METABOLIK SINDROME

Dr. I Gede Palgunadi, Sp.PD

SMF Ilmu Penyakit Dalam RSU Mataram
Disampaikan Pada Acara Siang Klinik Optimal Lipid Management Implementing an effective strategi For patients Sabtu, 24 Maret 2007

Metabolic Syndrome
Clustering of abdominal obesity, dyslipidemia hypertension, and insulin resistence. Defined as any 3 of the following risk factors (ATP III, 2001
Waist Circumference > 102 cm (men) : > 88cm (women) HDL<40mg/dl (men) : <50mg/dl (Women) TG 150 mg/dl Bp 130/ 85mm Hg FgG 110 mg/dl

Clustering Of Abdominal Obesity, dyslipidemia Hypertension, and Insulin Resistance Defined as any 3 of the following risk factors (ATP III 2001) (Asian Modification)
Waist circumference> 90 cm (men) or>80 cm (Women) HDL (<40 mg/dl (men) :<50 mg/dl (women) TG 150 mg/dl Bp 130/ 85 mm Hg FPG 110 mg/d/

Metabolik Syndrome (WHO Definition)

Type 2 DM. Impaired glucose tolerance (IGT) or normal glucose tolerance with insulin resistence together with 2 of the following
- Eleveted blood pressure 140/90 mm/hg - Abdominal obesity and/or BML > 30Kg/m2 WHR >0,9 men >0,8 women - Low HDL cholesterol < 0,9 mmol/2 (men) < 1.0 mmol/2 (women) - High trigly cerides > 1,7 mmol /2 - Microalbuminuria (AER 20 g/min or A/C 20mg/g)

Metabolic Syndrome : Aetiology

Is just a co-incidental clustering of CVD risk factors? Is there are asingle aetological determinant e.g. genetic, insulin resistance, visceral obesity, endothelial dysfunction or inflammation ? Are there multiple determinants ?

CVD morbidity & mortality & the metabolik syndrome (botnia study : 35-70 years)  Metabolik syndrome seen in :
- 10% females & 15% males with NGT (N=1988) - 42% & 86% with IFG/IGT (N=798) - 78% & 84% with type 2 diabetes (N=1697) 3-fold increase risk for CHD stroke in people with metabolik syndrome (P<0.0001) CVD mortality markedly increased in subjects with the metabolik syndrome in 6.9 years follow up (12% < 2.2 %, P<0.001) Mikroalbuminuria confered highest risk of CVD death RR 2.8 P= 0.002)

  

Faktor Risiko Kardiovaskular

Hipertensi SBP 165 mmHg X1.9 X3.5 X2.6 X4.5 X2.3 Dislipidemia TC 210 mg/dL X1.3 Hipertensi SBP 195 mmHg X3 X5.2 Merokok X1.7 X5.3 X8.7 X2.9 Dislipidemia TC 235 mg/dL X1.7

Toleransi glukosa X1.8

Bila 2 atau lebih faktor risiko bergabung, maka risiko terjadinya CV events menjadi lebih besar
Kannel WB. In: Genest J, et al, eds. Hypertension: Physiopathology and Treatment. New York, NY: McGraw Hill;1977:888-910.

Perubahan Fisiologis Terkait Resistansi Insulin (I)

Ganguan toleransi glukosa - Impaired fasting glukose - Impaired glukose tolerance Ganguan metabolisme asam urat - Palsma uric asid concentration - Renal uric acid clearance

Perubahan Fisiologis Terkait resistensi insulin (2)

Perubahan hemodinamik : - Symphotettic nervous system activity - Renal sodium retention - Blood pressure(~50% of patient with hypertention are insulin resistent ) Ganguan hemostatis - Plasminigen activator inhibitor I - Fibrinogen

Disfungsi Endotel : - Mononuclear cell adhesion - Plasma concentration of celular nadhesion molecules - Plasma concentration of acymmetric dimethyl arginine - Endothelial-dependent vosodilation Sistim reproduksi - Polycystic ovary syndrome

