Dr. I Gede Palgunadi, Sp.

PD
SMF Penyakit Dalam RSUD Mataram

More Effective Glycaemic Control

Turning Theory into Practice
 Current and Projected Prevalence
Rates for Diabetes
80 1995 2000 2025
Estimated Prevalence (millions)

70

60

50

40

30

20

10

0
Africa Americas Eastern Europe Southeast Western
Mediterranean Asia Pacific

World Health Organization. World Health Report 1997: Message from the Director-General. Available at
www.who.int/whr/1997/message.pdf. Accessed November 8, 2002.
 ESTIMATE DIABETES IN INDONESIA

250 239,3
Million

200
Million 175,4

150 140
Million
110,5
100 5
5 Mill
Million 4 Mill 4
3
3 Mill 2,5
50
2 Mill
Million
1 Mill

1994 1997 2000 2003 1994 1997 2000 2003

Top ten countries for estimated number of
adults with diabetes, 1995 and 2025
Country 1995 (millions) Country 2025 (millions)

Rank
1 India 19.4 India 57.2
2 China 16.0 China 37.6
3 U.S. 13.9 U.S. 21.9
4 Russian Fed. 8.9 Pakistan 14.5
5 Japan 6.3 Indonesia 12.4
6 Brazil 4.9 Russian Fed. 12.2
7 Indonesia 4.5 Mexico 11.7
8 Pakistan 4.3 Brazil 11.6
9 Mexico 3.8 Egypt 8.8
10 Ukraine 3.6 Japan 8.5
All other countries 49.7 103.6

Total 135.3 300.0

DEFINISI ADA 2003
• Diabetes mellitus adalah sekelompok penyakit
metabolik ditandai hiperglikemia, karena defek sekresi
insulin, kerja insulin, atau keduanya

• Gangguan kronik – jangka panjang dan berhubungan

erat dengan kerusakan organ tubuh tertentu, mis :
mata, ginjal, saraf, jantung serta pembuluh darah

Makna :
• Kronik – tidak dapat sembuh
• Progresif
• Untuk mencegah komplikasi perlu dicegah hiperglikemia
 Klasifikasi diabetes mellitus
1. DM tipe 1 : kerusakan sel beta karena sebab (a)
imunologis (b) idiopatik
2. DM tipe 2 : karena resistensi insulin yang dominan
(dengan defisiensi insulin relatif) sampai gangguan sekresi
sel beta dengan resistensi insulin

3. DM tipe lain : a, b, c, d, e, f, g, h
4. Gestational DM

• Diabetes tidak bisa sembuh namun dapat dikendalikan

• Pada saat diagnosis, sebagian DM tipe 2 sudah mengalami komplikasi
• Perubahan telah terjadi 5 – 12 tahun sebelum diagnosis ditegakkan
Perkembangan DM Tipe 2
Resistensi Insulin Kegagalan fungsi sel Beta

Resistensi insulin
Hiperinsulinemia
Toleransi glukosa normal

Resistensi insulin
Penurunan kadar insulin
Gangguan toleransi glukosa

DM Tipe 2
Adapted from Diabetes 1996;45:1661
 Perjalanan Alami DM Tipe 2

Sensitivitas Insulin Sekresi Insulin

30% T2DM 50%

50% IGT 70-100%

Impaired glucose
70% 150%
metabolism

100% Normal glucose metabolism 100%

Diabetes Obes Metab 1999; 1(1): S1

 ABNORMALITAS METABOLIK DM TIPE 2

HATI PANKREAS

Peningkatan Produksi Kegagalan Fungsi Sel

Glukosa Hepar Beta

DM tipe 2

Jar. Lemak
OTOT

Penurunan Penggunaan Penurunan Penggunaan

Glukosa Perifer Glukosa Perifer
 RESISTENSI INSULIN
 Definisi :

kegagalan terhadap efek fisiologi insulin,

termasuk terhadap metabolisme glukosa,
lipid, protein, serta fungsi endotel vaskuler
 Defek utama pada sebagian besar DM tipe 2

Diab Care 1999;22:562

Diab Care 2000; 23(Suppl 1):54
 EFEK RESISTENSI INSULIN
Glucose uptake 
Glucose oxidation 

Insulin Hyperinsulinemia
Lipolysis 
Hyperglycemia
resistance Free fatty acid 
Dyslipidemia

Glucose uptake 
Glucose production 
VLDL synthesis  Cardiovascular
disease
Interrelation Between Atherosclerosis and
Insulin Resistance
Hypertension
Obesity
Hyperinsulinemia

