More Effective Glycaemic Control

Turning Theory into Practice
Dr. I Gede Palgunadi, Sp.PD Dr. I Gede Palgunadi, Sp.PD
SMF Penyakit Dalam RSUD Mataram 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
19
94
3
19
97
4
20
00
5
20
03
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% 50%
Impaired glucose
metabolism
70% 150% 150%
Normal glucose metabolism 100%
100% 100%
IGT 50% 70-100% 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
resista
nce
Glucose
uptake ↓
Glucose
oxidation ↓
Lipolysis ↑
Free fatty
acid ↑
Glucose
uptake ↓
Glucose
production ↑
VLDL synthesis

Hyperinsuli
nemia
Hyperglyce
mia
Dyslipidemi
a
EFEK RESISTENSI
INSULIN
Cardiovasc
ular
disease
Interrelation Between
Atherosclerosis and Insulin
Resistance
Hypertension Hypertension
Obesity Obesity
Hyperinsulinemia Hyperinsulinemia
Diabetes Diabetes
Hypertriglyceridemia Hypertriglyceridemia
Small, dense LDL Small, dense LDL
Low HDL Low HDL
Hypercoagulability Hypercoagulability
Insulin
Insulin
Resistance
Resistance
Atherosclerosis
Atherosclerosis
STRATEGI TERAPI DM
TIPE 2
Pengelolaan :
Hiperglikemia
Hiperinsulinemia /
Resistensi Insulin
Dislipidemia
Komplikasi
Mikrovaskuler
Komplikasi
Makrovaskuler
Mencegah
terjadinya
Prinsip Dasar Terapi Diabetes Mellitus
2
PENGATURAN MAKAN
3
LATIHAN
OBAT - OBATAN
4
1
PENYULUHAN

Mengurangi resistensi insulin : derivat biguanide dan
thiazolidinedione

Mengubah metabolisme asam lemak : menghambat
keluarnya NEFA, penghambat oksidasi asam lemak

Stimulasi sekresi insulin : sulfonilurea, antagonis α-2
adrenergik

Penghambat naiknya glukosa post prandial : guar
gum, α-glukosidase inhibitor, α-amylase inhibitor

Mengurangi berat badan : bahan anorektik, β-3
agonist, antagonis neuropeptide Y

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 Biguanides
Thiazolidinediones Thiazolidinediones
LIVER
MUSCLE
PERIPHERAL
GLUCOSE UPTAKE
Thiazolidinediones Thiazolidinediones
Biguanides Biguanides
ADIPOSE
TISSUE
1.Menurunkan absorpsi karbohidrat
• Acarbose
• Metformin

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
TARGETS FOR GLYCEMIC
CONTROL
CONTROL
ADA
ADA
1 1
IDF (Europe)
IDF (Europe)
2 2
HbA1c%
HbA1c%
FPG mmol/L
FPG mmol/L
< 7
< 7
< 6.7 (120)*
< 6.7 (120)*
<
<
6.5
6.5
<
<
6.0
6.0
(110)*
(110)*
*mg/dl *mg/dl
1 1
Diabetes Care 1999;22(Suppl 1):S1-S114. Diabetes Care 1999;22(Suppl 1):S1-S114.
2 2
Diabetic Medicine 1999;16:716-30 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% EVERY 1%
reduction in A1C reduction in A1C
REDUCED REDUCED
RISK* RISK*
Deaths from diabetes Deaths from diabetes
Heart attacks Heart attacks
Microvascular complications Microvascular complications
Peripheral vascular disorders Peripheral vascular disorders
UKPDS 35. BMJ 2000; 321: 405-12. UKPDS 35. BMJ 2000; 321: 405-12.
LESSONS FROM UKPDS:
BETTER CONTROL MEANS FEWER
COMPLICATIONS
-37% -37%
-43% -43%
*p<0.0001 *p<0.0001
-14% -14%
-21% -21%
1%
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
β
Insulin
Concentration
-Cell Failure
Euglycaemia
H
y
p
e
r
g
l
y
c
a
e
m
i
a
Dual Defect of Type 2 Diabetes : Treating a Moving Target
β
-cell
Dysfunction
Insulin
Resistance
Type 2
Diabetes
Insulin
Resistance
I
n
s
u
l
i
n

