Peran Anti Diabetik Oral da

pada Managemen Diabete

 Penatalaksanaan Diabetes

2. Managemen
3. Aktivitas fisik
nutrisi

1.Edukasi

4. Obat Anti
5. Monitoring
Diabetik
 Terapi obat-obatan
1. Obat Hipoglikemik Oral (OHO)
 Insulin sensitisizer : biguanid ( metformin ),
thiazolidinedione (pioglitazone)
 Insulin secretagogue :
 Sulfonylurea :glibenclamide, glimepiride
 Non-sulfonylurea : nateglinide and repaglinide
 Glucosidase inhibitor ( acarbose )
 Incretin dan DPP-4 inhibitor
2. Insulin
Mekanisme kerja Obat Hipoglikemik Ora

Agents Site of action MOA

Sulphonylurea Insulin
secretion
Incretin Glucagon and insulin

Biguanides Glucose
Thiazolidinediones production 

-glucosidase
- Slow carbohydrate
inhibitors digestion

Thiazolidinediones Peripheral insulin

(biguanides) sensitivity

DeFronzo. Ann Intern Med 1999;131:281-303

 1. Metformin (biguanid)

• Derivat guanidin, dari Gallega officinalis

• Menurunkan produksi glukosa di hati
• Menurunkan kadar glukosa darah puasa
• Mempunyai efek terhadap sensitivitas otot terhadap insulin

Slides current until 2008

 Therapeutic Actions of Metformin:
correcting the pathophysiology of type 2 diabetes

Pancreas

Impaired
Insulin secretion

produksi glukosa Decreased

meningkat glucose
Hyperglycaemia uptake

Liver – + Muscle

Metformin
 Multiple Action Mechanisms of Metformin

Metformin Insulin Glucose

Plasma membrane
surface charge

Plasma membrane
fluidity, plasticity
of receptors &
transporters
Insulin-stimulated
receptor phosphorylation
& kinase activity
Glucose transporter
translocation and activation
Enzymatic effects on Glucose
metabolic pathways metabolism
and storage
 Efek pada RESITENSI INSULIN

SEBELUM metformin
insulin

glukosa
glucose
transporter

SESUDAH metformin
 Metformin:
multiple mechanisms for CVD protection
Metformin addresses CV risk by a range of mechanisms

Improved
• Insulin sensitivity
• Glycaemia
• Fibrinolysis
• Microcirculation
• Endothelial function
• Obesity management
Reduced
• Hypertriglyceridaemia
• AGE formation
• Intravascular thrombus
• Oxidative stress
• Atherogenesis
• Dyslipidaemia

Reduced cardiovascular risk

 Metformin
• Dosis awal: 500 mg OD dosis dinaikkan , 1-2 minggu
• Dosis maksimal 2.250 mg/ reached within 2-3 months,
medication should b2 atau 3 kali
• Jika target terapi belum tercapai, tambahkan obat
dari kelas lain
• Target harus tercapai dalam 6 bulan
 Biguanides
Kontra indikasi
• Gagal ginjal
• Ggn fungsi hati
• Gagal jantung
• Gangguan GITyang berat
Keuntungan
• Tidak menyebabkan hipoglikemia jika diberikan sebagai obat tunggal
• Tidak meningkatkan berat badan, bahkan berperan terhadap
menurunkan berat badan.
Efek samping:
• GIT ( mual, abdominal discomfort diarrhea dan kemungkinan konstipasi)
• asidosis laktat

Slides current until 2008

 Increasing or adding
• Jika target terapi belum tercapai dalam 2-3 bulan,
harus ditambahkan obat dari kelas lain
• Target harus tercapai dalam 6 bulan
• Insulin harus ditambahkan jika mungkin untuk
mencapai target terapi.
Golongan Generik Merk mg/tab Dosis Dosis Lama Frek.
Harian Awal Kerja / hari

