Antidiabetic Medications

Dr.Suhaemi, SpPD, Finasim

Kompetensi Dasar
( Tujuan Pembelajaran)
Mahasiswa mampu memahami
Patofisiologi Diabetes Mellitus
Mahasiswa mampu memahami
prinsip farmakoterapi pada
Diabetes Mellitus
Mahasiswa mampu menerapkan
farmakoterapi pada Diabetes
Mellitus

Normal Carbohydrate Metabolism

Glycogenolysis
Gluconeogenesis

Glucose
Postprandial metabolism

Counterregulatory Hormones:

Insulin
Incretin
Amylin

Glucagon
Epinephrine
Cortisol
Growth Hormone

Turns On
Glucose Glycogen
AA Protein
FFA TG

Fasting metabolism

Glucose

Turns Of

Nine to Know

The minimum that every pharmacist must know about drugs!

Brand & Generic Name

Mechanism of action
Therapeutic effect
Relevant pharmacokinetics and
pharmacodynamics
Dosing by route
Adverse reactions and contraindications
Monitoring parameters
Drug-drug and drug food interactions
Comparisons between agents w/in the same
class of drugs

Contraindications/Cautions/Adverse
Reactions
Adverse Reactions
Unwanted side effects: need to warn
patient

Cautions
Warnings for clinicians to be aware when
using medication.

Contraindications
Conditions which will render the
medication absolutely unusable in that
patient population

Cakupan Materi
1.
2.
3.
4.
5.

Definisi Diabetes Mellitus

Macam Diabetes Mellitus
Patofisiologi Diabetes Mellitus
Obat-Obat untuk Diabetes Mellitus
Farmakoterapi pada Diabetes
Mellitus

Tabel 1. Klasifikasi Diabetes Mellitus Berdasarkan Etiologinya (ADA, 2003)

1.

2.

3.

Diabetes Mellitus Tipe 1:

Destruksi sel umumnya menjurus ke
arah defisiensi insulin absolut
A. Melalui proses imunologik
(Otoimunologik)
B. Idiopatik
Diabetes Mellitus Tipe 2
Bervariasi, mulai yang predominan resistensi
insulin disertai defisiensi insulin relatif
sampai yang predominan gangguan sekresi
insulin bersama resistensi insulin
Diabetes Mellitus Gestasional
Diabetes mellitus yang muncul pada masa
kehamilan, umumnya bersifat
sementara, tetapi merupakan faktor risiko
untuk DM Tipe 2

4.

Diabetes Mellitus Tipe Lain

-Defek genetik fungsi sel
-Penyakit pankreas
-Autoimun

5.

Gangguan Toleransi Glukosa

A. IFG (Impaired Fasting Glucose) = GPT
(Glukosa Puasa Terganggu)
B. IGT (Impaired Glucose Tolerance) = TGT
(Toleransi Glukosa terganggu)

Patofisiologi
FUNGSI INSULIN :
Berikatan dengan reseptor pada sel /
jaringan untuk membuka jalan bagi
masuknya glukosa darah ke dalam
sel untuk dirubah menjadi tenaga.
INSULIN === PERANTARA

pulau Langerhans kelenjar pankreas

terdapat beberapa tipe sel, yaitu sel
, sel dan sel . Sel-sel
memproduksi insulin, sel-sel
memproduksi glukagon, sedangkan
sel-sel memproduksi hormon
somatostatin

DIABETES MELLITUS TIPE 1 :

- Jarang / populasinya sedikit (5-10 % dari penderita
diabetes mellitus)
- Gangguan produksi insulin pada DM Tipe 1
umumnya terjadi karena kerusakan sel-sel pulau
Langerhans yang disebabkan oleh reaksi otoimun,
virus, dsb
- Destruksi otoimun dari sel-sel pulau Langerhans
kelenjar langsung mengakibatkan defisiensi sekresi
insulin.

DIABETES MELLITUS TIPE 2

- sangat umum terjadi
- populasinya 90 95 % penderita Diabetes

Mellitus

- Etiologinya belum terungkap dengan jelas,

kebanyakan karena pola hidup, faktor genetik dan
pengaruh lingkungan.
- sel-sel sasaran insulin gagal atau tak mampu
merespon insulin secara normal. Keadaan ini
lazim disebut sebagai Resistensi Insulin.

