Management Diabetik Terkini

More Effective Glycaemic Control Turning Theory into Practice

Dr. I Gede Palgunadi, Sp.PDDr. I Gede Palgunadi, Sp.PDSMF Penyakit Dalam RSUD MataramSMF Penyakit Dalam RSUD Mataram

Current and Projected Prevalence

Rates for Diabetes80

0

10

20

30

40

50

Africa Americas EasternMediterranean

Europe SoutheastAsia

Est

imat

ed P

reva

len

ce (

mil

lio

ns) 1995 2000 2025

60

70

WesternPacific

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.

50 Million

100 Million

150 Million

200 Million

250 Million

110,5

140

175,4

239,3

1994 1997 2000 2003

2,5

1994

3

1997

4

2000

5

2003

1 Mill

2 Mill

3 Mill

4 Mill

5 Mill

ESTIMATE DIABETES IN INDONESIA

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

Country 1995 (millions) Country 2025 (millions)

Rank

1 India 19.4 India 57.2

2 China 16.0 China 37.6

3 U.S. 13.9 U.S. 21.9

4 Russian Fed. 8.9 Pakistan 14.5

5 Japan 6.3 Indonesia 12.4

6 Brazil 4.9 Russian Fed. 12.2

7 Indonesia 4.5 Mexico 11.7

8 Pakistan 4.3 Brazil 11.6

9 Mexico 3.8 Egypt 8.8

10 Ukraine 3.6 Japan 8.5

All other countries 49.7 103.6

Total 135.3 300.0

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

• Diabetes tidak bisa sembuh namun dapat dikendalikan • Pada saat diagnosis, sebagian DM tipe 2 sudah mengalami komplikasi

• Perubahan telah terjadi 5 – 12 tahun sebelum diagnosis ditegakkan

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

Perkembangan DM Tipe 2

DM Tipe 2

Adapted from Diabetes 1996;45:1661

Resistensi Insulin

Resistensi insulin

Hiperinsulinemia

Toleransi glukosa normal

Kegagalan fungsi sel Beta

Resistensi insulin

Penurunan kadar insulin

Gangguan toleransi glukosa

Diabetes Obes Metab 1999; 1(1): S1

Sensitivitas Insulin Sekresi Insulin

T2DM30% 50%50%

Impaired glucose metabolism

70% 150%150%

Normal glucose metabolism100% 100%100%

IGT50% 70-100%70-100%

Perjalanan Alami DM Tipe 2

ABNORMALITAS METABOLIK DM TIPE 2

OTOT

Jar. Lemak

Penurunan Penggunaan Glukosa Perifer

Penurunan Penggunaan Glukosa Perifer

PANKREASHATI

Peningkatan Produksi Glukosa Hepar

Kegagalan Fungsi Sel Beta

DM tipe 2

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

Insulin resistance

Glucose uptake Glucose oxidation

Lipolysis Free fatty acid

Glucose uptake Glucose production

VLDL synthesis

HyperinsulinemiaHyperglycemiaDyslipidemia

EFEK RESISTENSI INSULIN

Cardiovascular disease

Interrelation Between Atherosclerosis and Insulin Resistance

HypertensionHypertension

ObesityObesity

HyperinsulinemiaHyperinsulinemia

DiabetesDiabetes

HypertriglyceridemiaHypertriglyceridemia

Small, dense LDLSmall, dense LDL

Low HDLLow HDL

HypercoagulabilityHypercoagulability

InsulinInsulinResistanceResistance

AtherosclerosisAtherosclerosis

STRATEGI TERAPI DM TIPE 2

Pengelolaan :Hiperglikemia

Hiperinsulinemia / Resistensi Insulin Dislipidemia

Komplikasi Mikrovaskuler

Komplikasi Makrovaskuler

Mencegah terjadinya

Prinsip Dasar Terapi Diabetes Mellitus

2

PENGATURAN MAKAN

3

LATIHAN OBAT - OBATAN

4

1

PENYULUHAN

1. Mengurangi resistensi insulin : derivat biguanide dan thiazolidinedione

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

3. Stimulasi sekresi insulin : sulfonilurea, antagonis -2 adrenergik

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

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

6. Memberikan suplementasi insulin basal : glukagon like-peptide I (GLP-I), insulin secretagogue non-sulfoilurea (meglitinide, repaglinide)

