Ada Guideline

7/30/2019 Ada Guideline

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CardioprotectiveCombinations

M a h a t m a

F K U M S

The New Paradigm of (Type 2) DiabetesTreatment

( focus : metformin and glimipiride )

STANDING TOGETHER AGAINST DIABETES


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SlametS 2

350

300

250

200

150

100

50

0

Negara maju Negara

berkembang

DuniaJumlahpengid

apdiabetesdew

asa(dalamj

uta

)

1995

2000

2025

Jumlah Pengidap Diabetes

di Dunia 1995-2025

41%

170%

122%

URGENT NEED FOR ACTION

LATAR BELAKANG

LatarLatar

BelakangBelakang


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RISKESDAS 2008RISKESDAS 2008

Diagnosedpatients

Undiagnosedpatients

Indonesian BasicHealth Research

(RISKESDAS)

Total DM = 5,7%Diagnosed DM =

1,5%Undia nosed DM =

D M estimated( WHO )

2000

>17 million

2020

8

million

LATAR BELAKANG

LatarLatar

BelakangBelakang



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SlametS 4

Proyeksi WHO tentang Struktur Umum

Populasi Diabetes

Umur pasien diabetes

paling banyak > 65 th

1995-2025

Negara maju Negara berkembang

Umur non produktif Umur produktif

Umur pasien diabetes

paling banyak 45-65 th

(40-59 th)*

LATAR BELAKANG

LatarLatar

BelakangBelakang



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Distribusi Glukosa ke Jaringan

F i s i o l o g iF i s i o l o g i

INS

INSINS


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Diabetes Mellitus Kelainan bersifatkronik

Gangguan metabolismeKH-L-P

KomplikasiMakro & Mikro Vaskuler

Berkaitan denganfaktor genetik Gejala UtamaIntoleransi Glukosa

Faktor 2 Fungsi Endo. Pank ( DM ) Genetik

Virus & Bakteri Bahan Toksik

Nutrisi

EAGLE FLIES ALONE, MHT

D e f i n i s iD e f i n i s i


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Tipe 1 Destruksi sel beta, umumnya menjurus ke defisiensiinsulin 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 Lain Defek genetik fungsi sel betaDefek genetik kerja insulinPenyakit eksokrin pankreasEndokrinopatiKarena obat/zat kimia

InfeksiSebab imunologi yang jarangSindrom genetik lain yang berkaitan

dengan DM

DM

GestasionalEAGLE FLIES ALONE, MHT

KlasifikasiKlasifikasi


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Etiologi Diabetes tipe 2

Gangguan pada sekresi insulin dan resistensi

insulin

Diabetes Tipe 2

Gangguan toleransi

glukosa

Gangguan sekresi

insulinResistensi insulin+


patofisiologipatofisiologi


9/53SlametS

Chronic

hyperglycemia

High circulating

free fatty acidsPancreas

Amyloid

deposit

Glucotoxicity2 Lipotoxicity3

HGP

Uptake

Lipolysis

TNF


Insulin resistance

Hyperinsulinemiato compensate for insulin

resistance1,2

Insulin deficiency


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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

Nodiabetes

Pre-diabetes

Time

Insulin secretion

Glycemia

Insulin resistance



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Klinis

polidipsia(sering haus) beratbadanturun

poliuria(sering kencing)

gatal-gatalmata kabur impotensia

poliphagia(cepat lapar)

kesemutan

Cepat Lelah

Luka pada KakiSukar Sembuh

G e j a l aG e j a l a


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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

FPG

110-125FPG < 1102-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 iD i a g n o s i

ss


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hypoX-jsk-7-99

IGTPostprandial

Hyperglycemia Type 2

Diabetes

Phase 1 Type 2

Diabetes

Phase 2

Type 2

DiabetesPhase 3

- 12 - 10 - 6 - 2 0 2 6 10 14

Years from diagnosis

Betacellfunction

(%)

Stages of type 2 Diabetes in relationship toStages of type 2 Diabetes in relationship to--cell functioncell function

25

0

50

75

100

8 6 4 02

1

4 8 12


D i a g n o s iD i a g n o s i

ss


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Treatment :stepwise approach

Blood Glucose Control

1

2

3

4

5

Combinationof

oral medicines

Oral plusinsulin

Insulin

One oral

medicine

Diet&

exercise

+

++

PenatalaksanaanPenatalaksanaan

Th N P di f (T 2)


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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



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16

History of ADA/EASD consensus algorithm

First Consensus algorithm

August 20061

1st Update

January 2008: Update regardingthiazolidinediones2

2nd Update

January 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.