Diabetes Mellitus
Symptoms
Polyuria
Polydipsia
Polyphagia
Glycosuria
Unexplained
weight loss
Fatigue
Hyperglycemia

lymphocyte
CD 4

virus
facteurs
denvironnement?

molcules HLA de
classe II (DR3-DR4)

IFNg

Ag viraux
et de cell.

IL-2
CD 8

cell.

X
insuline

cytokines
NK

anticorps

activation

lymphocyteB

Histoire naturelle du diabte de type 1

Scrtion
dinsuline

Anticorps
anti-GAD

Dbut clinique
du DID

100%

Rmission
Transitoire
lune de miel

50%

10%
0%
Phase 1

Perbedaan dm TIPE 1 DAN DM TIPE

2
Mula muncul

Umumnya masa
kanakkanak
dan remaja,
walaupun ada juga
pada
masa dewasa < 40
tahun

Pada usia tua,

umumnya
> 40 tahun

Keadaan klinis
saat
diagnosis

Berat

Ringan

Kadar insulin
darah

Rendah, tak ada

Cukup tinggi, normal

Berat badan

Biasanya kurus

Gemuk atau normal

Pengelolaan
yang
disarankan
Check it out

Terapi insulin, diet,

olahraga

Diet, olahraga,
hipoglikemik oral
Check it out

Diabetes gestasional
DIABETES PADA KEHAMILAN (DM GESTASIONAL)
- Diabetes / intoleransi glukosa yang terjadi pada
masa kehamilan
- Umumnya timbul pada atau setelah trimester ke 2
- Sekitar 4-5 % wanita hamil menderita DM
- Berlangsung sementara dan dapat pulih setelah
kehamilan

Akibat dm gestasional
Malformasi kongenital
Berat badan bayi berlebih
Resiko mortalitas perinatal

Pra diabetes
Pra-diabetes adalah kondisi dimana
kadar gula darah seseorang berada
diantara kadar normal dan diabetes,
lebih tinggi dari pada normal tetapi
tidak cukup tinggi untuk
dikatagorikan ke dalam diabetes tipe
2.

 di Amerika diperkirakan ada sekitar

41 juta orang yang tergolong pradiabetes, disamping 18,2 orang
penderita diabetes (perkiraan untuk
tahun 2000).
Di Indonesia, angkanya belum
pernah dilaporkan, tetapi
diperkirakan cukup banyak terjadi

Macam pra diabetes

Impaired Fasting Glucose (IFG) :
Bila kadar Glukosa :
PUASA : 100-125 mg/dl (normal: <100 mg/dl)
Impaired Glucose Tolerance (IGT) atau
Toleransi Glukosa Terganggu (TGT),
Bila kadar glukosa :
2 jam setelah mengkonsumsi 75 gram glukosa
per oral berada diantara 140-199 mg/dl.

Kriteria penegakan diagnosis

diabetes secara umum
Glukosa Plasma
Puasa

Glukosa Plasma
2 jam setelah
makan

Normal

<100 mg/dL

<140 mg/dL

Pra Diabetes
IFG

100 125 mg/dL

IGT

diabetes

> 126 mg/dL

140 199 mg/dL

> 200 mg/dL

Diagnostic Criteria

Normal
Prediabetes

Diabetes

Fasting Glucose

2-h OGTT

Random Glucose

mg/dL

mg/dL

mg/dL

<100

<140

<200

100-125

140-199

(IFG)

(IGT)

126

200

A1c

<5.7%
5.7-6.4%

200

6.5%

Note: In the absence of unequivocal hyperglycemia, result(s) should

be confirmed by repeat testing.
ADA. I. Classification and Diagnosis. Diabetes Care 2012;35(suppl 1):S12. Table 2.

