METABOLIC SYNDROME: CURRENT CONCEPTS CURRENT CONCEPTS Josephine Carlos-Raboca, MD, FPCP, FPSEM...

METABOLIC METABOLIC SYNDROME:SYNDROME:

CURRENT CONCEPTSCURRENT CONCEPTS

Josephine Carlos-Raboca, MD, FPCP, FPSEMJosephine Carlos-Raboca, MD, FPCP, FPSEMChief, Section of Endocrinology, Diabetes and Chief, Section of Endocrinology, Diabetes and

MetabolismMetabolism

OUTLINEOUTLINE

Definition of Metabolic SyndromeDefinition of Metabolic Syndrome Clinical Significance of Metabolic Clinical Significance of Metabolic

SyndromeSyndrome What Causes Metabolic SyndromeWhat Causes Metabolic Syndrome Link up between Obesity, Insulin Link up between Obesity, Insulin

Resistance and Metabolic SyndromeResistance and Metabolic Syndrome Principles in Management of Principles in Management of

Metabolic SyndromeMetabolic Syndrome

Metabolic SyndromeMetabolic Syndrome Metabolic SyndromeMetabolic Syndrome

A constellation of major risk factors, life-habit risk A constellation of major risk factors, life-habit risk factors: factors:

Abdominal obesityAbdominal obesity Atherogenic dyslipidemiaAtherogenic dyslipidemia

− Elevated TGElevated TG− Small, dense LDL particlesSmall, dense LDL particles− Low HDL-CLow HDL-C

Elevated blood pressureElevated blood pressure Insulin resistanceInsulin resistance Prothrombotic and proinflammatory statesProthrombotic and proinflammatory states

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMAJAMA. 2001;285:2486-2497.. 2001;285:2486-2497.

WHO definition of ‘Metabolic WHO definition of ‘Metabolic Syndrome’Syndrome’

AT LEAST ONE OF:• glucose intolerance• IGT • type 2 diabetes• insulin resistance*

AT LEAST TWO OF:• impaired glucose regulation or diabetes• insulin resistance*• arterial pressure

140/90 mmHg• plasma triglycerides

1.7 mmol/l or 150 mg/dl and/or HDL cholesterol < 0.9 mmol/l or 35 mg/dl for men; < 1.0 mmol/l or 39 mg/dl for women

• central obesity waist:hip ratio > 0.90 for men, > 0.85 for women; and/or BMI > 30 kg/m2

• microalbuminuria urinary albumin excretion rate 20 g/min or albumin to creatinine ratio 30 mg/g

* Insulin resistance defined under hyperinsulinemic, euglycemic conditions as glucose uptake below the lowest quartile for the background population under investigation

+

World Health Organization. Definition, diagnosis and classification of diabetes mellitus and its complications. Part I: Diagnosis and classification of diabetes mellitus. WHO Department of Noncommunicable Disease Surveillance; 1999.

Measure (any 3 of 5 Measure (any 3 of 5 constitute diagnosis of constitute diagnosis of metabolic syndrome)metabolic syndrome)

Categorical cutpointsCategorical cutpoints

Elevated waist Elevated waist circumferencecircumference

≥≥102 cm in men102 cm in men≥88 cm in women≥88 cm in women

Elevated triglyceridesElevated triglycerides ≥≥150 mg/dl (1.7 mmol/l)150 mg/dl (1.7 mmol/l) or on or on drug treatment for elevated drug treatment for elevated triglyceridestriglycerides

Reduced HDL-cholesterolReduced HDL-cholesterol <40 mg/dl (0.9 mmol/l) in men<40 mg/dl (0.9 mmol/l) in men

<50 mg/dl (1.1 mmol/l) in <50 mg/dl (1.1 mmol/l) in womenwomen

Or on drug treatment for Or on drug treatment for reduced HDL-Creduced HDL-C

Elevated blood pressureElevated blood pressure ≥≥130 mmHg systolic blood 130 mmHg systolic blood pressure orpressure or

≥≥85 mmHg diastolic blood 85 mmHg diastolic blood pressurepressure

or on antihypertensive drug or on antihypertensive drug treatment in a patient with a treatment in a patient with a history of hypertensionhistory of hypertension

Elevated fasting glucoseElevated fasting glucose ≥≥100 mg/dl100 mg/dl or on drug or on drug treatment for elevated glucosetreatment for elevated glucose

