Metabolic Syndrome

is Related Cardio-cerebro vascular Disease

Dr. Pandji Moeljono,

Sp.PD-KEMD

Spesialis Penyakit Dalam

Konsultan Endokrinologi
Metabolik dan Diabet

FK UWKS
 Metabolic syndrome
Insulin resistance syndrome
Dysmetabolic syndrome
Cardiometabolic syndrome
Dyslipidemic hypertension
Hypertriglycerdemic waist
The deadly quartet.

Nowadays the name metabolic syndrome is generally accepted.

Krans HM., Insulin Resistence and The Metabolic Syndrome, SUMETSU 3, Surabaya, Februari 2007
 Tabel. Definitions of the Metabolic Syndrome
ATP III (American Heart World Health International Diabetes Federation
Association) (2005) Organisation 1999 (2005)

Minimal Any 3 or mor of the Diabetes, IFG, IGT, or Central obesity (see under) + any
requirements following criteria insulin resistance + any 2 or more of the following criteria
2 or more of the
following criteria
Waist In men < 102 cm In men 94 cm
circumference In women < 88 cm In womwn 80 cm
Waist to hip < 0,90 in men
ratio < 0,85 in womwn

Reduced HDL < 1.00 mmol/l in men < 0.90 mmol/l in men < 1.03 mmol/l (40 mg/dl) in men
cholesterol < 1.30 mmol/l in women < 1.00 mmol/l in women < 1.29 mmol/l (50 mg/dl) in women

Elevated > 1.70 mmol/l > 1.70 mmol/l 1.70 mmol/l (150 mg/dl)
Triglycerides
Elevated Blood > 130 / >85 140 / 90 130 / 85
Pressure
Urinary Albumin > 20 mg/min
Excretion
Serum glucose 6.1 (5.6) mmol/l 5.6 mmol/l (100 mg/dl)

ATP III (Expert panel etc, 2001)

American Heart Association (Grundy et al, 2005)
World Health Organisation (World Health Organisation, 1999)
International Diabetes Federation (Alberti et al, 2005)
 Penyakit Akibat Pola Hidup Tidak Sehat : Sindroma Metabolik = SIMET 5
(Pengalaman Klinik : Tjokroprawiro 2005-2007)

STAGE 0 STAGE 1 STAGE 2 STAGE 3 STAGE 4

Pola Hidup Tidak Sehat Obesitas Preklinikal Klinikal
Pola Hidup Sehat (Pola Makan dan Aktifitas) (Obesitas Abdominal) SIMET, Pre-DM, Obesitas Anak PJK, DMT2, DM-Anak,Stroke

Prevalensi Sindroma Metabolik di Surabaya 2005

(Penelitian Pendahuluan) Waist Circumference = WC
Non DM : 32.0% DM Sesudah Terapi : 43.3% > 90 cm > 80 cm
DM Nave : 59.0% DM Obesitas : 81.7%
Prevalensi Pria : 4 5 x lebih sering daripada Wanita

10 Komponen Kumpulan Penyakit 4 Gula Darah Puasa 1 Trigliserida

Pada Sindroma-Metabolik
1 Obesitas Abdominal
> 100 mg/dl > 150 mg/dl
2 Resistensi Insulin, Pre-Diabetes, Diabetes
3 Dislipidemia - Aterogenik : Kelainan salah satu atau lebih
dari Kol, Kol-HDL, Kol-LDL, TG
4 Kenaikan Tekanan Darah 2 Kolesterol-HDL
5 Kecenderungan Trombosis (Sumbatan) 3 Tekanan Darah < 40 mg/dl
6 Fungsi Antitrombosis Menurun
7 Gangguan Fungsi Endotel > 130/85 mmHg < 50 mg/dl
Petanda : Mikroalbuminuria, yaitu adanya Protein dalam
Urine > 30 mg/24 jam atau ACR > 30 mg/g kreatinin
8 Kenaikan kadar Kortisol Sindroma Metabolic LP (INA) : > 90 cm ( ) dan > 80 cm ( )
9 Perlemakan Hati
10 Penyakit Kardiovaskuler (PJK, IMA, Stroke, dll)
(Menurut IDF 2005) : Plus 2 dari 4 Faktor tersebut diatas

ACR = Albumin Creatinine Ratio, IDF = International Diabetes Federation, IMA = Infark Miokard Akut, PJK = Penyakit Jantung Koroner
International Diabetes Federation Definition:
Abdominal obesity plus two other components:
elevated BP, low HDL, elevated TG, or impaired
fasting glucose
 7
Lifestyle Related Diseases (LRD): from Stage- 0 to Stage- 4
(Clinical Experiences : Tjokroprawiro 1995-2007)

