Mahasiswa memahami klasifikasi OAD dan

membandingkan antar obat

Mahasiswa memahami farmakokinetik dan

farmakodinamik OAD

Mahasiswa memahami efek samping,

kontraindikasi, interaksi obat dan
memberikan edukasi kepada pasien
 Apakah
Diabetes itu
???

Penyakit yang ditandai dengan kadar gula darah

yang tinggi, yang disebabkan oleh
gangguan pada sekresi insulin
atau gangguan kerja insulin atau keduanya
 Glucose homeostasis

Body
cells
Insulin take up more
glucose

Beta cells
of pancreas stimulated
to release insulin into
the blood Liver takes Blood glucose level
up glucose declines to a set point;
High blood and stores it as stimulus for insulin
glucose level glycogen release diminishes

STIMULUS:
Rising blood glucose
level (e.g., after eating
a carbohydrate-rich
meal) Homeostasis: Normal blood glucose level
(about 90 mg/100 mL) STIMULUS:
Declining blood
glucose level
(e.g., after
skipping a meal)

Blood glucose level

rises to set point; Alpha
stimulus for glucagon cells of
release diminishes pancreas stimulated
to release glucagon
into the blood
Liver
breaks down
glycogen and Glucagon
releases glucose
Figure 26.8 to the blood
Mekanisme sekresi insulin (Harrison’s Principle of
Internal Medicine, 2005)
Type 2 Diabetes
 Klasifikasi obat hipoglikemik oral
• Biguanides: Metformin
• Thiazolidinediones: Rosiglitazone,
pioglitazone
• Sulphonylureas: glibenklamid, glicazide,
glipizide, glimepirid
•Meglitinide analogues: repaglinide
• -Glucosidase inhibitors: Acarbose
•DPP-4 Inhibitors: sitagliptin, vildagliptin
 Meglitinide Analogs
Sulphonylureas Alpha Glucosidase
Inhibitors

Metformin (Biguanides)

Thiazolindinediones
THERAPEUTIC OPTIONS : SITES OF ACTION

LIVER ADIPOSE TISSUE MUSCLE

PANCREAS

GLUCOSE PRODUCTION
PERIPHERAL
Biguanides
GLUCOSE UPTAKE
Thiazolidinediones
INSULIN Secretion Thiazolidinediones
Sulfonylureas (Biguanides)
Meglitinides
INTESTINE Insulin
Amylin

GLUCOSE ABSORPTION INTESTINAL HORMONES

Incretin
alpha-glucosidase inhibitors 12
Insulin sensitizer
Metformin
TZD
ADA: the primary DOC for diabetes
Biguanides / Metformin
Indikasi : DMT2
Mekanisme kerja:
• Bekerja langsung di hati
• Menghambat glukoneogenesis dan glikogenolisis di hati
• Menurunkan absorbsi glukosa di usus
• Insulin sensitizer  meningkatkan sensitivitas sel thd insulin:
Transport glukosa ke sel
Uptake dan penggunaan glukosa di organ perifer

• Metformin also decreases appetite.

• It is the only oral hypoglycemic shown to reduce cardiovascular
mortality.
• It can be used in combination with other oral agents and insulin.
Metformin Glucophage 500, 850, 1000 mg tablets

(Glucophage XR) 500, 750 mg tablets

 BIGUANIDES
PHARMACOKINETICS

• A: Given orally after meals:

• 250 to 500mg twice or thrice a day
• A: 50-60%, onset: respons glikemik maksimal 2 minggu
• Increase gradually if required in 1 or 2 weeks
• D: cepat ke jaringan perifer dan cairan, t.u.t GI tract. Not bind to
plasma proteins
• M: Not metabolized
• E: Excreted unchanged in urine excreted
intact in 2-5 h
• t 1/2 3-6 h

17
Advantages of Metformin over SUs
Does not cause hypoglycemia
Does not result in wt gain ( Ideal for obese pts )

18
 BIGUANIDES (Cont...)

SIDE EFFECTS
1. Metallic taste in the mouth
2. Gastrointestinal (anorexia, nausea, vomiting, diarrhea,
abdominal discomfort)
3. Vitamin B 12 deficiency (prolonged use)
4. Lactic acidosis ( rare – 01/ 30,000, exclusive
in renal & hepatic failure)

19
Biguanides (cont...)

Patient Info

 Upset stomach/dyspepsia – take with food

 Metallic taste

 Minimal Weight Loss

 Alcohol may increase likelihood of lactic acidosis

 Does not cause hypoglycemia

 Geriatric: limited data suggests starting doses should

be 33% lower for geriatric patients than that of
an adult dose. Titration should also to a lower
limit.
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 (KAD))
 Heart failure requiring pharmacologic therapy;
active liver failure
Th/ tunggal DMT1, DM dgn komplikasi
CHF yang membutuhkan obat
Insulin Sensitizers

