Insulin Pregnancy
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Transcript of Insulin Pregnancy
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TERAPI INSULIN ANALOG PADA
DIABETES DENGAN KEHAMILAN
OlehBowo Pramono, Suharnadi Fx
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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 SardjitoKetua PAPDI cabang Yogyakarta
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PENDAHULUAN
Pedersen (1954) hiperglikemia pada ibu hamilmenyebabkan makrosomia
Frienkel: asam amino rantai cabang dan asamlemak bebas meningkatkan sekresi insulinpada janin
Casson (UK) : DM tipe 1 yang hamilmalformasi janin (10x), lahir mati (5x),
kematian perinatal (3x)
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PENDAHULUAN
Intensifikasi insulin pada ibu hamilmenurunkan kejadian malformasi janin
(DCCT) pada 680 wanita hamil dengan DM Patogenesis hiperglikemia malformasi janin
multifaktorial : defisiensi myoinositol,defisiensi asam arakhidonat dan peningkatanradikal bebas
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PENDAHULUAN
Komplikasi hiperglikemia pada neonatus :Hipokalsemia
Hipoglikemia
HiperbilirubinemiaMakrosomia
Intra uterine growth retardation
Respiratory distress syndrome
Policitemia
Hipertropic cardiomyopati
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METABOLISME PADA IBU HAMIL
Trimester pertama : sensitivitas insulin masihnormal
Trimester kedua dan ketiga : menurun sampaiakhir kehamilan (50%)
Resistensi insulin disebabkan oleh hormon-hormon fetoplacenta : hormon placentallactogen, estrogen, progesteron, hormonchorionic somatropin
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METABOLISME PADA IBU HAMIL
Resistensi insulin pada ibu hamil lebihdominan pada otot skeletal dibandingkan
jaringan adiposa Sekresi insulin akan meningkat disertai
hipertrofi dan hiperplasi sel beta pankreasuntuk mengatasi resistensi insulin
Sensitifitas insulin menurun glukosa postprandial meningkat janin
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METABOLISME PADA IBU HAMIL
Sintesis asam lemak meningkat cadanganmakanan janin facilitated anabolism
Difusi glukosa dan transport aktif asam aminomelalui placenta akan menimbulkanhipoglikemia dan hipoalaninemia pada ibu accelerated starvation
Bila sekresi insulin tidak cukup untukmengatasi resistensi insulin gestationaldiabetes (5% dari kehamilan normal)
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KEBUTUHAN INSULIN MENINGKAT PADA IBUHAMIL
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KADAR GLUKOSA DARAH PADA IBU HAMIL YANGMEMERLUKAN INSULIN
Tabel 2.
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UPAYA MENCEGAH MALFORMASIKONGENITAL
Perencanaan makan Pemantauan gula darah mandiri
Pengaturan dosis insulin mandiri Penanganan terhadap hipoglikemia Aktifitas fisik yang benar Pengelolaan stres
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PENINGKATAN KEBUTUHAN DOSIS INSULIN
Tabel 3. Suggested Starting Total Daily Insulin During Pregnancy
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PENGGUNAAN INSULIN ANALOG
Insulin lispro digunakan pertama kali pada th1996
Bentuk heksamer yang cepat terdisosiasimenjadi monomer
Masa kerja cepat 2-4 jam, kadar puncak 1 jam Dibandingkan insulin reguler : penurunan gula
darah dan HBA1C lebih baik dan resikohipoglikemia lebih rendah
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Insulin glargine digunakan pertama kali th2000
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
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INSULIN ANALOG DAN KEHAMILAN
Rapid acting insulin analog bermanfaat padaibu 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 nokturnalhipoglikemia
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IMUNOGENESITAS
Insulin akan masuk placenta bila terbentukkomplek antigen-antibodi
Tidak terdapat kadar insulin lispro dalamdarah tali pusat (sejak umur 26 minggukehamilan)
Kadar antibodi anti insulin hampir samaantara insulin lispro dan insulin reguler
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TERATOGENESITAS DAN EMBRIOTOKSISITAS
Tidak ada bukti adanya teratogenesitas danembriotoksisitas baik pada inslin lispro, aspartmaupun reguler
Penelitian retrospektif pada 867 wanita hamildengan insulin, malformasi kongenital : 4,8%(lispro) dan 6,8% (reguler) meskipun tidakberbeda bermakna (Lapolla, 2005)
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MITOGENESITAS
Tidak ada perbedaan yang bermakna antarainsulin lispro, aspart maupun reguler terhadapkemungkinan menimbulkan retinopatidiabetik, atau memperburuk kondisi retinopatiyang sudah ada
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The usage of Basal Insulin Therapyin Special Population(Focus on Pregnancy)
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Insulin Usage in Pregnancy
23
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Background: diabetes and pregnancy
Pre-existing diabetes in pregnancy is associated with high ratesof fetal, neonatal and maternal complications 1
Recommended glycaemic control targets for pregnant womenare more strict than for regular patients with diabetes 2
Many women use long-acting insulin analogues and would liketo know that they are safe to continue doing so duringpregnancy 3
Data on the use of insulin detemir in pregnant women with type1 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 Care2012;35:2012 7
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RCT comparing insulin detemir with NPHinsulin in 310 pregnant women with type1 diabetes
1. Mathiesen et al. Diabetes Care 2012;35:2012 7; 2. Hod et al. J Matern Fetal Neonatal Med2014;27:7 13