Faktor resiko diabetes

Riwayat

Diabetes dalam keluarga

Diabetes Gestasional
Melahirkan bayi dengan berat
badan >4 kg
Kista ovarium (Polycystic
ovary syndrome)
IFG (Impaired fasting
Glucose) atau IGT (Impaired
glucose tolerance)

Obesitas

>120% berat badan ideal

Umur

20-59 tahun : 8,7%

> 65 tahun : 18%

Etnik/Ras
Hipertensi

>140/90mmHg

Hiperlipidemia

Kadar HDL rendah <35mg/dl

Kadar lipid darah tinggi
>250mg/dl

Faktor-faktor Lain

Kurang olah raga

Pola makan rendah serat

Dm tipe 1

Terapi pada dm
Penatalaksanaan diabetes
mempunyai tujuan akhir untuk
menurunkan morbiditas dan
mortalitas DM, yang secara spesifik
ditujukan untuk mencapai 2 target
utama, yaitu:
1. Menjaga agar kadar glukosa
plasma berada dalam kisaran normal
2. Mencegah atau meminimalkan

Glycemic Recommendations
Target
Treatment
Goal

AACE/ACE
2011

ADA 2012

A1c

6.5%

<7%

Fasting Glucose

FPG <110 mg/dl

Preprandial PG 70130mg/dl

Postprandial
Glucose

2-hr postprandial
<140mg/dl

Peak <180mg/dl

*Individualize goals based on these values.

Postprandial glucose measurements should be made 12 h after
the beginning of the meal, generally peak levels in patients with
diabetes

ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S20. Table 9.

Tugas
Pelajari Obat-Obat yang
digunakan dalam Diabetes
Mellitus

terapi non obat

Farmakoterapi Non Obat
1. Pengaturan Pola Makan
2. Pengaturan Pola hidup
3. Olahraga teratur
4. Pemantauan kadar glukosa teratur
Penderita DM sangat membutuhkan :
penyuluhan atau konseling pada
penderita diabetes oleh para praktisi kesehatan,
baik dokter, apoteker, ahli gizi
maupun tenaga medis lainnya.

DIET
Makanan seimbang : Karbohidrat,
Protein, dan lemak
Karbohidrat : 60-70%
Protein : 10-15%
Lemak : 20-25%

farmakoterapi
1. TERAPI INSULIN
2. ANTIDIABETIK ORAL

Terapi insulin
Indikasi :
Pada pasien yang mengalami kerusakan sel pankreas (DM
tipe 1)
Pada pasien DM tipe 2 yang kadar glukosanya tidak bisa
dipertahankan dg Obat Antidiabetik Oral
Stress, pembedahan
Wanita hamil, kerusakan ginjal berat
Ketoasidosis diabetik
Kontraindikasi/alergi terhadap Antidiabetik oral

Insulin (cont)
Dosing:
Starting daily dose: 0.5-1 unit/kg/day in divided doses
Adjust according to fasting (premeal) blood glucose of 80-130
mg/dL and peak postprandial blood glucose < 180 mg/dL
Provide 50% as long acting insulin and 50% as prandial insulin
1 unit of can account for 30 grams of carbohydrate (14-50)
1 unit can lower 50 mg/dL blood glucose (10-100)
Special Population Consderations:
Renal dysfunction
CrCl 10-50 mL/min: 75% of normal dose
CrCl < 10 ml/min: 25-50% of normal dose; monitor closely

Exercise??? ---- Acute Stress???

Insulin Dosing

Long-acting

Long-acting &
Short-acting
Normal insulin secretion
70/30
pre-mixed

Section 1
Chemistry:

Insulin

51 aa arranged in two chains (A & B)

linked by disulfide bridges.

Secretion: By cells in pancreatic islet.

Degradation: Liver & kidney

Endogenous: Liver (60 %) & kidney (35 %-40 %)
Exogenous: Liver (35 %-40 %) & kidney (60 %)

T1/2 in plasma: 3-5 min

40

Cara pemberian insulin

Penyuntikan i.m

Insulin Administration

Pharmacology for Technicians by Ballington, Lauglin. EMC Paradigm 2006, Fig. 14.9

1. Insulin masa kerja singkat (Shortacting/Insulin), disebut juga insulin

reguler.
2. Insulin masa kerja sedang
(Intermediate-acting)
3. Insulin masa kerja sedang dengan
mula kerja cepat
4. Insulin masa kerja panjang (Longacting insulin)

Jenis Sediaan
Insulin

Mula kerja
(jam)

Puncak
(jam)

Masa kerja
(jam)

Masa kerja
Singkat(Shortac
ting/
Insulin), disebut
juga insulin
reguler

0,5

1-4

6-8

Masa kerja
sedang

1-2

6-12

18-24

Masa kerja
sedang mula
kerja cepat

0-5

4-15

18-24

Masa kerja
panjang

4-5

14-20

24-36

 *Untuk tujuan terapi, dosis insulin

dinyatakan dalam unit internasional
(UI). Satu UI
merupakan jumlah yang diperlukan
untuk menurunkan kadar gula darah
kelinci
sebanyak 45 mg%. Sediaan
homogen human insulin
mengandung 25-30 U/mg.