Thiazolidinediones
(Glitazones)
 These agents are insulin
sensitizers,
 they do not promote
insulin secretion from
β-cells but insulin is
necessary for them to
be effective.
 Pioglitazone and
rosigglitazone
 Mechanism of Action:
activation of peroxisome proliferator-activated
receptor-γ (PPAR-γ)  GAMBAR
 In the liver: ↓glucose output dan kecepatan
glukoneogenesis
 In muscle: ↑glucose uptake
 In adipose: ↑glucose uptake, ↓FA release
 Pharmacokinetics:
 Both are extensively bound to albumin.
 Both undergo extensive P450 metabolism; metabolites
are excreted in the urine, the primary compound is
excrete unchanged in the bile.
 Adverse Effects:
 Fatal hepatotoxicity  hepatic function must be
monitored.
 Oral contraceptives levels are decreased with
concomitant administration, this has resulted in some
pregnancies.
Pioglitazone
 Meningkatkan jumlah protein transporter
glukosa
 Tdk untuk th/ tunggal
 KI: DC (memperberat edema)
ggg f(x) hati
Risiko hipoglikemia meningkat: insulin,
alkohol, fenformin, sulfonamida, salisilat
dosis besar, fenilbutazon, oksifenbutazon,
dikumarol, kloramfenikol, senyawa-
senyawa penghambat MAO (Mono Amin
Oksigenase), guanetidin, steroida
anabolik, fenfluramin, dan klofibrat.

Hormon pertumbuhan, hormon adrenal,

tiroksin, estrogen, progestin dan glukagon
bekerja berlawanan dengan efek
hipoglikemik insulin.
Guanetidin, kloramfenikol, tetrasiklin,
salisilat,fenilbutazon, memiliki interaksi
dengan insulin, sehingga sebaiknya tidak
diberikan bersamaan dengan pemberian
insulin, paling tidak perlu diperhatikan dan
diatur waktu dan dosis pemberiannya apabila
terpaksa diberikan pada periode yang sama.
FIRST GENERATION SULPHONYLUREA COMPOUNDS

Tolbutamid Acetohexamide Tolazamide Chlorpropamide

short-acting intermediate- intermediate long- acting
acting -acting

Absorption Well Well Slow Well

Metabolism Yes Yes Yes Yes
Metabolites Inactive* Active +++ ** Active ++ ** Inactive **
Half-life 4 - 5 hrs 6 – 8 hrs 7 hrs 24 – 40 hrs
Duration of Short Intermediate Intermediate Long
action (6 – 8 hrs) (12 – 20 hrs) (12 – 18 hrs) ( 20 – 60 hrs)
Excretion Urine Urine Urine Urine

* Good for pts with renal impairment

** Pts with renal impairment can expect long t1/2 29
SECOND GENERATION SULPHONYLUREA
COMPOUNDS

Glipizide Glibenclamide Glimepiride

Short- acting (Glyburide) Long-acting
Long-acting

Absorption Well Well Well

Metabolism Yes Yes Yes

Metabolites Inactive Inactive Inactive

Half-life 3 – 4 hrs Less than 3 hrs 5 - 9 hrs

Duration of 10 – 16 hrs 12 – 24 hrs 12 – 24 hrs

action

Excretion Urine Urine Urine

30
Mekanisme kerja sulfonilurea:
Stimulating insulin release from beta-cells of
pancreatic islets
Glimepiride (Amaryl) 1, 2, 4 mg tablets
Glipizide (Glucotrol, (2.5), 5, 10 tablets
Glucotrol XL) mg (XL)
Glyburide (DiaBeta) 1.25, 2.5, 5 tablets
mg

 15 minutes Before meals

 Efek samping:
 weight gain, hyperinsulinemia and
hypopglycemia.
 Hepatic or renal insufficiency
 Elderly patients appear particularly susceptible
to the toxicities of these agents.
 Tolbutamide is asociated with a 2.5X ↑ in
cardiovascular mortality. Glimepiride <<<

32
Sulfonylureas (cont...)
 Kontra indikasi :
 Diabetes complicated by ketoacidosis
 Type I DM
 Diabetes w/ pregnancy. Pregnancy Cat: C
(except glyburide: B)

Patient Info
 Hypoglycemia
 GI upset/abdominal pain
 Dizziness
 Weight gain
 Heartburn/epigastric fullness
 Onset: glucose lowering effect: 30 minutes with peak at
1.5-3 hours lasting 24 hours
Modes of action: Glimepiride
Most Sulphonylureas K+
Glimepiride