To compare the efficacy and safetyof insulin detemir with NPH insulin inpregnant women with type 1diabetes
Maternalendpoints:
Neonatalendpoints:
glycaemic control,hypoglycaemia andsafety 1perinatal and obstetricpregnancy outcomes 2
Treatment withinsulin for 12months
Planning to
become pregnantand HbA 1c 9.0% Pregnant with a
singletonpregnancy of 8 12 gestationalweeks
At confirmation ofpregnancy ,HbA 1c 8.0%
Impairedhepatic or renalfunction
Uncontrolledhypertension
Use of in vitrofertilisation orother medicalinfertilitytreatment
Previousrandomisationin this trial
Overall aims
Main inclusioncriteria
Main exclusioncriteria
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Study withdrawal criteria and participantdisposition
*2 women became pregnant again after a miscarriage1. Mathiesen et al. Diabetes Care 2012;35:2012 7 (and supplementary material)
142 (93%) pregnancy outcome
161 NPH insulin
Full analysis set: 15279 pregnant at randomisation73 randomised before pregnancy
Full analysis set: 15883 pregnant at randomisation75 randomised before pregnancy
Main withdrawalcriteria:
HbA 1c >8.0% at conception Remaining not pregnant
12 months after randomisation Multiple pregnancies Insufficient glycaemic control
313 randomly
assigned
3 participants did notreceive study drug
25 withdrawals
152 insulin detemir
145 (91%) pregnancy outcome
22 furtherwithdrawals
152 pregnancies 160 pregnancies*
Of 470 initial participants,313 were pregnant duringthe study
127 (84%) completed per protocol 137 (87%) completed per protocol
Adapted from 1
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Results: HbA 1c levels, insulin detemir vs.NPH insulin
Insulin detemir was non-inferior to NPH insulin in terms of HbA 1c
Total pregnantpopulation
Insulindetemir
NPHinsulin
Difference[95% CI]
Mean HbA 1c (%), GW 36 6.27 6.33 0.06 [ 0.21;0.08]
H b A
1 c ( % )
GA (weeks) GA (weeks)
H b A
1 c ( % )
7.00
5.75
0
6.00
6.25
6.50
6.75
8 12 16 20 24 28 32 36 44
7.00
5.75
0
6.00
6.25
6.50
6.75
8 12 16 20 24 28 32 36 44
Randomised beforepregnancy
Randomised duringpregnancy
Adapted from 1Adapted from 1
1. Mathiesen et al. Diabetes Care 2012;35:2012 7
CI, confidence interval; GW, gestational week
Insulin detemirNPH insulin
Overall, the treatmenttarget of HbA 1c 6.0%at GWs 24 and 36 was
obtained in 41% ofwomen treated with
insulin detemir vs. 32%those treated with NPH
insulin ( p =0.280)
HbA 1c levelswere similar
betweentreatments
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Results: maternal FPG, insulin detemir vs.NPH insulin
Mean FPG,total pregnant
population
Insulindetemir
NPHinsulin 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
H b A
1 c ( % )
GA (weeks) GA (weeks)
H b A
1 c ( % )
7.00
4.50
0
5.00
5.50
6.00
6.50
8 12 16 20 24 28 32 36
0
8 12 1 6 20 24 2 8 32 36
Randomised beforepregnancy
Randomised duringpregnancy
Adapted from 1Adapted from 1
1. Mathiesen et al. Diabetes Care 2012;35:2012 7
7.00
4.50
5.00
5.50
6.00
6.50
Insulin detemirNPH insulin
The difference wasmost pronounced in
those randomisedbefore pregnancy
Maternal FPG wassignificantly lower
with insulindetemir compared
with NPH insulin
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0,0
0,4
0,8
1,2
1,6
2,0
Overall Daytime Nocturnal
E p i s o d e s p e r y e a r
Results: maternal hypoglycaemia, insulindetemir vs. NPH insulin
p=NS for all ratesBased on: 1. Mathiesen et al. Diabetes Care 2012;35:2012 7
0,0
20,0
40,0
60,0
80,0
100,0
Overall Daytime Nocturnal
E p i s o d e s p e r y e a r
76 vs. 80%of patients
95 vs. 92%of patients
95 vs. 92%of patients
11 vs. 19%of patients
9 vs. 6%of patients
16 vs. 21%of patients
Major hypoglycaemia rate Minor hypoglycaemia rate
Maternal hypoglycaemia rates were similar with insulin detemirand NPH insulin
Based on 1 Based on 1
Insulin detemir
NPH insulin
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Summary (Levemir)
Insulin detemir is non-inferior to NPH insulin for HbA 1c at36 GW when given as a treatment for type 1 diabetes 1
FPG was significantly lower in patients receiving insulindetemir compared with NPH insulin at 24 and 36 GW 1
Rates of major hypoglycaemia were low and similarbetween groups 1
Studies in pregnant women with type 2 diabetes areongoing
1. Mathiesen et al. Diabetes Metab Res Rev 2011;27:543 51
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NovoRapid in Gestational
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Global Guideline Pregnancy and DiabetesInternational Diabetes Federation, 2009
The rapid -acting analogue,
insulin aspart, has been shownto be safe and effective inpregnancy in type 1 diabetes[85,86] and GDM [87].
The use of these analogues hasbeen the subject of a systematicreview [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.
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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
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Perinatal Outcomes
NovoRapid RHI
N 137 131
Birth weight (gm) 343871.5 355572.9
Preterm delivery, N (%) 28 (20%) 41 (31%)
Neonatal hypo requiring
treatment
46 (34%) 52 (40%)
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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
Summary (Novorapid)
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RINGKASAN
Kebutuhan insulin meningkat pada ibu hamil,karena adanya resistensi insulin dan hormon-hormon kontra insulin dari fetoplacental
Insulin analog lebih baik dibandingkan insulinreguler meskipun tidak terdapat perbedaanyang bermakna, karena lebih cepat
menurunkan glukosa postprandial denganefek hipoglikemik yang lebih rendah
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TERIMA KASIH