2005 Revised ATP III Clinical 2005 Revised ATP III Clinical Screening Criteria Screening Criteria

to Identify Metabolic Syndrome (AHA to Identify Metabolic Syndrome (AHA

and NHLBI)and NHLBI)

Diagnosis of The Diagnosis of The Metabolic SyndromeMetabolic SyndromeIDF CRITERIA (2005) Central obesity (defined as waist circumference Central obesity (defined as waist circumference 94 94

cm for Europid men and cm for Europid men and 80 cm for Europid women, 80 cm for Europid women, with ethnicity specific values for other groups)with ethnicity specific values for other groups)

Plus any two of the following four factorsPlus any two of the following four factors TG TG 150 mg/dl (1.7 mmol/l), or specific treatment for this lipid 150 mg/dl (1.7 mmol/l), or specific treatment for this lipid

abnormalityabnormality HDL <40 mg/l (1.03 mmol/l) in males and <50 mg/l (1.29 HDL <40 mg/l (1.03 mmol/l) in males and <50 mg/l (1.29

mmol/l) in females, or specific treatment for this lipid mmol/l) in females, or specific treatment for this lipid abnormalityabnormality

Systolic BP Systolic BP 130 or diastolic BP 130 or diastolic BP 85 mmHg, or treatment of 85 mmHg, or treatment of previously diagnosed hypertensionpreviously diagnosed hypertension

Fasting plasma glucose Fasting plasma glucose 100 mg/dl (5.6 mmol/l), or previously 100 mg/dl (5.6 mmol/l), or previously diagnosed type 2 diabetes. If above 5.6 mmol/l or 100 mg/dl, diagnosed type 2 diabetes. If above 5.6 mmol/l or 100 mg/dl, OGTT is strongly recommended but is not necessary to define OGTT is strongly recommended but is not necessary to define presence of the syndromepresence of the syndrome

Country/Ethnic groupCountry/Ethnic group Waist circumference Waist circumference (as measure of (as measure of central obesity)central obesity)

EuropidsEuropids MaleMale

FemaleFemale94 cm94 cm

80 cm80 cm

South AsiansSouth Asians MaleMale

FemaleFemale90 cm90 cm

80 cm80 cm

ChineseChinese MaleMale

FemaleFemale90 cm90 cm

80 cm80 cm

JapaneseJapanese MaleMale

FemaleFemale85 cm85 cm

90 cm90 cm

Ethnic-specific cut-points for waist circumference

Diagnosis of The Metabolic Diagnosis of The Metabolic SyndromeSyndrome

IDF CRITERIA (2005)

Country/Country/Ethnic groupEthnic group

Waist circumference (as Waist circumference (as measure of central obesity)measure of central obesity)

Ethnic South Ethnic South and Central and Central AmericansAmericans

Use South Asian Use South Asian recommendations until more recommendations until more specific data are availablespecific data are available

Sub-Saharan Sub-Saharan AfricansAfricans

Use European data until more Use European data until more specific data are availablespecific data are available

Eastern Eastern Mediterranean Mediterranean and Middle and Middle East (Arab) East (Arab) populationspopulations

Use European data until more Use European data until more specific data are availablespecific data are available

Ethnic-specific cut-points for waist circumference

Diagnosis of The Diagnosis of The Metabolic SyndromeMetabolic SyndromeIDF CRITERIA (2005)

A Major Health Issue A Major Health Issue WorldwideWorldwide

Prevalence of the metabolic syndrome (ATP III)

*Obesity criteria adjusted to waist circumference appropriatefor an Indian population

Clinical Significance of Clinical Significance of Metabolic SyndromeMetabolic Syndrome

High LDL-CHigh LDL-C

Metabolic SyndromeMetabolic Syndrome

Coronary Heart Disease Coronary Heart Disease

T2DMT2DM

Metabolic syndrome predicts future CHD and DM

Metabolic syndrome predicts future CHD and DM

Dekker JM, et al. (Hoorn study). Circulation 2005;112:666-673.

Metabolic Syndrome and Metabolic Syndrome and Risk of CV EventsRisk of CV Events

Whatever The Whatever The Definition, The Definition, The Metabolic Syndrome Metabolic Syndrome

Increases 1.5 to 2-Increases 1.5 to 2-fold The Risk of CV fold The Risk of CV EventsEvents

3.7 Fold Increase CHD Risk 3.7 Fold Increase CHD Risk with 4-5 Features of the with 4-5 Features of the

Metabolic SyndromeMetabolic Syndrome

Sattar et a Circ 2003;108:414-419lSattar et a Circ 2003;108:414-419l

CH

D D

eath

or

No

n-f

atal

MI

G Levantesi G, et al. (GISSI-Prevenzione). J Am Coll Cardiol 2005;46:277-283.

