The New Paradigm of (Type 2) Diabetes Treatment ( focus : metformin and glimipiride ) STANDING TOGETHER AGAINST DIABETES

Cardioprotective Combinations

M a h a t ma
FK UMS

Topik
LATAR BELAKANG

EAGLE FLIES ALONE, MHT

RISKESDAS 2008

LATAR BELAKANG Latar Belakang

STANDING TOGETHER AGAINST DIABETES

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 )
2020
>17 million

8 million 2000

DM Prevalence
INDONESIA

2000 5.6 million people with DM 2020 31.3 million people with DM The 4th of world largest prevalence !! (International Diabetes Federation)

Pre-diabetes ??
Faktor yg berperan dlm jml DM : usia >40 tahun yg , kemakmuran, pola hidup serba berkecukupan, penyakit infeksi, angka harapan hidup
Other 10% Glomerulonephritis 13% Hypertension 27%

Nefropati Diabetika (ND) :

Primary Diagnosis for Patients Who Start

Dialysis

Diabetes 50.1%

EAGLE FLIES ALONE, MHT

LATAR BELAKANG Latar Belakang

Proyeksi WHO tentang Struktur Umum Populasi Diabetes

1995-2025 Negara maju Negara berkembang

Umur pasien diabetes paling banyak > 65 th

Umur pasien diabetes paling banyak 45-65 th (40-59 th)*

Umur non produktif

SlametS

Umur produktif
5

STANDING TOGETHER AGAINST DIABETES

Topik
TINJAUAN ANATOMIS FISIOLOGIS

EAGLE FLIES ALONE, MHT

PROINSULIN

C-PEPTIDE INSULIN
EAGLE FLIES ALONE, MHT

Fisiologi

Distribusi Glukosa ke Jaringan

INS
INS

INS

Overview of Carbohydrate metabolism

INS

INS

INS

INS

INS INS INS

INS
INS

EAGLE FLIES ALONE, MHT

Insulin

Glucose

Insulin receptor

Synthesis GLUT 4 PPARg

RXR mRNA

PPRE

promoter

Coding reg

transcriptio n

EAGLE FLIES ALONE, MHT

Topik
DEFINISI

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.

Insulin kurang jumlahnya Insulin kurang baik kerjanya

EAGLE FLIES ALONE, MHT

Diabetes Mellitus
Kelainan bersifat kronik Gangguan metabolisme KH-L-P Komplikasi Makro & Mikro Vaskuler Berkaitan dengan faktor genetik Gejala Utama Intoleransi Glukosa

Definisi

Faktor 2 Fungsi Endo. Pank ( DM )

Genetik Virus & Bakteri Bahan Toksik Nutrisi
EAGLE FLIES ALONE, MHT

Klasifikasi
Tipe 1
Destruksi sel beta, umumnya menjurus ke defisiensi insulin absolut Autoimun Idiopatik Bervariasi, mulai yang terutama dominan resistensi insulin disertai defisiensi insulin relatif sampai yang terutama defek sekresi insulin disertai resistensi insulin Defek genetik fungsi sel beta Defek genetik kerja insulin Penyakit eksokrin pankreas Endokrinopati Karena obat/zat kimia Infeksi Sebab imunologi yang jarang Sindrom genetik lain yang berkaitan dengan DM