Stage - 0 Stage - 1 Stage - 2

"Healthy Lifestyle" "Westernized Lifestyle" Obesity
(Abdominal Obesity)

INTENSIVE
INTENSIVE "Well Programmed"
1 HEALTH EDUCATION 1 HEALTH EDUCATION 1 HEALTH EDUCATION
2 TLC : GULOH-CISAR 2 TLC : GULOH-CISAR 2 TLC : GULOH-CISAR

LEVEL OF INTERVENTION A and B

A FAMILY and B COMMUNITY PHARMACOTHERAPY
Continued
 8
Lifestyle Related Diseases (LRD): from Stage- 0 to Stage- 4
(Clinical Experiences : Tjokroprawiro 1995-2006)

Stage - 3 Stage - 4
Preclinical Diseases Clinical Diseases
the MetS, Pre-DM, Adolescent Obesity CAD, T2DM, Adolescent-T2DM, Stroke
Intensive - Well Programmed Intensive - Well Programmed
TLC : GULOH-CISAR TLC : GULOH-CISAR

DRUG INTERVENTIONS : 6 MAJOR COMPONENTS :

1 Metformin 1 Abdominal Obesity
2 Acarbose 2 Insulin Resistance (IFG, IGT)
3 Glitazones 3 Atherogenic Dyslipidemia
4 Sibutramine - Orlistat
4 Raised Blood Pressure
5 Rimonabant
6 Glitazars : MRT (Mu-Ra-Te) 5 Proinflammatory State : Fibrinogen, CRP, etc
7 Metaglidasen 6 Prothrombotic State:Fibrinogen,FVII,PAI-1,FXIIIa
 TEN GUIDELINES FOR HEALTHY LIFE 9

GULOH-CISAR = SYNDROME-10
(Tjokroprawiro 1995,1996,1997,1998,1999,2000,2001,2003,2006)

1 G Limit Sugar Consumption 6 C Stop Smoking

2 U Restrict Purine Intake : JAS-BUKET +300 kcal/day or 3 km walk
7 I Daily Regular Exercise : +Sit up 50-100 x/day
3 L Consume Low Fat Diet : TEK-KUK-CS2
( < 90) 8 S TAKE MINIMALLY : 6-HOUR SLEEP/DAY
4 O Prevent Obesity WC (cm) : ( o
o < 80) 9 A Stop Alcohol
+
5 H Avoid Excess of Sodium Intake 10 R Regular Check-Up
(Less than 3 g Sodium/day) Esp. > 40 years Old : 3, 6 or 12 Months
G = Glucose U = Uric Acid L = Lipids O = Obesity H = Hypertension
C = Cigarette I = Inactivity S = Stress A = Alcohol R = Regular Check Up

JAS-BUKET : Jerohan, Alkohol, Sarden - Burung Dara, Unggas, Kaldu, Emping, Tape
(Bowels, Alcohol, Sardines - Pigeon, Fowls, Meat-Broth, Beaten Nut, Fermented Cassava)

TEK-KUK-CS2 : Telor, Keju - Kepiting, Udang, Kerang - Cumi, Susu, Santen

(Egg, Cheese - Crab, Shrimp, Mussel - Squid, Milk, Coconut - Juice)

"MABUK" (Rich in Chromium) : Mrica, Apel, Brokoli, Udang, Kacang-kacangan; good for DM

Recommended Food Supplements G

: reen Bean, Onions, Green Tea, Pepper, ARGININE, TKW-PJKA-BK
 Modified NCEP-ATP III 2001
3 Kriteria dari variabel dibawah ini

1. Lingkar perut
wanita 80 cm
pria 90 cm
2. Trigliserida 150mg/dL
3. HDLkolesterol
wanita < 50mg/dL
pria < 40mg/dL
4. Tekanan Darah 130/85mmHg
5. Gula Darah Puasa 110mg/dL. (sekarang > 100)
METABOLIC SYNDROME
THE PREVALENCE

USA NHANES III 1988 1994, of adult population

> 20 years, 22.0% or 47 million

Indonesia Clinical setting 2003, of 669 subjects,

> 20 years, 35.6% (Adam, Sambo 2003)
Dari 752 DM 58,64% MetS
Pria > Wanita = 59% vs 41% (Penelitian di RSAL Dr. Ramelan)
(Mulyono P, Perkeni-Makasar, 2005)

