ada guideline dm
DESCRIPTION
DMTRANSCRIPT
Cardioprotective Combinations
Cardioprotective Combinations
M a h a t m a
F K U M S
The New Paradigm of (Type 2) Diabetes Treatment
( focus : metformin and glimipiride )STANDING TOGETHER AGAINST DIABETES
Topik
LATAR BELAKANG
EAGLE FLIES ALONE, MHT
RISKESDAS 2008 RISKESDAS 2008 RISKESDAS 2008 RISKESDAS 2008
Diagnosed patients
Undiagnosed patients
Indonesian Basic Health Research (RISKESDAS)
Total DM = 5,7%Diagnosed DM = 1,5%
Undiagnosed DM = 4,2%IGT = 10,2 %
D M estimated ( WHO )
2000
>17 million
2020
8 million
LATAR BELAKANGLatar Latar BelakangBelakang
STANDING TOGETHER AGAINST DIABETES
Pre-diabetes ?? Faktor yg berperan dlm jml DM : usia >40 tahun yg ,
kemakmuran, pola hidup serba berkecukupan, penyakit infeksi,
angka harapan hidup
Nefropati Diabetika (ND) :
INDONESIA 2000 5.6 million people with DM
2020 31.3 million people with DM
The 4th of world largest prevalence !!(International Diabetes Federation)
DM Prevalence
Diabetes50.1%
Hypertension27%
Glomerulonephritis
13%
Other
10%
Primary Diagnosis for Patients Who
Start Dialysis
EAGLE FLIES ALONE, MHT
SlametS 5
Proyeksi WHO tentang Struktur UmumPopulasi Diabetes
Proyeksi WHO tentang Struktur UmumPopulasi Diabetes
Umur pasien diabetes paling banyak > 65 th
Umur pasien diabetes paling banyak > 65 th
1995-20251995-2025
Negara majuNegara maju Negara berkembangNegara berkembang
Umur non produktifUmur non produktif Umur produktifUmur produktif
Umur pasien diabetes paling banyak 45-65 th
(40-59 th)*
Umur pasien diabetes paling banyak 45-65 th
(40-59 th)*
LATAR BELAKANGLatar Latar BelakangBelakang
STANDING TOGETHER AGAINST DIABETES
Topik
TINJAUAN ANATOMIS FISIOLOGIS
EAGLE FLIES ALONE, MHT
EAGLE FLIES ALONE, MHT
PROINSULIN
C-PEPTIDEINSULIN
Distribusi Glukosa ke JaringanF i s i o l o g iF i s i o l o g i
INS
INSINS
Overview of Carbohydrate metabolism
INS
INS
INS
INS
INS
INSINS
INS
INS
EAGLE FLIES ALONE, MHT
promoter Coding reg
transcription
mRNA
Synthesis GLUT 4
translocation
PPAR
PPRE
Insulinreceptor
Insulin
RXR
Glucose
EAGLE FLIES ALONE, MHT
Topik
• D E F I N I S I
EAGLE FLIES ALONE, MHT
APAKAH D.M. ITU ?
Adalah suatu kumpulan gejala yang timbul pada seseorang disebabkan karena adanya
peningkatan kadar gula (glukosa) dalam darah akibat kekurangan insulin, mutlak maupun relatif.