Tipe 2

Tipe Lain

DM

Gestasional
EAGLE FLIES ALONE, MHT

Topik

PATOFISIOLOGI

EAGLE FLIES ALONE, MHT

DIABETES TIPE 1
Gluc Gluc

Tidak Ada Insulin

Gluc

Gluc

Gluc

Gluc

Gluc

Kadar glukosa darah meningkat

Tidak ada insulin yang membuka pintu masuk sel

Tak ada Sel otot

Tenaga yang dibakar

Gluc

Glukosa darah SlametS

Pintu masuk sel

EAGLE FLIES ALONE, MHT

DIABETES Kerja Insulin Kurang Baik TIPE 2

Gluc Gluc

Gluc

Gluc

Gluc

Insulin
Gluc

Gluc

Kadar glukosa darah meningkat

Ada insulin tapi tak mampu membuka pintu masuk sel

Tak ada Sel otot

Tenaga yang dibakar

Gluc

Glukosa darah SlametS

Pintu masuk sel

EAGLE FLIES ALONE, MHT

patofisiologi

Insulin deficiency
Hyperinsulinemia
to compensate for insulin resistance1,2

Glucotoxicity2
Amyloid deposit

Lipotoxicity3

Chronic hyperglycemia

Pancreas

High circulating free fatty acids

HGP Uptake

Lipolysis

Insulin resistance

TNF a

SlametS

patofisiologi

Natural History of Type 2 Diabetes

Insulin sensitivity Insulin secretion Insulin resistance Glycemia

30% 50%

Type 2 diabetes

50%

70 % IGT Impaired glucose 150% 70% metabolism 100% Normal glucose 100%

Insulin secretion

Time
No Prediabetes diabetes

60 ng/ml

Individu normal
Insulin plasma

FASE 1
3-5 mnt waktu

FASE-2

50-60 menit

Penderita DM tipe-2
Insulin plasma FASE-1 FASE-2 Comparative profiles Secretion of insulin Normally and D M Waktu (Delayed Insulin secretion) (Tumpul)

Lebih tinggi dan lama

EAGLE FLIES ALONE, MHT

Gejala

Klinis

poliphagia poliuria polidipsia (sering kencing) (cepat lapar) (sering haus) Cepat Lelah

berat badan turun

Luka pada Kaki Sukar Sembuh

kesemutan mata kabur impotensia

gatal-gatal

Topik
DIAGNOSA

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

Diagnosis

Criteria for the Diagnosis of Pre-DM (IGT & IFG) and DM

Normal
(mg/dl)

Pre - Diabetes
(mg/dl)

Diabetes Mellitus
(mg/dl)

IGT
FPG < 110 2-h PG < 140

IFG

T2DM
FPG > 126 2-h PG > 200 CPG > 200 with Classical Symptoms

FPG 2h-PG 140-199 110-125

New IFG*:

100-125

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 FPG Glucose Load : 75g Anhydrous Glucose in Water EAGLE FLIES ALONE, MHT

Diagnosis Stages of type 2 Diabetes in relationship to 100 -cell function

75
Beta cell function (%)

50

IGT
25

Postprandial Hyperglycemia

Type 2 Diabetes Phase 1

Type 2 Diabetes Phase 2

2

Type 2 Diabetes Phase 3

8 - 10 6 - 12

-4 6

1 hypoX-jsk-7-99 Years from diagnosis

-2 2

0 0

4 6

8 10

12 14
EAGLE FLIES ALONE, MHT

Topik
PENATALAKSANAAN

EAGLE FLIES ALONE, MHT

Treatment : stepwise approach Blood Glucose Control

+ +
5

Penatalaksanaan

+
3
2 1

The New Paradigm of (Type 2) Diabetes Treatment

Penatalaksanaan

Aggressive Treatment Driven by Target (AIC < 7%) Early Combinations Oral agent oral agent Oral agent insulin Aggressive Insulin Treatment

Target Pengendalian Kadar Glukosa Darah (ADA2005)

Kadar glukosa darah

HbA1C (%)

<7%

Puasa

90 to 130 mg/dl

Setelah makan

<180 mg/dl

Untuk anak-anak, wanita hamil dan usia lanjut diperlukan pertimbangan lain

Adapted from American Diabetes Association . Standard of medical care for patients with diabetes mellitus Diabetes Care 2005

Hb A1c = Kadar Gula Dalam Sel Darah Merah, Menggambarkan Kadar Rata Rata Gula Darah Selama 2-3 Bulan Yang Lalu
HbA1c
Gula darah mg/dl

200

8%
160

7%
130

6%
Target pengendalian = 7%

100

Hasil dari UKPDS: Kontrol yang baik pada DM T2 mampu menurunkan resiko komplikasi