Penyimpanan insulin
Pada suhu 2-8C
Insulin vial Eli Lily yang sudah
dipakai dapat disimpan selama 6
bulan atau sampai 200 suntikan bila
dimasukkan dalam lemari es.
Vial Novo Nordisk insulin
yang sudah dibuka, dapat disimpan
selama 90 hari bila dimasukkan
lemari es.
Insulin dapat disimpan pada suhu

 Penelitian menunjukkan bahwa

insulin yang disimpan pada suhu
kamar lebih dari 30 C akan lebih
cepat kehilangan potensinya.
Penderita dianjurkan untuk memberi
tanggal pada vial ketika pertama kali
memakai dan sesudah satu bulan
bila masih tersisa sebaiknya tidak
digunakan lagi.

 Penfill dan pen yang disposable

berbeda masa simpannya. Penfill
regular dapat disimpan pada
temperatur kamar selama 30 hari
sesudah tutupnya ditusuk. Penfill
30/70 dan NPH dapat disimpan pada
temperatur kamar selama 7 hari
sesudah tutupnya ditusuk.

 Untuk mengurangi terjadinya iritasi

lokal pada daerah penyuntikan yang
sering terjadi bila insulin dingin
disuntikkan, dianjurkan untuk
mengguling-gulingkan alat suntik di
antara telapak tangan atau
menempatkan botol insulin pada
suhu kamar, sebelum disuntikkan.

Meglitinide Analogs
Sulphonylureas

Metformin (Biguanides)

Thiazolindinediones

Alpha Glucosidase
Inhibitors

Spectrum of Oral
HypoglycaemicMetformin
Agents(Biguanides)

Biguanides

Sulphonylureas

Glybenclemide, Glicliazide

-Glucosidase

Acarbose , Miglitol,
Voglibose
Repaglinide, Nateglinide

inhibitors

Meglitinide
analogues

Glipizide, Glimepiride

Rosiglitazone , Pioglitazone
Thiazolidinediones Sitagliptin, Vildagliptin,

Terapi dengan obat

PENGGOLONGAN ANTIDIABETIK ORAL / OBAT
HIPOGLIKEMIK ORAL (OHO)
1. Obat-obat yang meningkatkan sekresi insulin, meliputi
obat hipoglikemik oral golongan sulfonilurea dan
glinida (meglitinida dan turunan fenilalanin).
2. Sensitiser insulin (obat-obat yang dapat meningkatkan
sensitifitas sel terhadap insulin), meliputi obat-obat
hipoglikemik golongan biguanida dan
tiazolidindion, yang dapat membantu tubuh
untuk memanfaatkan insulin secara lebih efektif

3. Inhibitor katabolisme karbohidrat,

antara lain inhibitor -glukosidase
yang bekerja menghambat absorpsi
glukosa dan umum digunakan untuk
mengendalikan hiperglikemia postprandial (post-meal hyperglycemia).
Disebut juga starch-blocker.

Sulfonylureas (Oral Hypoglycemic drugs)

First generation

Short
acting

Intermediate
acting

Second generation

Long
acting

Tolbutamide Acetohexamide Chlorpropamide

Tolazamide

Short
acting

Long
acting

Glyburide
Glipizide
(Glibenclamide
Glimepiride
54

MECHANISM OF ACTION OF
SULPHONYLUREAS

1) Release of insulin from -cells

2) Reduction of serum glucagon
concentration
3) Potentiation of insulin action on target
tissues
55

 Hypoglycemic mechanism
1. Rapid mechanism: stimulation of insulin secretion
Sulfonylurea receptor in -cell membrane activated
ATP-sensitive K+-channel inhibited
Cellular membrane depolarized
Ca2+ entry via voltage-dependent Ca2+ channel
Insulin release

2. Long term profit involved mechanism

Inhibition of glucagon secretion by pancreas cells;
Ameliorating insulin resistance
Increase insulin receptor number & the affinity to insulin
56