Biguanid Metformin Glucophage 500-850 250-3000 - 6-8 1-3

Diabex
Glumin
Mechanism of Glucose-Mediated Insulin Secretion

GLUT-2 Sulfonylurea/non
Glucokinase sulfonylurea
Glucose
Glucose G-6-P

Metabolism

Signal (S) ATP

ADP K+
ATP

Secretory Depolarization
Granules Ca++

Ca++

Insulin Secretion
 Sulphonylureas

• Meningkatkan sekresi insulin

• Ada banyak jenis

Efek samping
• Hipoglikemia
• Stimulasi nafsu makan dan meningkatkan berat badan
• Mual, rasa penuh di perut, dan rasa terbakar di ulu hati
• Kadang –kadang timbul rash
• pembengkakan

Slides current until 2008

 Class Generic Brand mg/tab Daily dose Initial Duration Frequency
dose of action /day
Sulfonyl Glibenclamide Daonil 2.5 , 5 2.5 – 15 2.5 12-24 1-2
urea Euglucon
Glipizide Minidiab 5, 10 5-20 5 10-16 1-2
Glucotrol XL
Gliclazide Diamicron 80 80-240 80 10-20 1-2
Gliquidone Glurenorm 30 30-120 30 - 1-3
Glimepiride Amaryl 1, 2, 3, 4 0.5
Non- Nateglinide Starlix 60, 120 tid with 60 6-8 With meal
sulfonyl meal
urea Repaglinide Novonorm 1, 2, 3, 4 tid with 1 6-8 With meal
meal
 Pharmacological Comparison of Sulfonylureas
Gliben- Glime-
Tolbutamide Gliclazide Glipizide clamide piride

Relative potency 1 30 50 - 100 150 - 400 400-1000

mg/tablet 500 80 5 5 1

Plasma peak (h) 3 4 1 3 2.4

Duration of 6 - 10 10 -20 10 -16 12 -24 24

action (h)

• Gerich N. Engl. J. Med 321 (18) 1231-45,1989

• HMR Amaryl Monograph
 Sulphonylureas

Kontra indikasi
• DM tipe 1
• Kehamilan
• Menyusui

Sulphonylureas - hati-hati pada ggn fs hati dan ginjal

Meglitinides – ggn. Fungsi hati berat

Slides current until 2008

 Sulfonil urea

Ingat !!
• Hipoglikemia
• Ada yang dapat diberikan satu kali sehari, sehingga lebih
mudah diingat untuk minum obat
• Generasi I, spt, chlorpropamide dapat terakumulasi dan
menyebabkan hipoglikemia .
 Alpha glucosidase
inhibitors(Acabose)
• Acarbose is a pseudo-
oligosaccharide that
reversibly
inhibits -glucosidases
• -glucosidases are enzymes
Glucobay®
in the gut that breakdown
complex carbohydrates –
• This reduces and delays the
postprandial rise in blood
glucose levels
Oligosaccharides
from starch
 Acarbose acts non-systemically to delay
carbohydrate absorption

Without With acarbose

Acarbose
Stomach

Upper small
Carbohydrate
intestine
absorption

Carbohydrates

Lower small
Carbohydrate
intestine absorption
Alpha glucosidase inhibitors

• Memperlambat pemecahan sukrosa dan starch dengan

demikian memperlambat absorpsi.
• Memperlambat kenaikan glukosa post-prandial

Efek samping:
• Flatulence, abdominal discomfort , diarrhoea
• Sebagai dosis tunggal, tidak menyebabkan hipoglikemia
• Hipoglikemia dapat terjadi jika ditambahkan dengan
golongan insulin sekretagogue(e.g. a sulphonylurea)

Slides current until 2008

 Prinsip mekanisme kerja acarbose

Glucose absorption is slower

and stretched over a longer
time period Resorption of glucose in the small intestine

normale
absorption

Less glucose per time unit under acarbose

will reach the blood stream (same integral)

