insulin pregnancy

7/25/2019 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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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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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




9 vs. 6%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

insulin pregnancy

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