Penurunan 1% HbA1c

Menurunkan resiko*
-21%

Kematian karena diabetes

Infark miokard

-14%

1%
Komplikasi mikrovaskuler
-37%

Gangguan pembuluh darah perifer

-43%

EAGLE FLIES ALONE, MHT

Penatalaksanaan

History of ADA/EASD consensus algorithm

First Consensus algorithm August 20061

1st Update January 2008: Update regarding thiazolidinediones2 2nd Update January 20093
32

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

Penatalaksanaan

ADA/EASD consensus algorithm

Tier 1: Well validated core therapies
Lifestyle + Metformin plus Basal Insulin Lifestyle + Metformin plus Sulfonylureaa Check HbA1C every 3 months until <7%. Change treatment if HbA1C 7% Lifestyle + Metformin plus Intensive Insulin
At diagnosis:

Lifestyle + Metformin

Step 1

Step 2
Lifestyle + Metformin plus Pioglitazone
No hypoglycemia Oedema / CHF Bone Loss

Step 3
Lifestyle + Metformin plus Pioglitazone plus Sulfonylureaa

Tier 2: Less well validated therapies

Lifestyle + Metformin plus GLP-1 agonistb

No hypoglycemia Weight loss Nausea / vomiting

Lifestyle + Metformin plus Basal Insulin

a Sulfonylureas other than glibenclamide or chlorpropamide b Insufficient clinical safety data; CHF = congestive heart failure

Penatalaksanaan

A logical stepwise approach

STEP 3
Basal bolus Basal plus STEP 2 Basal plus STEP 2 Basal insulin
once daily (treat-to-target) Basal + 1 prandial Basal + 2 prandial Basal + 3 prandial

STEP 1

SU
HbA1c 7.0%
HbA1c 7.0%, FBG on target PPG 160 mg/dL

Lifestyle + Metformin

T i m e
34

Penatalaksanaan ADA/EASD consensus algorithm: step 2 Addition of sulfonylurea

STEP 1 STEP 2

Lifestyle + Metformin + Basal insulin At diagnosis: Lifestyle + Metformin

HbA1c 7%

Lifestyle + Metformin + Sulfonylurea

* Sulfonylureas other than glybenclamide (glyburide) or chlorpropamide Nathan DM, et al. Diabetes Care 2009;32:193-203.

35

Insulin Target Tissues

Biguanides TZDs Decrease Lipolysis
Adipose Tissue
Increased Lipolysis

Thiazolidinediones (TZDs) Increase Glucose Uptake

Skeletal Muscle
Decreased Glucose Uptake

Decrease TZDs Hepatic Glucose Production ?

Liver
Increased Glucose Production

Sulfonylureas and Nonsulfonylurea Secretagogues Increase Insulin Secretion

Increased Free Fatty Acids

Pancreatic Beta Cells

Decreased Insulin Secretion

Glucotoxicity
a-Glucosidase Inhibitors

Lipotoxicity

INSULIN RESISTANCE

Delay Intestinal Carbohydrate Absorption

DEFECTIVE INSULIN SECRETION

Small Intestine
Carbohydrate Absorption

(type 2 diabetes)

EAGLE FLIES ALONE, MHT

Intervensi Farmakologik (1)

Obat Hipoglikemik Oral Pemicu Sekresi Insulin Penambah sensitivitas insulin
Meningkatkan sekresi insulin oleh sel beta Pilihan utama untuk pasien dengan BB normal/kurang namun masih boleh diberikan untuk BB lebih Menurunkan resistensi insulin dengan meningkatkan jumlah orotein pengangkut glukosa shg meningkatkan pengambilan glukosa perifer Kontra indikasi pada pasien gagal jantung Sulfonilurea Glinid

Tiazolidindion (Rosiglitazon, pioglitazon)

TZD tidak digunakan sebagai obat tunggal

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 A1c
Cara Kerja Utama Sulfonilurea Glinid Metformin
Meningkatkan sekresi insulin Meningkatkan sekresi insulin Menekan prod glukosa & menambah sensitivitas thd insulin Menghambat absorbsi glukosa

Efek Samping Utama

BB naik, hipoglikemi BB naik, hipoglikemi Diare, dispepsis, asidosis laktat Flatulens, tinja lembek

Penurunan A1c
1.5 2 %

1.5 2 %

Penghambat alpha glukosidase TZD Insulin

0.5 1 %

menambah sensitivitas thd insulin Menekan prod glukosa hati, stimulasi pemanfaatan glukosa

Edema BB naik, hipoglikemi

1.3% Potensial sampai normal

EAGLE FLIES ALONE, MHT

Penatalaksanaan

Are All Sulphonylurea the Same?