EAGLE FLIES ALONE, MHT
Insulin Insulin kurang jumlahnya kurang jumlahnya Insulin Insulin kurang baik kerjanyakurang baik kerjanya
Diabetes Mellitus• Kelainan bersifat kronik• Gangguan metabolisme KH-L-P• Komplikasi Makro & Mikro Vaskuler• Berkaitan dengan faktor genetik• Gejala Utama Intoleransi Glukosa
Faktor 2 Fungsi Endo. Pank ( DM ) Genetik
Virus & Bakteri Bahan Toksik
NutrisiEAGLE FLIES ALONE, MHT
D e f i n i s iD e f i n i s i
Tipe 1Destruksi sel beta, umumnya menjurus ke defisiensi insulin absolut
Autoimun
Idiopatik
Tipe 2 Bervariasi, mulai yang terutama dominan resistensi insulin disertai defisiensi insulin relatif sampai yang terutama defek sekresi insulin disertai resistensi insulin
Tipe LainDefek genetik fungsi sel betaDefek genetik kerja insulinPenyakit eksokrin pankreasEndokrinopatiKarena obat/zat kimiaInfeksiSebab imunologi yang jarangSindrom genetik lain yang berkaitan
dengan DM
DM
GestasionalEAGLE FLIES ALONE, MHT
KlasifikasiKlasifikasi
Topik
PATOFISIOLOGI
EAGLE FLIES ALONE, MHT
SlametS
Tidak Ada InsulinTidak Ada Insulin
TenagaTenaga
Sel ototSel otot
GlucGluc Glukosa darah Glukosa darah Pintu masuk sel Pintu masuk sel
Gluc
DIABETESTIPE 1
DIABETESTIPE 1
Gluc Gluc
Gluc GlucKadar glukosa
darah meningkat Kadar glukosa
darah meningkat
Gluc Gluc
Tidak ada insulin yang membuka pintu
masuk sel
Tidak ada insulin yang membuka pintu
masuk sel
Tak ada yang dibakar Tak ada yang dibakar
EAGLE FLIES ALONE, MHT
SlametS
TenagaTenaga
Sel ototSel otot
GlucGluc Glukosa darah Glukosa darah Pintu masuk sel Pintu masuk sel
Gluc
DIABETESTIPE 2
DIABETESTIPE 2
Gluc Gluc
Gluc Gluc Kadar glukosa darah meningkat Kadar glukosa
darah meningkat
Gluc Gluc
Ada insulin tapitak mampu membuka
pintu masuk sel
Ada insulin tapitak mampu membuka
pintu masuk sel
Tak ada yang dibakar Tak ada yang dibakar
Kerja Insulin Kurang Baik
Kerja Insulin Kurang Baik
Insulin
EAGLE FLIES ALONE, MHT
SlametS
Chronic hyperglycemia
Chronic hyperglycemia
High circulating free fatty acids High circulating free fatty acids
PancreasPancreas
Amyloid
deposit
Glucotoxicity2Glucotoxicity2 Lipotoxicity3Lipotoxicity3
HGPHGP
UptakeUptake
Lipolysis
TNF
patofisiologipatofisiologi
Insulin resistance
Hyperinsulinemia to compensate for insulin
resistance1,2
Hyperinsulinemia to compensate for insulin
resistance1,2
Insulin deficiency
Normal glucose
Impaired glucose metabolism
Type 2 diabetes
Insulin sensitivity Insulin secretion
30%
70%
100%
50%
150%
100%
IGT50% 70 %
Natural History of Type 2 Diabetes
No diabetes
Pre-diabetes
Time
Insulin secretion
Glycemia
Insulin resistance
patofisiologipatofisiologi
F A S E 1 F A S E - 2
F A S E - 1 F A S E - 2
Individu normal
Penderita DM tipe-2
Insulin
plasma
waktu
Insulin
plasma
(Tumpul) Lebih tinggi dan lama
(Delayed Insulin secretion)Waktu
3-5 mnt 50-60 menit
60 ng/ml
Comparative profiles Secretion of insulin Normally and D M
EAGLE FLIES ALONE, MHT
Klinis
polidipsia(sering haus) berat
badanturun
poliuria(sering kencing)
gatal-gatalmata kaburimpotensia
poliphagia(cepat lapar)
kesemutan
Cepat Lelah
Luka pada Kaki Sukar Sembuh
Luka pada Kaki Sukar Sembuh
G e j a l aG e j a l a
Topik
D I A G N O S A
EAGLE FLIES ALONE, MHT
Pengukuran hiperglikemi/GD
• Kadar gula darah sewaktu – Tanpa memperhitungkan waktu makan terakhir
• Gula darah puasa (GDP) – Sebelum makan pagi
• Test toleransi glukosa oral (TTGO) – 2 hours after a 75-g oral glucose drink
• Gula darah post prandial (GDPP) – 2 jam setelah makan
• Hemoglobin A1c (HbA1c) – Merefleksikan rata-rata gula darah selama 2-3 bulan
EAGLE FLIES ALONE, MHT
Criteria for the Diagnosis of Pre-DM (IGT & IFG) and DM
A Dx of Diabetes must be confirmed on a subsequent day by any one of the 3 Methods. Fasting means : No Calorie intake for at least 8 hours *IGT by OGTT; *IFG by FPGGlucose Load : 75g Anhydrous Glucose in Water
FPG > 126
2-h PG > 200
CPG > 200with Classical Symptoms
IGT IFG T2DM
2h-PG
140-199
FPG110-125
FPG < 110