DAFTAR OBAT-OBAT HIPOGLIKEMIK

GOLONGAN
CONTOH
MEKANISME
ORAL
(OHO)
SENYAWA
KERJA
SULFONILUREA

Gliburida/Glibe
nklamida
Glipizida
Glikazida
Glimepirida
GLIKUIDON

Merangsang
sekresi insulin
di
kelenjar
pankreas,
sehingga hanya
efektif pada
penderita
diabetes yang
sel-sel
pankreasnya
masih
berfungsi
dengan baik

DRUGS THAT AUGMENT THE

HYPOGLYCEMIC ACTION OF
SULPHONYLUREAS
WARFARIN
SULFONAMIDES
SALICYLATES
PHENYLBUTAZONE
PROPRANOLOL
ALCOHOL
CHLORAMPHENICOL
FLUCONAZOLE
58

GOLONGAN

CONTOH
SENYAWA

MEKANISMME
KERJA

Meglitinida

Repaglinide

Merangsang
sekresi insulin di
kelenjar pankreas

Turunan
fenilalanin

Nateglinide

Meningkatkan
kecepatan sintesis
insulin oleh
pankreas

Golongan Meglitinida dan Turunan

Fenilalanin
- Cara kerja mirip dg gol
sulfonilurea
- meningkatkan sintesis dan sekresi
insulin oleh kelenjar pankreas
- Umumnya digunakan dg kombinasi
bersama OHO lain

MEGLITINIDES (Contd.)
MECHANISM OF ACTION
Bind to the same KATP Channel
as do Sulfonylureas,
to cause insulin release from -cells.

61

Repaglinide/ Nateglinide
Nonsulphonylurea insulin
secretagogues
Mechanism:
Closes ATP-sensitive potassium channels
on -cells.
Binds to a site distinctly separate from the
sulphonylureas.

GOLONGAN

CONTOH
SENYAWA

MEKANISME KERJA

Biguanid

Metformin

Bekerja langsung
pada hati (hepar),
menurunkan
produksi glukosa
hati.
Tidak merangsang
sekresi insulin
oleh kelenjar
pankreas.

Tiazolidindion

Rosiglitazone
Troglitazone
Pioglitazone

Meningkatkan
kepekaan tubuh
terhadap insulin.
Berikatan dengan
PPAR (peroxisome
proliferator
activated receptorgamma) di otot,
jaringan lemak, dan
hati untuk
menurunkan
resistensi insulin

GOLONGAN

CONTOH SENYAWA

MEKANISME KERJA

Inhibitor glukosidase

Acarbose
Miglitol

Menghambat kerja
enzim-enzim
pencenaan yang
mencerna
karbohidrat, sehingga
memperlambat
absorpsi glukosa ke
dalam darah

-GLUCOSIDASE INHIBITORS
e.g. Acarbose
PHARMACOKINETICS
Given orally
Not absorbed from intestine except small
amount
t1/2 3 - 7 hr
65

-GLUCOSIDASE INHIBITORS
(Contd.)
MECHANISM OF ACTION
Inhibits intestinal alpha-glucosidases and
delays carbohydrate absorption, reducing
postprandial increase in blood glucose

66

-GLUCOSIDASE INHIBITORS (Contd.)

MECHANISM OF ACTION

Acarbose

Acarbos
e

Acarbose

67

-GLUCOSIDASE INHIBITORS (Contd.)

MECHANISM OF ACTION

68

-GLUCOSIDASE INHIBITORS
(Contd.)
SIDE EFFECTS
Flatulence
Loose stool or diarrhea
Abdominal pain
Alone does not cause hypoglycemia
69

GOLONGAN SULFONILUREA
- Drug of choice utk penderita yang
baru terdeteksi DM dg BB normal
atau kurang dan tidak mengalami
ketoasidosis
- Hati-hati pada pasien dg gangguan
fungsi hati, ginjal dan tiroid
- Hanya efektif untuk penderita dg sel
pankreas yang masih berproduksi

Sulfonylureas
Glimepiride

(Amaryl)

1, 2, 4 mg

tablets

Glipizide

(Glucotrol,
Glucotrol XL)

(2.5), 5, 10 mg tablets
(XL)

Glyburide

(DiaBeta)