39
1

Dasar Cardioprotective

Combination Therapy

Back-up

Dasar Cardioprotective

Vascular Complications
Diabetes Macroangiopathy

Microangiopathy

Nephropathy Retinopathy Neuropathy

C V D
P V D Stroke

EAGLE FLIES ALONE, MHT

Dasar Cardioprotective

Reaching glucose goals is important to reduce complications Overall,

75% of people with type 2 diabetes will die from 1,2 cardiovascular disease

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; 120:672676.

42

Dasar Cardioprotective

When Macrovascular & Microvascular Complication in T2DM?

350 300 250 200 150 100 50 250 200 150 100 50 0

Glucose (mg/dl)

DIAGNOSIS Post-meal glucose Fasting glucose

Relative -cell function (%)

Insulin resistance Insulin level -cell failure Obesity IGT Diabetes

Uncontrolled hyperglycaemia

Clinical features

Type 2 diabetes Prediabetes Macrovascular complications

Microvascular complications
-10 -5 0 5 10 15 20 25
43

Years

Adapted from Type 2 Diabetes BASICS. Minneapolis, Minn: International Diabetes Center; 2000.

Dasar Cardioprotective

Glukosa Post Prandial Korelasi

Mortalitas Kardiovaskuler

Hiperglikemi Hipertrigliseridemi

Disfungsi endotel Aterogenesis

PJK

Dasar Cardioprotective

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

Atherosclerosis

Visceral Obesity

ANTI INSULIN RESISTANCE

ANTIATHEROSCLEROSIS

1 TISSUE TG CONTENT 2 UPREGULATE INSULIN

SIGNALING

1 ENDOTHELIUM THE Expression of Adhesion Mol. :

ICAM-1, VCAM-1, E-selectin, also TNF-induced NFkB Activation

ROLES OF ADIPONECTIN

Endothelial Cell Apoptosis via

AMPK Activation by HMW multiform Of Adiponectin

3 4

ACTIVATE PPAR ACTIVATE AMPK

2 MACROPHAGE 3
SMC :

SRA- 1 Uptake of Ox-LDL, Foam Cell Cell Proliferation Migration

V
APOPTOSIS BRAIN, HEART, - CELL

IV
ANTI INFLAMMATION INFLAMMATORY MARKERS

III
ANTI OXIDANT OXIDATIVE STRESS

FIGURE 2 ADIPONECTIN WITH ITS CARDIOPROTECTIVE PROPERTIES

Ouchi et al 2000-2001, Yamauchi et al 2001-2003, Arita et al 2002 Kobayashi et al 2004, IIIustrated : Tjokroprawiro 2007-2011

Hipertensi pada diabetes

Dasar Cardioprotective

2/3 penderita diabetes menderita hipertensi Diabetes + hipertensi meningkatkan risiko:

risiko penyakit jantung, stroke, gangguan mata dan gangguan ginjal

Risk of complications
Benefits of lowering HbA1c

Dasar Cardioprotective

of complications

16 12 8 4 0

Relative Risk

10

11

12

Adapted from UKPDS 33: Lancet 1998;352:837-853. Adapted from DCCT Study Group. N Engl J Med 1993;329:977.

Hemoglobin HbA1c (%) 210 240 270 300

Average Glucose mg/dl

120

150

180

Dasar Cardioprotective

Results from UKPDS: Lowering HbA1c Reduces the Risk of Complications

HbA1c
1% reduces A1C

-21%

Deaths related to diabetes

-37%

Microvascular complications

-14%

Myocardial infarction

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

49

15

T2DM guidelines focus on glycaemic control and CVD risk factors

Dasar Cardioprotective

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 factors is 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 J 2007;28:88136.

