Management Diabetik Terkini

Dr. I Gede Palgunadi, Sp.PD SMF Penyakit Dalam RSUD Mataram

More Effective Glycaemic Control Turning Theory into Practice

Estimated Prevalence (millions)

Current and Projected Prevalence Rates for Diabetes 80

1995

2000

2025

70 60 50 40 30 20 10 0

Africa

Americas

Eastern Mediterranean

Europe

Southeast Asia

Western Pacific

World Health Organization. World Health Report 1997: Message from the Director-General. Available at www.who.int/whr/1997/message.pdf. Accessed November 8, 2002.

ESTIMATE DIABETES IN INDONESIA 239,3

250 Million 200 Million 150 Million

175,4 140 110,5

100 Million

5

5 Mill

4

4 Mill 3 Mill

50 Million

2,5

3

2 Mill 1 Mill

1994

1997

2000

2003

19 94

19 97

20 00

20 03

Top ten countries for estimated number of adults with diabetes, 1995 and 2025 Country

1995 (millions)

Rank 1 India 2 China 3 U.S. 4 Russian Fed. 5 Japan 6 Brazil 7 Indonesia 8 Pakistan 9 Mexico 10 Ukraine All other countries

19.4 16.0 13.9 8.9 6.3 4.9 4.5 4.3 3.8 3.6 49.7

Total

135.3

Country

2025 (millions)

India China U.S. Pakistan Indonesia Russian Fed. Mexico Brazil Egypt Japan

57.2 37.6 21.9 14.5 12.4 12.2 11.7 11.6 8.8 8.5 103.6 300.0

DEFINISI ADA 2003 • Diabetes mellitus adalah sekelompok penyakit metabolik ditandai hiperglikemia, karena defek sekresi insulin, kerja insulin, atau keduanya • Gangguan kronik – jangka panjang dan berhubungan erat dengan kerusakan organ tubuh tertentu, mis : mata, ginjal, saraf, jantung serta pembuluh darah

Makna : • Kronik – tidak dapat sembuh • Progresif • Untuk mencegah komplikasi perlu dicegah hiperglikemia

Klasifikasi diabetes mellitus 1. DM tipe 1 : kerusakan sel beta karena sebab (a) imunologis (b) idiopatik 2. DM tipe 2 : karena resistensi insulin yang dominan (dengan defisiensi insulin relatif) sampai gangguan sekresi sel beta dengan resistensi insulin 3. DM tipe lain : a, b, c, d, e, f, g, h 4. Gestational DM •Diabetes tidak bisa sembuh namun dapat dikendalikan •Pada saat diagnosis, sebagian DM tipe 2 sudah

Perkembangan DM Tipe 2 Resistensi Insulin

Kegagalan fungsi sel Beta

Resistensi insulin Hiperinsulinemia Toleransi glukosa normal Resistensi insulin Penurunan kadar insulin Gangguan toleransi glukosa

DM Tipe 2 Adapted from Diabetes 1996;45:1661

Perjalanan Alami DM Tipe 2 Sensitivitas Insulin

Sekresi Insulin

30%

T2DM

50%

50%

IGT

70-100%

70%

Impaired glucose metabolism

150%

100%

Normal glucose metabolism

100%

Diabetes Obes Metab 1999; 1(1): S1

ABNORMALITAS METABOLIK DM TIPE 2 HATI

PANKREAS

Peningkatan Produksi Glukosa Hepar

DM tipe 2

Kegagalan Fungsi Sel Beta

Jar. Lemak OTOT

Penurunan Penggunaan Glukosa Perifer

Penurunan Penggunaan Glukosa Perifer

RESISTENSI INSULIN  Definisi

:

kegagalan terhadap efek fisiologi insulin, termasuk terhadap metabolisme glukosa, lipid, protein, serta fungsi endotel vaskuler  Defek

utama pada sebagian besar DM tipe 2

Diab Care 1999;22:562 Diab Care 2000; 23(Suppl 1):54

EFEK RESISTENSI INSULIN Glucose uptake ↓ Glucose oxidation ↓

Insulin resista nce

Lipolysis ↑ Free fatty acid ↑

Glucose uptake ↓ Glucose production ↑ VLDL synthesis

Hyperinsuli nemia Hyperglyce mia Dyslipidemi a

Cardiovasc ular

Interrelation Between Atherosclerosis and Insulin Resistance Hypertension Obesity Hyperinsulinemia