Time

Less insulin is needed

Should protect the ß-cell

Golongan Generik Merk mg/tab Dosis Dosis Lama Frek.
Harian Awal Kerja / hari

 Gluk. Acarbose Glucobay 50 - 100 150 50 - 1-3

- Inhibitor
 4. Thiazolidinedion
• Troglitazone
• Rosiglitazone
• Pioglitazone

• Spesifik pada Reseptor PPAR gama

 Thiazolidinediones

• Meningkatkan sensitivitas terhadap insulin di otot, jaringan

lemak dan hati.
• Mengurangi sekresi glukosa dari hati
• Mengubah distribusi lemak melalui penurunan lemak visceral
dan meningkatkan lemak perifer.
efek samping
• Peningkatan berat badan, retensi air
• ISPA dan sakit kepala
• Menurunkan haemoglobin

Slides current until 2008

 Insulin Glucose

Insulin
receptor

Synthesis GLUT 4

PPARg RXR mRNA

PPRE transcription
promoter Coding reg

Modified from Howard L. Foyt et al. Thiazolidinediones. Diabetes Mellitus: a Fundamental and Clinical Text, 2nd Ed.
Resistensi Insulin
Insulin
Glucose

receptor X

PPARg +RXR
X Synthesis GLUT 4
mRNA

PPRE transcription
promoter Coding reg

Modified from Howard L. Foyt et al. Thiazolidinediones. Diabetes Mellitus: a Fundamental and Clinical Text, 2nd Ed.
Pioglitazone reduced Insulin resistance
Insulin Glucose

Insulin
receptor

PPARg +RXR
Synthesis GLUT 4
mRNA
Pio

PPRE transcription
promoter Coding reg

Modified from Howard L. Foyt et al. Thiazolidinediones. Diabetes Mellitus: a Fundamental and Clinical Text, 2nd Ed.
 Thiazolidinediones
Kontra indikasi
• Penyakit hati, gagal ginjal dan riwayat penyakit jantung
• tidak dikontra indikasikan pada gagal ginjal.
Keuntungan
• Menurunkan kadar kolester olLDL- dan meningkatkan kadar
kolesterol HDL

Slides current until 2008

 Hormon Incretin

• Di sekresi oleh usus kedalam

sirkulasi setelah mendapat stimulasi
makanan
• Glucagon-Like Peptide-1 ( GLP-1 )
• Glucose Dependen Insulinotropic
Polypeptide ( GIP )
• Mempengaruhi sekresi insulin post
prandial sampai 70 %

• Pada diabetes terdapat penurunan

efek incretin sampai 30 %
Efek Incretin : GLP-1 dan GIP
 DPP-4 Inhibition
Prevent DPP-1v destruction by DPP-4 enzym
Increases Levels GLP-1 and GIP

Meal DPP-4 inhibitor

DPP-4
Intestinal enzyme
GIP and GLP-1
release

GIP (1-42)
GIP (1–42) Rapid degradation
GLP-1 (7-36)
GLP-1 (7–36) (minutes)

GIP and GLP-1 actions

Adapted from Deacon CF et al Diabetes 1995;44:1126–1131; Kieffer TJ et al Endocrinology 1995;136:3585–3596; Ahrén B Curr Diab Rep
35
2003;3:365–372; Deacon CF et al J Clin Endocrinol Metab 1995;80:952–957; Weber AE J Med Chem 2004;47:4135–4141.
Blocking DPP-4 Can Improve Incretin Activity and Correct
the Insulin:Glucagon Ratio in T2DM
 Insulin
T2DM
Incretin
Further impaired
response Hyperglycemia
islet function
diminished