1 2 Achieving glycemic control with insulin glargine


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Check HbA1C every

3 months until


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18

Basal plusBasal +

1 prandial

A logical stepwise approach

Basal insulinonce daily

(treat-to-target)

Basal plusBasal +

2 prandial

Basal bolusBasal +

3 prandial

Lifestyle+

Metformin

SU

HbA1c 7.0%, FBG on target

PPG 160 mg/dLHbA1c 7.0%

T i m e


STEP 1

STEP 2

STEP 3

STEP 2

l k


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19

At diagnosis:Lifestyle

+Metformin

Lifestyle

+ Metformin+ Basal insulin

Lifestyle+ Metformin

+ Sulfonylurea

STEP 1 STEP 2

HbA1c7%


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.

l kP l k


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20201

Are All SulphonylureaAre All Sulphonylurea

the Same?the Same?


DD


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DasarDasar

CardioprotectiveCardioprotective

Back-up

Combination Therapy

DDasar


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Vascular Complications

Microangiopathy

C V D

P V D

Stroke

Nephropathy

Retinopathy

Neuropathy

Diabetes

Macroangiopathy


DasarDasar


DasarDasar


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23

Reaching glucose goals is important to reducecomplications

1Gray RP & Yudkin JS. Cardiovascular disease in diabetes mellitus. In Textbook of Diabetes 2nd

Edition, 1997. Blackwell Sciences.

2Kannel WB, et al. Am Heart J1990; 120:672676.

Overall, 75% of people with type 2 diabetes will die

from cardiovascular

disease

1,2

DasarDasar


DasarDasar


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24Adapted from Type 2 Diabetes BASICS.

Minneapolis, Minn: International Diabetes Center; 2000.

Years -10 -5 0 5 10 15 20 25

350300

250

200

150

100

50

Insulinlevel

Insulin resistance

-cell failure

250200

150

100

50

0Relative-ce

ll

function(%)

Fastingglucose

Post-mealglucose

Glucose(mg/dl)

DIAGNOSIS

Clinical

features

Obesity IGT Diabetes Uncontrolled hyperglycaemia

Prediabetes

Type 2 diabetes

Macrovascular complicationsMicrovascular complications

When Macrovascular & Microvascular Complication in

T2DM?

DasarDasar


DasarDasar


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Mortalitas

Kardiovaskuler

Disfungsiendotel

Aterogenesis

Glukosa

Post Prandial

Hiperglikemi

Hipertrigliseridemi

Korelasi

PJK

DasarDasar


DasarDasar


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Adiponectin and Clinical

ConsequencesType 2 diabetes andglycemic disorders

Dyslipidemia

Low HDL Small, dense LDL

Hypertriglyceridemia

Hypertension

Endothelial dysfunction/inflammation (hsCRP)

Impaired thrombolysis PAI-1

VisceralObesity

Ath

e

ros

cle

rosis

DasarDasar



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ANTI INSULIN RESISTANCE ANTIATHEROSCLEROSIS

TISSUE TG CONTENT

UPREGULATE INSULINSIGNALING

ACTIVATE PPAR

ACTIVATE AMPK

1

2

3

4

THE Expression of Adhesion Mol. :ICAM-1, VCAM-1, E-selectin, also

TNF-induced NFkB Activation Endothelial Cell Apoptosis viaAMPK Activation by HMW multiform

Of Adiponectin

1 ENDOTHELIUM

Cell Proliferation Migration

SRA- 1 Uptake of Ox-LDL, Foam Cell

2 MACROPHAGE

3SMC :

ROLES OF

ADIPONECTIN

V IV III

ANTI OXIDANT

OXIDATIVE STRESS

ANTI INFLAMMATION

INFLAMMATORY MARKERS

APOPTOSIS

BRAIN, HEART, - CELL

Ouchi et al 2000-2001, Yamauchi et al 2001-2003, Arita et al 2002

Kobayashi et al 2004, IIIustrated : Tjokroprawiro 2007-2011

FIGURE 2 ADIPONECTIN WITH ITS CARDIOPROTECTIVE PROPERTIES

DasarDasar


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Hipertensi padadiabetes

2/3 penderita diabetes menderitahipertensi

Diabetes + hipertensi meningkatkan risiko:

risiko penyakit jantung, stroke, gangguan mata dangangguan ginjal

DasarDasar


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


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Risk of complicationsBenefits of lowering HbA1c

0

4

8

12

16

6 7 8 9 10 11 12

Hemoglobin HbA1c (%)

RelativeRisk

o

fcomplications

Adapted from UKPDS 33: Lancet1998;352:837-853.Adapted from DCCT Study Group. N EnglJ Med

1993;329:977.

