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PENATALAKSANAAN

DIABETES MELLITUS
TERKINI

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
50
3 Mill 2,5
Million 2 Mill

1 Mill

1994 1997 2000 2003 199 199 200 200


4 7 0 3
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
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 Kegagalan
Produksi Glukosa Fungsi Sel
Hepar Beta
DM tipe 2

Jar. Lemak

OTOT

Penurunan Penurunan
Penggunaan Penggunaan
Glukosa Perifer Glukosa Perifer
RESISTENSI INSULIN
Definisi :
kegagalan terhadap efek fisiologi insulin,
termasuk terhadap metabolisme glukosa,
lipid, protein, serta fungsi endotel vaskuler
Defek utamapada 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 Hyperinsuli
Lipolysis ↑ nemia
resista Free fatty Hyperglycem
nce acid ↑ ia
Dyslipidemi
a

Glucose uptake

Glucose
production ↑ Cardiovascu
VLDL synthesis lar disease

Interrelation Between
Atherosclerosis and Insulin
Resistance
Hypertension
Obesity
Hyperinsulinemia
Insulin Diabetes Atherosclerosi
Resistance Hypertriglyceridemia
s

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 α -2
adrenergik
4.Penghambat naiknya glukosa post prandial : guar gum, α -
glukosidase inhibitor, α -amylase inhibitor
5.Mengurangi berat badan : bahan anorektik, β -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
Biguanides GLUCOSE UPTAKE
Thiazolidinediones Thiazolidinediones
Hyperglyce Biguanides
mia
PANCREAS

INTESTI
NE
alpha-glucosidase INSULIN Secretion
inhibitors Sulphonylurea (SU)
GLUCOSE Non-SU : Meglitinides
ABSORPTION
& 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


90
TARGETS FOR GLYCEMIC CONTROL

HbA1c% FPG mmol/L

ADA1 <7 < 6.7 (120)*

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

*mg/dl

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


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*
%
2
1
Deaths from diabetes -

%
1
4
Heart attacks -

%
3
7
Microvascular complications
1% -

Peripheral vascular disorders %


4
3
-
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,
reasonably possible Dyslipidaemia,
Hypertension,
Procoagulant State

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

Insulin Type 2 β-cell


Resistance Diabetes Dysfunction

ia
em
y ca
Ins
β -Cell Failure r gl
uli pe
nA
cti Hy
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
HbA 1C < 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
Glibenclamide Sulphonylureas Voglibose

TZDs Metformin α -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

1Sulphonylurea or meglitinide ; TZD: thiazolidinedione ; AGI: α -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

aCompared 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 Reduced
Insulin sensitivity Hypertriglyceridaemia
Fibrinolysis AGE formation

Nutritive capillary flow Crosslinked fibrin

Haemorrheology Neovascularisation

Postischaemic flow 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
Glycated thiazolidinedione or basal insulin
Haemoglobin ≥ 7 %

Metformin + Metformin + Intensif


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

Intensive insulin + metformin ±


thiazolidinedione
atment should be a glycated haemoglobin value as close to the non - diabetic
%) as possible ; treatment should be started or changed if the value is ≥ 7 %
most effective regimen ( metformin plus insulin ) if glycated haemoglobin is > 8 ,
be started at any poit in the course of diabetes , including at the time of diag
dia
atment ( plus metformin ) is generally preferred to three oral agent as it is at
e 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
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
TERIMAKASIH....