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 hormonhormon 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;32:12056. 2. Kitzmiller et al.

Diabetes Care 2008;31:106079. 3. Mathiesen et al. Diabetes Care
2012;35:20127

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
pregnant women with type 1
diabetes
Maternal
endpoints:
Neonatal
endpoints:

glycaemic control,
hypoglycaemia and
safety1
perinatal and obstetric
pregnancy outcomes2

Main inclusion
criteria

Main exclusion
criteria

Treatment with
insulin for 12
months
Planning to
become pregnant
and HbA1c 9.0%
Pregnant with a
singleton
pregnancy of 8
12 gestational
weeks
At confirmation of
pregnancy,

Impaired
hepatic or renal
function
Uncontrolled
hypertension
Use of in vitro
fertilisation or
other medical
infertility
treatment
Previous
randomisation
in this trial

HbA1c 8.0%

1. Mathiesen et al. Diabetes Care 2012;35:20127; 2. Hod et al. J Matern Fetal Neonatal Med
2014;27:713

Study withdrawal criteria and participant

disposition
313 randomly
assigned

Main withdrawal
criteria:

152 insulin detemir 161 NPH insulin

HbA1c >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

3 participants did not

receive study drug
Full analysis set: 152
79 pregnant at randomisation
73 randomised before pregnancy

Full analysis set: 158

83 pregnant at randomisation
75 randomised before pregnancy

22 further
withdrawals

25 withdrawals

152 pregnancies

142 (93%) pregnancy outcome

160 pregnancies*
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;35:20127 (and supplementary material)

Results: HbA1c levels, insulin detemir vs.

NPH insulin
Randomised during
pregnancy

7.00

7.00

6.75

6.75

HbA1c (%)

HbA1c (%)

Randomised before
pregnancy

6.50
6.25
6.00
5.75

Insulin detemir
NPH insulin

HbA1c levels
were similar
between
treatments

6.50
6.25
6.00
5.75

0
8 12 16 20 24 28 32 36
GA (weeks)

44
Adapted from1

8 12 16 20 24 28 32 36
GA (weeks)

44
Adapted from1

Insulin detemir was non-inferior to NPH insulin in terms of HbA1c

Total pregnant
population

Insulin
detemir

NPH
insulin

Difference
[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;35:20127

Overall, the treatment

target of HbA1c 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)

Results: maternal FPG, insulin detemir vs.

NPH insulin
Randomised during
pregnancy

7.00

7.00

6.50

6.50

HbA1c (%)

HbA1c (%)

Randomised before
pregnancy

6.00
5.50
5.00
4.50

Maternal FPG was

significantly lower
with insulin
detemir compared
with NPH insulin

5.50
5.00

0
8 12 16 20 24 28 32 36
GA (weeks)
Mean FPG,
total pregnant
population

NPH insulin

6.00

4.50

Insulin detemir

Adapted from1

8 12 16 20 24 28 32 36
GA (weeks)

Insulin
detemir

NPH
insulin

95% CI

P-value

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

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

Adapted from1

The difference was

most pronounced in
those randomised
before pregnancy

Results: maternal hypoglycaemia, insulin

detemir vs. NPH insulin
Major hypoglycaemia rate

Minor hypoglycaemia rate

95 vs. 92%
of patients

1,6

16 vs. 21%
of patients
11 vs. 19%
of patients

1,2
9 vs. 6%
of patients

0,8
0,4

Episodes per year

Episodes per year

2,0

0,0

100,0

Insulin detemir
NPH insulin

95 vs. 92%
of patients

80,0
60,0
76 vs. 80%
of patients

40,0
20,0
0,0

Overall

Daytime

Nocturnal
Based

Overall
on1

Daytime Nocturnal
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;35:20127

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;27:54351

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.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

Better PPG control during Gestation

Plasma glucose (mmol/L)

Mean prandial increments

2.0

* p < 0.01

* p < 0.05

(n = 322)

1.5
1.0

NovoRapid
(mean2SEM)

0.5

HI
(mean2SEM)

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.

Lower Risk of Hypoglycemia

NovoRapid
HI
2.5

p=0.362

Rate
(episodes/year)

28% lower risk

p=0.660

2.0

15% lower risk

1.5

p=0.096
52% lower risk

1.0
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

137

131

Birth weight (gm)

343871.5

355572.9

Preterm delivery, N (%)

28 (20%)

41 (31%)

Neonatal hypo requiring

treatment

46 (34%)

52 (40%)

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 hormonhormon 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