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More Effective Glycaemic Control

Turning Theory into Practice
Dr. I Gede Palgunadi, Sp.PD
SMF Penyakit Dalam RSUD Mataram
Current and Projected Prevalence
Rates for Diabetes
80
0
10
20
30
40
50
Africa Americas Eastern
Mediterranean
Europe Southeast
Asia
E
s
t
i
m
a
t
e
d

P
r
e
v
a
l
e
n
c
e

(
m
i
l
l
i
o
n
s
)

1995 2000 2025
60
70
Western
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.
50
Million
100
Million
150
Million
200
Million
250
Million
110,5
140
175,4
239,3
1994 1997 2000 2003
2,5
1994
3
1997
4
2000
5
2003
1 Mill
2 Mill
3 Mill
4 Mill
5 Mill
ESTIMATE DIABETES IN INDONESIA
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
• 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
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
Perkembangan DM Tipe 2
DM Tipe 2
Adapted from Diabetes 1996;45:1661
Resistensi Insulin
Resistensi insulin
Hiperinsulinemia
Toleransi glukosa normal
Kegagalan fungsi sel Beta
Resistensi insulin
Penurunan kadar insulin
Gangguan toleransi glukosa
Diabetes Obes Metab 1999; 1(1): S1
Sensitivitas Insulin Sekresi Insulin
T2DM
30% 50%
Impaired glucose
metabolism
70% 150%
Normal glucose metabolism 100%
100%
IGT 50% 70-100%
Perjalanan Alami DM Tipe 2
ABNORMALITAS METABOLIK DM TIPE 2
OTOT
Jar. Lemak
Penurunan Penggunaan
Glukosa Perifer
Penurunan Penggunaan
Glukosa Perifer
PANKREAS
HATI
Peningkatan Produksi
Glukosa Hepar
Kegagalan Fungsi
Sel Beta
DM tipe 2
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
Insulin
resistance
Glucose uptake 
Glucose oxidation 
Lipolysis 
Free fatty acid 
Glucose uptake 
Glucose production 
VLDL synthesis 
Hyperinsulinemia
Hyperglycemia
Dyslipidemia
EFEK RESISTENSI INSULIN
Cardiovascular
disease
Interrelation Between Atherosclerosis
and Insulin Resistance
Hypertension
Obesity
Hyperinsulinemia
Diabetes
Hypertriglyceridemia
Small, dense LDL
Low HDL
Hypercoagulability
Insulin
Resistance
Atherosclerosis
STRATEGI TERAPI DM TIPE 2
Pengelolaan :
wHiperglikemia
wHiperinsulinemia / Resistensi Insulin
wDislipidemia
Komplikasi Mikrovaskuler
Komplikasi Makrovaskuler
Mencegah
terjadinya
Prinsip Dasar Terapi Diabetes Mellitus
2
PENGATURAN MAKAN
3
LATIHAN
OBAT - OBATAN
4
1
PENYULUHAN
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)
Berdasarkan titik tangkapnya telah dikembangkan
berbagai obat dengan khasiat sebagai berikut :
MEKANISME KERJA OHO
Sonnenberg and Kotchen. Curr Opin Nephrol Hypertens 1998;7(5):551–5
Hyperglycemia
GLUCOSE
ABSORPTION
alpha-glucosidase inhibitors
INTESTINE
PANCREAS
INSULIN Secretion
Sulphonylurea (SU)
Non-SU : Meglitinides
& Nateglinide
GLUCOSE
PRODUCTION
Biguanides
Thiazolidinediones
LIVER
MUSCLE
PERIPHERAL
GLUCOSE UPTAKE
Thiazolidinediones
Biguanides
ADIPOSE
TISSUE
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
OHO di Indonesia
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
Gula Darah Puasa
Gula Darah 2 JSM
HbA
1C
(%)
Kolesterol Total
Kolesterol LDL
Kolesterol HDL
Trigliserida
BMI
Tekanan Darah
80 - 109
80 - 144
< 6,5
< 200
< 130
> 45
< 150
18,5 - 22,9
< 130 / 80
BAIK
110 - 125
145 - 179
6.5 - 8
200 - 239
100 - 129

150 - 199
23 - 25
130-140/ 80-90
SEDANG
> 126
> 180
> 8
> 240
> 130

> 200
> 25
> 140 / 90
BURUK
TARGETS FOR GLYCEMIC CONTROL
ADA
1
IDF (Europe)
2
HbA1c% FPG mmol/L
< 7 < 6.7 (120)*
< 6.5 < 6.0 (110)*
*mg/dl
1
Diabetes Care 1999;22(Suppl 1):S1-S114.
2
Diabetic 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
EVERY 1%
reduction in A1C
REDUCED
RISK*
Deaths from diabetes
Heart attacks
Microvascular complications
Peripheral vascular disorders
UKPDS 35. BMJ 2000; 321: 405-12.
LESSONS FROM UKPDS:
BETTER CONTROL MEANS FEWER COMPLICATIONS
-37%
-43%
*p<0.0001
-14%
-21%
1%
Treatment algorithm for type 2 diabetes
Aim
Improved control
Diet, exercise, health education
Oral combinations
Insulin
Insulin plus oral agents
Sulphonylurea, metformin
Glucosidase Inhibitors
Glitinides
Thiazolidinediones
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
to normal as
reasonably possible
Control of Insulin resistance,
Hyperinsulinemia, Obesity,
Dyslipidaemia, Hypertension,
Procoagulant State
Microvascular
Disease
Macrovascular
Disease
Normal IFG IGT + Obesity Dx T2DM Progression of
T2DM