2-h PG < 140
Normal Pre - Diabetes Diabetes Mellitus(mg/dl) (mg/dl) (mg/dl)
New IFG*:100-125
EAGLE FLIES ALONE, MHT
D i a g n o s i D i a g n o s i ss
hypoX-jsk-7-99
IGT Postprandial Hyperglycemia Type 2
DiabetesPhase 1 Type 2
DiabetesPhase 2
Type 2DiabetesPhase 3
- 12 - 10 - 6 - 2 0 2 6 10 14Years from diagnosis
Bet
a ce
ll fu
nctio
n (%
)Stages of type 2 Diabetes in relationship to Stages of type 2 Diabetes in relationship to
--cell functioncell function
25
0
50
75
100
8 6 4 021
4 8 12
EAGLE FLIES ALONE, MHT
D i a g n o s i D i a g n o s i ss
Topik
• PENATALAKSANAAN
EAGLE FLIES ALONE, MHT
Treatment : stepwise approach Blood Glucose Control
1
2
3
4
5
Combination oforal medicines
Oral plus insulin
Insulin
One oral medicine
Diet &exercise
+
++
PenatalaksanaanPenatalaksanaan
The New Paradigm of (Type 2) Diabetes Treatment
Aggressive Treatment – Driven by Target (AIC < 7%)
Early Combinations • Oral agent – oral agent• Oral agent – insulin
Aggressive Insulin Treatment
PenatalaksanaanPenatalaksanaan
SlametS
Target Pengendalian Kadar Glukosa Darah (ADA2005)
Target Pengendalian Kadar Glukosa Darah (ADA2005)
Kadar glukosa darahKadar glukosa darah
Puasa Puasa
Setelah makan Setelah makan
HbA1C (%) HbA1C (%)
Adapted from American Diabetes Association . Standard of medical care for patients with diabetes mellitus Diabetes Care 2005
Untuk anak-anak, wanita hamil dan usia lanjut diperlukan pertimbangan lain
90 to 130 mg/dl
<180 mg/dl
< 7 % ?
SlametS
Hb A1c = Kadar Gula Dalam Sel Darah Merah,Menggambarkan Kadar Rata – Rata Gula Darah
Selama 2-3 Bulan Yang Lalu
Hb A1c = Kadar Gula Dalam Sel Darah Merah,Menggambarkan Kadar Rata – Rata Gula Darah
Selama 2-3 Bulan Yang Lalu
8%
Target pengendalian = 7%Target pengendalian = 7%
7%
6%
Gula darahmg/dl
Gula darahmg/dl
160
130
HbA1cHbA1c
200
100
1%
Hasil dari UKPDS: Kontrol yang baik pada DM T2 mampu menurunkan resiko
komplikasi
Kematian karena diabetes
Infark miokard
Komplikasi mikrovaskuler
Gangguan pembuluh darah perifer
-21%
-14%
-37%
-43%
Menurunkan resiko*Penurunan 1% HbA1c
EAGLE FLIES ALONE, MHT
32
History of ADA/EASD consensus algorithm
First Consensus algorithmAugust 20061
1st UpdateJanuary 2008: Update regarding thiazolidinediones2
2nd UpdateJanuary 20093
1. Nathan DM, et al. Diabetes Care 2006;29(8):1963-72. 2. Nathan DM, et al. Diabetes Care 2008;31(1):173-5. 3. Nathan DM, et al. Diabetes Care 2009;32:193-203.
PenatalaksanaanPenatalaksanaan
Check HbA1C every3 months until <7%. Change treatment
if HbA1C ≥7%
Step 3
Lifestyle + Metforminplus
Basal Insulin
Lifestyle + Metformin plus
Sulfonylureaa
Tier 1: Well validated core therapies
At diagnosis:
Lifestyle+
Metformin
Step 1 Step 2
Lifestyle + Metformin plus
PioglitazoneNo hypoglycemia
Oedema / CHFBone Loss
Lifestyle + Metformin plus
GLP-1 agonistb
No hypoglycemiaWeight loss
Nausea / vomiting
Tier 2: Less well validated therapies
Lifestyle + Metformin plus
Pioglitazone plus
Sulfonylureaa
Lifestyle + Metformin plus
Basal Insulin
Lifestyle + Metforminplus
Intensive Insulin
1.2 Achieving glycemic control with insulin glargine
a Sulfonylureas other than glibenclamide or chlorpropamideb Insufficient clinical safety data; CHF = congestive heart failure
ADA/EASD consensus algorithm
PenatalaksanaanPenatalaksanaan
34
Basal plusBasal +
1 prandial
A logical stepwise approach
Basal insulinonce daily
(treat-to-target)
Basal plusBasal +
2 prandial
Basal bolus Basal +
3 prandial
Lifestyle+
Metformin
± SU
HbA1c ≥7.0%, FBG on targetPPG ≥160 mg/dLHbA1c ≥7.0%
T i m e
PenatalaksanaanPenatalaksanaan
STEP 1
STEP 2
STEP 3
STEP 2
35
At diagnosis:Lifestyle
+Metformin
Lifestyle+ Metformin
+ Basal insulin
Lifestyle+ Metformin
+ Sulfonylurea
STEP 1 STEP 2
HbA1c 7%
PenatalaksanaanPenatalaksanaan
ADA/EASD consensus algorithm: step 2Addition of sulfonylurea
* Sulfonylureas other than glybenclamide (glyburide) or chlorpropamide Nathan DM, et al. Diabetes Care 2009;32:193-203.