Penelitian di RSU Dr. Soetomo

60 DM 81,67% Mets
(Adi S, Perkeni, 2005

Rural area 2004, of 500 subjects,

> 19 years,19.2% (Suastika, 2004)

Pre Diabetes 9% and Diabetes 5,2% (n = 5873)

(Manaf A, SUMETSU 3, 2007) at Padang Sumatera Barat.
GLOBAL SIZE OF THE ( MTS ) PROBLEM

20-25 % of the world adult population have the

metabolic syndrome ( MTS) , and these are :

- twice likely to die

- 3 times likely to have a heart attack
or stroke
- 5 times at risk to develop diabetes type 2
 THE CV RISK IN DIABETES AND IN THE
METABOLIC SYNDROME ( MTS)

Diabetes is the leading cause of CVD

The existence of Metabolic Syndrome confers an

additional risk for CVD

The more components of MTS the higher the CVD risk

and mortality

The MTS , even before the diagnosis of diabetes ,

increases the risk and mortality of CVD
 Natural History of Type 2 Diabetes
Years from -10 -5 0 5 10 15
diagnosis
Onset Diagnosis

Insulin resistance
Insulin secretion

Impaired Fasting Metabolic Syndrome

Glucose

Post-Meal glucose
Microvascular complications
Fasting glucose
Cardiovascular Complications
Pre-diabetes Type 2 diabetes

Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789 13

Nathan DM. N Engl J Med. 2002;347:1342-1349
 Perjalanan Alami DM Tipe 2

Sensitivitas Insulin Sekresi Insulin

Type 2
30% diabetes 50%

50% IGT 70-100%

Impaired glucose
70% metabolism 150%

100% Normal glucose metabolism 100%

Diabetes Obes Metab 1999; 1(1): S1

Causative Factors in the Metabolic Syndrome

The Two significant factors :

( Insulin Resistance ) and ( Central Obesity )

Other possible Factors :

- Genetics
- physical inactivity
- aging
- a pro inflammatory state
- a hormonal state

(These may play variable roles in different ethnic groups)

OBESITY is defined as
condition in which there is an excess of body fat

The operational of OBESITY and OVERWEIGHT

are based on BMI which is correlated closely with
body fatness

BODY MASS INDEX (BMI)

Weight (kilogram)
kg
Height (meter2) m2
 CLASSIFICATION (NIH, 1998)
Disease Risk *) Relative to Normal

BMI Obesity Weight and Waist Circumference

(Kg / m2) Class Men < 102 cm > 102 cm >
Women < 88 cm 88 cm
UNDERWEIGHT < 18,5 - -
NORMAL *) 18,5 - 24,9 - -
OVERWEIGH 25,0 - 29,9 Increased High
OBESITY 30,0 - 34,9 I High Very High
35,0 - 39,9 II Very High Very High
EXTREME OBESITY > 40 III Extremly high Extremly high
Classification of Overweight and Obesity in Adult Indonesians
BMI, WC and Associated Disease Risks

Risk of Commorbidities
Waist Circumference
Classification BMI (kg/m2) < 90 cm (Men) > 90 cm (Men)
< 80 cm (Women) > 80 cm (Women)
Underweight < 18.5 Low Average
(but increased risk
of other clinical
problems)
Normal range 18.5 - 22.9 Average Increase
Overweight : > 23
At risk 23-24.9 Increase Moderate
Obese I 25-29.9 Moderate Severe
Obese II > 30 Severe Very severe

NOS-III, ISSO, Soegih et al, Jakarta

 Consequences of Obesity
Stroke
Respiratory disease

Heart Disease Cardiovascular risk fa

Gall bladder disease Diabetes

Osteoarthritis
monal abnormalities Cancer

Hyperuricemia
and gout
 Obesity and Metabolic Risk
Abdominal vs. Peripheral Obesity
Large Insulin-Resistant
Adipocytes

Small Insulin-Sensitive
Adipocytes

Android Obesity Gynoid Obesity

Sharma 2002
 Obesity and Metabolic Risk
Abdominal vs. Peripheral Obesity
Adrenergic Receptors

Adrenergic Receptors

Android Obesity Gynoid Obesity

Sharma 2002
 Abdominal Obesity is associated with Increased
Plasma Non-Esterified Fatty Acids