Insulin
Concentration
-Cell Failure
Euglycaemia
Dual Defect of Type 2 Diabetes : Treating a Moving Target

-cell
Dysfunction
Insulin
Resistance
Type 2
Diabetes
Insulin
Resistance
Lifestyle change: an option?
g The potentially most efective but most
dificult !
g 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
Sulphonylureas
Metformin
Meglitinides
TZDs
-glucosidase
inhibitors
Acarbose
Miglitol
Voglibose
Rosiglitazone
Pioglitazone
Glipizide
Gliclazide
Glimepiride
Glibenclamide
Repaglinide
Nateglinide
Combination therapy and the dual
endocrine defect of type 2 diabetes
1
Sulphonylurea or meglitinide ; TZD: thiazolidinedione ; AGI: -glucosidase inhibitor


Metformin + insulin secretagogue
1

Metformin + TZD
Metformin + AGI
Sulphonylurea + TZD
Sulphonylurea + AGI
TZDs + AGI
Insulin
resistance

E
E
E
E
E
E
β-cell
deficiency

E
E
E
E
E
E
Is metformin still the first line drug?
g Metformin ¬ biguanide yg diterima secara
luas sbg first line drug. Safe, effective, dan
murah.
g Menurunkan resiko penyakit kardiovaskuler
pada pasien obese dengan DM type 2.
Metformin: foundation therapy for prevention of
type 2 diabetes and its complications
Þ Reduced morbidity and mortality in the UKPDS
– Unique reduction of cardiovascular complications beyond
that expected from blood glucose control
Þ IDF and ADA guidelines favour the use of metformin as
foundation therapy for type 2 diabetes where possible
Þ The antihyperglycaemic efficacy of metformin is dose-related with
an optimal daily dose of 2000 mg/day
Þ 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
Þ Proven to prevent or delay type 2 diabetes (DPP)
UKPDS clinical outcomes for metformin


Any diabetes-related complication
Diabetes deaths
Myocardial infarction
Stroke
Microvascular complications
Retinal photocoagulation
Clinical endpoints
a
Compared with conventional diet-based therapy (overweight patients)
UKPDS 34. Lancet 1998;352:854-65
 risk
a

 32%
 42%
 39%
 41%
 29%
 31%
p

0.002
0.017
0.01
0.13
0.19
0.17
Metformin therapy
Metformin and myocardial infarction
Follow-up 3 years

Clinical endpoints (%)

Reinfarction
Symptoms of angina
Acute cardiovascular events
Fatalities
Controls
(n=123)

8.9
10.6
6.5
10.3
Metformin
(n=187)

1.6
4.8
4.0
8.0
Diabetic 34% / IGT 52% / Normal 14%
Sgambato et al. Clin Ter 1980;94:77-85
Kontrol Metabolik Metformin pada DM Tipe 2
Metformin
Glucose uptake
& utilisation q
Muscle
Glucose uptake q

VLDL synthesis +
Liver
Fat storage q
Lipolysis +
Free fatty acids +
Adipose
Euglycaemia
Normolipidaemia
Metformin: multiple mechanisms for
vascular protection
Þ Insulin sensitivity
Þ Fibrinolysis
Þ Nutritive capillary flow
Þ Haemorrheology
Þ Postischaemic flow
Metformin addresses CV risk by a range
of direct and indirect mechanisms
Improved Reduced
Þ Hypertriglyceridaemia
Þ AGE formation
Þ Crosslinked fibrin
Þ Neovascularisation
Þ Oxidative stress
Reduced cardiovascular risk
100
ß

C
e
l
l

f
u
n
c
t
i
o
n

(
%
)

Glycated haemoglobin
ß Cell function
Insulin
Lifestyle Monotherapy Dual ± oral drugs
Therapy for lowering
Blood glucose
9
8
7
6
5
G
l
y
c
a
t
e
d

h
a
e
m
o
g
l
o
b
i
n

(
%
)

>15
0
0
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 !
g Insulin ditambahkan bila HbA1C > 8,5% tapi
komorbid yang menyertai DM type 2 lebih
dipertimbangkan!
g 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?
g Kombinasi (Su + Met + Thz) lebih mahal
dibandingkan insulin + Met.
g Bila target HbA1C tak tercapai dg dual terapi
¬ mulai basal insulin atau Intermediate/long
acting insulin.
g 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
Metformin +
Sulfonylurea +
Basal insulin
Metformin +
Thiazolidenedione
+ sulfonylurea
Or
Metformin +
Thiazolidinedione
+ basal insulin
Intensify
Insulin
Therapy
Intensive insulin + metformin ± thiazolidinedione
Glycated
Haemoglobin ≥ 7%
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.
Glycated
Haemoglobin ≥ 7%
BMJ 333; 9 Des.2006. Management of hyperglycaemia in type 2 diabetes
Obat Baru
Þ Vildagliptin 50mg/tablet, Sitagliptin, Saxagliptin
Þ Bekerja pada sel α & sel ß pankreas suatu
DPP-4 inhibitor oral (dipeptidyl peptidase IV).
Þ Meningkatkan sekresi insulin dan menurunkan
sekresi glukagon
Þ 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
g Initial treatment should consist of lifestyle
intervention and metformin
g Treatment should aim to keep blood glucose
concentrations as close to the non-diabetic range
as possible
g 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
g Good glycaemia control will reduce the
occurrence of inicrovascular and perhaps
cardiovascular complications of type 2 diabetes
g Scientific evidence for any algorithm is largely
lacking