Glucotoxicity Lipotoxicity
IncreasedFree Fatty
Acids
INSULIN RESISTANCE DEFECTIVE INSULINSECRETION
-GlucosidaseInhibitors
Delay IntestinalCarbohydrate
Absorption
LiverIncreased Glucose
Production
Adipose TissueIncreased Lipolysis
Thiazolidinediones(TZDs)
Increase GlucoseUptake
TZDs?
Biguanides
DecreaseHepatic Glucose
Production
TZDs
DecreaseLipolysis
Insulin Target Tissues
Pancreatic Beta CellsDecreased Insulin
Secretion
Sulfonylureasand
NonsulfonylureaSecretagogues
Increase InsulinSecretion
Small IntestineCarbohydrateAbsorption
Skeletal MuscleDecreased
Glucose Uptake
(type 2 diabetes)
EAGLE FLIES ALONE, MHT
Intervensi Farmakologik (1)• Obat Hipoglikemik Oral
Pemicu Sekresi Insulin
Meningkatkan sekresi insulin oleh sel beta
Pilihan utama untuk pasien dengan BB normal/kurang namun masih boleh diberikan untuk BB lebih
Sulfonilurea
Glinid
Penambah sensitivitas insulin
Menurunkan resistensi insulin dengan meningkatkan jumlah orotein pengangkut glukosa shg meningkatkan pengambilan glukosa perifer
Kontra indikasi pada pasien gagal jantung
TZD tidak digunakan sebagai obat tunggal
Tiazolidindion (Rosiglitazon, pioglitazon)
Penghambat Glukoneogenesis
Menurunkan glukoneogenesis disamping memperbaiki ambilan glukisa perifer
Penggunaan terutama pada orang gemuk
Kontra indikasi pada pasien dengan gangguan fs ginjal (kreatinin serum > 1.5)
Metformin
Penghambat Glukosidase alpha (Acarbose)
Mengurangi absorbsi glukosa di usus halus shg mempunyai efek menurunkan kadar glukosa darah setelah makan
Tidak menimbulkan efek samping hipoglikemi
Acarbose
EAGLE FLIES ALONE, MHT
Mekanisme Kerja, Efek samping utama dan pengaruh terhadap penurunan A1cCara Kerja
UtamaEfek Samping
UtamaPenurunan A1c
Sulfonilurea
Meningkatkan sekresi insulin
BB naik, hipoglikemi 1.5 – 2 %
Glinid Meningkatkan sekresi insulin
BB naik, hipoglikemi
Metformin Menekan prod glukosa & menambah sensitivitas thd insulin
Diare, dispepsis, asidosis laktat
1.5 – 2 %
Penghambat alpha glukosidase
Menghambat absorbsi glukosa
Flatulens, tinja lembek 0.5 – 1 %
TZD menambah sensitivitas thd insulin
Edema 1.3%
Insulin Menekan prod glukosa hati, stimulasi pemanfaatan glukosa
BB naik, hipoglikemi Potensial sampai normalEAGLE FLIES ALONE, MHT
39391
Are All Sulphonylurea Are All Sulphonylurea the Same?the Same?
PenatalaksanaanPenatalaksanaan
DasarDasarCardioprotectiveCardioprotective
Back-up
Combination Therapy
Vascular ComplicationsVascular Complications
MicroangiopathyMicroangiopathy
C V DP V D
Stroke
C V DP V D
Stroke
Nephropathy
Retinopathy
Neuropathy
Nephropathy
Retinopathy
Neuropathy
DiabetesDiabetes
MacroangiopathyMacroangiopathy
EAGLE FLIES ALONE, MHT
DasarDasarCardioprotectiveCardioprotective
42
Reaching glucose goals is important to reduce complications
1Gray RP & Yudkin JS. Cardiovascular disease in diabetes mellitus. In Textbook of Diabetes 2nd Edition, 1997. Blackwell Sciences.