Insulin Resistance

Diabetes Hypertriglyceridemia Small, dense LDL Low HDL Hypercoagulability

Atherosclerosis

STRATEGI TERAPI DM TIPE 2 Pengelolaan : Hiperglikemia Hiperinsulinemia / Resistensi Insulin Dislipidemia Mencegah terjadinya

Komplikasi Mikrovaskuler Komplikasi Makrovaskuler

Prinsip Dasar Terapi Diabetes Mellitus 1

2

PENYULUHAN 3

PENGATURAN MAKAN 4

LATIHAN

OBAT - OBATAN

•

Berdasarkan titik tangkapnya telah dikembangkan berbagai obat dengan khasiat sebagai Mengurangi resistensi insulin : derivat biguanide dan thiazolidinedione berikut :

•

Mengubah metabolisme asam lemak : menghambat keluarnya NEFA, penghambat oksidasi asam lemak

•

Stimulasi sekresi insulin : sulfonilurea, antagonis α-2 adrenergik

•

Penghambat naiknya glukosa post prandial : guar gum, α-glukosidase inhibitor, α-amylase inhibitor

•

Mengurangi berat badan : bahan anorektik, β-3 agonist, antagonis neuropeptide Y

•

Memberikan suplementasi insulin basal : glukagon like-peptide I (GLP-I), insulin secretagogue nonsulfoilurea (meglitinide, repaglinide)

MEKANISME KERJA OHO ADIPOSE TISSUE

LIVER

GLUCOSE PRODUCTION

MUSCLE

PERIPHERAL GLUCOSE UPTAKE

Biguanides Thiazolidinediones

Hyperglycemia

Thiazolidinediones Biguanides

PANCREAS INTESTINE alpha-glucosidase inhibitors GLUCOSE ABSORPTION

INSULIN Secretion

Sulphonylurea (SU) Non-SU : Meglitinides & Nateglinide

Sonnenberg and Kotchen. Curr Opin Nephrol Hypertens 1998;7(5):551–5

OHO di Indonesia 1.Menurunkan absorpsi karbohidrat • Acarbose • Metformin

• Meningkatkan Secretagogues)

sekresi

insulin

(Insulin

• Sulfonilurea : Glibenclamide, glipizide, gliclazide, gliquidone, glimepirid • Non-Sulfonilurea : Nateglinide, Repaglinide

3.Menurunkan produksi glukosa hepar • Metformin • Thiazolidinediones : Pioglitazone 4. Meningkatkan ambilan glukosa perifer • Thiazolidinediones : Pioglitazone • Metformin • Sulfonilurea : Glibenclamide,

glipizide,

Obat Anti-hiperglikemia Oral Yang Ideal • Dapat mengontrol gula darah puasa & 2 jam SM • Tidak ada risiko hipoglikemia • Mempunyai dampak yang menguntungkan pada parameter lipid • Aman dan dapat ditoleransi dengan baik Pemberian sederhana • Dapat digunakan oleh semua

KRITERIA PENGENDALIAN DM Konsensus PERKENI 2002

BAIK

SEDANG

BURUK

Gula Darah Puasa

80 - 109

110 - 125

> 126

Gula Darah 2 JSM

80 - 144

145 - 179

> 180

< 6,5

6.5 - 8

>8

Kolesterol Total

< 200

200 - 239

> 240

Kolesterol LDL

< 130

100 - 129

> 130

Kolesterol HDL

> 45 < 150

150 - 199

> 200

BMI

18,5 - 22,9

23 - 25

> 25

Tekanan Darah

< 130 / 80

130-140/ 80-

> 140 / 90

HbA1C (%)

Trigliserida

TARGETS FOR GLYCEMIC CONTROL HbA1c%

FPG mmol/L

ADA1

<7

< 6.7 (120)*

IDF (Europe)2

< 6.5

< 6.0 (110)*

*mg/dl

Diabetes Care 1999;22(Suppl 1):S1-S114. 2Diabetic Medicine 1999;16:716-30

1

What level of glycaemic control should we aim for ? 

  

Untuk menurunkan komplikasi mikrovaskuler  HbA1c harus senormal mungkin Awas hipoglikemia ! ! ! HbA1c normal 6.1% PERKENI HbA1c menganjurkan  < 7% (Sesuai konsensus ADA).

