Diabetes Mellitus

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Budi Enoch DSPD

 Diabetes Mellitus

A group of metabolic diseases

Characterized by hyperglycemia
Resulting from defects in insulin
secretion , insulin action, or both
 Natural History of Type II DM
obesity Impaired diabetes Uncontrolled
glucosa hyperglycaemia
tolerance

pp

n
120
mgr%

-20 -10 0 +10 +20 +30

Years of diabetes
 Natural History of Type II DM
obesity Impaired diabetes Uncontrolled
glucosa hyperglycaemia
tolerance
Relative cells function

Insulin resistance

100%

Decline cell Insulin level

function

-20 -10 0 +10 +20 +30

Years of diabetes
 klasifikasi
Controversies in Classification
=
Controversies in Management
 Obes vs Non-obese
Juvenile Onset vs Adult Onset
IDDM vs NIDDM
Primary vs Secondary
Type 1 vs Type 2
???
 Classification of Diabetes and Allied
Categories of Glucose Intolerance
A. Clinical Classification
1. Diabetes Mellitus
IDDM
NIDDM Obese
Non-obese
Secondary Diabetes
MRDM
2. Gestational Diabetes
3. Impaired Glucose Tolerance

B. Statistical Risk Classification

(WHO, 1985; PERKENI, 1993)
 Etiologic Clasification
I. Type 1 (-cell destruction leading to absolut
deficiency)
A. Immune mediated
B. Idiopathic

II. Type 2
Predominantly insulin resistance + relative
insulin
deficiency
Predominantly secretory defect + insulin
resistance

III. Other specific types

IV. Gestasional diabetes mellitus

The Expert Committee,1997; WHO 1999; PERKENI 2006

 Criteria Diagnosis of Diabetes Mellitus
. 1. Symptoms (+) & casual plasma
glucose > 200 mg%
(11.1 mmol/L)
or
2. FPG 126 mg% (7.0 mmol/L)
or
3. 2hPG 200 mg/dl during OGTT

(The Expert Committee,1997)

 Tentang DM type 2
Prevalensi meningkat diseluruh dunia
Diperkirakan naik 3% pertahun
Diperkirakan 210 juta orang pada 2010
Lebih kenaikan didaerah Asia-Pasifik dimana
pada 2030, 7 dari 10 negara tertinggi kasus
didaerah tersebut dengan angka tertinggi
dipimpin oleh India & China
Kenaikan itu karena meningkatnya prevalensi
obesitas (diabesiti), terutama obesitas
sentral, suatu resiko independen yang penting
untuk terjadinya DM dan komplikasi kardio-
vaskuler
Estimasi WHO, Indonesia menjadi 20,3 juta
pada 2030, naik dari 2,4 juta di 2005
 Prevalensi DMT2 di Indonesia

Prevalensi meningkat sesuai dengan perubahan

gaya hidup !
Koja Utara, Tg Priok (1982) 1,7 %
Kayu Putih, Jakarta Utara (1992) 5,7 %
Abadi Jaya, Depok (2001) 13,6 %

(Sarwono W, Simposium Endokrin Klinik V, 2004)

 Diabetes mellitus is a group of metabolic
diseases characterized by hyperglycemia
resulting from defects in insulin secretion
insulin resistance
Type 2 Diabetes Mellitus is the Tip of the
Iceberg, where metabolic syndrome developed
long before diabetes manifests
Incidence of type 2 diabetes rises with
increasing severity of obesity diabesity
Morbidity and mortality of diabetic patients
are high due to cardiovascular complications
CHD equivalent
 Type 2 Diabetes Mellitus:
the Tip of the Iceberg

Stage III
Type 2
DM

Macrovascular Postprandial Microvascular

Stage II complications plasma glucose complications
IGT Glucose
production
Metabolic Syndrome
Glucose transport
Insulin secretory deficiency
Lipogenesis Atherogenesis
Stage I TG
Obesity Hyperinsulinaemia
Normal HDL
Insulin Resistance
glucose
Waisthip ratio Hypertension
tolerance
Diabetes genes
 Two Faces of Diabetes