Average Glucosemg/dl

120 150 180 210 240 270 300

DasarDasar


DasarDasar


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30

Results from UKPDS: Lowering HbA1c

Reduces the Risk of Complications

Microvascular

complications

Myocardial

infarction

HbA1c Deaths related todiabetes

Stratton IM, et al. BMJ 2000; 321: 405412. 15

1%r

educes

1%r

educe

s

A1C

A1C

-21%

-37%

-14%

DasarDasar


DasarDasar


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31

T2DM guidelines focus on glycaemiccontrol andCVD risk factors

HbA1c

levels correlate with the development of diabeticcomplications

Multiple CVD risk factors cluster in T2DM

DyslipidaemiaHypertension

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):S1254.Ryden L, et al. Eur Heart J2007;28:88136.

DasarDasar


Th C bi ti f Gli i id d M tf iTh C bi ti f Gli i id d M tf i


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32

Glimepiride

improves beta-cellfunction and

increases insulin

synthesis and

release.

Glimepiride reduces HGO

through suppression of glucagonfrom alpha cells.

Metformin decreases HGO by

targeting the liver to decreasegluconeogenesis and

glycogenolysis.

Metformin has insulin-

sensitizing properties.Beta-CellDysfunction

Hepatic GlucoseOverproduction

(HGO)

The Combination of Glimepiride and MetforminThe Combination of Glimepiride and Metformin

InsulinResistance

53

CombinationCombination


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34

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 hepaticglucose

production

(gluconeogenesis)

Improves

periphral

glucose uptake

(probably a

secondary

effect of

decreasing

glucose toxicity)

Improves periphral

glucose uptake

(probably asecondary effect of

decreasing glucose

toxicity); may

decrease lipolysis

May improve

insulin secretion

(probably asecondary effect

of decreasing

glucotoxicity)

Decreases

appetite and

caloric intake;may decrease

intestinal

glucose

absorption





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Vascular benefits of metformin

Reduced cardiovascular risk

Improved

Insulin sensitivity

Fibrinolysis

Nutritive capillary flow

Haemorrheology

Postischaemic flow

Reduced

Hypertriglyceridaemia

AGE formation

Cross-linked fibrin

Neovascularisation

Oxidative stress




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M tf i * h ld b tit t d



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37

Metformin* should be uptitratedover 1-2 months

5-7 days

If GI side effects, decreaseto previous lower dose andtry to advance the dose at alater time

If GI side effects, decreaseto previous lower dose andtry to advance the dose ata 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

1to2months

*Longer-acting formulation can be given once per day

Adapted from Nathan DM, et al. Diabetes Care 2009;32:193-203.





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38

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 needsto be confirmed

Adapted from Nathan DM, et al. Diabetes Care 2009;32:193-203.

CombinationCo b a o




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Co b a oCardioprotectiveCardioprotective



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SULFONILUREA

Metabolik

Vaskuler

Mencegah angiopati

membersihkan

radikal bebas Memperbaikifungsi trombosit

Memacufibrinolisis

Pengendalian

Kadar glukosa darah

Memacu

sekresi insulin

Meningkatkan

Afinitas Reseptor-Insulin



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Berikatandenganreseptor 65

kDaPengeluaran K+

dihambat

Depolarisasi

Saluran Ca++

terbuka

[Ca++] intraselmeningkat

Sekresi insulin

Metabo

lism

[ATP][ADP]

K+_

cAMP

+ADP

Ca++K+

[Ca++]i

Sekresi Insulin

DepolarisasiDepolarisasi

glimipiride

GlukosaGlukosa

&&

Asam AminoAsam Amino

+

+

Pro-insulinSelbeta

pankreas

Selbeta

pankreas

65 kDa65 kDaSU lain

reseptor SUreseptor SU

140140

kDakDa

MEKANISME KERJA SULFONILUREA

K - ATP Channel



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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 aktif

(Generasi ketiga terbaru)