BMJ 333; 9 Des. 2006

LESSONS FROM UKPDS: BETTER CONTROL MEANS FEWER COMPLICATIONS EVERY 1% reduction in A1C

REDUCED RISK*

Deaths from diabetes

-21%

Heart attacks

1%

-14%

Microvascular complications Peripheral vascular disorders

UKPDS 35. BMJ 2000; 321: 405-12.

-37%

-43% *p<0.0001

Treatment algorithm for type 2 diabetes Aim

Diet, exercise, health education Sulphonylurea, metformin Glucosidase Inhibitors Glitinides Thiazolidinediones

Oral combinations Insulin Improved control

Insulin plus oral agents

Stepped management of This is illogical in most cases of diabetes where there is both type 2 diabetes insulin deficiency and resistance

UKPDS shows diet therapy alone worsens pancreatic function in 356 patients by 50% in 6 years

Treatment Priority of Type 2 DM Glucose control as near to normal as reasonably possible

Microvascular Disease

Control of Insulin resistance, Hyperinsulinemia, Obesity, Dyslipidaemia, Hypertension, Procoagulant State

Macrovascular Disease

Defect of Type 2 Diabetes : Treating a Moving T Insulin Resistance

β-cell Type 2 Diabetes Dysfunction

ia

Ins

em a c

uli

y gl r e yp

β-Cell Failure

nA

cti

on

H

Insulin Concentration

Insulin Resistance Euglycaemia Normal IFG IGT + Obesity

Dx T2DM

Progression of T2DM

Lifestyle change: an option? 



The potentially most efective but most dificult ! Chochrane analysis  no high quality data to support the efectiveness of dietary treatment.

BMJ 333; 9 Des. 2006

Rationale for Early Combination Therapy Pathophysiology – dual defects Glycaemic burden – FPG and PPG Monotherapy targets one defect and HbA1C < 7.0% seldom achieved Diabetes is progressive – durable control means multiple therapies Switch to combined therapy after ‘treatment failure’ leads to excessive hyperglycaemic exposure

Choice of agents in current use Glipizide Gliclazide Glimepiride Glibenclamide

TZDs

Sulphonylureas

Metformin

Acarbose Miglitol Voglibose

α-glucosidase inhibitors

Meglitinides Rosiglitazone Pioglitazone

Repaglinide Nateglinide

Combination therapy and the dual endocrine defect of type 2 diabetes

Metformin + insulin secretagogue1 Metformin + TZD Metformin + AGI Sulphonylurea + TZD Sulphonylurea + AGI TZDs + AGI 1

Insulin resistance

β-cell deficiency

     

     

Sulphonylurea or meglitinide ; TZD: thiazolidinedione ; AGI: α-glucosidase inhibitor

Is metformin still the first line drug? 



Metformin  biguanide yg diterima secara luas sbg first line drug. Safe, effective, dan murah. Menurunkan resiko penyakit kardiovaskuler pada pasien obese dengan DM type 2.

Metformin: foundation therapy for prevention of type 2 diabetes and its complications 

Reduced morbidity and mortality in the UKPDS –

Unique reduction of cardiovascular complications beyond that expected from blood glucose control



IDF and ADA guidelines favour the use of metformin as foundation therapy for type 2 diabetes where possible



The antihyperglycaemic efficacy of metformin is dose-related with an optimal daily dose of 2000 mg/day



Metformin is well tolerated across its dosage range



–

Gastrointestinal side-effects are usually transient

–

Minimised by slow dosage titration

–

Only about 5% of patients cannot tolerate metformin

Proven to prevent or delay type 2 diabetes (DPP)

UKPDS clinical outcomes for metformin Clinical endpoints

Metformin therapy ∆ riska

p

Any diabetes-related complication

↓ 32%

0.002

Diabetes deaths

↓ 42%

0.017

Myocardial infarction

↓ 39%

0.01

Stroke

↓ 41%

0.13

Microvascular complications

↓ 29%

0.19

Retinal photocoagulation

↓ 31%

0.17

a

Compared with conventional diet-based therapy (overweight patients) UKPDS 34. Lancet 1998;352:854-65

Metformin and myocardial infarction

Clinical endpoints (%) Reinfarction Symptoms of angina Acute cardiovascular events Fatalities

Controls (n=123)

Metformin (n=187)

8.9 10.6 6.5 10.3

1.6 4.8 4.0 8.0

Diabetic 34% / IGT 52% / Normal 14% Follow-up 3 years Sgambato et al. Clin Ter 1980;94:77-85

