Difference
population detemir insulin [95% CI]

Mean HbA1c (%), 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;35:2012–7

 Results: maternal FPG, insulin detemir vs.
NPH insulin
Randomised before Randomised during Insulin detemir
pregnancy pregnancy
NPH insulin
7.00 7.00
6.50 6.50
HbA1c (%)

HbA1c (%)
6.00 6.00
5.50 5.50 Maternal FPG was
significantly lower
5.00 5.00 with insulin
4.50 4.50 detemir compared
with NPH insulin
0 0
8 12 16 20 24 28 32 36 8 12 16 20 24 28 32 36
GA (weeks) Adapted from1 GA (weeks)
Adapted from1

The difference was

Mean FPG,
total pregnant
Insulin
detemir
NPH
insulin
95% CI P-value most pronounced in
population those randomised
At GW 36,
4.8 5.4 −1.2;−0.1 0.017 before pregnancy
mmol/L

At GW 24,
5.4 6.3 −1.7;−0.2 0.012
mmol/L

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

Results: maternal hypoglycaemia, insulin
detemir vs. NPH insulin

Major hypoglycaemia rate Minor hypoglycaemia rate

95 vs. 92% Insulin detemir
of patients
2,0 95 vs. 92% NPH insulin
16 vs. 21% of patients
100,0

Episodes per year

of patients
Episodes per year

1,6
11 vs. 19%
of patients 80,0
1,2
60,0
9 vs. 6% 76 vs. 80%
0,8 of patients of patients
40,0

0,4 20,0

0,0 0,0
Overall Daytime Nocturnal Overall Daytime Nocturnal
Based on1 Based on1

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;35:2012–7
Summary (Levemir)
• Insulin detemir is non-inferior to NPH insulin for HbA1c at
36 GW when given as a treatment for type 1 diabetes1
• FPG was significantly lower in patients receiving insulin
detemir compared with NPH insulin at 24 and 36 GW1
• Rates of major hypoglycaemia were low and similar
between groups1
• Studies in pregnant women with type 2 diabetes are
ongoing

1. Mathiesen et al. Diabetes Metab Res Rev 2011;27:543–51

NovoRapid® in Gestational
Global Guideline Pregnancy and Diabetes
International Diabetes Federation, 2009

• “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.e1–186.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
 Better PPG control during Gestation

• Mean prandial increments

2.0
Plasma glucose (mmol/L)

* p < 0.01 * p < 0.05 (n = 322)

1.5
NovoRapid®
1.0 (mean±2SEM)

HI
0.5 (mean±2SEM)

-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.

 Lower Risk of Hypoglycemia

NovoRapid®
HI
2.5 p=0.362
28% lower risk
2.0 p=0.660
(episodes/year)

15% lower risk

1.5
Rate

p=0.096
1.0 52% lower risk

0.5

0
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 (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