Metabolik Sindrome

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 µ g/min or A/C ≥ 20mg/g)

Metabolic Syndrome : Aetiology  

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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 X2.6 X1.9 X3.5

Dislipidemia TC 210 mg/dL X1.3

X4.5 X2.3

Toleransi glukosa X1.8

Hipertensi SBP 195 mmHg X3 X5.2

X5.3 X8.7

Dislipidemia TC 235 mg/dL X1.7 X2.9

Merokok X1.7

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) 

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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) 

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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

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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

Adult Life

- Low birth weight - Poor nutrition

- Sedentory life style - Dietary factor

Metabolik Syndrome Cardiovascular disease

GENES

The metabolik syndrome : 

The epidemic strikes back !!! High social & ekonomic infact Globalozation Modernization migration Morbidity & Mortality

Diabesity (Metabolic Syndrome)

Diabetes & CVD Risk factors

Hipertension

Hyperglykemia

Obesity

Dyslipidemia

Metabolik syndrome Intervention/ Control

Atherosclerosis Cardiovascular disease

Treatment of obesity Multiple risk reducer

Microalbuminuria

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

Myocardial Ischemia

CAD Atherosclerosis Primary prevention

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

Arrhythmia and Loss of Muscle Remodeling

Ventricular Dilatation Congestive Heart Failure End-stage Heart Disease Adapted from Dzau et al. Am Heart J. 1991;121:1244-1263

Kita Akan Fokus Pada… Secondary prevention Myocardial Ischemia

Why primary prevention ?

CAD Atherosclerosis Primary prevention

Risk Factors ( Dyslipidemia, ↑ 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

LDL-C

0-1

> 160 mg/dl

³ 2

>130 mg/dl

CHD and CHD risk equivalent

> 100 mg/dl

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

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.

Plaque instability and thrombus

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 → unstable angina → 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 → unstable angina → Myocardial infarction (MI) / heart attack

Pulmonary embolism (PE)

Deep vein thrombosis (DVT)

Atherosclerosis: Penyakit Sistemik

From a prospective analysis of 1886 patients aged ≥62 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 35–74 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

Cardiovascular mortality (10,000 person-years)

Faktor Resiko dan Kematian 140 120

Diabetics

100 80 60 40

Non-diabetics

20 0 0

1

2

3

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

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LDL-C: Primary target of therapy Risk factor

LDL-C

0-1

< 160 mg/dl < 130

≥ 2 CHD and CHD risk equivalent

mg/dl < 100 mg/dl

Very high risk

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 LDL < 160 mg/dL

LDL > 160 mg/dL

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

Cari & obati penyebab sekunder

LDL > 160 mg/dL

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

LDL >190 mg/dL

• Teruskan diet, aktifitas fisik • Pertimbangkan statin • Periksa ulang 3bln

• Mulai statin • Periksa ulang 3bln

Sasaran: LDL < 160 mg/dL

Faktor Risiko >2 LDL < 130 mg/dL

LDL > 130 mg/dL

Gaya hidup sehat Periksa ulang setiap 1-2th

Cari & obati penyebab sekunder

LDL > 130 mg/dL

Diet, periksa ulang 3 bln

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

LDL 130 – 159 mg/dL

LDL >160 mg/dL

• Teruskan diet, aktifitas fisik • Pertimbangkan statin • Periksa ulang 3bln

• Mulai statin • Periksa ulang 3bln

Sasaran: LDL < 130 mg/dL

Pencegahan Primer Pada Pasien dengan > 2 Faktor Risiko Mulai dengan obat hipolipidemik

6 minggu

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

Tingkatkan dosis statin / + resin / asam nikotinat 6 minggu

Pemantauan respons dan ketaatan berobat

Bila sasaran LDL blm tercapai, intensifkan obat hipollipidemik

Tiap 4-6 bln

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

Gaya hidup sehat Periksa ulang setiap 6-12 bln

LDL > 100 mg/dL

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

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)

RSV 10 mg (n=165)

RSV 20 mg

ATV 10 mg (n=157)

ATV 20 mg

Placebo (n=79)

RSV 20 mg

Metabolic syndrome CHD risk >10% Statin naïve ≥18 years

Visit: 1 Week: –4

2 –2

Dietary run in/ eligibility

3 0

4 6

5 12

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):A409–1147

COMETS – Change in Lipid Profile at 6 Weeks† RSV 10 mg (n=164) ATV 20 mg (n=155) Placebo (n=78)

LSM change from baseline (%)

20 9.5

10 0 –10

** 5.1*** 1.1 –0.7 ***

–0.3 ***

–20

–19

–30 –40

–2.8 ***

–0.9 ***

–21

–28 –32 ***

–35 *** –41

–37 *** –43

–50 LDL-C

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):A409–1147

COMETS – Achievement of NCEP ATP III LDL-C Goals† Patients at goal (%)

100

91 83

80

*** 79

* 72

60 40 20 0

*** 10 n=164

n=155

n=78

RSV 10 mg

ATV 10 mg

Placebo

6 weeks

n=242

n=155

RSV ATV combined 10/20 mg

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):A409–1147

Potential Benefits of Moderate (5-10%) Weight Loss Subkutaneus Adipose Tissue 5-10% Weight loss

Visceral Adipose Tissue

23% voceral adivose Tissue loss physical Activity pharmacotheraphy

Blood Preasure Deteriorated lipid profile improved Impaired

Insulin sensitivity

Improved

Insulinaemia alycaemia

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 

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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.