Diabetes and Metabolic Syndrome Worsen Diabetes and Metabolic Syndrome Worsen Long-term Prognosis in Patients with Long-term Prognosis in Patients with

Acute Myocardial InfarctionAcute Myocardial Infarction

24.5 Fold Increase Risk of New 24.5 Fold Increase Risk of New Onset Diabetes with 4-5 Features Onset Diabetes with 4-5 Features

of the Metabolic Syndromeof the Metabolic Syndrome

Sattar et a Circ 2003;108:414-419lSattar et a Circ 2003;108:414-419l

On

set

of

new

DM

On

set

of

new

DM

Other Associated Other Associated DisordersDisorders

Obstructive Sleep ApneaObstructive Sleep Apnea Fatty Liver (Non Alcoholic Fatty Liver (Non Alcoholic

Steatorrheic Hepatitis)Steatorrheic Hepatitis) ArthritisArthritis Polycystic Ovarian Syndrome Polycystic Ovarian Syndrome MalignancyMalignancy

What is the root cause What is the root cause of Metabolic Syndrome?of Metabolic Syndrome?

Insulin Resistance?Insulin Resistance?

Obesity?Obesity?

Inflammation?Inflammation?

The Metabolic Syndrome: a The Metabolic Syndrome: a network of atherogenic network of atherogenic

factorsfactors

The Metabolic Syndrome: a The Metabolic Syndrome: a network of atherogenic network of atherogenic

factorsfactors

AtherosclerosisAtherosclerosis

McFarlane S, et al. J Clin Endocrinol Metab 2001; 86:713–718.

Genetic factorsEnvironmentalFactors(Obesity,

Physical Inactivity)

Insulin Insulin ResistanceResistance

Hyperglycemia/IGT

Dyslipidemia

Hypertension

Endothelial dysfunction/ Microalbuminuria

Hypofibrinolysis

Inflammation

Link between Insulin Link between Insulin Resistance and Resistance and Metabolic SyndromeMetabolic Syndrome

Insulin resistance – a reduced Insulin resistance – a reduced response of target tissues to response of target tissues to

circulating insulincirculating insulinCarbohydrate

Glucose (G)

Insulin (I)

I

I

II

I

I

I

G

G

G

G

G

G

G

GI

G

G

G

Defective insulin secretion

Excessive fatty acid release

Reduced glucoseuptake

IG

Excess glucoseproduction

Resistance to the action of insulin

Endothelial dysfunction

Indicators of Insulin Indicators of Insulin ResistanceResistance

HOMAHOMA

HyperinsulinemiaHyperinsulinemia

Triglyceride/HDL >4Triglyceride/HDL >4

Insulin Resistance Insulin Resistance SyndromeSyndrome

Dyslipidemia Hypertension

Central obesity

HyperglycemiaEndothelial dysfunction/

microalbuminuria

Cardiovascular disease

Insulin resistance

Festa A et al. Circulation 2000; 102:42–47;Reaven GM et al. Annu Rev Med 1993; 44:121–131.

InflammationHypofibrinolysis

n = 888Metabolic disorders: glucose intolerance, dyslipidemia, hyperuricemia and/or hypertension. P < 0.001 for differences between all categories. Bonora E, et al. Diabetes 1998; 47:1643.

Pre

vale

nce

of

HO

MA

-est

imat

edin

suli

n r

esis

tan

ce (

%)

100

0

80

60

40

20

0 1 2 3 4

Number of metabolic disorders

Prevalence of insulin Prevalence of insulin resistance correlates with resistance correlates with

increasing number of increasing number of metabolic disordersmetabolic disorders

Link between Obesity and Link between Obesity and Metabolic SyndromeMetabolic Syndrome

Fat accumulation leads to systemic Fat accumulation leads to systemic oxidative stressoxidative stress

Increase ROS (eg H2O2) Increase ROS (eg H2O2)