The metabolik syndrome Genes & evironment Interecting

ENVIRONMENT

Early Life
- Low birth weight - Poor nutrition

Adult Life
- Sedentory life style - Dietary factor

Metabolik Syndrome

GENES

Cardiovascular disease

The metabolik syndrome :

The epidemic strikes back !!! High social & ekonomic infact
Globalozation Modernization migration Morbidity & Mortality Diabetes & CVD Risk factors Diabesity (Metabolic Syndrome)

Hipertension

Hyperglykemia

Obesity

Dyslipidemia

Microalbuminuria

Metabolik syndrome Intervention/ Control

Atherosclerosis
Cardiovascular disease

Treatment of obesity Multiple risk reducer

Insulin resistence is linded to cardiovascular disease

Hyperglycaemia Hyperinsulinaemia Hypertension Dyslipidaemia

INSULIN RESISTENCE

Decraesed fibrinolitic Octivity ( PAI-1 ) Endothelial dysfunction Inflammatory markers Of a the rosclerosis

Mikroalbuminuria

Gangguan toleransi glukosa berkelanjutan ?

Normal TGT Diabetes Tipe 2 komplikasi kematian

Tahap
Preklinik Klinik Komplikasi

Pencegahan primer

Pencegahan Skunder

Pencegahan Tertier

The Cardiovascular Continuum of

ACS
Secondary prevention Coronary Thrombosis

Events
Stroke

Arrhythmia and Loss of Muscle

Myocardial Ischemia

Remodeling

CAD

Ventricular Dilatation Congestive Heart Failure End-stage Heart Disease

Adapted from Dzau et al. Am Heart J. 1991;121:1244-1263

Atherosclerosis Primary prevention

Risk Factors ( Dyslipidemia, o BP, DM, Dyslipidemia Insulin Resistance, Platelets, Fibrinogen, etc)

Kita Akan Fokus Pada

Secondary prevention Myocardial Ischemia

Why primary prevention ?

CAD

Atherosclerosis Primary prevention

Risk Factors ( Dyslipidemia, o BP, DM, Insulin Resistance, Platelets, Fibrinogen, etc)

Adapted from Dzau et al. Am Heart J. 1991;121:1244-1263

Primary Prevention
Cost-effective Less painful Better quality of life Easier to manage But..
No symptoms (low compliance)  Investment


1. 2. 3. 4.

Total cholesterol > 200 mg/dl HDL-C < 40 mg/dl Triglyceride > 150mg/dl LDL-C:
Faktor Resiko 0-1 2 LDL-C > 160 mg/dl >130 mg/dl > 100 mg/dl

CHD and CHD risk equivalent

NCEP-ATP III Report. JAMA 2001;285:2486-2497

DISLIPIDEMIA
LDL Primary target of therapy Total cholesterol HDL TG

NCEP-ATP III Report. JAMA 2001;285:2486-2497

Atherosclerosis: Penyakit Yang Progresif

Plaque rupture

Monocyte

LDL-C

Adhesion molecule

Macrophage

Oxidized LDL-C Foam cell

CRP

Smooth muscle cells

Endothelial dysfunction

Inflammation

Oxidation

Plaque instability and thrombus

CRP=C-reactive protein; LDL-C=low-density lipoprotein cholesterol. Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126.

Aterosklerosis Dimulai Sejak Usia Muda

Tuzcu EM, Kapadia SR, Tutar E, et al. High Prevalence of Coronary Atherosclerosis in Asymptomatic Teenagers And Young Adults: EvidenceFrom Intravascular Ultrasound. Circulation 2001;103:2705-2710

KERUSAKAN APA SAJA YANG BISA DISEBABKAN OLEH PLAK?

Stroke Coronary artery
Plaque rupture p unstable angina p Myocardial infarction (MI) / heart attack

Pulmonary embolism (PE)

Deep vein thrombosis (DVT)

KERUSAKAN APA SAJA YANG BISA DISEBABKAN OLEH PLAK?