1.25, 2.5, 5
mg

tablets

Indications

Adjuncts to diet and exercise to lower blood glucose in patients

w/ type II diabetes mellitus

MOA
Stimulating insulin release from beta-cells of pancreatic islets

Sulfonylureas (cont)
Patient Info

Hypoglycemia
GI upset/abdominal pain
Dizziness
Weight gain
Heartburn/epigastric fullness
Possible disulfiram-like reaction with alcohol (mainly w/
glyburide)
Onset: glucose lowering effect: 30 minutes with peak at
1.5-3 hours lasting 24 hours

Sulfonylureas (cont)
Special Population Considerations:
Pediatric: safety and efficacy not established for pts
under age 16
Hepatic/Renal Dysfunction: conservative dosing and
titration recommended.
Caution/Severe Adverse Reactions
Syndrome of Inappropriate Anti-diuretic Hormone (SIADH)
CONTRAINDICATIONS
Diabetes complicated by ketoacidosis
Type I DM
Diabetes w/ pregnancy. Pregnancy Cat: C (except
glyburide: B)

Modes of action:
Glimepiride
Most Sulphonylureas

++
K
Glimepiride

140
140
kDa
kDa

Glimepiride

Sulphonylurea

-- cell
cell
membrane
membrane

65
65
kDa
kDa

Receptor

GLUT4

K
K++

K
channel
KATP
ATP channel

So What ??

65kDa Component absent in Cardiovascular System

Safer to use in patients with a higher cardiovascular
risk

 Golongan Biguanid
contoh : Metformin
- bekerja langsung pada hepar,
menurunkan produksi glukosa hepar
- tidak merangsang sekresi insulin

Biguanides
Act by inhibiting liver
gluconeogenesis &
increasing insulin
sensitivity in other
tissues
Metformin is not
metabolized, but
excreted intact in 2-5 h

Biguanides
Metformi
n

Glucophage

500, 850, 1000

mg

tablets

(Glucophage XR)

500, 750 mg XR

tablets

Indication

Type II Diabetes Mellitus, Antipsychotic-induced weight gain

MOA

Decrease hepatic glucose production, decrease intestinal

absorption of glucose and increase insulin sensitivity therefore
increasing peripheral glucose uptake

Biguanides (cont)
Patient Info
N/V/D
Upset stomach/dyspepsia take
with food
Metallic taste
Minimal Weight Loss
Alcohol may increase likelihood of
lactic acidosis

Biguanides (cont)
CONTRAINDICATIONS
Renal disease or renal dysfunction (Scr >
1.5 mg/dL in males, >1.4 mg/dL in
females)
Abnormal Scr from any cause including:
shock, acute MI, or septicemia
Metabolic acidosis (including diabetic
ketoacidosis (DKA))
Heart failure requiring pharmacologic
therapy; active liver failure

 Golongan Tiazolidindion (TZD)

cara kerja : meningkatkan kepekaan
tubuh terhadap insulin
menurunkan kecepatan
glikoneogenesis

Thiazolidinediones (TZD)
Pioglitazone

(Actos)

15, 30, 45 mg

tablets

Rosiglitazone

(Avandia)

2, 4, 8 mg

tablets

Indications
As adjunct to diet and exercise for type II diabetes

MOA
Increase insulin sensitivity by affecting PPAR- (peroxisome
proliferators-activated receptor) at adipose tissue, skeletal
muscle and in the liver.
Special Alert February 2011: Addition of Risk Evaluation and
Mitigation Strategy to rosiglitazone. The medication is restricted
to those patients already on rosiglitazone for fails pioglitazone or
cannot be managed by other oral antidiabetic medications.

THIAZOLIDINEDIONE DERIVATIVES
(Contd.)
MECHANISM OF ACTION
- Increase target tissue sensitivity to
insulin by:
reducing hepatic glucose output &
increase glucose uptake & oxidation in
muscles & adipose tissues.
They do not cause hypoglycemia (similar
to metformin and acarbose ) .
82

TZD (cont)
Patient Info
Weight gain
Edema
Hypoglycemia esp. when used with other antidiabetic
medications and insulin (not w/ metformin)
May cause or exacerbate heart failure with risk of
fluid retention
URI, sinusitis, pharyngitis
Myalgia
Headache

TZD (cont)
Cautions/Severe Adverse Reactions
Black Box: Heart Failure (for all
thiazolidinediones, mainly due to rosiglitazone)
Hepatic failure
Anemia
Bone loss
Ovulation in premenopausal women
Pregancy Cat: C