-increase NADPH oxidase activity and -increase NADPH oxidase activity and decreased antioxidant enzymes – leads decreased antioxidant enzymes – leads

to to dysregulated adipocytokine dysregulated adipocytokine productionproduction

- insulin resistance- insulin resistance

- increase MCP -1 – HPN and - increase MCP -1 – HPN and atherosclerosisatherosclerosis

Insulin resistant adipocytes secrete Insulin resistant adipocytes secrete multiple signaling molecules linked multiple signaling molecules linked

with inflammation & insulin with inflammation & insulin resistanceresistance

Adiponectin

Resistin

Angiotensin II

TNF

PAI-1

Free fatty acids

Leptin

Adipokines Mediates IR Adipokines Mediates IR and Inflammationand Inflammation

Adipokines Mediates IR Adipokines Mediates IR and Inflammationand Inflammation

Adiponectin, Adiponectin, TNF TNF, , Leptin, Leptin, PAI-1, PAI-1, IL-6, Angiotensinogen IL-6, Angiotensinogen

Insulin Sensitivity Insulin Resistance

Vascular InfllammationVascular Infllammation Endothelial DysfunctionEndothelial Dysfunction

ReducedPhysicalActivity

Excessive food intake

Geneticfactors

ABDOMINALABDOMINAL

OBESITYOBESITY

adiponectin

leptin

IL-6 TNF-

insulinreceptor

Substrate(IRS-1 & IRS-2)

blood FFA

various cytokines

How Does Abdominal How Does Abdominal Obesity Cause Insulin Obesity Cause Insulin

ResistanceResistanceInflammation

Insulin Resistance of Abdominal Insulin Resistance of Abdominal Adipose Tissue Adipose Tissue

and Atherogenic Dyslipidaemiaand Atherogenic Dyslipidaemia

TGTG Apo BApo B

VLDVLDLL

LDLLDL

(CETP)(CETP) TGTGCECE

InsulinInsulinResistantResistantAbdominaAbdomina

llAdipocyteAdipocyte

ss

LiverLiver

FFAFFA CECE

TGTG

(( HL) HL)small, small, DenseDense

LDLLDL

HDHD22

((HL)HL)

KidneKidneyy

Apo A-Apo A-11

HDL3(CETP)(CETP)

LDL

Adapted from Pouliot MC, et al. Diabetes 1992;41:826-834.

Visceral Fat Associates Visceral Fat Associates with Atherogenic with Atherogenic

DyslipidaemiaDyslipidaemia

Low HDL-C is an independent predictor of CHD riskeven when LDL-C is low

Castelli WP. Can J Cardiol. 1998;4 (suppl A):5A-10A.

Low HDL-C Predicts CHD Low HDL-C Predicts CHD RiskRisk

Castelli WP. Can J Cardiol. 1998;4 (suppl A):5A-10A.

High TG associates with higher relative risk for CHD in the Framingham Heart Study

Patients with Elevated Triglycerides are at Patients with Elevated Triglycerides are at IncreasedIncreased

Risk for CHDRisk for CHD

St Pierre, et al. Circulation. 2001:104:2295.

Small, Dense, LDL Particles were an Small, Dense, LDL Particles were an IndependentIndependent

Risk Factor for CAD in Quebec Risk Factor for CAD in Quebec Cardiovascular StudyCardiovascular Study

Obesity Is An Obesity Is An Inflammatory StimulusInflammatory Stimulus

Metabolic syndrome is a proinflammatory, Metabolic syndrome is a proinflammatory, proatherogenic conditionproatherogenic condition

Many adipose tissue products can cause Many adipose tissue products can cause insulin resistance and inflammation:insulin resistance and inflammation: Cytokines (e.g., TNF-Cytokines (e.g., TNF-, IL-6), IL-6) ChemokinesChemokines Growth factorsGrowth factors Procoagulants (e.g., PAI-1)Procoagulants (e.g., PAI-1) Free fatty acidsFree fatty acids ResistinResistin AdiponectinAdiponectin Nitric oxide synthaseNitric oxide synthase

Atherosclerosis Is An Atherosclerosis Is An Inflammatory DiseaseInflammatory Disease

Initial step of atherosclerosis: leukocyte recruitment by Initial step of atherosclerosis: leukocyte recruitment by the dysfunctional endothelium, facilitated by chemo-the dysfunctional endothelium, facilitated by chemo-attractants and adhesion molecules (VCAM-1, ICAM-1)attractants and adhesion molecules (VCAM-1, ICAM-1)