2Kannel WB, et al. Am Heart J 1990; 120:672–676.
Overall, 75% of people with type 2 diabetes will die
from cardiovascular disease1,2
DasarDasarCardioprotectiveCardioprotective
43Adapted from Type 2 Diabetes BASICS. Minneapolis, Minn: International Diabetes Center; 2000.
Years -10 -5 0 5 10 15 20 25
350300250200150100
50
Insulinlevel
Insulin resistance
-cell failure
250
200
150
100
50
0
Rel
ativ
e -
cell
func
tion
(%)
Fastingglucose
Post-mealglucose
Glu
cose
(m
g/dl
) DIAGNOSIS
Clinicalfeatures
Obesity IGT Diabetes Uncontrolled hyperglycaemiaPrediabet
esType 2 diabetes
Macrovascular complicationsMicrovascular complications
When Macrovascular & Microvascular Complication in T2DM?
DasarDasarCardioprotectiveCardioprotective
MortalitasKardiovaskuler
Disfungsi
endotel
Aterogenesis
Glukosa
Post Prandial
Hiperglikemi
Hipertrigliseridemi
Korelasi
PJK
DasarDasarCardioprotectiveCardioprotective
Adiponectin and Clinical Consequences
Type 2 diabetes and glycemic disorders
Dyslipidemia – Low HDL
– Small, dense LDL – Hypertriglyceridemia
Hypertension
Endothelial dysfunction/inflammation (hsCRP)
Impaired thrombolysis PAI-1
VisceralObesity
Atherosclerosis
DasarDasarCardioprotectiveCardioprotective
ANTI INSULIN RESISTANCE ANTIATHEROSCLEROSIS
↓ TISSUE TG CONTENT
UPREGULATE INSULINSIGNALING
ACTIVATE PPARœ
ACTIVATE AMPK
1
2
3
4
•↓ THE Expression of Adhesion Mol. : ICAM-1, VCAM-1, E-selectin, also ↓ TNFœ-induced NFkB Activation
•↓ Endothelial Cell Apoptosis via AMPK Activation by HMW multiform
Of Adiponectin
1 ENDOTHELIUM
↓ Cell Proliferation↓ Migration
↓ SRA- 1 ↓ Uptake of Ox-LDL,↓ Foam Cell2 MACROPHAGE
3 SMC :
⑤ ROLES OF
ADIPONECTIN
V IV III
ANTI OXIDANT
↓ OXIDATIVE STRESS
ANTI INFLAMMATION
↓ INFLAMMATORY MARKERS
↓ APOPTOSIS
BRAIN, HEART, β - CELL
Ouchi et al 2000-2001, Yamauchi et al 2001-2003, Arita et al 2002Kobayashi et al 2004, IIIustrated : Tjokroprawiro 2007-2011
FIGURE – 2 ADIPONECTIN WITH ITS CARDIOPROTECTIVE PROPERTIES
Hipertensi pada diabetes• 2/3 penderita diabetes menderita hipertensi
• Diabetes + hipertensi meningkatkan risiko:
risiko penyakit jantung, stroke, gangguan mata dan gangguan ginjal
DasarDasarCardioprotectiveCardioprotective
Risk of complicationsBenefits of lowering HbA1c
0
4
8
12
16
6 7 8 9 10 11 12Hemoglobin HbA1c (%)
Rela
tive R
isk
of
com
plic
ati
on
s
Adapted from UKPDS 33: Lancet 1998;352:837-853.Adapted from DCCT Study Group. N Engl J Med
1993;329:977.
Average Glucose mg/dl
120 150 180 210 240 270 300
DasarDasarCardioprotectiveCardioprotective
49
Results from UKPDS: Lowering HbA1c Reduces the Risk of Complications
Microvascular complications
Myocardial infarction
HbA1c Deaths related to diabetes
Stratton IM, et al. BMJ 2000; 321: 405–412. 15
1%
red
uce
s 1
% r
ed
uce
s A
1C
A
1C
-21%
-37%
-14%
DasarDasarCardioprotectiveCardioprotective
50
T2DM guidelines focus on glycaemic control and CVD risk factors
HbA1c levels correlate with the development of diabetic complications
Multiple CVD risk factors cluster in T2DM Dyslipidaemia
Hypertension
Obesity
Hypercoagulability
Insulin resistance
Thus, control of hyperglycaemia and CVD risk factorsis the focus of T2DM treatment
IDF Clinical Guidelines Task Force. Brussels, 2005.ADA. Diabetes Care 2008;31(Suppl. 1):S12–54.Ryden L, et al. Eur Heart J 2007;28:88–136.