Berdasarkan titik tangkapnya telah dikembangkan berbagai obat dengan khasiat sebagai berikut :

MEKANISME KERJA OHO

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

Hyperglycemia

GLUCOSE ABSORPTION

alpha-glucosidase inhibitors

INTESTINE

PANCREAS

INSULIN SecretionSulphonylurea (SU)

Non-SU : Meglitinides & Nateglinide

GLUCOSE PRODUCTION

BiguanidesBiguanidesThiazolidinedionesThiazolidinediones

LIVER MUSCLE

PERIPHERAL GLUCOSE UPTAKEThiazolidinedionesThiazolidinediones

BiguanidesBiguanides

ADIPOSE TISSUE

1. Menurunkan absorpsi karbohidrat • Acarbose• Metformin

2. Meningkatkan sekresi insulin (Insulin Secretagogues)• 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, gliclazide, gliquidone, glimepirid

OHO di Indonesia

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 penderita DM tipe 2

Menurunkan morbiditas/ mortalitas kardiovaskuler

dan mikrovaskuler

KRITERIA PENGENDALIAN DMKonsensus PERKENI 2002

Gula Darah Puasa

Gula Darah 2 JSM

HbA1C (%)

Kolesterol Total

Kolesterol LDL

Kolesterol HDL

Trigliserida

BMI

Tekanan Darah

80 - 109

80 - 144

< 6,5

< 200

< 130

> 45

< 150

18,5 - 22,9

< 130 / 80

BAIK

110 - 125

145 - 179

6.5 - 8

200 - 239

100 - 129

150 - 199

23 - 25

130-140/ 80-

90

SEDANG

> 126

> 180

> 8

> 240

> 130

> 200

> 25

> 140 / 90

BURUK

TARGETS FOR GLYCEMIC TARGETS FOR GLYCEMIC CONTROLCONTROL

ADAADA11

IDF (Europe)IDF (Europe)22

HbA1c%HbA1c% FPG mmol/LFPG mmol/L

< 7< 7 < 6.7 (120)*< 6.7 (120)*

<< 6.5 6.5 << 6.0 6.0 (110)*(110)*

*mg/dl*mg/dl

11Diabetes Care 1999;22(Suppl 1):S1-S114. Diabetes Care 1999;22(Suppl 1):S1-S114. 22Diabetic Medicine 1999;16:716-30Diabetic Medicine 1999;16:716-30

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

EVERY 1% EVERY 1% reduction in A1Creduction in A1C

REDUCED REDUCED RISK*RISK*

Deaths from diabetesDeaths from diabetes

Heart attacksHeart attacks

Microvascular complicationsMicrovascular complications

Peripheral vascular disordersPeripheral vascular disorders

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

LESSONS FROM UKPDS:BETTER CONTROL MEANS FEWER COMPLICATIONS

-37%-37%

-43%-43%

*p<0.0001*p<0.0001

-14%-14%

-21%-21%

1%1%

Treatment algorithm for type 2 diabetes

Aim

Improved control

Diet, exercise, health education

Oral combinations

Insulin

Insulin plus oral agents

Sulphonylurea, metforminGlucosidase InhibitorsGlitinidesThiazolidinediones

Stepped management of type 2 diabetesThis is illogical in most cases of diabetes where there is both 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

Control of Insulin resistance, Hyperinsulinemia, Obesity,

Dyslipidaemia, Hypertension, Procoagulant State

Microvascular Disease

Macrovascular Disease

Normal IFG IGT + Obesity Dx T2DM Progression ofT2DM

Insulin Concentration

-Cell Failure

Euglycaemia

Hyperg

lycaemia

Dual Defect of Type 2 Diabetes : Treating a Moving Target

-cellDysfunction

InsulinResistance

Type 2Diabetes

Insulin Resistance

Insulin Action

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

Sulphonylureas

Metformin

Meglitinides

TZDs -glucosidaseinhibitors

AcarboseMiglitolVoglibose

RosiglitazonePioglitazone

GlipizideGliclazideGlimepirideGlibenclamide

RepaglinideNateglinide

Combination therapy and the dual endocrine defect of type 2 diabetes

1Sulphonylurea or meglitinide ; TZD: thiazolidinedione ; AGI: -glucosidase inhibitor