Metabolic disease Cardiovascular disease

Glycemic control Control of
Metabolic Syndrome

Treatment ?
Mean ( SEM) rates of Insulin Secretion in Type 2
Diabetic Patients compared with Control Subjects
 Hyperglycemia
A
T
H
FVII E
Oxidative R
O
stress S
LDL oxidation
FVII C
L
LDL oxidation Oxidative E
Free radicals stress R
Free redical O
consumption
consumption S
I
Hypertriglyceridemia
Hypertriglyceridemia S

Breakfast
Breakfast Lunch
Lunch Dinner
Dinner
Ceriello A 2002
 Cardiovascular complications prevailed
before diabetes developed, usually at the
stage of IFG/IGT
Diabetes mellitus is a component of
metabolic syndrome
Metabolic syndrome is responsible for the
increased cardiovascular complications in
diabetic patients
Treatment of diabetes must be considered
as one of the components of metabolic
syndrome that must also be treated to
prevent cardiovascular disease
 Prevalence of diabetic tissue damage at
the time of diagnosis of type 2 diabetes
Urine albumin 4

Absent reflexes 8

Absent foot pulses 12

Cardiovascular 17

Retinopathy 18

0 2 4 6 8 10 12 14 16 18 20

Prevalence (%)

Dagogo Jack S et al. Arch Intern Med. 1997; 157: 1802 - 1817
Are these complications
preventable?
 YES !!!

Controlled clinical trials have shown

that risk of developing these
complications can be reduced by:

Glycemic control
BP control
Lipid control
UKPDS 35: Tight glycemic control
Prevents complications

Every 1% drop in HbA1c resulted in:

14% 12%
21%
Decrease
Decrease 37%
in risk
Decrease in risk of stroke
in any myocardial
diabetes- infarction
related Decrease in
endpoint risk of
microvascular
disease
N = 3642
Stratton IM et al. BMJ. 2000; 321: 405 - 412
 Trend baru
dalam pengukuran gaya hidup
 Pentingnya diet dan olahraga dalam
pencegahan dan terapi DMT2 tidak
terbantahkan
Overweight dengan gagal GT yang diberi
diet hipokalori, rendah lemak, karbohidrat
yang 50% nya dari yang kaya serat
disertai dengan latihan teratur akan
menurunkan resiko terjadinya DMT2
sebesar 58% dalam 3 tahun
Intervensi gaya hidup akan menurunkan
GDP dan HbA1c yang sejalan dengan
penurunan BB
 Olahraga
Moderate intensity exercise
Jalan cepat, minimal 30 menit perhari
Atau 150 menit perminggu
Interval diantara latihan harus < 72 jam
Terbukti meningkatkan sensitifitas insulin
dan menurunkan HbA1c yang tidak
tergantung pada penurunan BB, menurunkan
TD, TG, cholesterol, disfungsi endotel,
disfungsi diastol dan adipositas viseral
 penanganan
diabetes mellitus type 2
 Treatment Objectives
of Diabetes Mellitus
Relief of symptoms
Improvement of quality of life
Prevention of acute and chronic
complications
Reduction of mortality and morbidity
Reduction of burden and side effects
of treatment

Heine RJ Current perspective 2000

 Diagnosis

Pilar Pengobatan
I II III IV

edukasi Aktifitas nutrisi obat

fisik

Edukator Dokter
 Timeline of Anti-diabetic Therapies
and Clinical CV Trials
ACCORD
ADVANCE
VADT
PROactive
RECORD
ORIGIN
UGDP UKPDS DREAM
DCCT NAVIGATOR
STOP-NIDDM
1920 1940 1950 1970 1980 1990 2000 - present
Banting/Best SU Biguanide: Recomb Insulin GLP analogues
Insulin Metformin Human Analogs
isolated from dogs
DPPIV-inhibitors
insulin
1990-2000
Acarbose
UGDP = the University Group Diabetes Program;
Glitazones
UKPDS = the UK Prospective Diabetes Study;
ACCORD = the Action to Control Cardiovascular Risk in Diabetes Glinides
 DMT2 BB tak lebih