DasarDasarCardioprotectiveCardioprotective
51
Glimepiride improves beta-cell function and increases insulin synthesis and release.
Glimepiride reduces HGO through suppression of glucagon from alpha cells.
Metformin decreases HGO by targeting the liver to decrease
gluconeogenesis and glycogenolysis.
Metformin has insulin- sensitizing properties.Beta-Cell
Dysfunction
Hepatic Glucose Overproduction
(HGO)
The Combination of Glimepiride and MetforminThe Combination of Glimepiride and Metformin
Insulin Resistance
53
CombinationCombinationCardioprotectiveCardioprotective
53
METFORMIN Mode of Action
Mode of Action
Stimulation of glucose uptake
Suppression of excessive hepatic glucose production
Reduced intestinal glucose absorption
50
Hundal RS and Inzucchi SE. Drugs 2003; 63 (18): 1879-1894.
Liver Skeletal muscle Gut Pancreas Fat
Decreases hepatic glucose
production (gluconeogenesis)
Improves periphral
glucose uptake (probably a secondary effect of
decreasing glucose toxicity)
Improves periphral glucose uptake
(probably a secondary effect of decreasing glucose
toxicity); may decrease lipolysis
May improve insulin secretion
(probably a secondary effect
of decreasing glucotoxicity)
Decreases appetite and
caloric intake; may decrease
intestinal glucose
absorption
CombinationCombinationCardioprotectiveCardioprotective
Vascular benefits of metformin
Reduced cardiovascular risk
ImprovedInsulin sensitivity
Fibrinolysis
Nutritive capillary flow
Haemorrheology
Postischaemic flow
ReducedHypertriglyceridaemia
AGE formation
Cross-linked fibrin
Neovascularisation
Oxidative stress
CombinationCombinationCardioprotectiveCardioprotective
↓ ↓ INSULIN RESISTANCEINSULIN RESISTANCE1↓ 1 h PP (↓ PmH)
METFORMINMIRACLE
56EFFECTS
51
50
49
48
47
46
45
44
43
42
41
40
39
38
37
36
35
34
33
32
31
30
29
28
27
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
↓ FPG
↓ VAT
↓ WC
↓ Glucose Absorption
↑ Glycogenesis
↑ Insulin Rec. Binding
↑ GUT : GLUT-5 Expression
↑ Post-Receptor Effect
↓ Glucolipotoxicity
↓ Oxidative Stress
↓ Inflammation
↓ FFA
↓TG, ↑ HDL-C, ↓Tot-C, ↓ LDL-C
Synthesis & Secretion of GLP-1
↓ AGE
↓ Fibrinogen
↓ Factor-VII (TF)
↓ PAI-1
↓ Factor-XVIIIA
↓ TSH
↓ Respiratory Complexl
↑ Erythrocyte Deformability
↓ Platelet Aggregation
26 ↓ Hyperinsulinemia
↓ AMPK
β-Endorphin
↓ ADMA
↑ Apn
↓ Resistin
↓ Leptin
↓ NFKB
↓Cytosolic Ca++
↓SMC Fibroblast
↑ Plaque Regression
↑ NO (↑ HSP-90, ↑ eNOS)
↓ Capillary Permeability
↓MMP-9
↑ Peripheral A. Blood Flow
↑ PTEN
↓HT-29
↓ LNCaP
↓ PC-3
↓DU 145
↓ cyclin D1
↑ TSC2
↑ TSC1
↓ mTORC1
↑ LBK1
↑ p53
(MMC : Metabolic Cardiovascular Cancer protector IIIustrated : Tjokroprawiro 1994-2011
FIGURE-4 MET with Metabolic-Cardiovascular-Carner (MMC) Protective EffectsFIGURE-4 MET with Metabolic-Cardiovascular-Carner (MMC) Protective Effects56
↓ ↓ FOXO1/ ↓FABP4FOXO1/ ↓FABP456
56
Metformin* should be uptitratedover 1-2 months
5-7 days
If GI side effects, decrease to previous lower dose and try to advance the dose at a later time
If GI side effects, decrease to previous lower dose and try to advance the dose at a later time
Begin with • 500 mg x1 or x2, or • 850 mg x1
INITIATE
If well tolerated, advancedose to
• 850mg x2, or • 1,000mg x2
TITRATE
Maximum effective dose:• Most often 850 mg x2• Can be up to 1,000 mg x2• Modest benefit up to 2,500mg
MAX DOSE
1 to
2 m
on
ths
*Longer-acting formulation can be given once per dayAdapted from Nathan DM, et al. Diabetes Care 2009;32:193-203.