140  - cell
Glimepiride kDa membrane
65
Sulphonylurea kDa
Receptor
KATP channel
K+
GLUT-4
So What ??
65kDa Component absent in Cardiovascular System
Safer to use in patients with a higher cardiovascular risk
 Repaglinide/ Nateglinide

Nonsulphonylurea insulin secretagogues

Mechanism:

Closes ATP-sensitive potassium channels on

ß-cells.
Binds to a site distinctly separate from the
sulphonylureas.
 Nateglinide/Repaglinide

K+

140
kDa
65
kDa
Sulphonylurea Receptor

KATP channel
K+

Quicker attachment
Earlier Detachment
Repaglinide / Nateglinide
 Nonsulphonylurea insulin
secretagogues
 Mekanisme kerja :
 Menutup kanal K (pada reseptor
sulfonylurea, namun beda
tempat)  meningkatkan
sekresi insulin
 Perbedaan dg SU
 Quicker attachment
 Earlier Detachment
 Rapid absorption, metabolism &
clearance, T1/2 < 1
Kelebihan Nateglinide/Repaglinide
 Menurunkan insiden hipoglikemia
 Tidak signifikan meningkatkan BB
 Dapat digunakan pada pasien dengan fungsi ginjal
dan hepar yang terganggu, atau pada pasien dengan
pola makan yang tidak teratur
Dosis:
Repaglinide:
0.5mg/1mg/2mg/4mg per dose per meal
Nateglinide: 60mg/120mg per dose per meal
α-GLUCOSIDASE INHIBITORS
(Acarbose)
 Mekanisme kerja
 Menghambat enzim intestinal alpha-
glucosidases  memperlambat absorpsi
glukosa  menurunkan hiperglikemia
post prandial
 farmakokinetik : tidak diserap, diekskresi
lewat feses
 Tidak ada risiko hipoglikemia
 Efek samping flatus
α-GLUCOSIDASE INHIBITORS
(Cont...)
MECHANISM OF ACTION

Acarbose

Acabose
Acarbose

Acarbose

Acarbose
41
α-GLUCOSIDASE INHIBITORS (Cont...)
MECHANISM OF ACTION

42
 Alpha Glucosidase inhbitors
 PHARMACOKINETICS : Given orally 25-50 mg, not
absorbed from intestine except small amount
 t1/2 3-7h
 Excreted with stool

Advantages:
Selective for postprandial hyperglycaemia
No hypoglycaemic symptoms
Disadvantages:
Abdominal Distension and flatus
Only effective in mild hyperglycaemia
Contraindications

 an inflammatory bowel disease, such as

ulcerative colitis or Crohn's disease; or
any other disease of the stomach or
intestines
 ulcers of the colon
 Intestinal Obstruction
 kidney disease
Incretin concept

Insulin
secretion dynamics is dependent on
the method of administration of glucose

Intravenous glucose gives a marked first and

second phase response
Oral glucose gives less marked first and
second phase insulin response, but a
prolonged and higher insulin concentration
Insulin secretion profiles

Glucose given orally

Insulin concentration

Glucose given intravenously

0 10 20 30 40 50 60 70 80 90
minutes
 New Therapies: Incretin System

Glucose
dependent
 Insulin  Glucose
Ingestion (GLP-1and uptake by
of food Pancreas GIP) peripheral
Release of tissue
active incretins Beta cells
GI tract GLP-1 and GIP Alpha cells  Blood glucose in
fasting and
postprandial states

Glucose-
X
DPP-4
enzyme dependent
Exenatide
 Glucagon  Hepatic
(GLP-1) glucose
Sitagliptin Inactive Inactive production
GLP-1 GIP

GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide.

 What are the incretins?
 are naturally occurring hormones that the gut
releases throughout the day; the level of active
incretins increases significantly when food is
ingested.
 GIP: Glucose-dependent insulinotrophic polypeptide
Small effect in Type 2 diabetes.
 is secreted by endocrine K cells mainly present in the
proximal gastrointestinal (GI) tract (duodenum and
proximal jejunum).
 GLP-1(glucagon-like peptide 1)
augmented in the presence of hyperglycaemia.
Action less at euglycaemia and in normal subjects.
is secreted by L cells located predominantly in the
distal GI tract (ileum and colon).
Incretin Therapy
Januvia (sitagliptin)
Dipeptidyl Peptidase-4 (DPP-4)
Inhibitors