Kontrol Metabolik Metformin pada DM Tipe 2 Muscle

Glucose uptake & utilisation 

Adipose Fat storage  Lipolysis  Free fatty acids 

Metformin

Euglycaemia Normolipidaemia

Liver Glucose uptake  VLDL synthesis 

Metformin: multiple mechanisms for vascular protection Metformin addresses CV risk by a range of direct and indirect mechanisms

Improved     

Insulin sensitivity Fibrinolysis Nutritive capillary flow Haemorrheology Postischaemic flow

Reduced     

Hypertriglyceridaemia AGE formation Crosslinked fibrin Neovascularisation Oxidative stress

Reduced cardiovascular risk

Lifestyle

Monotherapy

Dual Therapy

Insulin ± oral drugs for lowering Blood glucose

9 8 7 6

Glycated haemoglobin

5

ß Cell function

0 0

>15

Traditional treatment strategy for type 2 diabetes and its consequences. In type 2 Diabetes ß cell function declines over the years, irrespective of treatment with metformin, Sulfonylurea (as monotherapy or dual therapy), or insulin. Treatment therefore has to be Adjusted at regular intervals according to the level of glycaemia. Because doctor and patient Recurrently fail to reach target. BMJ 333; 9 Des 2006.

Glycated haemoglobin (%)

ß Cell function (%)

100

Sulfonylurea, thiazolidinedion, or insulin ? add to metformin ! 



Insulin ditambahkan bila HbA1C > 8,5% tapi komorbid yang menyertai DM type 2 lebih dipertimbangkan! Bila tidak ada komorbid yang gawat maka kombinasi Su + Met lebih disukai pasien dibandingkan insulin.

BMJ 333; 9 Des. 2006

And then? 3oral agents, insulin as add-on, or insulin alone? 





Kombinasi (Su + Met + Thz) lebih mahal dibandingkan insulin + Met. Bila target HbA1C tak tercapai dg dual terapi  mulai basal insulin atau Intermediate/long acting insulin. Inhaled insulin baru2 ini di US mulai dipakai. Belum tau keberhasilan dan efek samping.

Lifestyle counselling and metformin

Glycated Haemoglobin ≥ 7%

Add sulfonylurea or or thiazolidinedione or basal insulin

Metformin + Metformin + Sulfonylurea +Thiazolidenedione Basal insulin + sulfonylurea Or Metformin + Thiazolidinedione + basal insulin Glycated Haemoglobin ≥ 7%

Intensif y Insulin Therapy

Intensive insulin + metformin ± thiazolidinedione

reatment should be a glycated haemoglobin value as close to the non-diabetic <6,1%) as possible; treatment should be started or changed if the value is ≥ 7% he most effective regimen (metformin plus insulin) if glycated haemoglobin is > the n be started at any poit in the course of diabetes, including at the time of diagno reatment (plus metformin) is generally preferred to three oral agent as it is at le tive in lowering glycamia and is much cheaper. BMJ 333; 9 Des.2006. Management of hyperglycaemia in type 2 diabetes

Obat Baru  





Vildagliptin 50mg/tablet, Sitagliptin, Saxagliptin Bekerja pada sel α & sel ß pankreas suatu DPP-4 inhibitor oral (dipeptidyl peptidase IV). Meningkatkan sekresi insulin dan menurunkan sekresi glukagon obat ini merupakan kandidat sebagai obat pilihan pertama selain regulasi gula darah dan tidak meningkatkan berat badan. Suastika, Konas VII PERSADIA 2008

RINGKASAN • DM tipe 2 merupakan ~95 dari seluruh kasus DM • DM tipe 2 terutama disebabkan oleh resistensi insulin • Adanya resistensi insulin akan berpengaruh terhadap jaringan otot, lemak dan liver dengan akibat terjadinya hiperinsulinemia, hipergikemia dan dislipidemia • Adanya resistensi insulin akan

Summary points 









Initial treatment should consist of lifestyle intervention and metformin Treatment should aim to keep blood glucose concentrations as close to the non-diabetic range as possible The relentless decline of ß cell function requires early intervention, regular monitoring of glycaemia, and prompt adjustment of the (combination of) blood glucose lowering drugs, including insulin Good glycaemia control will reduce the occurrence of inicrovascular and perhaps cardiovascular complications of type 2 diabetes Scientific evidence for any algorithm is largely lacking