CombinationCombinationCardioprotectiveCardioprotective
57
Attributes of metformin
How it works• Decreases hepatic glucose output
• Lowers fasting glycemia
Expected HbA1c reduction
1 to 2% (monotherapy)
Adverse events• GI side effects
• Lactic acidosis (extremely rare)
Weight effects Weight stability or modest weight loss
CV effects Demonstrated beneficial effect in UKPDS which needs to be confirmed
Adapted from Nathan DM, et al. Diabetes Care 2009;32:193-203.
CombinationCombinationCardioprotectiveCardioprotective
CombinationCombinationCardioprotectiveCardioprotective
SULFONILUREA
Metabolik
Vaskuler
Mencegah angiopati
membersihkan
radikal bebas
Memperbaiki
fungsi trombosit
Memacu
fibrinolisis
PengendalianKadar glukosa darah
Memacu sekresi insulin
MeningkatkanAfinitas Reseptor-Insulin
CombinationCombinationCardioprotectiveCardioprotective
Berikatan dengan
reseptor 65 kDa
Pengeluaran K+
dihambat
Depolarisasi
Saluran Ca++
terbuka
[Ca++] intrasel meningkat
Sekresi insulin
M
eta
bolis
m
[ATP] [ADP]
K+_
cAMP+
ADP
Ca++K+
[Ca++]i
Sekresi Insulin
DepolarisasiDepolarisasi
glimipiride
GlukosaGlukosa&&
Asam AminoAsam Amino
+
+
Pro-insulin Sel b
eta
pan
kre
as
Sel b
eta
pan
kre
as
65 kDa65 kDaSU lain
reseptor SUreseptor SU
140 140 kDakDa
MEKANISME KERJA SULFONILUREA
K - ATP Channel
• Diabsorbsi sempurna (1 jam)
• Kadar maksimal dalam plasma (2 - 3 jam)
• Waktu paruh eliminasi (9.2 3.6 jam)
• Jangka waktu kerja (2 jam)
• Metabolit 60% - urine
40% - feses
• Efek samping hipoglikemik <
Metabolit > aktif
(Generasi ketiga terbaru)
• Makin efektif
• Potensi ekstra pankreas
> efektif
• Kerja cepat & bertahan lama
• Dosis kecil
CombinationCombinationCardioprotectiveCardioprotective
6262
GlimepirideThe first and only antidiabetic drug
with a dual mode of action
Insulin secretion
Sonnenberg GE et al. Ann Pharmacother 1997; 31: 671-676.Weitgasser R et al. Diabetes Res Clin Pract 2003; 61: 13-19.