In the intima, maturation of the mononuclear phagocyte In the intima, maturation of the mononuclear phagocyte towards the foam cell (capture of modified lipoproteins)towards the foam cell (capture of modified lipoproteins)

Activated foam cells Activated foam cells express the procoagulant tissue factor express the procoagulant tissue factor generate reactive oxygen species and pro-inflammatory generate reactive oxygen species and pro-inflammatory

cytokines cytokines (CRP, IL-6)(CRP, IL-6)

can also be the source of enzymes that alter the metabolism of can also be the source of enzymes that alter the metabolism of the extracellular matrixthe extracellular matrix

Death of the mononuclear phagocyte by either oncosis Death of the mononuclear phagocyte by either oncosis or apoptosis leads to formation of the lipid core of the or apoptosis leads to formation of the lipid core of the atherosclerotic plaqueatherosclerotic plaque

Atherosclerosis Is An Atherosclerosis Is An Inflammatory DiseaseInflammatory Disease

The endothelium and smooth muscle The endothelium and smooth muscle vascular cells can themselves elaborate vascular cells can themselves elaborate pro-inflammatory cytokines. pro-inflammatory cytokines.

In the initial phase of inflammation, In the initial phase of inflammation, elaboration of elaboration of pro-inflammatory cytokines and the pro-inflammatory cytokines and the cross talk between leukocytes and cross talk between leukocytes and intrinsic vascular wall cells play a key intrinsic vascular wall cells play a key role in the initiation of the progression role in the initiation of the progression phase. phase.

Atherosclerosis Is An Atherosclerosis Is An Inflammatory DiseaseInflammatory Disease

Alterations in the metabolism of the extracellular Alterations in the metabolism of the extracellular matrix under the plaque arterial matrix under the plaque arterial remodelling remodelling Suppression of new collagen synthesis by smooth Suppression of new collagen synthesis by smooth

muscle cells muscle cells Overproduction of collagen-degrading proteinases Overproduction of collagen-degrading proteinases

that attack the collagen within the fibrous cap that attack the collagen within the fibrous cap Inflammatory mediators tightly control the Inflammatory mediators tightly control the

biosynthesis of tissue factor (a procoagulant)biosynthesis of tissue factor (a procoagulant) Weakening of the fibrous cap thrombosis Weakening of the fibrous cap thrombosis

of a disrupted atheroma of a disrupted atheroma

C-Reactive Protein andC-Reactive Protein andMetabolic SyndromeMetabolic Syndrome

Ridker et al. Circulation. 2003;107:391.

Malik S, et al. (NHANES 1999-2000). Diabetes Care. 2005;28:690-93.

High CRP Levels Predict CVD in High CRP Levels Predict CVD in Patients with and without Patients with and without

Metabolic DisordersMetabolic Disorders

Iwashima Y, et al. Hypertension 2004;43:1318-1323.

Adiponectin Levels are Adiponectin Levels are Significantly Lower in Significantly Lower in Hypertensive SubjectsHypertensive Subjects

FFA

FA CoA

DAG

PKC

Insulin Resistance Inflammation

ROS

IBNFB

Inoguchi et al. Diabetes 2000;49:1939-45.Yu et al. Diabetologia 2001;44:614-20; Lu et al. Circ.Res. 1996;79:611-8.

P --Ser—IRS1

Excess FFA are linked to both Excess FFA are linked to both Insulin Resistance and Insulin Resistance and

InflammationInflammation

Increased lipolysis

Decreased glucose uptake into muscle and adipose tissue and raised hepatic

glucose output

Hyperglycemia

Insulin resistance

-cell dysfunction

High insulin demand and insulin resistance in

pancreas

Elevated circulating FFA

glucotoxicitylipotoxicity

Elevated circulating FFA is a Elevated circulating FFA is a central factor in the development central factor in the development

of type 2 diabetesof type 2 diabetes

Arner P. Diabetes Obes Met 2001;3 (Suppl.1); S11–S19.

>1 billion adults worldwide were:

- Overweight in 2002 1

- BMI>25 kg/m2

At least 300 million are clinically obese 2

- BMI>30 kg/m2

1- World Health Organization. Global strategy on diet, physical activity and health, 2003.Available at: http://www.who.int/hpr/NPH/docs/gs_obesity.pdf. Accessed November 11, 2003.2- International Obesity Task Force. Available at: http://www.iotf.org. Accessed November 13, 2003.