Insulin Diabetes
Atherosclerosis
Resistance Hypertriglyceridemia
Small, dense LDL
Low HDL
Hypercoagulability
STRATEGI TERAPI DM TIPE 2
Pengelolaan :
 Hiperglikemia
 Hiperinsulinemia / Resistensi Insulin
 Dislipidemia

Mencegah
terjadinya

Komplikasi Mikrovaskuler
Komplikasi Makrovaskuler
 Prinsip Dasar Terapi Diabetes Mellitus
1 2

PENYULUHAN PENGATURAN MAKAN

3 4

LATIHAN OBAT - OBATAN

 Berdasarkan titik tangkapnya telah dikembangkan
berbagai obat dengan khasiat sebagai berikut :
1. Mengurangi resistensi insulin : derivat biguanide dan thiazolidinedione
2. Mengubah metabolisme asam lemak : menghambat keluarnya NEFA,
penghambat oksidasi asam lemak
3. Stimulasi sekresi insulin : sulfonilurea, antagonis -2 adrenergik
4. Penghambat naiknya glukosa post prandial : guar gum, -glukosidase
inhibitor, -amylase inhibitor
5. Mengurangi berat badan : bahan anorektik, -3 agonist, antagonis
neuropeptide Y
6. Memberikan suplementasi insulin basal : glukagon like-peptide I (GLP-I),
insulin secretagogue non-sulfoilurea (meglitinide, repaglinide)
 MEKANISME KERJA OHO
LIVER ADIPOSE MUSCLE
TISSUE

GLUCOSE
PRODUCTION PERIPHERAL
GLUCOSE UPTAKE
Biguanides
Thiazolidinediones
Thiazolidinediones
Biguanides
Hyperglycemia

PANCREAS

INTESTINE

alpha-glucosidase inhibitors INSULIN Secretion

Sulphonylurea (SU)
GLUCOSE
ABSORPTION
Non-SU : Meglitinides
& Nateglinide
Sonnenberg and Kotchen. Curr Opin Nephrol Hypertens 1998;7(5):551–5
 OHO di Indonesia
1. Menurunkan absorpsi karbohidrat
• Acarbose
• Metformin
2. Meningkatkan sekresi insulin (Insulin Secretagogues)
• Sulfonilurea : Glibenclamide, glipizide, gliclazide, gliquidone, glimepirid
• Non-Sulfonilurea : Nateglinide, Repaglinide
3. Menurunkan produksi glukosa hepar
• Metformin
• Thiazolidinediones : Pioglitazone
4. Meningkatkan ambilan glukosa perifer
• Thiazolidinediones : Pioglitazone
• Metformin
• Sulfonilurea : Glibenclamide, glipizide, gliclazide, gliquidone, glimepirid
Obat Anti-hiperglikemia Oral Yang Ideal

Dapat mengontrol gula darah puasa & 2 jam SM

Tidak ada risiko hipoglikemia
Mempunyai dampak yang menguntungkan pada
parameter lipid
Aman dan dapat ditoleransi dengan baik
Pemberian sederhana
Dapat digunakan oleh semua penderita DM tipe 2
Menurunkan morbiditas/ mortalitas kardiovaskuler dan
mikrovaskuler
 KRITERIA PENGENDALIAN DM
Konsensus PERKENI 2002

BAIK SEDANG BURUK

Gula Darah Puasa 80 - 109 110 - 125 > 126

Gula Darah 2 JSM 80 - 144 145 - 179 > 180

HbA1C (%) < 6,5 6.5 - 8 >8

Kolesterol Total < 200 200 - 239 > 240

Kolesterol LDL < 130 100 - 129 > 130

Kolesterol HDL > 45

Trigliserida < 150 150 - 199 > 200

BMI 18,5 - 22,9 23 - 25 > 25

Tekanan Darah < 130 / 80 130-140/ 80- > 140 / 90

TARGETS FOR GLYCEMIC CONTROL

HbA1c% FPG mmol/L

ADA1 <7 < 6.7 (120)*

IDF (Europe)2 < 6.5 < 6.0 (110)*

*mg/dl

Diabetes Care 1999;22(Suppl 1):S1-S114. 2Diabetic Medicine 1999;16:716-30

1
What level of glycaemic control should we aim
for ?

 Untuk menurunkan komplikasi mikrovaskuler

 HbA1c harus senormal mungkin
 Awas hipoglikemia ! ! !
 HbA1c normal 6.1%
 PERKENI HbA1c menganjurkan  < 7%
(Sesuai konsensus ADA).

