You are on page 1of 40

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
Association) (2005)
Minimal
requirements

Any 3 or mor of the


following criteria

Waist
circumference

In men < 102 cm


In women < 88 cm

Waist to hip
ratio

World Health
Organisation 1999
Diabetes, IFG, IGT, or
insulin resistance + any
2 or more of the
following criteria

International Diabetes Federation


(2005)
Central obesity (see under) + any
2 or more of the following criteria

In men 94 cm
In womwn 80 cm
< 0,90 in men
< 0,85 in womwn

Reduced HDL
cholesterol

< 1.00 mmol/l in men


< 1.30 mmol/l in women

< 0.90 mmol/l in men


< 1.00 mmol/l in women

< 1.03 mmol/l (40 mg/dl) in men


< 1.29 mmol/l (50 mg/dl) in women

Elevated
Triglycerides

> 1.70 mmol/l

> 1.70 mmol/l

1.70 mmol/l (150 mg/dl)

Elevated Blood
Pressure

> 130 / >85

140 / 90

130 / 85

Urinary Albumin
Excretion
Serum glucose

> 20 mg/min
6.1 (5.6) mmol/l

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)

5.6 mmol/l (100 mg/dl)

Penyakit Akibat Pola Hidup Tidak Sehat : Sindroma Metabolik = SIMET

(Pengalaman Klinik : Tjokroprawiro 2005-2007)

STAGE 0

STAGE 1

STAGE 2

STAGE 3

STAGE 4

Preklinikal
Klinikal
Obesitas
Pola Hidup Tidak Sehat
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
> 90 cm

Non DM : 32.0% DM Sesudah Terapi : 43.3%


DM Nave : 59.0% DM Obesitas
: 81.7%
Prevalensi Pria : 4 5 x lebih sering daripada Wanita
10 Komponen Kumpulan Penyakit
Pada Sindroma-Metabolik
1 Obesitas Abdominal
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
5 Kecenderungan Trombosis (Sumbatan)
6 Fungsi Antitrombosis Menurun
7 Gangguan Fungsi Endotel
Petanda : Mikroalbuminuria, yaitu adanya Protein dalam
Urine > 30 mg/24 jam atau ACR > 30 mg/g kreatinin
8 Kenaikan kadar Kortisol
9 Perlemakan Hati
10 Penyakit Kardiovaskuler (PJK, IMA, Stroke, dll)

> 80 cm

4 Gula Darah Puasa

1 Trigliserida

> 100 mg/dl

> 150 mg/dl

3 Tekanan Darah
> 130/85 mmHg

2 Kolesterol-HDL
< 40 mg/dl
< 50 mg/dl

Sindroma Metabolic LP (INA) : > 90 cm ( ) dan > 80 cm ( )


(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

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)

1 HEALTH EDUCATION
2 TLC : GULOH-CISAR

INTENSIVE

INTENSIVE
"Well Programmed"

1 HEALTH EDUCATION
2 TLC : GULOH-CISAR

1 HEALTH EDUCATION
2 TLC : GULOH-CISAR

LEVEL OF INTERVENTION
A FAMILY and B COMMUNITY

A and B
PHARMACOTHERAPY
Continued

Lifestyle Related Diseases (LRD): from Stage- 0 to Stage- 4


(Clinical Experiences : Tjokroprawiro 1995-2006)

Stage - 3

Stage - 4

Preclinical Diseases
the MetS, Pre-DM, Adolescent Obesity

Clinical Diseases
CAD, T2DM, Adolescent-T2DM, Stroke

Intensive - Well Programmed


TLC : GULOH-CISAR

Intensive - Well Programmed


TLC : GULOH-CISAR

DRUG INTERVENTIONS :

6 MAJOR COMPONENTS :

1
2
3
4
5
6
7

Metformin
Acarbose
Glitazones
Sibutramine - Orlistat
Rimonabant
Glitazars : MRT (Mu-Ra-Te)
Metaglidasen

1
2
3
4
5
6

Abdominal Obesity
Insulin Resistance (IFG, IGT)
Atherogenic Dyslipidemia
Raised Blood Pressure
Proinflammatory State : Fibrinogen, CRP, etc
Prothrombotic State:Fibrinogen,FVII,PAI-1,FXIIIa