Makin efektif

Potensi ekstra pankreas

> efektif

Kerja cepat & bertahan lama

Dosis kecil




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4343

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: 24

Insulin resistance

Glimepiride as a Unique Dual Mode of Action


GLUT 4 (Gl t t 4) d i li ti


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Adapted from Shepherd PR et al. Glucose transporters and insulin action. NEJM, July 22, 1999

GLUT 4 (Glucose transporters 4) and insulin action

1


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In type 2 Diabetes(insulin resistance),

defective intracellulersignaling affects GLUT 4

translocation to the cellmembrane

Glimepiride increasedGLUT 4 translocation 4

fold to the cell membrane,therefor increased

glucose uptake to the cell

1

h i di i i



46/53

IP adalah suatu mekanismeIP adalah suatu mekanismeendogen jantung untukendogen jantung untukmelindungi dirinya darimelindungi dirinya dari

suatu kejadian iskemi yangsuatu kejadian iskemi yangmematikan (parah)mematikan (parah)

IP terjadi jika kanal/saluranIP terjadi jika kanal/saluranKKATPATP di jantung terbukadi jantung terbuka

secarasecara otomatisotomatismenyusulmenyusulkejadian iskemik miokardkejadian iskemik miokard

yang singkatyang singkat

Obat-obatan yangObat-obatan yangmenghambat terbukanyamenghambat terbukanya

KKATPATP di jantung dapatdi jantung dapat

membahayakan kondisimembahayakan kondisiiskemik miokardiskemik miokard

Ischemic PreconditioningIschemic Preconditioning

(IP)(IP)

Oklusi/hambatanOklusi/hambatan

yangyang

berkepanjanganberkepanjanganpada arteripada arteri

epicardial akanepicardial akan

menyebabkanmenyebabkan

infark miokardinfark miokard

Oklusi/hambatan yangOklusi/hambatan yang

singkat dan berulang-singkat dan berulang-

ulang pada pembuluhulang pada pembuluhdarah yang samadarah yang sama

menyusul oklusi yangmenyusul oklusi yang

berkepanjangan akanberkepanjangan akan

menghasilkan luas infarkmenghasilkan luas infark

yang lebih kecilyang lebih kecil

(ischemic(ischemic

preconditioning)preconditioning)


.Bbrp Sulfonilurea kerja pd kanal KATP pankreas /


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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 selkanal kalium (Kir6.2) adalah kunci untuk pelepasan insulin dari sel pankreas yangpankreas yangdi erantarai lukosadi erantarai lukosa

p j p pjantung.

.Glimepiride bekerja selektif pada kanal KATP dipankreas

Adiponectin and Clinical


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Adiponectin and ClinicalConsequences

Type 2 diabetes andglycemic disorders

Dyslipidemia

Low HDL Small, dense LDL

Hypertriglyceridemia

Hypertension

Endothelial dysfunction/inflammation (hsCRP)

Impaired thrombolysis PAI-1

VisceralObesity

Ath

e

ros

cle

rosis


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The 3rd Gen. of SU with CARDIOMETABOLIC Effects

TABLE 1 AMARYL : ITS EFFECTS INCLUDINGADIPONECTIN 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 EFFECTS

GLIM : No Effect at CV KATP-Channels-Reduced Coronary Bloood Flow

-Proarrythmogenic Effects GLIM : (NE, 5HT, KCL, PGF2)

II

GLYCOGEN SYNTHESIS

OSTEOBLAST ADIPONECTIN - RAISER

TFN-REDUCER

III V

IV

VI VIIIVII

Efficacy as a combination


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Efficacy as a combinationtherapy

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)

Closing Remark


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The NEJM, Vol. 342 : 145-153, Jan2000

51

Basalplus

Basal +

1 prandial

Basal

insulin

once daily

(treat-to-

target)

Basal

plus

Basal +2 prandial

Basal

bolus

Basal +

3 prandial

Lifestyle+

Metformin

SUHbA1c 7.0%, FBG on target

PPG 160 mg/dLHbA1c 7.0%

TimeProgressive deterioration of-cell function

Diabetes Mellitus Insulin secretion 50%

Closing Remark

Closing Remark


52/53

The NEJM, Vol. 342 : 145-153, Jan2000

DISLIPIDEMIOVERWEIGHT

HIPERTENSID M

AcceleratedAtherosclerosis

P J K

GLIMIPIRIDEMETFORMIN

CARDIOPROTECTIVE

A M A R Y L M

Closing Remark


53/53

ndon

esiaku

nan

Indah

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