Metformin + insulin secretagogue1

Metformin + TZD

Metformin + AGI

Sulphonylurea + TZD

Sulphonylurea + AGI

TZDs + AGI

Insulinresistance

β-celldeficiency

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

Any diabetes-related complication

Diabetes deaths

Myocardial infarction

Stroke

Microvascular complications

Retinal photocoagulation

Clinical endpoints

aCompared with conventional diet-based therapy (overweight patients)

UKPDS 34. Lancet 1998;352:854-65

riska

32%

42%

39%

41%

29%

31%

p

0.002

0.017

0.01

0.13

0.19

0.17

Metformin therapy

Metformin and myocardial infarction

Follow-up 3 years

Clinical endpoints (%)

Reinfarction Symptoms of angina Acute cardiovascular eventsFatalities

Controls(n=123)

8.910.6 6.510.3

Metformin(n=187)

1.64.84.08.0

Diabetic 34% / IGT 52% / Normal 14%

Sgambato et al. Clin Ter 1980;94:77-85

Kontrol Metabolik Metformin pada DM Tipe 2

Metformin

Glucose uptake & utilisation

Muscle

Glucose uptake

VLDL synthesis

Liver

Fat storage Lipolysis Free fatty acids

Adipose

EuglycaemiaNormolipidaemia

Metformin: multiple mechanisms for vascular protection

Insulin sensitivity Fibrinolysis Nutritive capillary flow Haemorrheology Postischaemic flow

Metformin addresses CV risk by a range of direct and indirect mechanisms

Improved Reduced Hypertriglyceridaemia AGE formation Crosslinked fibrin Neovascularisation Oxidative stress

Reduced cardiovascular risk

100100

ß C

ell f

unct

ion

(%)

ß C

ell f

unct

ion

(%)

Glycated haemoglobinGlycated haemoglobin

ß Cell functionß Cell function

InsulinInsulinLifestyle Monotherapy Dual Lifestyle Monotherapy Dual ± oral drugs± oral drugs

Therapy for loweringTherapy for lowering Blood glucoseBlood glucose

99

88

77

66

55

Gly

cate

d ha

emog

lobi

n (%

)G

lyca

ted

haem

oglo

bin

(%)

>15>150000

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

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 metforminLifestyle counselling and metformin

Add sulfonylurea or or thiazolidinedione or basal insulinAdd sulfonylurea or or thiazolidinedione or basal insulin

Metformin +Metformin +Sulfonylurea +Sulfonylurea +Basal insulinBasal insulin

Metformin +Metformin +ThiazolidenedioneThiazolidenedione

+ sulfonylurea + sulfonylurea OrOr

Metformin +Metformin +ThiazolidinedioneThiazolidinedione

+ basal insulin+ basal insulin

IntensifyIntensifyInsulinInsulin

TherapyTherapy

Intensive insulin + metformin Intensive insulin + metformin ± thiazolidinedione± thiazolidinedione

GlycatedGlycatedHaemoglobin Haemoglobin ≥ 7%≥ 7%

Goal of treatment should be a glycated haemoglobin value as close to the non-diabeticGoal of treatment should be a glycated haemoglobin value as close to the non-diabeticRange (<6,1%) as possible; treatment should be started or changed if the value is Range (<6,1%) as possible; treatment should be started or changed if the value is ≥ 7%≥ 7%Choose the most effective regimen (metformin plus insulin) if glycated haemoglobin is > 8,5%Choose the most effective regimen (metformin plus insulin) if glycated haemoglobin is > 8,5%Insuli can be started at any poit in the course of diabetes, including at the time of diagnosisInsuli can be started at any poit in the course of diabetes, including at the time of diagnosisInsulin treatment (plus metformin) is generally preferred to three oral agent as it is at least Insulin treatment (plus metformin) is generally preferred to three oral agent as it is at least As effective in lowering glycamia and is much cheaper.As effective in lowering glycamia and is much cheaper.

GlycatedGlycatedHaemoglobin Haemoglobin ≥ 7%≥ 7%

BMJ 333; 9 Des.2006.BMJ 333; 9 Des.2006. Management of hyperglycaemia in type 2 diabetes 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 berpengaruh terhadap perkembangan komplikasi vascular diabetik

• Setiap terapi DM tipe 2 haruslah selalu mengingat pada perbaikan resistensi insulin

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