TEN GUIDELINES FOR HEALTHY LIFE

GULOH-CISAR = SYNDROME-10

(Tjokroprawiro 1995,1996,1997,1998,1999,2000,2001,2003,2006)

1 G Limit Sugar Consumption


2 U Restrict Purine Intake : JAS-BUKET
3 L Consume Low Fat Diet : TEK-KUK-CS2

6 C Stop Smoking

+300 kcal/day or 3 km walk

7 I Daily Regular Exercise : +Sit up 50-100 x/day

4 O Prevent Obesity WC (cm) : ( o


o < 80)

8 S TAKE MINIMALLY : 6-HOUR SLEEP/DAY


9 A Stop Alcohol

5 H Avoid Excess of Sodium Intake

10 R Regular Check-Up

< 90)

(Less than 3 g Sodium/day)

G = Glucose
C = Cigarette

U = Uric Acid
I = Inactivity

Esp. > 40 years Old : 3, 6 or 12 Months

L = Lipids
S = Stress

O = Obesity
A = Alcohol

H = Hypertension
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
pria

80 cm
90 cm

2. Trigliserida
3. HDLkolesterol

150mg/dL

wanita
pria

< 50mg/dL
< 40mg/dL

4. Tekanan Darah
5. Gula Darah Puasa

130/85mmHg
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
diagnosis

-10

-5
Onset

10

15

Diagnosis

Insulin resistance
Insulin secretion
Impaired Fasting
Glucose

Post-Meal glucose
Fasting glucose

Pre-diabetes
Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789
Nathan DM. N Engl J Med. 2002;347:1342-1349

Metabolic Syndrome

Microvascular complications

Cardiovascular Complications
Type 2 diabetes
13

Perjalanan Alami DM Tipe 2


Sekresi Insulin

Sensitivitas Insulin
30%

Type 2
diabetes

50%

50%

IGT

70-100%

70%

Impaired glucose
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)
Height (meter2)

kg

m2

CLASSIFICATION (NIH, 1998)


Disease Risk *) Relative to Normal

BMI
(Kg / m2)

Obesity
Class

Weight and Waist Circumference


Men < 102 cm

> 102 cm

Women < 88 cm

88 cm

< 18,5

NORMAL *)

18,5 - 24,9

OVERWEIGH

25,0 - 29,9

Increased

High

OBESITY

30,0 - 34,9

High

Very High

35,0 - 39,9

II

Very High

Very High

> 40

III

Extremly high

Extremly high

UNDERWEIGHT

EXTREME OBESITY

>

Classification of Overweight and Obesity in Adult Indonesians


BMI, WC and Associated Disease Risks
Risk of Commorbidities
Classification

BMI (kg/m2)

Underweight

< 18.5

Normal range
Overweight :
At risk
Obese I
Obese II

18.5 - 22.9
> 23
23-24.9
25-29.9
> 30

Waist Circumference
< 90 cm (Men)
> 90 cm (Men)
< 80 cm (Women)
> 80 cm (Women)
Low
Average
(but increased risk
of other clinical
problems)
Average
Increase
Increase
Moderate
Severe

Moderate
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

monal abnormalities

Osteoarthritis
Cancer

Hyperuricemia
and gout

Obesity and Metabolic Risk


Abdominal vs. Peripheral Obesity
Large Insulin-Resistant
Adipocytes
Small Insulin-Sensitive
Adipocytes

Android Obesity
Sharma 2002

Gynoid Obesity

Obesity and Metabolic Risk


Abdominal vs. Peripheral Obesity
Adrenergic Receptors
Adrenergic Receptors

Android Obesity
Sharma 2002

Gynoid Obesity

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

A Cluster of 10 Metabolic-Cardiovascular Risk Components

(Abdominal Obesity is the Key Player)


(Summarized : Tjokroprawiro 2002-2007)

Fatty Acid Deposition


Liver Steatosis = NASH

10
9

Hyperuricemia

Vascular Abnormalities
- Urinary Albumin Excretion
(ACR >30 g/mg creatinine)
- Endothelial Dysfunction

PAI-1 (Esp. Omental Fat)


Factor VII
Fibrinogen
vWF
Adhesion Molecules

Adrenal Incidentaloma
ACTH, Cortisol
( Salivary Cortisol)

Prothrombotic State

Visceral Fat
"The Black Goat"

Insulin Resistance
IGT-IFG
Hyperinsulinemia

ABDOMINAL
OBESITY
GABRA-6 ?