A
c
t
i
o
n
Lifestyle change: an
option?
x
The potentially most efective but most
dificult !
x
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
α-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: α-glucosidase inhibitor

Metformin + insulin secretagogue
1

Metformin + TZD
Metformin + AGI
Sulphonylurea + TZD
Sulphonylurea + AGI
TZDs + AGI
Insulin
resistance
E
E
E
E
¨
E
β-cell
deficiency
E
¨
¨
E
E
¨
Is metformin still the
first line drug?
x
Metformin ¬ biguanide yg diterima secara
luas sbg first line drug. Safe, effective, dan
murah.
x
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 +
Muscle
Glucose uptake +
VLDL synthesis +
Liver
Fat storage +
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
100 100
ß

C
e
l
l

f
u
n
c
t
i
o
n

(
%
)
ß

C
e
l
l

f
u
n
c
t
i
o
n

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

h
a
e
m
o
g
l
o
b
i
n

(
%
)
G
l
y
c
a
t
e
d

h
a
e
m
o
g
l
o
b
i
n

(
%
)
>15 >15
0 0
0 0
Traditional treatment strategy for type 2 diabetes and its consequences. In type 2 Traditional treatment strategy for type 2 diabetes and its consequences. In type 2
Diabetes Diabetes ß cell function declines over the years, irrespective of treatment with metformin, 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 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 Adjusted at regular intervals according to the level of glycaemia. Because doctor and patient
Recurrently fail to reach target. Recurrently fail to reach target. BMJ 333; 9 Des 2006. BMJ 333; 9 Des 2006.
Sulfonylurea, thiazolidinedion,
or insulin ? add to metformin !
x
Insulin ditambahkan bila HbA1C > 8,5% tapi
komorbid yang menyertai DM type 2 lebih
dipertimbangkan!
x
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?
x
Kombinasi (Su + Met + Thz) lebih mahal
dibandingkan insulin + Met.
x
Bila target HbA1C tak tercapai dg dual terapi
¬ mulai basal insulin atau Intermediate/long
acting insulin.
x
Inhaled insulin baru2 ini di US mulai dipakai.
Belum tau keberhasilan dan efek samping.
Lifestyle counselling and metformin Lifestyle counselling and metformin
Add sulfonylurea or or thiazolidinedione Add sulfonylurea or or thiazolidinedione
or basal insulin or basal insulin
Metformin + Metformin +
Sulfonylurea + Sulfonylurea +
Basal insulin Basal insulin
Metformin + Metformin +
Thiazolidenedione Thiazolidenedione
+ sulfonylurea + sulfonylurea
Or Or
Metformin + Metformin +
Thiazolidinedione Thiazolidinedione
+ basal insulin + basal insulin
Intensif Intensif
y y
Insulin Insulin
Therapy Therapy
Intensive insulin + metformin Intensive insulin + metformin ± ±
thiazolidinedione thiazolidinedione
Glycated Glycated
Haemoglobin Haemoglobin ≥ 7% ≥ 7%
Goal of treatment should be a glycated haemoglobin value as close to the non-diabetic 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 Range (<6,1%) as possible; treatment should be started or changed if the value is ≥ 7% ≥ 7%
Choose the most effective regimen (metformin plus insulin) if glycated haemoglobin is > 8,5% 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 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 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. As effective in lowering glycamia and is much cheaper.
Glycated Glycated
Haemoglobin Haemoglobin ≥ 7% ≥ 7%
BMJ 333; 9 Des.2006. BMJ 333; 9 Des.2006. Management of hyperglycaemia in type 2 diabetes 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
x
Initial treatment should consist of lifestyle
intervention and metformin
x
Treatment should aim to keep blood glucose
concentrations as close to the non-diabetic range
as possible
x
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
x
Good glycaemia control will reduce the
occurrence of inicrovascular and perhaps
cardiovascular complications of type 2 diabetes
x
Scientific evidence for any algorithm is largely
lacking

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