TZD (cont)
Special Populations Considerations:
Congestive Heart Failure: should be initiated
at lowest approved dose with longer intervals
between dose increases for NYHA class II. Use is
not recommended in patients with NYHA Class III
or IV CHF
CONTRAINDICATIONS
NYHA Class III-IV heart failure
Active liver disease (ALT > 2.5 upper limit of
normal)

Dipeptidyl Peptidase-4 (DPP-4) Inhibitors

Sitagliptin

(Januvia)

25, 50, 100 mg

tablets

Sitagliptin/metform (Janumet)
in

50/500, 50/1000 mg

tablets

Saxagliptin

(Onglyza)

2.5, 5 mg

tablets

Saxagliptin/metfor
min

(Kombigly
ze XR)

2.5/1000, 5/500,
5/1000 mg

tablets

Indications
Diabetes Mellitus Type II

MOA
Inhibits the breakdown of GLP-1 by DPP-4 therefore increasing
GLP-1 levels resulting in increased glucose-dependent
insulin release and decreased level of circulating
glucagon and hepatic glucose production

Mechanism of Action of Sitagliptin

Ingestion
of food
Release of
active incretins
GLP-1 and GIP

Pancreas

GI
tract

Sitaglipti
n
(DPP-4
inhibitor) Inactive
GLP-1

Glucose
depende
nt Insulin

(GLP-1 and
GIP)

DPP-4
enzym
e

cells

Blood
glucose in
fasting and
postprandial
states

cells
Glucosedependen
t Glucagon
(GLP-1)

Inactive
GIP

Glucose
uptake by
peripheral
tissues

Hepatic
glucose
production

Incretin hormones GLP-1 and GIP are released by the intestine

throughout the day, and their levels increase in response to a meal.
Concentrations of the active intact hormones are increased by sitagliptin, thereby increasing and
prolonging the actions of these hormones.
30

DPP-4 (cont)
Patient Info
N/V
Hypoglycemia
Weight neutral
Nasopharyngitis/URI
Headache
Onset: Reduction in postprandial
serum glucose: 60 minutes

DPP-4 (cont)
Special Population Considerations:
Renal Impairment: avoid combo drugs w/ metformin
For sitagliptin:

CrCl 30-50 mL/min : 50 mg daily

CrCl < 30 mL/min: 25 mg daily
End Stage Renal Disease Requiring
dialysis: 25 mg daily

Geriatric: caution due to age related renal function

decreases
Cautions/Severe Adverse Reactions
Acute pancreatitis
Rash (Stevens-Johnson syndrome)

Sitagliptin Has a
Weight Neutral Profile
Monotherapy studies
No increase in body weight from baseline with sitagliptin
compared with a small decrease in the placebo group
Add-on to metformin
A similar decrease in body weight for both treatment
groups
Add-on to pioglitazone
No significant difference in body weight between
treatment groups
Noninferiority vs Sulfonylurea
A significant reduction in body weight with sitagliptin
versus weight gain with glipizide
46

Pharmacology Incretin Enhancers

Class

DPP-4 inhibitors (incretin enhancers)

Compound

Mechanism

Inhibits DPP-4 activity, prolongs survival of endogenously

released incretin hormones

Action(s)

Active GLP-1 concentration

Insulin secretion
Glucagon secretion

Advantages

No hypoglycemia
Weight neutrality

Disadvantages

Occasional reports of urticaria/angioedema

Cases of pancreatitis observed
Long-term safety unknown (cancer ?)

Cost

High

Sitagliptin (Januvia)
Vildagliptin (available in Europe)
Saxagliptin (Onglza)
Linagliptin (Tradjenta)

ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S23.

Adapted with permission from Silvio Inzucchi, Yale University.

What are the incretins?

GIP: Glucose-dependent insulinotrophic
polypeptide
Small effect in Type 2 diabetes.
GLP-1(glucagon-like peptide 1)
augmented in the presence of
hyperglycaemia.
Action less at euglycaemia and in normal
subjects.
Pituitary Adenylate Cyclase Activating
Peptide (PACAP)

Iso-glycaemic profiles
Incretin effect

Insulin concentration

Glucose given orally

Glucose given intravenously to

achieve the same profile

10

20

30

40

50

60 70
minutes

80

90

History of GLP-1
Discovered as
Insulinotropic
action of
incretins
confirmed

Incretin
defined

1930 1960

proglucagon
gene product
Incretin and
enteroinsular Normalisation
of BG in type
axis further
2 diabetes
defined