Penyuluhan menyeluruh & modifikasi gaya hidup

Insulin secretagouges
TERUSKAN

Kombinasi 2 OHO
IS + PG / B / T

Kombinasi 3 OHO OHO + Insulin Insulin

IS + PG + B / T

Kombinasi 4OHO IS OHO + Insulin Insulin

+ PG + B +T

Insulin

Sasaran tercapai Sasaran tak tercapai Penilaian 2-4 minggu

 Major Classes of Medications

1. Drugs that sensitize the Thiazolidinediones

body to insulin and/or Biguanides
control hepatic glucose
production

2. Drugs that stimulate the Sulfonylureas

pancreas to make more Meglitinides
insulin

3. Drugs that slow the Alpha-

glucosidase
absorption of starches inhibitors
 Sites of Action of Current OAD
GLUCOSE ABSORPTION

INTESTINE

-glucosidase inhibitors
GLUCOSE
PRODUCTION PERIPHERAL GLUCOSE
UPTAKE & UTILIZATION
LIVER
Glucose
MUSCLE
Biguanides
Thiazolidinediones ADIPOSE TISSUE

Thiazolidinediones
INSULIN SECRETION Biguanides
Sulphonylureas
Meglitinides
PANCREAS Modified: Ann Intern Med 1999;131:281
 Generasi Sulfonilurea
Berikatan pada SUR1 subunit 65
kD, reseptor ini terutama terdapat
Berikatan pada SUR1 di pankreas

subunit 140 kD, reseptor 1994

ini terdapat di pankreas, Generasi ke-3 SU:
jantung, hati, pembuluh Glimepiride
darah
1969
Generasi ke-2
SU:
-Glibenclamide
1955
-Glipizide
Generasi ke-1 SU:
-Gliclazide
-Tolbutamide
-Gliquidone
-Chlorpropamide
Choice of SU in the Management of
Two Faces of Diabetes

SU
?

Metabolic disease Cardiovascular disease

Glycemic control Control of
) b-cell selective Metabolic Syndrome
b) Insulin mimmetic Cardioprotective
Cardiovascular Effects of Glimepiride
(1)

Glimepiride is one of the K ATP channel inhibitor

KATP channels exists all over the body including islet
cell and cardiomyocite
KATP channels are thought to play a role in
cardioprotective mechanism that may be inhibited by
SU
Glimepiride and gliclazide have no such effect because
of its higher islet selectivity compared to
glibenclamide
 Other Cardiovascular Effects of
Glimepiride (1)

Glibenclamide inhibits stimulatory effect of

diaxozide on FBF (Forearm Blood Flow), an
endothelial function, that causes vasodilatation
Glimepiride does not inhibit diaxozide induced
vasodilatation
Glimepiride as beneficial effect on endothelial
function
 Other Cardiovascular Effects of
Glimepiride (2)
Mitochondrial membrane depolarisation caused
by KATP channel opener (nicorandil) was
inhibited by glibenclamide but not by
glimepiride1
Glimepiride prevents the development of
atherosclerosis by inhibiting endothelial cell
mediated LDL oxidation2
Glimepiride appeared to be a more potent ADP-
induced platelet aggregation inhibitor than
gliclazide3
Glimepiride may be associated with more
favourable LDL-cholesterol profile 4.
1Maddock et al Circulation 2001 2 Shakuto S 2002
3 Siluk Diabetologia 2002 4 Britton ME et al Clin Drug Invest1998
 glimepirid vs glibenklamid

1. Tetapan disosiasi: 8 9 kali lebih tinggi

2. Tetapan asosiasi: 2,5 3 kali lebih tinggi
3. Afinitas terhadap sel : 2,5 3 kali lebih rendah

1. Mula kerja lebih cepat

2. Masa kerja lebih pendek
3. Sekresi insulin lebih rendah
 KESIMPULAN
Efektifitas dan keamanan Glimepiride sudah terbukti
Glimipiride bekerja lebih spesifik terhadap SUR-1
pada pankreas diharapkan tidak mempunyai efek buruk
terhadap risiko penyakit jantung koroner,
dibandingkan dengan SU generasi sebelumnya.
Glimipiride juga mempunyai efek mirip insulin terhadap
metabolisme glukosa di jaringan perifer Membantu
mengatasi keadaan Resistensi Insulin
Glimepiriede bersifat protektif terhadap kejadian
kardiovaskuler pada penderita DM type 2
Glimepiride mempunyai efek menguntungkan pada
endothel
Glimepiride meningkatkan produksi adinopektin yang
merupakan mediator untuk meningkatkan sensitifitas
terhadap insulin
Are -cells a therapeutic
target for slowing or
preventing disease
progression ?
 metformin
Melalui jalur perangsangan AMPK sel
(AMP-activated protein-kinase)
Menurunkan produksi glukosa hati
Meningkatkan pengeluaran glukosa dari
darah
Menurunkan FFA dan TG
UKPDS (1998) dipakai sebagai first line
terapi pada DM awal
Standard care should begin with metformin
unless there is evidence of contraindications
 UKPDS :
metformin mempunyai efek
superior pada diabetes-related
end-points, all-cause mortality
dan stroke, bila dibandingkan
dengan dengan sulfonilurea atau
insulin
 Lessons from UKPDS:
Legacy Effect of Metformin
ukpds-ptm
ukpds
PosT-Trial Monitoring
Diabetes-related deaths
1977 - 1997 1997 - 2007
-42% -30%