Sitagliptin (Januvia) 25, 50, 100 mg tablets

Sitagliptin/metfo (Janumet) 50/500, 50/1000 tablets
rmin mg
Saxagliptin (Onglyza) 2.5, 5 mg tablets
Saxagliptin/metf (Kombigly 2.5/1000, 5/500, tablets
ormin ze XR) 5/1000 mg

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
 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)

Insulin therapy
INDIKASI TERAPI INSULIN
Penurunan berat badan yang cepat •
Hiperglikemia berat disertai ketosis
Ketoasidosis diabetik
 Hiperglikemia hiperosmolar non ketotik
Hiperglikemia dengan asidosis laktat •
Gagal dengan kombinasi Obat Hipoglikemia Oral (OHO)
dosis hampir maksimal •
 Kendali kadar glukosa darah buruk (Hb A1c > 7,5% atau
kadar glukosa darah puasa >250 mg/dL •
 Stress berat (infeksi sistemik, operasi besar, IMA, stroke)
Kehamilan dengan DM gestasional yang tidak terkendali
dengan diet •
Gangguan fungsi ginjal atau hati yang berat •
 Kontra indikasi dan atau alergi terhadap OHO
Riwayat pankreatektomi
 TYPES OF INSULIN PREPARATIONS

1. Ultra-short-acting
2. Short-acting (Regular)
3. Intermediate-acting
4. Long-acting

56
 Short-acting (regular) insulins Ultra-Short acting insulins
e.g. Humulin R, Novolin R e.g. Lispro, aspart, glulisine

Uses Designed to control postprandial Similar to regular insulin but

hyperglycemia & to treat designed to overcome the
emergency diabetic ketoacidosis limitations of regular insulin

Physical Clear solution at neutral pH Clear solution at neutral pH

characteristics
Chemical Hexameric analogue Monomeric analogue
structure
Route & time of S.C. 30 – 45 min before meal S.C. 5 min (no more than
administration I.V. in emergency 15 min) before meal
(e.g. diabetic ketoacidosis) I.V. in emergency
(e.g. diabetic ketoacidosis)

Onset of action 30 – 45 min ( S.C ) 0 – 15 min ( S.C )

Peak serum levels 2–4h 30 – 90 min

Duration of action 6 – 8 h 3–4h

Usual 2 – 3 times/day or more 2 – 3 times / day or more 57

 Mechanism of Insulin Action
 Insulin binds to specific high
affinity membrane receptors
with tyrosine kinase activity
 Phosphorylation cascade
results in translocation of Glut-
4 (and some Glut-1) transport
proteins into the plasma
membrane.
 It induces the transcription of
several genes resulting in
increased glucose catabolism
and inhibits the transcription
of genes involved in
gluconeogenesis.
 TYPES OF INSULIN PREPARATIONS

1. Ultra-short-acting : Lispro, aspart, glulisine

2. Short-acting (Regular) : Humulin R, Novolin R
Designed to control postprandial hyperglycemia
& to treat emergency diabetic ketoacidosis
3. Intermediate-acting : Lente insulin, sophane NPH
insulin: Neutral protamine Hagedorn insulin
4. Long-acting : uktralente, insulin glargine

59
Intermediate –acting Insulin Preparations
The Goal of Insulin Therapy
Administration of insulins are arranged to
mimic the normal basal, prandial and post-
prandial secretion of insulin. Short acting
forms are usually combined with longer acting
preparations to achieve this effect.
Insulin (cont)

Administration:
Subcutaneous injection : Insulin Syringe, Pre-filled
insulin pens, External insulin pump

Rotate site
Check blood sugars regularly
Storage:
Refrigerate until use
Once vial is punctured, it is good for 28 days and can be
left at room temperature (except for glargine which is 90
days)
Insulin Administration

Pharmacology for Technicians by Ballington, Lauglin. EMC Paradigm 2006, Fig. 14.9
Insulin (cont)

Cautions/Severe Adverse Reactions

Severe hypoglycemia (seizure/coma) (BG < 40 mg/dL)
Edema

Lipoatrophy or lipohypertropy at injection site

CONTRAINDICATIONS
Severe hypoglycemia
Allergy or sensitivity to any ingredient of the product
Action of Insulin on Various Tissues

Liver Muscle Adipose

↓ glucose production ↑ Glucose transport ↑ glucose transport

↑ glycolysis ↑ glycolysis ↑ lipogenesis&

lipoprotein lipase
activity
↑ TG synthesis ↑ glycogen deposition ↓ intracellular lipolysis