Enteroinsular
axis named

1970

Receptor
cloned

1980

1990

2000

GLP-1 localisation
Cleaved from
proglucagon in intestinal
L-cells (and neurons in
hindbrain/hypothalamus)
Secreted in response to
meal ingestion
Cleared via the kidneys

Pharmacology Incretin Mimetics

Class

GLP-1 receptor agonists (incretin mimetics)

Compound

Exenatide (Byetta)
Liraglutide (Victoza)

Mechanism

Activates GLP-1 receptors (-cells/endocrine pancreas;

brain/autonomous nervous system

Action(s)

Advantages

Weight reduction
Potential for improved -cell mass/function

Disadvantages

Gastrointestinal side effects (nausea, vomiting, diarrhea)

Cases of acute pancreatitis observed
C-cell hyperplasia/medullary thyroid tumors in animals
(liraglutide)
Injectable
Long-term safety unknown

Cost

High

Insulin secretion (glucose-dependent)

Glucagon secretion (glucose-dependent)
Slows gastric emptying
Satiety

ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S23.

Adapted with permission from Silvio Inzucchi, Yale University.

GLP-1 Modes of Action in

Humans
Stimulates glucose-dependent
Upon ingestion of food
insulin secretion
Suppresses glucagon secretion
Slows gastric emptying
GLP-1 is secreted
from the L-cells
in the intestine

Reduces food intake

Long term effects

demonstrated in animals
This in turn

Increases beta-cell mass and

maintains beta-cell efficiency

GLP-1
DPP IV
7
His

Ala

Glu

Gly

Thr

Phe

Thr

Ser

Asp
Val
Ser

Lys

Ala

Ala

Gln

Gly

Glu

Leu

Tyr

Ser

Glu
Phe
Ile

Ala

Trp

Leu

Val

Lys

Gly

Arg

NH2

Native GLP-1 has short duration of action

(t=2.6 minutes) when given intravenously

Gly

37

Pharmacology Amylin Analog

Class

Antihyperglycemic Synthetic Analog

Compound

Pramlintide (Symilin)

Mechanism

Amylinomimetic

Action(s)

Glucagon secretion (glucose-dependent)

Slows gastric emptying
Satiety

Advantages

Potential weight loss

Disadvantages

Meal time injections

Nausea
Hypoglycemia in combination with insulin

Cost

High

Lexi-Drugs Online [Internet]. Hudson (OH) : Lexi-Comp, Inc. 19782012[cited 2012 August 1].

TERAPI KOMBINASI
- Pada kondisi tertentu diperlukan
kombinasi
- Antar OHO, atau OHO dgn insulin
- Contoh : kombinasi sulfonilurea dan
biguanid

Fasting vs. Postprandial Effect

AACE/ACE Consensus Panel for Type 2 Diabetes. Endocrine Practice

2009; 25: 540-559

Fasting vs. Postprandial Effect

Mostly targets FASTING
hyperglycemia

Mostly targets
POSPRANDIAL
hyperglycemia

Insulin (long and intermediate

action)

Insulin (regular, rapid-action)

Colesevelam

-glucosidase inhibitors

Sulfonylureas

Meglitinides

TZD

Pramlinitide

Metformin

DPP-4 inhibitors
GLP-1 agonist

HAL-HAL YANG PERLU DIPERHATIKAN DALAM PENGGUNAAN OBAT

HIPOGLIKEMIK ORAL
1. Dosis selalu harus dimulai dengan dosis rendah yang kemudian dinaikkan
secara bertahap.
2. Harus diketahui betul bagaimana cara kerja, lama kerja dan efek samping
obat-obat tersebut.
3. Bila diberikan bersama obat lain, pikirkan kemungkinan adanya interaksi
obat.
4. Pada kegagalan sekunder terhadap obat hipoglikemik oral, usahakanlah
menggunakan obat oral golongan lain, bila gagal lagi, baru pertimbangkan
untuk beralih pada insulin.
5. Hipoglikemia harus dihindari terutama pada penderita lanjut usia, oleh
sebab itu sebaiknya obat hipoglikemik oral yang bekerja jangka panjang
tidak diberikan pada penderita lanjut usia.
6. Usahakan agar harga obat terjangkau oleh penderita.

QUESTIONS