 Glucagon

DPP-4 inhibitor
 Insulin

Incretin
Improved islet Improved
activity
function glycemic control
prolonged

 Glucagon
DPP-4=dipeptidyl peptidase-4; T2DM=type 2 diabetes mellitus
Adapted from Unger RH. Metabolism. 1974; 23: 581–593. Ahrén B. Curr Enzyme Inhib. 2005; 1: 65–73.
 DPP-4 inhibitor
• Sitagliptin (Januvia)
• Vildagliptin ( Galvus)
• Saxagliptin (Onglyza)
 Clinical implication
Characteristic Sitagliptin Vildagliptin Saxagliptin
MK-0431 LAF237 BMS-477118
Therapeutic dose 100 2x50 5
(mg/day)
Half life Long Short Short (but active
metabolite)
Administration Once daily Twice daily Once daily
Active metabolite No No Yes (BMS-510849)
Fraction bound to Intermediate Low Very low
protein (%)
Renal excretion Predominant Intermediate Predominant
Dose reduction Yes (25-50 mg) No Yes (2.5 mg)
with renal
impairment
 Which the alternative therapy?
HbA1C Advantages Disadvantages
Metformin 1-2 No hypoglycemia,no weigh gain GI symptomps
Broad benefit CI renal insufisiency
SU 1.5 Rapidly effective Weight gain and hypoglycaemia
inexpensive
TZD 0.5–1.4 No hypoglycaemia, some benefits on fluid retention, heart failure,
lipids and inflamtion weight gain, expensive
Insulin 1.5–3+ Most effective, no maximum doze, Hypoglycaemia, weight gain, need
improved lipid profile for SMBG
AGI 0.5–0.8 No hypoglycaemia, weight neutral GI side-effects, expensive

GLP-1 analogue 0.5–1.0 No hypoglycaemia, weight loss GI side-effects, expensive, injected

DPP-4 inhibitor, 0.5–0.8 Weight neutral Long-term safety not established,

expensive
Meglitinide 1.0–1.5 Fewer hypos than sulfonylurea TID dosing, expensive

Pramlintide 0.5–1.0 Weight loss Three injections daily, frequent GI side

effects, long-term safety notestablished,
expensive

Nathan, et al. Diabetes Care 2009;32: 193-203

 Jika OHO TIDAK Efektif
• analisa diet dan olah raga
• pertimbangkan pemberian insulin long-akting
pada malam hari
• pertahankan metformin
• pertimbangkan mengurangi atau
menghentikan sulphonylurea di pagi hari

Slides current until 2008

 Algoritme Perkeni (2011)

<7%
Factors to Consider when Choosing an Anti Hyperglycemic
agents

• Effectiveness in lowering glucose

• Extraglycemic effects that may reduce long-
term complications
• Safety profile
• Tolerability
• Expense
• Effect on body weight

Nathan DM et al. Diabetes Care 2006;29(8):1963-72.

 prinsip terapi kombinasi

• Dua atau lebih OHO yang mempunyai mekanisme kerja

yang berbeda
• Jika pemberian obat kombinasi menghindari dosis
maksimal
• Efek samping lebih sedikit dibandingkan mono terapi

Slides current until 2008

 Target Pengendalian Diabetes (Perkeni
2006)
Baik Sedang Buruk

Gula darah puasa ( mg/dl) 80-109 110-125 ≥126

Gula darah 2 jam (mg/dl) 80-144 145-179 ≥180

A1c (%) <6,5 6,5-8 >8

Kolesterol total (mg/dl) <200 200-239 ≥240

Kolesterol LDL ( mg/dl) <100 100-129 ≥130
Kolesterol HDL (mg/dl) >45
Trigliserida( mg/dl) <150 150-199 ≥200
>25
IMT ( kg/m2) 18,5-22,9 23-25

Tekanan darah (mmHg) <130/80 130-140/80-90 >140/90

 Indikasi Terapi Insulin
Temporal : Permanen :

• Kadar gula terlalu tinggi • gagal jantung yang tidak taha

• Hamil obat minum
• Penyakit akut dg GD tinggi • Gagal kombinasi ADO
• Penggunaan obat yang • Efek samping obat ADO
meningkatkan GD • DM tipe 1
• Sekitar operasi • Gangguan fungsi hati berat
• Gagal ginjal
• Selama perawatan di rumah
sakit
• Serangan jantung atau strok
Humalog, Novorapid, Apidra