↑ Protein synthesis ↑ protein synthesis

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
66
Insulin Action

Rapid/immediate

Intermediate
Blood concentration

Fast

Slow

0 2 4 6 8 10 12 14 16 18 20 22 24

Time (hr)
 Insulin preparations and treatment
 Various types of insulin are characterized by their onset
and duration of action
Adjunctive Therapy in
Diabetes Mellitus Type II
 Hypoglycemia
 Complication of treatment!
 Make sure patients inform the people
around them of these symptoms and what
to do!
 Symptoms: Anxiety, blurred vision,
palpitations, shakiness, slurred speech,
sweating
 Treatment: glucose/simple sugars,D40%
 Adjunctive Therapy (cont..)
Energy balance, diet, exercise
 Low-carb, low-fat, calorie-restricted diet is recommended

Cardiovascular disease/Hypertension
 Systolic blood pressure goal < 130 mm Hg
 Angiotensin Converting Enzyme II Inhibitor (ACE-I) is first
line
 Renal protective

 Angiotensin Receptor Blockers (ARB) can be used if patient

fails or is intolerant to ACE-I

Adjunctive Therapies (cont...)

Dislipidemia
 Patients with type II diabetes have an LDL goal <
100 mg/dL
 Weight loss
 First line therapy: statins (i.e. atorvastatin,
simvastatin, rosuvastatin etc.)
 Fiber, omega-3 fatty acids (fish oils) can be used as
adjunct therapy
Antiplatelet agents
 Consider starting daily low dose aspirin (81 mg) to
prevent ischemic events
Adjunctive Therapies (cont...)

 Smoking cessation
 Diabetic neuropathies especially in
extremities need to be screened for on a
regular basis
 Fastidious foot care
 Regular foot exams (annually)
 Eye exams
 Monitor kidney function
Indikasi :
 Pada pasien yang mengalami kerusakan sel β
pankreas (DM tipe 1)
 Pada pasien DM tipe 2 yang kadar glukosanya
tidak bisa dipertahankan dgn Antidiabetik Oral
 Keadaan stress berat, seperti pada infeksi
berat, tindakan pembedahan, infark miokard
akut atau stroke.
 DM gestasional dan penyandang DM yang
hamil membutuhkan insulin bila diet saja tdk
dapat mengendalikan kadar glukosa darah
 Gangguan fungsi ginjal atau hati yang berat
 Ketoasidosis diabetik
 HONK (Hiperglikemik hiperosmotik non ketotik)
 Kontraindikasi/alergi terhadap Antidiabetik oral
1. Insulin masa kerja singkat (Short-
acting/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 (Long-acting
insulin)
Jenis Sediaan Insulin Mula kerja Puncak Masa kerja
(jam) (jam) (jam)
Masa kerja Singkat (Short 0,5 1-4 6-8
acting/insulin), disebut
juga insulin reguler

Masa kerja sedang 1-2 6-12 18-24

Masa kerja sedang mula 0-5 4-15 18-24

kerja cepat

Masa kerja panjang 4-5 14-20 24-36

Untuk Th/ DM tipe II
 Bisa memakai hanya insulin kerja menengah
(intermediate) saja, atau campuran insulin
cepat dan menengah.
 Biasanya 2/3 unit diberikan sebelum makan
pagi dan 1/3 unit diberikan sebelum makan
malam.
 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.
Pada suhu 2-8°C
 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 kamar
dengan penyejuk 15-20°C bila seluruh isi
vial akan digunakan dalam satu bulan.
 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.
TERAPI KOMBINASI
 Pada kondisi tertentu diperlukan kombinasi
 Antar OHO, atau OHO dg insulin
 Contoh : kombinasi sulfonilurea dan biguanid
HAL-HAL YANG PERLU DIPERHATIKAN DALAM
PENGGUNAAN OBAT HIPOGLIKEMIK ORAL

1. Dosis dimulai dengan dosis rendah  dinaikkan bertahap

2. Harus diketahui cara kerja, lama kerja dan efek samping obat2 tersebut.
3. Bila diberikan bersama obat lain, pikirkan kemungkinan interaksi obat.
4. Pada kegagalan Obat Hipoglikemik Oral (OHO), gunakan obat oral
golongan lain gagal lagi, pertimbangkan beralih pada insulin.
5.Terapi dengan OHO kombinasi, harus dipilih 2 macam obat kelompok dgn
mekanisme kerja berbeda  sasaran blm tercapai kombinasi 3 OHO
kelompok berbeda, atau OHO + insulin. Jk alasan klinik insulin tidak
memungkinkan dipakai kombinasi 3 OHO
6. Hipoglikemia harus dihindari terutama pada penderita lanjut usia 
sebaiknya OHO kerja jangka panjang tidak diberikan
7. Harga obat terjangkau oleh penderita.
TERIMA KASIH