BMJ 333; 9 Des. 2006

LESSONS FROM UKPDS:
BETTER CONTROL MEANS FEWER COMPLICATIONS
EVERY 1% REDUCED
reduction in A1C RISK*

Deaths from diabetes -21%

Heart attacks -14%

Microvascular complications
1%
-37%

Peripheral vascular disorders -43%

UKPDS 35. BMJ 2000; 321: 405-12.

*p<0.0001
Treatment algorithm for type 2 diabetes

Aim Diet, exercise, health education

Sulphonylurea, metformin
Glucosidase Inhibitors
Glitinides
Thiazolidinediones
Oral combinations

Insulin

Improved control Insulin plus oral agents

 Stepped management of type 2 diabetes
This is illogical in most cases of diabetes where there is both
insulin deficiency and resistance

UKPDS shows diet therapy alone worsens pancreatic

function in 356 patients by 50% in 6 years
 Treatment Priority of Type 2 DM

Glucose control as near Control of Insulin resistance,

to normal as Hyperinsulinemia, Obesity,
Dyslipidaemia, Hypertension,
reasonably possible Procoagulant State

Microvascular Macrovascular
Disease Disease
Dual Defect of Type 2 Diabetes : Treating a Moving Target

Insulin Type 2  -cell

Resistance Diabetes Dysfunction

ia
aem
Ins lyc
uli -Cell Failure erg
nA yp
cti H
on Insulin
Concentration
Insulin
Resistance

Euglycaemia
Normal IFG IGT + Obesity Dx T2DM Progression of
T2DM
Lifestyle change: an option?
 The potentially most efective but most
dificult !
 Chochrane analysis  no high quality data to
support the efectiveness of dietary
treatment.

BMJ 333; 9 Des. 2006

 Rationale for Early Combination Therapy

 Pathophysiology – dual defects

 Glycaemic burden – FPG and PPG
 Monotherapy targets one defect and HbA1C < 7.0%
seldom achieved
 Diabetes is progressive – durable control means multiple
therapies
 Switch to combined therapy after ‘treatment failure’ leads
to excessive hyperglycaemic exposure
Choice of agents in current use
Glipizide
Acarbose
Gliclazide
Miglitol
Glimepiride Sulphonylureas Voglibose
Glibenclamide

TZDs Metformin -glucosidase

inhibitors

Meglitinides
Rosiglitazone Repaglinide
Pioglitazone Nateglinide
Combination therapy and the dual endocrine
defect of type 2 diabetes
Insulin β-cell
resistance deficiency

Metformin + insulin secretagogue1  

Metformin + TZD  
Metformin + AGI  
Sulphonylurea + TZD  
Sulphonylurea + AGI  
TZDs + AGI  
1
Sulphonylurea or meglitinide ; TZD: thiazolidinedione ; AGI: -glucosidase inhibitor
Is metformin still the first line drug?

 Metformin  biguanide yg diterima secara

luas sbg first line drug. Safe, effective, dan
murah.
 Menurunkan resiko penyakit kardiovaskuler
pada pasien obese dengan DM type 2.
Metformin: foundation therapy for prevention of type 2
diabetes and its complications
 Reduced morbidity and mortality in the UKPDS
– Unique reduction of cardiovascular complications beyond
that expected from blood glucose control
 IDF and ADA guidelines favour the use of metformin as
foundation therapy for type 2 diabetes where possible
 The antihyperglycaemic efficacy of metformin is dose-related with
an optimal daily dose of 2000 mg/day
 Metformin is well tolerated across its dosage range
– Gastrointestinal side-effects are usually transient
– Minimised by slow dosage titration
– Only about 5% of patients cannot tolerate metformin
 Proven to prevent or delay type 2 diabetes (DPP)
UKPDS clinical outcomes for metformin
Clinical endpoints Metformin therapy
 riska p

Any diabetes-related complication  32% 0.002

Diabetes deaths  42% 0.017
Myocardial infarction  39% 0.01
Stroke  41% 0.13
Microvascular complications  29% 0.19
Retinal photocoagulation  31% 0.17
a
Compared with conventional diet-based therapy (overweight patients)

UKPDS 34. Lancet 1998;352:854-65

Metformin and myocardial infarction

Controls Metformin
Clinical endpoints (%) (n=123) (n=187)

Reinfarction 8.9 1.6

Symptoms of angina 10.6 4.8
Acute cardiovascular events 6.5 4.0
Fatalities 10.3 8.0

Diabetic 34% / IGT 52% / Normal 14%

Follow-up 3 years
Sgambato et al. Clin Ter 1980;94:77-85
 Kontrol Metabolik Metformin pada DM Tipe 2

