ada guideline dm

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


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



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


promoter Coding reg

transcription

mRNA

Synthesis GLUT 4

translocation

PPAR

PPRE

Insulinreceptor

Insulin

RXR

Glucose


Topik

• D E F I N I S I


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.


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


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


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


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


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


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


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


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


D i a g n o s i D i a g n o s i ss

Topik

• PENATALAKSANAAN


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


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


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.


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


PioglitazoneNo hypoglycemia

Oedema / CHFBone Loss


GLP-1 agonistb

No hypoglycemiaWeight loss

Nausea / vomiting

Tier 2: Less well validated therapies


Pioglitazone plus

Sulfonylureaa


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


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


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%


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)


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


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?


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



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


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?


MortalitasKardiovaskuler

Disfungsi

endotel

Aterogenesis

Glukosa

Post Prandial

Hiperglikemi

Hipertrigliseridemi

Korelasi

PJK


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


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


http://www.netdoctor.co.uk/images/bva__100148000_bvi0000025.jpg

http://www.netdoctor.co.uk/images/bva__100148000_bvi0000025.jpg

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


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%


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.


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


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


↓ ↓ 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.


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.


SULFONILUREA

Metabolik

Vaskuler

Mencegah angiopati

membersihkan

radikal bebas

Memperbaiki

fungsi trombosit

Memacu

fibrinolisis

PengendalianKadar glukosa darah

Memacu sekresi insulin

MeningkatkanAfinitas Reseptor-Insulin


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


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


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)


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

ada guideline dm

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