50

The Combination of Glimepiride and Metformin

Glimepiride improves beta-cell function and increases insulin synthesis and release.

Beta-Cell Dysfunction

Insulin Resistance

Metformin has insulinsensitizing properties.

Glimepiride reduces HGO through suppression of glucagon from alpha cells.

Metformin decreases HGO by targeting the liver to decrease gluconeogenesis and glycogenolysis.

Hepatic Glucose Overproduction (HGO)

51
53

Combination Cardioprotective

METFORMIN Mode of Action

Combination Cardioprotective

Liver

Skeletal muscle
Improves periphral glucose uptake (probably a secondary effect of decreasing glucose toxicity)

Gut
Decreases appetite and caloric intake; may decrease intestinal glucose absorption

Pancreas
May improve insulin secretion (probably a secondary effect of decreasing glucotoxicity)

Fat
Improves periphral glucose uptake (probably a secondary effect of decreasing glucose toxicity); may decrease lipolysis

Decreases hepatic glucose production (gluconeogenesis)

Mode of Action
Stimulation of glucose uptake Suppression of excessive hepatic glucose production Reduced intestinal glucose absorption
Hundal RS and Inzucchi SE. Drugs 2003; 63 (18): 1879-1894.

53
50

Combination Cardioprotective

Vascular benefits of metformin

Improved
Insulin sensitivity Fibrinolysis Nutritive capillary flow Haemorrheology Postischaemic flow

Reduced
Hypertriglyceridaemia AGE formation Cross-linked fibrin Neovascularisation Oxidative stress

Reduced cardiovascular risk

 AMPK -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

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

1 INSULIN RESISTANCE

56 FOXO1/ FABP4

METFORMIN MIRACLE 56 EFFECTS

2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26

1 h PP ( PmH) 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 Hyperinsulinemia

FIGURE-4 MET with 56 Metabolic-Cardiovascular-Carner (MMC) Protective Effects

(MMC : Metabolic Cardiovascular Cancer protector IIIustrated : Tjokroprawiro 1994-2011

Metformin* should be uptitrated over 1-2 months

Begin with

Combination Cardioprotective

INITIATE

500 mg x1 or x2, or 850 mg x1 5-7 days

1 to 2 months

TITRATE

If well tolerated, advance dose to

850mg x2, or 1,000mg x2

If GI side effects, decrease to previous lower dose and try to advance the dose at a later time

Maximum effective dose:

MAX DOSE

Most often 850 mg x2 Can be up to 1,000 mg x2 Modest benefit up to 2,500mg

If GI side effects, decrease to previous lower dose and try to advance the dose at a later time

*Longer-acting formulation can be given once per day Adapted from Nathan DM, et al. Diabetes Care 2009;32:193-203.

56

Attributes of metformin

Combination Cardioprotective

Decreases hepatic glucose output How it works Expected HbA1c reduction Adverse events Lowers fasting glycemia

1 to 2% (monotherapy)
GI side effects Lactic acidosis (extremely rare)

Weight effects
CV effects

Weight stability or modest weight loss

Demonstrated beneficial effect in UKPDS which needs to be confirmed

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

57

Combination Cardioprotective

Memacu sekresi insulin

Combination Cardioprotective

Metabolik

Pengendalian Kadar glukosa darah

Meningkatkan Afinitas Reseptor-Insulin

SULFONILUREA
Mencegah angiopati membersihkan radikal bebas Memperbaiki fungsi trombosit Memacu fibrinolisis

Vaskuler

MEKANISME KERJA SULFONILUREA

K - ATP Channel
glimipiride SU lain 140 kDa
reseptor SU 65 kDa

K+
Depolarisasi

Ca++

Berikatan dengan reseptor 65 kDa Pengeluaran K+ dihambat

_
Metabolism

[Ca++]i
Glukosa & Asam Amino

Sel beta pankreas

K+

Depolarisasi
Saluran Ca++ terbuka

[ATP] [ADP]

cAMP + ADP

Pro-insulin

[Ca++] intrasel meningkat

Sekresi insulin

Sekresi Insulin

Combination Cardioprotective

(Generasi ketiga terbaru)

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 <
Makin efektif Potensi ekstra pankreas > efektif
Kerja cepat & bertahan lama Dosis kecil

Metabolit > aktif

Combination Cardioprotective

Glimepiride as a Unique Dual Mode of Action

Glimepiride
The first and only antidiabetic drug with a dual mode of action

Insulin secretion

Insulin resistance

Sonnenberg GE et al. Ann Pharmacother 1997; 31: 671-676. Weitgasser R et al. Diabetes Res Clin Pract 2003; 61: 13-19.