*
6

ADIPONECTIN-RAISERS
GLIM, GLITAZONES, GLITAZARS

Atherogenic Dyslipidemia
1
2
3
4
5
6
7

Increased Fasting FFA


Elevated Apolipoprotein B
Elevated Remnant Lipoproteinemia
Elevated Fasting Triglyceride
Elevated Post Prandial TG
"Normal" LDL
Increased LDL
LDL
8 Increased Small-dense LDL : Apo B < 1.2
9 Reduced HDL-C and Increased "Small HDL"
10 Increased Cholesterol/HDL-C Ratio

Raised Blood Pressure


LVH, CHF
Prolonged QT Syndrome

Proinflammatory State
CRP , TNF, IL - 1,
IL - 6, Fibrinogen

ADIPONECTIN = ADIPO Q

T2DM

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
Activity

Rich Meal

Visceral Fat Obesity


Abnormal Secretion of Adipocytokines
Adiponectin PAI-1

Insulin Resistance
Hyperlipidemia

SUMETSU 2007

Diabetes

Hypertension

Atherosclerosis
YAMATO INSTITUTE OF LIFESTYLE-RELATED DISEASES 070217

EFEK RESISTENSI INSULIN


Glucose uptake
Glucose oxidation

Insulin
resistance

Lipolysis
Free fatty acid

Glucose uptake
Glucose production
VLDL synthesis

Hyperinsulinemia
Hyperglycemia
Dyslipidemia

Insulin Resistance
Hyperinsulinemia

Glucose
intolerance

Increased
triglyceride

Small dense LDL


cholesterol

Decreased HDL Cholesterol

Increased
Uric acid

Coronary heart
disease

Increased blood
pressure

Increased
PAI - 1

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
Impact

Complex CHO, lean protein, Lose weight, stable BS,


healthy fat
high energy

Mayo Clinic
Exercise

Unlimited fruits and


vegetables + food groups

BP, cholesterol and


heart disease

South Beach
No exercise

Right carbs, right


fats

bad cholesterol
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

Visceral adipose
tissue

Weight loss
5-10%
~30% visceral adipose
tissue loss (diet,
physical activity,
pharmacotherapy)

Blood pressure

impairment Lipid profile

improved

Insulin
impaired

sensitivity, Improve

Glycemia

Susceptibillity to thrombosis
Inflammation markers

Abdomin
of coronary heart disease

al obesity Risk
(waist
circumference

Desprs JP, BMJ 2001;322:716-20

Reduced
obesity
(waist
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
Hypertension
(SBP 140-159 or DBP
90-99 mmHg)

Stage 2
Hypertension
(SBP >160 or DBP >100
mmHg)

Drug(s) for the compelling


indications
See Compelling Indications
for Individual Drug Classes

Thiazide-type diuretics
for most. May consider
ACEI, ARB, BB, CCB, or
combination

2-drug combination for


most (usually thiazide-type
diuretic and ACEI, or ARB,
or BB, or CCB).

Other antihypertensive drugs


(diuretics, ACEI, ARB, BB,
CCB) as needed.

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 +
pharmacological
treatment

140

90

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
mmol/L (mg/dL)

Total cholesterol
mmol/L (mg/dL)

<3.0 (115)

<5.0 (190)

Joint European Societies1


Established CHD, other
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
Lack of exercise
Adiposis

Increased cellular
insulin resistance

Impaired rapid
insulin secretion

Genetic
dispositio
n

Postprandial
hyperglycemia
Hyperinsulinemia
through
compensatory
other production

The point of action


of oral antidiabetic in
the pathophysiology
of type 2 diabetes

Raised blood sugar


becomes toxic
(glucose toxicity)

Prediabetes

Increased insulin
resistance and
decreased insulin
secretion
Chronic
Hyperlgycemia and
hyperinsulinemia
Further increase in
insulin resistance
Gradual decrease
in insulin secretion

Manifest
diabetes

Advanced
diabetes