Peran Anti Diabetik Oral d

pada Managemen Diabe

Penatalaksanaan Diabetes

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 O

Agents

Sulphonylurea
Incretin
Biguanides
Thiazolidinediones
-glucosidase
inhibitors
Thiazolidinediones
(biguanides)

Site of action

MOA

Insulin
secretion
Glucagon and insulin
Glucose
production
Slow carbohydrate
digestion
Peripheral insulin
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
meningkat

Liver

Hyperglycaemia

Metformin

Decreased
glucose
uptake

Muscle

Multiple Action Mechanisms of

Metformin
Metformin

Insulin

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
metabolic pathways

Glucose
metabolism
and storage

Glucose

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 , 12 minggu
Dosis maksimal 2.250 mg/ reached within 23 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

Biguanid

Generik

Metformin

Merk

Glucophage
Diabex
Glumin

mg/tab

500-850

Dosis
Harian

250-3000

Dosis Lama
Awal Kerja

6-8

Frek.
/ hari

1-3

Mechanism of Glucose-Mediated
Insulin Secretion
GLUT-2
Glucose

Glucokinase
Glucose
G-6-P

Sulfonylurea/non
sulfonylurea

Metabolism
Signal (S)
Secretory
Granules

ATP K+
ATP
ADP
Ca++

Depolarization

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

Sulfon
ylurea

Glibenclam
ide

Nonsulfon
ylurea

Brand

mg/tab

Daily
dose

Initial
dose

Duratio
n of
action

Freque
ncy/day

Daonil
Euglucon
Minidiab
Glipizide
Glucotrol
XL
Gliclazide
Diamicron
Gliquidone Glurenorm
Glimepiride Amaryl

2.5 , 5

2.5 15

2.5

12-24

1-2

5, 10

5-20

10-16

1-2

80
30
1, 2, 3, 4

80-240
30-120

80
30
0.5

10-20
-

1-2
1-3

Nateglinide

60, 120

tid with
meal
tid with
meal

60

6-8

With
meal

6-8

Starlix

Repaglinide Novonorm

1, 2, 3, 4

With
meal

Pharmacological Comparison of
Sulfonylureas
Gliclazide

Glipizide

Glibenclamide

30

50 - 100

150 - 400 400-1000

500

80

2.4

6 - 10

10 -20

10 -16

12 -24

24

Tolbutamide
Relative potency
mg/tablet
Plasma peak (h)
Duration of
action (h)

Glimepiride

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 pseudooligosaccharide that
reversibly
inhibits -glucosidases
Glucobay

Oligosaccharides
from starch

-glucosidases are
enzymes in the gut that
breakdown complex
carbohydrates
This reduces and delays
the postprandial rise in
blood glucose levels

Acarbose acts non-systemically to delay

carbohydrate absorption
Without
Acarbose

With acarbose
Stomach

Carbohydrate
absorption

Upper small
intestine
Carbohydrates

Lower small
intestine

Carbohydrate
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

will reach the blood stream

under acarbose
(same integral)
Time

Less insulin is needed

Should protect the -cell

Golongan

Generik

Acarbose
Gluk.
- Inhibitor

Merk

mg/tab

Dosis
Harian

Glucobay

50 - 100

150

Dosis Lama
Awal Kerja

50

Frek.
/ hari

1-3

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
Insulin
receptor

Glucose
transloca

tion

Synthesis GLUT 4
PPAR

mRNA

RXR

PPRE

transcription

promoter

Coding reg

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

Resistensi Insulin

Glucose

Insulin
receptor

PPAR +RXR

X Synthesis GLUT 4
mRNA

PPRE

promoter

transcription

Coding reg

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

Pioglitazone reduced Insulin resistance

Insulin
Insulin
receptor

Glucose
transloca

tion

PPAR +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

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
enzyme

Intestinal
GIP and GLP-1
release
GIP (142)
GLP-1 (736)

Rapid degradation
(minutes)

GIP (1-42)
GLP-1 (7-36)

GIP and GLP-1

actions
Adapted from Deacon CF et al Diabetes 1995;44:11261131; Kieffer TJ et al Endocrinology 1995;136:35853596; Ahrn B Curr
Diab Rep 2003;3:365372; Deacon CF et al J Clin Endocrinol Metab 1995;80:952957; Weber AE J Med Chem 2004;47:4135
35
4141.

Blocking DPP-4 Can Improve Incretin Activity and

Correct the Insulin:Glucagon Ratio in T2DM
T2DM
Incretin
response
diminished

Insulin
Further
impaired islet
function

Hyperglycemia

Glucagon

DPP-4 inhibitor
Incretin
activity
prolonged

Insulin
Improved islet
function

Improved
glycemic control

Glucagon
DPP-4=dipeptidyl peptidase-4; T2DM=type 2 diabetes mellitus
Adapted from Unger RH. Metabolism. 1974; 23: 581593. Ahrn B. Curr Enzyme Inhib. 2005; 1: 6573.