Insulin-Mediated
Antilipolysis

Plasma Non-Esterified
Fatty Acids

Catecholamine-Mediated
Lipolysis

Sharma 2002
Atherogenic
dyslipidemia

Insulin
resistance

Thrombotic
state

Inflammatory
 "The Widened Metabolic Syndrome : The Widened MetS 6
A Cluster of 10 Metabolic-Cardiovascular Risk Components
(Abdominal Obesity is the Key Player)
(Summarized : Tjokroprawiro 2002-2007)

10 Visceral Fat Insulin Resistance

Fatty Acid Deposition
Liver Steatosis = NASH "The Black Goat" * 2 Hyperinsulinemia
IGT-IFG T2DM *
1 Atherogenic Dyslipidemia
Adrenal Incidentaloma 3
ACTH, Cortisol 9 1 Increased Fasting FFA *
2 Elevated Apolipoprotein B
( Salivary Cortisol)
3 Elevated Remnant Lipoproteinemia
4 Elevated Fasting Triglyceride
Hyperuricemia 8 5 Elevated Post Prandial TG
ABDOMINAL 6 "Normal" LDL
7 Increased LDL
Vascular Abnormalities 7 OBESITY LDL
8 Increased Small-dense LDL : Apo B < 1.2
- Urinary Albumin Excretion GABRA-6 ? 9 Reduced HDL-C and Increased "Small HDL"
(ACR >30 g/mg creatinine) 10 Increased Cholesterol/HDL-C Ratio
- Endothelial Dysfunction
* 4 Raised Blood Pressure
*
Prothrombotic State 6 LVH, CHF
PAI-1 (Esp. Omental Fat) Prolonged QT Syndrome
Factor VII
ADIPONECTIN = ADIPO Q
5 Proinflammatory State
Fibrinogen
vWF ADIPONECTIN-RAISERS CRP , TNF, IL - 1, *
Adhesion Molecules GLIM, GLITAZONES, GLITAZARS IL - 6, Fibrinogen

1 , 2 , 3 , 4 , 5 , 6 are the 6-Major Components* of the Metabolic Syndrome

(AHA/NHLBI/ADA-2004 : Grundy et al 2004)
 ATHEROSCLEROSIS INDUCED BY
NON-APPROPRIATE LIFESTYLE
Poor Physical
Rich Meal
Activity

Visceral Fat Obesity

Abnormal Secretion of Adipocytokines

Adiponectin PAI-1

Insulin Resistance

Hyperlipidemia Diabetes Hypertension

Atherosclerosis
SUMETSU 2007
YAMATO INSTITUTE OF LIFESTYLE-RELATED DISEASES 070217
 EFEK RESISTENSI INSULIN
Glucose uptake
Glucose oxidation

Insulin Hyperinsulinemia
Lipolysis
Hyperglycemia
resistance Free fatty acid
Dyslipidemia

Glucose uptake
Glucose production
VLDL synthesis
 Insulin Resistance

Hyperinsulinemia

Glucose Increased Decreased HDL - Increased blood

intolerance triglyceride Cholesterol pressure

Small dense LDL Increased Increased

cholesterol Uric acid PAI - 1

Coronary heart
disease
1. Weight Loss 5 - 10 % from baseline
2. Prevents the Yoyo Syndrome ( Weight Regain )
3. Improves Comorbid Conditions
4. Improves Quality of life

1. Behavior Modification
2. Medical Nutrition Therapy (MNT), e.g., LCDs or VLCDs
3. Healthy Life Style (Physical Exercise, etc)
4. Medications
5. Surgery
Should it?
Food Patterns and Metabolic Syndrome

High Carbohydrate diet (glucocentric) is strongly

associated with obesity
- White bread pattern hyperinsulinemia and dyslipidemia
- Sweets and cakes pattern hypertension,
hyperinsulinemia
and central obesity