62
24

GLUT 4 (Glucose transporters 4) and insulin action

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

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

Combination Cardioprotective

Ischemic Preconditioning (IP)

IP adalah suatu mekanisme endogen jantung untuk melindungi dirinya dari suatu kejadian iskemi yang mematikan (parah)

Oklusi/hambatan yang berkepanjangan pada arteri epicardial akan menyebabkan infark miokard

singkat dan berulang-ulang pada pembuluh darah yang sama menyusul oklusi yang berkepanjangan akan menghasilkan luas infark yang lebih kecil

IP terjadi jika kanal/saluran KATP di jantung terbuka secara otomatis menyusul kejadian Oklusi/hambatan yang iskemik miokard yang singkat

Obat-obatan yang menghambat terbukanya KATP di jantung dapat membahayakan kondisi iskemik miokard (ischemic preconditioning)

.Bbrp Sulfonilurea kerja pd kanal KATP pankreas / jantung. .Glimepiride bekerja selektif pada kanal KATP di pankreas

SUR 2

SUR 1

Kanal KATP, sebuah kompleks yang terdiri dari reseptor sulfonilurea (SUR2A, SUR1) dan kanal kalium (Kir6.2) adalah kunci untuk pelepasan insulin dari sel pankreas yang diperantarai glukosa

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

Atherosclerosis

Visceral Obesity

ADIPONECTIN RAISER TABLE 1 AMARYL : ITS EFFECTS INCLUDING

The 3rd Gen. of SU with CARDIOMETABOLIC Effects

3B

3A

9D

Rapid B inding to Rec.

Low A ffinity to Rec.

Rapid D issociation to Rec

RAPID ACTION

LESS HYPOGLIKEMIA LESS WEIGHT GAIN

IV GLYCOGEN SYNTHESIS

CARDIOPROTECTIVE EFFECTS GLIM : No Effect at CV KATP-Channels -Reduced Coronary Bloood Flow -Proarrythmogenic Effects GLIM : (NE, 5HT, KCL, PGF2)
V INHIBITS PLATELET AGGREGATION

II

III

INSULIN MIMETIC EFFECT

VI ADIPONECTIN - RAISER

VIII OSTEOBLAST

VII

TFN-REDUCER

Efficacy as a combination therapy

Regimen
Sulfonylurea + metformin Sulfonylurea + rosiglitazone Sulfonylurea + pioglitazone Sulfonylurea + acarbose Repaglinide + metformin Pioglitazone + metformin Rosiglitazone + metformin Dipeptidyl peptidase 4 inhibitor + metformin Dipeptidyl peptidase 4 inhibitor + pioglitazone

HbA1c reduction (%)

1.7 (16) 1.4 (18) 1.2 (19) 1.3 (20) 1.4 (17) 0.7 (21) 0.8 (22) 0.7 (23) 0.7 (23)

46

Closing Remark

Basal insulin once daily (treat-totarget) Lifestyle + Metformin

Basal plus Basal + 1 prandial

Basal plus Basal + 2 prandial

Basal bolus Basal + 3 prandial

SU
HbA1c 7.0%
HbA1c 7.0%, FBG on target PPG 160 mg/dL

Time

Progressive deterioration of -cell function

Insulin secretionThe NEJM, Vol. 342 : 145-153, 50%Jan 70
2000

Diabetes Mellitus

Closing Remark

Accelerated DISLIPIDEMI OVERWEIGHT Atherosclerosis HIPERTENSI

DM

PJK

GLIMIPIRIDE METFORMIN

CARDIOPROTECTIVE

The NEJM, Vol. 342 : 145-153, Jan 2000