Stroke Coronary artery
Plaque rupture p unstable angina p Myocardial infarction (MI) / heart attack

Pulmonary embolism (PE)

Deep vein thrombosis (DVT)

Atherosclerosis: Penyakit Sistemik

From a prospective analysis of 1886 patients aged u62 years, 810 patients were diagnosed with CAD as defined by a documented clinical history of MI, ECG evidence of Q-wave MI, or typical angina without previous MI. (Adapted from Aronow et al.)

Coronary Artery Disease (CAD): Diagnosa Sering Terlambat

Murabito JM, Evans JC, Larson MG, et al. Prognosis After the Onset of Coronary Heart Disease. An Investigation of Differences In Outcome Between the Sexes According To Initial Coronary Disease Presentation. Circulation 1993;88:2548-2555

Mortality from CVD and CHD in Selected Countries Rate per 100,000 population (men aged 3574 years)
1500

CVD deaths CHD deaths

1000

500

0 Russia Poland Finland New England/ USA Zealand Wales Italy Spain Japan

(Adapted from 1998 World Health Statistics)

Hubungan Level Kolesterol dengan kematian Penyakit Jantung Koroner

18 16 14 12
CHD death 10 rate per 8 1000 men

6 4 2 0 140 160 180 200 220 240 260 280 Serum total cholesterol (mg/dL) 300

Multiple Risk Factor Intervention Trial. LaRosa et al, 1990

Faktor Resiko dan Kematian

Cardiovascular mortality (10,000 person-years)
140 120 100 80 60 40

Diabetics

Non-diabetics
20 0 0 1 2 3

hypercholesterolaemia, smoking, hypertension

Adapted from: Stamler, J. et al., Diabetes Care 1993; 16: 434-44

LDL-C: Primary target of therapy

Risk factor 0-1 u2 CHD and CHD risk equivalent Very high risk LDL-C < 160 mg/dl < 130 mg/dl < 100 mg/dl

70 mg/dl

Total cholesterol < 200 mg/dl  HDL-C > 40 mg/dl  Triglyceride < 150mg/dl

NCEP-ATP III Report. JAMA 2001;285:2486-2497 Grundy SM, et al. NCEP Report. Circulation 2004;110:227-239

Faktor Risiko 0-1 0LDL < 160 mg/dL LDL > 160 mg/dL

Gaya hidup sehat Periksa ulang setiap 1-2th 1Atau 3-5 th bila LDL <130 mg/dL 3-

Cari & obati penyebab sekunder

LDL > 160 mg/dL

Diet, periksa ulang 3 bln LDL 160 189 mg/dL

Teruskan diet, aktifitas fisik Pertimbangkan statin Periksa ulang 3bln

LDL >190 mg/dL

Mulai statin Periksa ulang 3bln

Sasaran: LDL < 160 mg/dL

NCEP-ATP III Report. JAMA 2001;285:2486-2497

Faktor Risiko >2

LDL < 130 mg/dL LDL > 130 mg/dL Gaya hidup sehat Periksa ulang setiap 1-2th 1Cari & obati penyebab sekunder

LDL > 130 mg/dL

Diet, periksa ulang 3 bln LDL 130 159 mg/dL

Teruskan diet, aktifitas fisik Pertimbangkan statin Periksa ulang 3bln

LDL >160 mg/dL

Mulai statin Periksa ulang 3bln

NCEP-ATP III Report. JAMA 2001;285:2486-2497

Sasaran: LDL < 130 mg/dL

Pencegahan Primer Pada Pasien dengan > 2 Faktor Risiko

Mulai dengan obat hipolipidemik
Mulai dengan statin / resin / asam nikotinat, teruskan dengan terapi non farmakologis