All Cause Mortality

-36% -27%

Myocardial Infarction

-39% -33%

CV Complications CV Complications
Survival Survival
vs. other therapies maintained

UKPDS 34. Lancet 1998; 352: 854-65 UKPDS 80. NEJM 2008; 359
ukpds-ptm
Long-term Protection from Complications
10-year post-trial follow-up in the UKPDS

Any DM-related Microvascular

endpoint endpoints MI All-cause death
0
-9
10 -13
% Risk reduction

p=0.039 -16 -15

-21 p=0.006
20 -24 p=0.30 p=0.014
-27
p=0.012 p=0.001
30 -33 p=0.002
Sulfonylurea/insulin p=0.005
40
Metformin
% risk reduction vs. diet

Holman RR et al. N Engl J Med 2008

 UKPDS : Risk of complications decreases as HbA1c decreases

Microvascular
80
complications
Normal
HbA1c P=0.009
1,000 patient-years

60 The most debated clinical questions in T2DM :

Incidence per

levels
Whether glycemic control is associated

UKPDS
ADA
Myocardial
with a reduction in CV disease ?
IDF
infarction
40

P=0.052

20 Microvascular complications much

more associated with hyperglycemia
than Macrovascular complications

0
0 5 6 7 8 9 10 11
HbA1c (%)

No lower threshold of glycemia, below which risk no longer decreased

Stratton IM, et al. BMJ 2000; 321:405412.

 Sulfonil-urea (SU) secara tradisionil
dipakai sbg terapi pertama pada DM
non-obese
MF ditambahkan kalau SU tunggal gagal
untuk menjaga kadar GD
Ternyata walaupun sukses pada sebagian
kecil kasus, kebanyakan kombinasi SU
ditambah MF gagal menjaga kadar GD
pada kasus yang mempunyai kegagalan
sekunder terhadap SU
 Kalau kombinasi dosis kecil dipakai
sejak awal, dibandingkan dengan
dosis tunggal (SU atau MF),
succes rate lebih tinggi dan
efektifitasnya lebih lama
Juga kombinasi memberi efek less
hyperinsulinism, less weight gain,
efek pada profil lipid lebih baik
dan efek samping makin berkurang
 Treatment Based on the Pathogenic
Mechanisms of Type 2 Diabetes

b-cell dysfunction Insulin resistance

Insulin Insulin
Insulin Secretagogues Insulin Sensitizer
SU Metformin
Glinide Glitazone
Acarbose
 When to start combination ?

Any single oral therapy is unlikely to

lower A1c >1.5 2.0%, it is logical to
consider initial combination therapy
for patients presenting with an A1c
8.09.0%

Dailey GE. Diabetes Care 2005; 28:220-221

 RULE OF
COMBINATION
Use combinations of oral
antidiabetic agents with
complementary mechanisms
of action
 Two (or more ?) Oral Hypoclycaemic
Agents with Different Class of Action
SU Met TZD Glinide Acarbose
SU

Met

TZD

Glinide

Acarbose

Insulin

Combine Do not combine

 The Ideal Combination

Insulin secretion Insulin sensitivity

More than 50 years proven safety and efficacy

 Safe
Better glycaemic control than mono
therapy
Does not require maximal oral hypo
glycaemic dose
 such an aproach is logical
and will likely result in
quicker achievement of target
glucose levels, particularly in
those with greatest degree of
baseline glycemia
Kimmel B and Inzuchhi SE. Clinical Diabetes 2005; 23: 64 76.