Obesity, Type 2 Diabetes, and Obesity, Type 2 Diabetes, and Metabolic Syndrome: 3 Interrelated Metabolic Syndrome: 3 Interrelated

EpidemicsEpidemicsOverweight/Obesity: a worldwide epidemic

The Metabolic Syndrome The Metabolic Syndrome Is Is

A Metabolic Time BombA Metabolic Time Bomb With the elevated With the elevated

risk of diabetes andrisk of diabetes and

cardiovascular cardiovascular

disease from the disease from the

metabolic metabolic

syndrome, there is syndrome, there is

an urgent need for an urgent need for

strategies to defuse strategies to defuse

this metabolic timethis metabolic time

bombbomb

Management ofManagement of

Metabolic SyndromeMetabolic Syndrome

What to do About the What to do About the Metabolic Syndrome?Metabolic Syndrome?

A.A. Intervening in the Metabolic Syndrome:Intervening in the Metabolic Syndrome: Cardiovascular Risk AssessmentCardiovascular Risk Assessment Metabolic Syndrome Metabolic Syndrome Traditional Risk FactorsTraditional Risk Factors

B. Lifestyle ModificationB. Lifestyle Modification

C. Drug TreatmentC. Drug Treatment

First Step: Assessment of Global Cardiovascular Risk

Risk engines incorporate the major Risk engines incorporate the major cardiovascular risk factors into a summary cardiovascular risk factors into a summary 10-year CHD risk score10-year CHD risk score Framingham: age, sex, smoking, total cholesterol, Framingham: age, sex, smoking, total cholesterol,

HDL-C, systolic blood pressure or treated HDL-C, systolic blood pressure or treated hypertensionhypertension

PROCAM: age, smoking, LDL-C, HDL-C, PROCAM: age, smoking, LDL-C, HDL-C, triglycerides, SBP, fasting blood glucose, triglycerides, SBP, fasting blood glucose, diabetes, treated hypertension, family history of diabetes, treated hypertension, family history of CHDCHD

UKPDS risk engine: estimation of cardiovascular UKPDS risk engine: estimation of cardiovascular risk in patients with type 2 diabetes and no risk in patients with type 2 diabetes and no previous MIprevious MI

Therapeutic Objectives

To reduce underlying causes:To reduce underlying causes: Overweight and obesityOverweight and obesity Physical inactivityPhysical inactivity

To treat associated lipid and non-lipid risk To treat associated lipid and non-lipid risk factors:factors:

HypertensionHypertension Prothrombotic stateProthrombotic state Atherogenic dyslipidaemiaAtherogenic dyslipidaemia Insulin Resistance or Glucose IntoleranceInsulin Resistance or Glucose Intolerance

Lifestyle Therapies: First-Line Lifestyle Therapies: First-Line Interventions to Reduce Metabolic Interventions to Reduce Metabolic

Risk FactorsRisk Factors The major lifestyle interventions The major lifestyle interventions include:include: Weight loss in overweight or obese subjectsWeight loss in overweight or obese subjects Increased physical activityIncreased physical activity Modification of an atherogenic dietModification of an atherogenic diet

These changes will produce a reduction These changes will produce a reduction in all of the metabolic risk factors in all of the metabolic risk factors simultaneouslysimultaneously

In the long run, the greatest benefit for In the long run, the greatest benefit for those with the metabolic syndrome will those with the metabolic syndrome will be derived from effective lifestyle be derived from effective lifestyle interventionintervention

Weight reduction through caloric Weight reduction through caloric restriction:restriction: Caloric intake should be reduced by 500-Caloric intake should be reduced by 500-

1000 calories per day to produce a weight 1000 calories per day to produce a weight loss of 0.5-1.0 kg per weekloss of 0.5-1.0 kg per week

The goal is to reduce bodyweight by about 7-The goal is to reduce bodyweight by about 7-10% over 6-12 months10% over 6-12 months

Weight maintenance can be achieved Weight maintenance can be achieved throughthroughlong-term lifestyle changeslong-term lifestyle changes