--FOOD PATTERNS AND COMPONENTS OF METSy IN MEN AND WOMEN

Wirfalt et al, August 15, 2001
 Glucocentric Diet: Glycemic Load

High carbohydrate,
high glycemic index food

exhaust pancreatic cells

hyperinsulinemia

increase in inflammatory markers

risk for MS

Glycemic Load ability to raise blood sugar

Glycemic Index rapidly digested and absorbed

--EPIDEMILOGIC EVIDENCE LINKING DIET TO METABOLIC SYNDROME--

 Glucocentric diet and metabolic syndrome

Excessive high CHO diet contributes highly to

metabolic syndrome; High dairy intake prevents

Diet Components Results

Atkins Diet CHO, fats; CHON Weight loss, lipids
Mediterranean Low fat, high calorie Reduce inflammation
Glycemic Complex CHO, lean protein, Lose weight, stable BS,
Impact healthy fat high energy
Mayo Clinic Unlimited fruits and BP, cholesterol and
Exercise vegetables + food groups heart disease
South Beach Right carbs, right bad cholesterol
No exercise fats good cholesterol
 Physical Activity and Metabolic Syndrome
Physical activity doesnt necessarily mean an exercise
program but refers to daily routines that boosts
activity level
Physical activity is an important etiological factor in
the development of metabolic syndrome
Higher levels of physical activity lowers a persons
chances of CV risks regardless of the persons level of
aerobic fitness and weight

Physical Activity expenditure predicts progression towards metabolic syndrome

independently of aerobic fitness in Middle-Aged Healthy Caucasians.
Jan. 17, 2004. Eukland, and colleagues
 Potential benefit of
Moderate (5-10%) weigh loss
Subcutan adipose tissue
Weight loss
Visceral adipose 5-10%
~30% visceral adipose
tissue tissue loss (diet,
physical activity,
pharmacotherapy)

Blood pressure
impairment Lipid profile improved
Insulin sensitivity, Improve
impaired

Glycemia
Susceptibillity to thrombosis

Inflammation markers
Abdomin Reduced
al obesity Risk
of coronary heart disease
obesity
(waist (waist
circumference Desprs JP, BMJ 2001;322:716-20 circumference
JNC 7 Algorithm for Treatment of Hypertension

Lifestyle modifications Lifestyle modifications

Not at Goal Blood Pressure (<140/90 mmHg)

(<130/80 mmHg for patients with diabetes or chronic kidney disease)

Initial Drug Choices

Without
Without Compelling
Compelling Indications
Indications With
With Compelling
Compelling Indications
Indications

Stage 1 Stage 2 Drug(s) for the compelling

Hypertension Hypertension indications
(SBP 140-159 or DBP (SBP >160 or DBP >100 See Compelling Indications
90-99 mmHg) mmHg) for Individual Drug Classes

Thiazide-type diuretics 2-drug combination for Other antihypertensive drugs

for most. May consider most (usually thiazide-type (diuretics, ACEI, ARB, BB,
ACEI, ARB, BB, CCB, or diuretic and ACEI, or ARB, CCB) as needed.
combination or BB, or CCB).

Not at Goal BP

Optimize dosages or add additional drugs until goal blood

pressure is achieved. Considered consultation with
hypertension specialist.
Indications for initial treatment and goals for
adult hypertensive diabetic patients

Systolic Diastolic
Goal (mm Hg) < 130 < 80
Behavioral therapy alone 130-139 80- 89
(Max 3 mos) then add
pharmacologic treatment

Behavioral therapy + 140 90

pharmacological
treatment

Treatment of Hypertension in Adults with Diabetes. American Diabetes Association.

Diabetes Care, Vol 26, Supplement 1, Jan 2003.
 Lipid-lowering Goals in
Recent Major Guidelines
LDL-C Total cholesterol
mmol/L (mg/dL) mmol/L (mg/dL)

Joint European Societies1

Established CHD, other <3.0 (115) <5.0 (190)
atherosclerotic disease or high
absolute risk
US National Cholesterol Education Program2
<2 CHD risk factors <4.1 (160)
2 CHD risk factors <3.4 (130)
CHD or CHD risk factor 2.6 (100)
equivalents
National Heart Foundation of Australia/Cardiac Society of Australia & New
Zealand3
Established CHD, other <2.5 (95) <4.0 (155)
atherosclerotic disease or high
absolute risk

[Source: 1Wood et al. Eur Heart J 1998;19:1434-1503. 2NCEP Expert Panel. JAMA
2001;285:2486-2497.
3
Med J Aust 2001;175(suppl):S57-S85.]
 Exogenous factors Increased cellular Impaired rapid
Lack of exercise insulin resistance insulin secretion Genetic
Adiposis dispositio
n
Postprandial
hyperglycemia

Hyperinsulinemia
Raised blood sugar
through Pre-
becomes toxic
compensatory
other production
(glucose toxicity) diabetes

Increased insulin
resistance and
The point of action decreased insulin
secretion
of oral antidiabetic in
the pathophysiology Chronic
Hyperlgycemia and Manifest
of type 2 diabetes hyperinsulinemia diabetes

Further increase in
insulin resistance
Advanced
diabetes
Gradual decrease
in insulin secretion