Actrapid, Humulin R

Humulin N, Insulatard

Lantus
Levemir
 The Basal-Bolus Insulin Concept

Endogenous Insulin
Bolus Insulin
Insulin Effect

Basal Insulin

B L D HS
Time of Administration
B, breakfast; L, lunch; D, dinner; HS, bedtime.
Adapted from:
1. Leahy JL. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker, Inc.; 2002.
2. Bolli GB et al. Diabetologia. 1999;42:1151-1167.
 The BENEFITS AND RISKS OF MEDICATIONS (Endocr Pract.
2009;15)(No.6)
MEDICATIONS*

GLP-3 Sulfonyl
Metformin DPP4 Agonist urea Glinide** Thiazolidinedione Colesevelam Alpha- Insulin Pramlintide
(MET) inhibitor (Increatin (SU) TZD) glucosidase
mimetic) Inhibitor (AGI)

BENEFITS

Postprandial Mild Moderate Moderate to Moderate Moderate Mild Mild Moderate Moderate Moderate to
Glucose (PPG)- marked to marked marked
lowering

Fasting glucose Moderate Mild Mild Moderate Mild Moderate Mild Neutral Moderate Mild
(FPG) –lowering to marked

Nonalcoholic fatty
liver disease Mild Neutral Mild Neutral Neutral Moderate Neutral Neutral Neutral Neutral
(NAFLD)

RISKS

Hypoglycemia Neutral Neutral Neutral Moderate Mild Neutral Neutral Neutral Moderate Neutral
To severe

Gastrointestinal Moderate Neutral Moderate Neutral Neutral Neutral Moderate Moderate Neutral Moderate
symptoms

Risk of use with Severe Moderate Moderate Moderate Neutral Mild Neutral Neutral Moderate Unknown
renal insufficiency
Contraindicated in
liver failure or Severe Neutral Neutral Moderate Moderate Moderate Neutral Neutral Neutral Neutral
predisposition to
lactic acidosis

Heart failure/ Use with Mild/Moderate Neutral

Edema caution in Neutral Neutral Neutral Neutral Contraindicated Neutral Neutral Uniess with Neutral
CHF In class 3,4 CHF TZD
Weight gain Benefit Neutral Benefit Mild Mild Moderate Neutral Neutral Mild to Benefit
Moderate

Fractures Neutral Neutral Neutral Neutral Neutral Moderate Neutral Neutral Neutral Neutral

Drug-Drug Neutral Neutral Neutral Moderate Moderate Neutral Neutral Neutral Neutral Neutral
interaction

Glycemic Control Algorithm,

Type of Insulin Preparation & Action
PENDAHULUAN:

Insulin :
▪ hormon utama yang mengontrol metaolisme
▪ effek : menurunkan kadar gula darah (BG)
▪  insulin ( insulin resistance)  DM

konsekuensi
STRUKTUR KIMIA:

Fig . Insulin molecule

SINTESIS & SEKRESI INSULIN
Sintesis & sekresi
Faktor-faktor yang mempengaruhi sekresi insulin
Fig . 2-phases release of insulin
Efek insuli pada saat puasa dan makan
Mekanisme kerja insulin