DPP-4 inhibitor
Sitagliptin (Januvia)
Vildagliptin ( Galvus)
Saxagliptin (Onglyza)

Clinical implication
Characteristic

Sitagliptin
MK-0431

Vildagliptin
LAF237

Saxagliptin
BMS-477118

Therapeutic
100
dose (mg/day)

2x50

Half life

Long

Short

Short (but
active
metabolite)

Administratio
n

Once daily

Twice daily

Once daily

Active
metabolite

No

No

Yes (BMS510849)

Fraction
bound to
protein (%)

Intermediate

Low

Very low

Renal
excretion

Predominant

Intermediate

Predominant

Dose
reduction
with renal

Yes (25-50 mg)

No

Yes (2.5 mg)

Which the alternative therapy?

HbA1C

Advantages

Disadvantages

Metformin

1-2

No hypoglycemia,no weigh gain

Broad benefit

GI symptomps
CI renal insufisiency

SU

1.5

Rapidly effective
inexpensive

Weight gain and

hypoglycaemia

TZD

0.51.4

No hypoglycaemia, some
benefits on lipids and inflamtion

fluid retention, heart failure,

weight gain, expensive

Insulin

1.53+

Most effective, no maximum

doze, improved lipid profile

Hypoglycaemia, weight gain,

need for SMBG

AGI

0.50.8

No hypoglycaemia, weight
neutral

GI side-effects, expensive

GLP-1
analogue

0.51.0

No hypoglycaemia, weight loss

GI side-effects, expensive,
injected

DPP-4 inhibitor,

0.50.8

Weight neutral

Long-term safety not

established, expensive

Meglitinide

1.01.5

Fewer hypos than sulfonylurea

TID dosing, expensive

Pramlintide

0.51.0

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

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)

Gula darah 2 jam (mg/dl)

80-109
80-144

110-125
145-179

126
180

A1c (%)

<6,5

6,5-8

>8

Kolesterol total (mg/dl)

Kolesterol LDL ( mg/dl)
Kolesterol HDL (mg/dl)
Trigliserida( mg/dl)

<200
<100
>45
<150

200-239
100-129

240
130

150-199

IMT ( kg/m2)

200
>25

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

Hamil
Penyakit akut dg GD
tinggi
Penggunaan obat yang
meningkatkan GD
Sekitar operasi
Gagal ginjal
Selama perawatan di
rumah sakit
Serangan jantung atau
strok

gagal jantung yang tidak taha

obat minum
Gagal kombinasi ADO
Efek samping obat ADO
DM tipe 1
Gangguan fungsi hati berat

Humalog, Novorapid, Apidra

Actrapid, Humulin R
Humulin N, Insulatard
Lantus
Levemir

The Basal-Bolus Insulin Concept

Endogenous Insulin

Insulin Effect

Bolus Insulin
Basal Insulin

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

2009;15)(No.6)

(Endocr Pract.

MEDICATIONS*
Metfor
mi
n
(MET)

DPP4
inhibito
r

GLP-3
Agonist
(Increati
n
mimetic)

Sulfonyl
urea
(SU)

Glinide*
*

Thiazolidined
ione
TZD)

Coleseve
lam

Alphaglucosidas
e Inhibitor
(AGI)

Insulin

Pramlinti
de

BENEFITS
Postprandial
Glucose
(PPG)lowering

Mild

Modera
te

Moderat
e to
marked

Modera
te

Modera
te

Mild

Mild

Moderate

Moderat
e to
marked

Moderate
to
marked

Fasting
glucose
(FPG)
lowerin
g

Modera
te

Mild

Mild

Modera
te

Mild

Moderate

Mild

Neutral

Moderat
e to
marked

Mild

Nonalcoholic
fatty
liver disease
(NAFLD)

Mild

Neutral

Mild

Neutral

Neutral

Moderate

Neutral

Neutral

Neutral

Neutral

RISKS
Hypoglycemi
a

Neutral

Neutral

Neutral

Modera
te

Mild

Neutral

Neutral

Neutral

Moderat
e
To
se
ver
e

Neutral

Gastrointesti
nal
symptoms

Modera
te

Neutral

Moderat
e

Neutral

Neutral

Neutral

Moderat
e

Moderate

Neutral

Moderate

Risk of use
with
renal
insufficiency

Severe

Modera
te

Moderat
e

Modera
te

Neutral

Mild

Neutral

Neutral

Moderat
e

Unknown

Severe

Neutral

Neutral

Modera

Modera

Moderate

Neutral

Neutral

Neutral

Neutral

te

te

Contraindicat
ed in liver
failure or
predispositio
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, kadangkadang 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

82