6 minggu

Bila sasaran LDL blm tercapai, intensifkan obat hipollipidemik

Tingkatkan dosis statin / + resin / asam nikotinat
6 minggu 6 minggu

Pemantauan respons dan ketaatan berobat

Tiap 4-6 bln 4-

Bila sasaran LDL blm tercapai, intensifkan obat hipollipidemik atau rujuk ke spesialis
Obati faktor rsisiko lipid lainnya (TG / HDL)

NCEP-ATP III Report. JAMA 2001;285:2486-2497

PJK Atau Yang Disamakan

LDL < 100 mg/dL LDL > 100 mg/dL Diet & aktifitas fisik Pertimbangkan statin LDL>130mg/dL LDL>

Gaya hidup sehat Periksa ulang setiap 6-12 bln 6-

Diet, periksa ulang 3 bln

LDL >100 mg/dL

Berikan Statin Periksa ulang 3 bln

Sasaran: LDL < 100 mg/dL

NCEP-ATP III Report. JAMA 2001;285:2486-2497

COMETS Study Design

Patients (n=401) Metabolic syndrome CHD risk >10% Statin nave 18 years Placebo (n=79) RSV 20 mg ATV 10 mg (n=157) ATV 20 mg RSV 10 mg (n=165) RSV 20 mg

Visit: 1 Week: 4

2 2

3 0

4 6

5 12

Dietary run in/ eligibility

Lipids hsCRP Safety

Lipids hsCRP Safety

Lipids hsCRP Safety

COMETS=COmparative study with rosuvastatin in subjects with METabolic Syndrome; CHD=coronary heart disease; RSV=rosuvastatin; ATV=atorvastatin; hsCRP=high-sensitivity C-reactive protein

Stalenhoef AFH et al. Diabetologia 2004;47 (suppl):A4091147

COMETS Change in Lipid Profile at 6 Weeks

20

LSM change from baseline (%)

10 0 10 20 30 40 50 LDL-C
37 *** 43 0.3 ***

9.5

** 5.1*** 1.1 0.7 ***

RSV 10 mg (n=164) ATV 20 mg (n=155) Placebo (n=78)

2.8 ***

0.9 ***

19 28 32 ***

21

35 *** 41

HDL-C

TC

TG

nonHDL-C

ITT

population by as allocated treatment; **P<0.01, ***P<0.001 vs RSV

Stalenhoef AFH et al. Diabetologia 2004;47 (suppl):A4091147

COMETS Achievement of NCEP ATP III LDL-C Goals

100
91 83 * 72 *** 79

Patients at goal (%)

80

60

40

20
n=164 n=155

*** 10 n=78 n=242 n=155

RSV 10 mg

ATV 10 mg

Placebo

RSV ATV combined 10/20 mg

6 weeks

12 weeks

ITT population by as allocated treatment; *P<0.05, ***P<0.001 vs RSV at same time point

Stalenhoef AFH et al. Diabetologia 2004;47 (suppl):A4091147

Potential Benefits of Moderate (5-10%) Weight Loss

Subkutaneus Adipose Tissue
Visceral Adipose Tissue

5-10% Weight loss

23% voceral adivose Tissue loss physical Activity pharmacotheraphy

Blood Preasure Deteriorated lipid profile improved Impaired

Insulin sensitivity Insulinaemia alycaemia

Improved

Susceptibility to thrombosis

Imflamation Markers
Abdominally Obese (Hight Waist Measurement) Hight Risk of coronary heart disease low
Despres JP, BMJ. 2001, 322. 716.20.

Reduced Obesity (Low Waist measure ment)

KESIMPULAN


 

Metabolik sindrom bukan satu penyakit kumpulan fenomena klinis terkait resistensi insulin Metabolik sindrom risiko tinggi PKV Intervensi terhadap metabolik sindrom termasuk penurunan berat badan (perubahan gaya hidup, obat) dapat menunda ataupun mencegah DM tipe 2 serta menurunkan resiko PKV. Pengidap Diabetes mempunyai resiko yg disamakan dg penderita PJK.