Fig. Insulin Signaling Pathway

 Farmakokinetik Insulin

☺ GIT : dirusak sc, iv

☺ paru:  inhalasi insulin
☺ Eliminasi : hati & ginjal
gagal ginjal  dosis diturunkan
☺ masalah : fluktuasi insulin plasma
 fluktuasi gula darah
 Sediaan insulin
Prinsip:
1. Kerja cepat : (lispro dan aspart)
– Onset of action dan duration of action sangat cepat
– Onset of action : 5-15 menit (lispro); 10-12 menit(aspart)
– Puncak : 1 jam
– Duration of action : 3-5 jam
– menyerupai sekresi insulin endogen secara fisiologis pada saat
makan
– Pemberian :SC, CSII
– Dapat dicampur dengan NPH, lente, atau ultralente dalam satu
siring tanpa mempengaruhi absorpsi
– Diberikan segera sebelum makan (5 menit sebelum makan)
 Sediaan insulin
2. Kerja pendek: (regular insulin)
– Onset of action cepat
– Onset of action : 30 menit (lispro)
– Puncak : 2 dan 3 jam
– Duration of action : 5-8 jam
– Hexamer  mula kerja dan lama kerjanya lebih
lama
– Pemberian : dapat diberikan iv (ketoasidosis, setelah
operasi atau infeksi akut)
– Diberikan 30 menit sebelum makan
 Sediaan insulin
3. Kerja sedang : (lente,NPH)insulin
 Lente insulin:
 Campuran 30% semilente (onset of action cepat) +
70% ultralente insulin (onset and duration of action
panjang)
 NPH
 onset of action lambat
 Terdiri dari kombinasi protamin dan insulin
 Setiap molekul protamin mengandung 6 molekul
insulin
 Setelah pemberian SC, enzim proteolitik jaringan
mendegradasi protamin  insulin dapat
diabsorpsi 
 Sediaan insulin
4. Kerja panjang:
• ultra lente
• Glargin insulin
– Onset of action: 1-1,5 jam
– Duration of action: 11-24 jam atau lebih
– Biasanya diberikan 1 kali sehari tapi, kadang-
kadang 2 kali sehari.
– Tidak dapat dicampur dengan insulin lain dalam
satu siring
– Pola absorpsi tergantung tempat injeksi
Cara pemberian insulin
Lokasi/tempat
injeksi
Tabel. Beberapa sediaan insuli yang dipakai di AS
Fig. Extent and DOA of various insulin
Glargine

72
Profile of Insulin Glargine vs NPH
NPH
Glargine

73
 Indikasi Insuli n

☺ DM tipe 1
☺ diabetic ketoacidosis, nonketotic coma
☺ DM tipe 2  yang tidak terkontrol hanya dengan diit / OHO
☺ penggunaan jangka pendek : operasi, infeksi, AMI
☺ gestational diabetes
☺ EMG treatment of hyperkalemia
insulin + glucose   extra cellular K+ (redistribution into the cell)
Preparasi insulin

1. Portable pen injections

2. Continuous Subcutaneous Insulin Infusion Devices

(CSII, INSULIN PUMPS)

3. Inhaled Insulin
 - Replaceable cartridge of 100 U
- Portable, comfortable
- No need of syringe & bottle

1. PORTABLE PEN INJECTORS

 - The most physiologic method of insulin replacement
-  Individual basal & bolus insulin  BG self monitoring result

2. CONTINUOUS SUBCUTANEOUS INSULIN INFUSION DEVICES

(CSII, INSULIN PUMPS)
 3. INHALED INSULIN

- Aerosol insulin
- Small particle  alveolar wall  circulation
- Rapid onset & short DOA 
[ to correct High BG / cover meal time
BUT not to provide basal insulin coverage ]
• Insulin Degradation
• Hydrolysis of the disulfide linkage between
A&B chains.
• 60% liver, 40% kidney(endogenous insulin)
• 60% kidney,40% liver (exogenous insulin)
• Half-Life 5-7min (endogenous insulin)
Delayed-release form( injected one)
• Usual places for injection: upper arm,
front& side parts of the thighs& the
abdomen.
• Not to inject in the same place ( rotate)
• Should be stored in refrigerator& warm up
to room temp before use.
• Must be used within 30 days.
79
Efek samping

A. Hipoglikemia ….!!!!
• Menunda jadwal makan
• Aktivitas berlebihan dari biasanya
• Kurang asupan karbohidrat

B. Insulin allergy & resistance

- insulin allergy (type-1 hy-sensitivity rx)  very rare
- immune insulin resistance (IgG anti-insulin Ab)
C. Lipodystrophy pada tempat suntikan
- atrophy / hypertrophy subcutaneous fatty tissue
 Methods of Adminisration
• Insulin Syringes
• Pre-filled insulin pens
• External insulin pump
Under Clinical Trials
• Oral tablets
• Inhaled aerosol
• Intranasal, Transdermal
• Insulin Jet injectors
• Ultrasound pulses

81
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