Muscle
Glucose uptake
& utilisation 

Adipose

Fat storage  Euglycaemia

Metformin Lipolysis 
Normolipidaemia
Free fatty acids 

Liver

Glucose uptake 
VLDL synthesis 
Metformin: multiple mechanisms for
vascular protection
Metformin addresses CV risk by a range
of direct and indirect mechanisms

Improved
 Insulin sensitivity
 Fibrinolysis
 Nutritive capillary flow
 Haemorrheology
 Postischaemic flow
Reduced
 Hypertriglyceridaemia
 AGE formation
 Crosslinked fibrin
 Neovascularisation
 Oxidative stress

Reduced cardiovascular risk

ß Cell function (%)

100 Insulin
Lifestyle Monotherapy Dual ± oral drugs
Therapy for lowering
Blood glucose

Glycated haemoglobin (%)

9
8
7
6
Glycated haemoglobin
ß Cell function 5
0
0 >15

Traditional treatment strategy for type 2 diabetes and its consequences. In type 2
Diabetes ß cell function declines over the years, irrespective of treatment with metformin,
Sulfonylurea (as monotherapy or dual therapy), or insulin. Treatment therefore has to be
Adjusted at regular intervals according to the level of glycaemia. Because doctor and patient
Recurrently fail to reach target. BMJ 333; 9 Des 2006.
Sulfonylurea, thiazolidinedion, or insulin ? add
to metformin !

 Insulin ditambahkan bila HbA1C > 8,5% tapi

komorbid yang menyertai DM type 2 lebih
dipertimbangkan!
 Bila tidak ada komorbid yang gawat maka
kombinasi Su + Met lebih disukai pasien
dibandingkan insulin.

BMJ 333; 9 Des. 2006

And then? 3oral agents, insulin as add-on, or
insulin alone?
 Kombinasi (Su + Met + Thz) lebih mahal
dibandingkan insulin + Met.
 Bila target HbA1C tak tercapai dg dual terapi
 mulai basal insulin atau Intermediate/long
acting insulin.
 Inhaled insulin baru2 ini di US mulai dipakai.
Belum tau keberhasilan dan efek samping.
 Lifestyle counselling and metformin

Add sulfonylurea or or thiazolidinedione or basal insulin

Glycated
Haemoglobin ≥ 7%

Metformin + Metformin + Intensify

Sulfonylurea + Thiazolidenedione Insulin
Basal insulin + sulfonylurea Therapy
Or
Metformin +
Thiazolidinedione
Glycated + basal insulin
Haemoglobin ≥ 7%

Intensive insulin + metformin ± thiazolidinedione

Goal of treatment should be a glycated haemoglobin value as close to the non-diabetic

Range (<6,1%) as possible; treatment should be started or changed if the value is ≥ 7%
Choose the most effective regimen (metformin plus insulin) if glycated haemoglobin is > 8,5%
Insuli can be started at any poit in the course of diabetes, including at the time of diagnosis
Insulin treatment (plus metformin) is generally preferred to three oral agent as it is at least
As effective in lowering glycamia and is much cheaper.

BMJ 333; 9 Des.2006. Management of hyperglycaemia in type 2 diabetes

Obat Baru
 Vildagliptin 50mg/tablet, Sitagliptin, Saxagliptin
 Bekerja pada sel α & sel ß pankreas suatu
DPP-4 inhibitor oral (dipeptidyl peptidase IV).
 Meningkatkan sekresi insulin dan menurunkan
sekresi glukagon
 obat ini merupakan kandidat sebagai obat
pilihan pertama selain regulasi gula darah dan
tidak meningkatkan berat badan.

Suastika, Konas VII PERSADIA 2008

 RINGKASAN
• DM tipe 2 merupakan ~95 dari seluruh kasus DM
• DM tipe 2 terutama disebabkan oleh resistensi insulin
• Adanya resistensi insulin akan berpengaruh terhadap
jaringan otot, lemak dan liver dengan akibat terjadinya
hiperinsulinemia, hipergikemia dan dislipidemia
• Adanya resistensi insulin akan berpengaruh terhadap
perkembangan komplikasi vascular diabetik
• Setiap terapi DM tipe 2 haruslah selalu mengingat pada
perbaikan resistensi insulin
Summary points
 Initial treatment should consist of lifestyle
intervention and metformin
 Treatment should aim to keep blood glucose
concentrations as close to the non-diabetic range
as possible
 The relentless decline of ß cell function requires
early intervention, regular monitoring of
glycaemia, and prompt adjustment of the
(combination of) blood glucose lowering drugs,
including insulin
 Good glycaemia control will reduce the
occurrence of inicrovascular and perhaps
cardiovascular complications of type 2 diabetes
 Scientific evidence for any algorithm is largely
lacking