24
Insulin resistance
Glimepiride as a Unique Dual Mode of Action
CombinationCombinationCardioprotectiveCardioprotective
Adapted from Shepherd PR et al. Glucose transporters and insulin action. NEJM, July 22, 1999
GLUT 4 (Glucose transporters 4) and insulin action
In type 2 Diabetes (insulin resistance),
defective intracelluler signaling affects GLUT 4 translocation to the cell
membrane
Glimepiride increased GLUT 4 translocation 4
fold to the cell membrane, therefor increased
glucose uptake to the cell
1
• IP adalah suatu mekanisme IP adalah suatu mekanisme endogen jantung untuk endogen jantung untuk melindungi dirinya dari melindungi dirinya dari
suatu kejadian iskemi yang suatu kejadian iskemi yang mematikan (parah) mematikan (parah)
• IP terjadi jika kanal/saluran IP terjadi jika kanal/saluran KKATPATP di jantung terbuka di jantung terbuka
secara secara otomatisotomatis menyusul menyusul kejadian iskemik miokard kejadian iskemik miokard
yang singkatyang singkat
• Obat-obatan yang Obat-obatan yang menghambat terbukanya menghambat terbukanya
KKATPATP di jantung dapat di jantung dapat membahayakan kondisi membahayakan kondisi
iskemik miokardiskemik miokard
Ischemic Preconditioning Ischemic Preconditioning (IP)(IP)
Oklusi/hambatan Oklusi/hambatan yang yang berkepanjangan berkepanjangan pada arteri pada arteri epicardial akan epicardial akan menyebabkan menyebabkan infark miokardinfark miokard
Oklusi/hambatan yang Oklusi/hambatan yang singkat dan berulang-singkat dan berulang-ulang pada pembuluh ulang pada pembuluh
darah yang sama darah yang sama menyusul oklusi yang menyusul oklusi yang berkepanjangan akan berkepanjangan akan
menghasilkan luas infark menghasilkan luas infark yang lebih kecil yang lebih kecil
(ischemic (ischemic preconditioning) preconditioning)
CombinationCombinationCardioprotectiveCardioprotective
SURSUR 22
SURSUR 11
Kanal KKanal KATPATP, sebuah kompleks yang terdiri dari reseptor sulfonilurea (SUR2A, SUR1) dan , sebuah kompleks yang terdiri dari reseptor sulfonilurea (SUR2A, SUR1) dan kanal kalium (Kir6.2) adalah kunci untuk pelepasan insulin dari sel kanal kalium (Kir6.2) adalah kunci untuk pelepasan insulin dari sel pankreas yang pankreas yang
diperantarai glukosadiperantarai glukosa
.Bbrp Sulfonilurea kerja pd kanal KATP pankreas / jantung.
.Glimepiride bekerja selektif pada kanal KATP di pankreas
Adiponectin and Clinical Consequences
Type 2 diabetes and glycemic disorders
Dyslipidemia – Low HDL
– Small, dense LDL – Hypertriglyceridemia
Hypertension
Endothelial dysfunction/inflammation (hsCRP)
Impaired thrombolysis PAI-1
VisceralObesity
Atherosclerosis
The 3rd Gen. of SU with CARDIOMETABOLIC Effects
TABLE – 1 AMARYL ®: ITS ⑧ EFFECTS INCLUDING ADIPONECTIN RAISER
Rapid inding to Rec. Low ffinity to Rec.
LESS HYPOGLIKEMIA – LESS WEIGHT GAINRAPID ACTION
Rapid issociation to RecB
↑ 3B ↓ 3A ↑ 9D
A D
I I I
INSULIN MIMETIC EFFECT INHIBITS PLATELET AGGREGATION
CARDIOPROTECTIVE EFFECTS① GLIM : No Effect at CV KATP-Channels
-Reduced Coronary Bloood Flow ↓ -Proarrythmogenic Effects ↓②GLIM : ↓ (NE, 5HT, KCL, PGF2œ)
II
↑ GLYCOGEN SYNTHESIS
↑ OSTEOBLAST ADIPONECTIN - RAISER TFNœ-REDUCER
III V
IV
VI VIII VII
Efficacy as a combination therapy
46
Regimen HbA1c reduction (%)
Sulfonylurea + metformin 1.7 (16)
Sulfonylurea + rosiglitazone 1.4 (18)
Sulfonylurea + pioglitazone 1.2 (19)
Sulfonylurea + acarbose 1.3 (20)
Repaglinide + metformin 1.4 (17)
Pioglitazone + metformin 0.7 (21)
Rosiglitazone + metformin 0.8 (22)
Dipeptidyl peptidase 4 inhibitor + metformin 0.7 (23)
Dipeptidyl peptidase 4 inhibitor + pioglitazone
0.7 (23)
The NEJM, Vol. 342 : 145-153, Jan 2000
70
Basal plus
Basal +1 prandial
Basal insulin
once daily(treat-to-target)
Basal plus
Basal +2 prandial
Basal bolus
Basal +3 prandial
Lifestyle+
Metformin± SU
HbA1c ≥7.0%, FBG on targetPPG ≥160 mg/dLHbA1c ≥7.0%
TimeProgressive deterioration of -cell
functionDiabetes Mellitus Insulin secretion 50%
Closing Remark
The NEJM, Vol. 342 : 145-153, Jan 2000
DISLIPIDEMIOVERWEIGHTHIPERTENSI
D M
AcceleratedAtherosclerosis
P J K
GLIMIPIRIDE METFORMIN
CARDIOPROTECTIVE
A M A R Y L M
Closing Remark
Indonesiaku
nan
Indah
Terima
kasih