Weight Reduction or Weight Reduction or MaintenanceMaintenance

Dietary ChangesDietary Changes

Caloric restriction must be combined Caloric restriction must be combined with a set of dietary principles:with a set of dietary principles: Saturated fat: 7% of total caloriesSaturated fat: 7% of total calories Reduced trans fatReduced trans fat Dietary cholesterol: <200 mg dailyDietary cholesterol: <200 mg daily Total fat: 25-35% of total caloriesTotal fat: 25-35% of total calories Reduced consumption of simple sugarsReduced consumption of simple sugars Increased intakes of fruits, vegetables, Increased intakes of fruits, vegetables,

and whole grainsand whole grainsThe relative amounts of carbohydrate and The relative amounts of carbohydrate and

unsaturated fats is more controversialunsaturated fats is more controversial

Regular and sustained Regular and sustained physical activityphysical activity will will improve all risk factors of the metabolic improve all risk factors of the metabolic syndromesyndrome

Combination of weight loss and exercise Combination of weight loss and exercise reduces the incidence of type 2 diabetes in reduces the incidence of type 2 diabetes in patients with glucose intolerancepatients with glucose intolerance

Current guidelines recommend Current guidelines recommend 30-60 min 30-60 min moderate-intensity exercise dailymoderate-intensity exercise daily (e.g., brisk (e.g., brisk walking)walking)

Physical ActivityPhysical Activity

Third Step: Using Drug Therapy to Third Step: Using Drug Therapy to Modify CV Modify CV

Risk Factors in High-Risk PatientsRisk Factors in High-Risk Patients

Therapeutic lifestyle changes will Therapeutic lifestyle changes will reduce the severity of all components reduce the severity of all components of the metabolic syndromeof the metabolic syndrome

However, drug therapy may be However, drug therapy may be necessary in people at particularly necessary in people at particularly high risk or if a given risk factor is high risk or if a given risk factor is severely abnormalseverely abnormal

Therapy of Metabolic Risk Therapy of Metabolic Risk FactorsFactors

Atherogenic dyslipidaemiaAtherogenic dyslipidaemia Primary target: Primary target: LDL-C levels to ATP III goal LDL-C levels to ATP III goal

levelslevels Secondary target: TG >200 mg/dl, Secondary target: TG >200 mg/dl, non-HDL-C non-HDL-C

to ATP goalsto ATP goals Tertiary targets: HDL-C <40 (men) or Tertiary targets: HDL-C <40 (men) or

<50( women) – after attaining non-HDL-C goal, <50( women) – after attaining non-HDL-C goal, raise HDL-C to extent possibleraise HDL-C to extent possible

Elevated BPElevated BP BP to at least achieve BP <140/90 mmHg BP to at least achieve BP <140/90 mmHg

(or <130/80 mmHg if diabetes)(or <130/80 mmHg if diabetes) Elevated glucose – for IGF, delay progression Elevated glucose – for IGF, delay progression

to type 2 DM; for diabetes, HbAto type 2 DM; for diabetes, HbA1C1C <7.0 % <7.0 % Prothrombotic state: reduce thrombotic and Prothrombotic state: reduce thrombotic and

fibrinolytic risk factorsfibrinolytic risk factors

Drug TreatmentDrug Treatment Weight ReductionWeight Reduction

OrlistatOrlistat SibutramineSibutramine

DyslipidiemiaDyslipidiemia Statins, Fibrates, Nicotinic Acid,EzetimibeStatins, Fibrates, Nicotinic Acid,Ezetimibe

Diabetes MellitusDiabetes Mellitus Insulin Enhancers –SU,Meglitinides,IncretinsInsulin Enhancers –SU,Meglitinides,Incretins Insulin Sensitizers – Biguanides, TZDInsulin Sensitizers – Biguanides, TZD

Metabolic Syndrome ?Metabolic Syndrome ? PPARs , RomonabantPPARs , Romonabant

PPARs

Regulators of energy homeostasis,lipid and glucose metabolism and

inflammation

=

Modulators of the metabolic syndromeand its cardiovascular complications

From Basic Science to From Basic Science to TreatmentTreatment

PPARS: Modulators of the Metabolic Syndrome

Control of Gene Expression by Control of Gene Expression by PPARsPPARs

Targetgene

AGGTCA (N) 1, 2 AGGTCA

PPRE

PPAR

PPAR RXR

RXR

Lipid homeostasis

Glucose homeostasis

Trans- activation

GGGGACTTTCCC TGAGTCA CTGGGA

p65 p50 Fos Jun STAT1 STAT3

NF-B-RE TRE ISGF-RE

PPAR

Anti-inflammatory properties

Trans-repression

PPAR agonists(fatty acids, fibrates, glitazones, glitazars)

Glucose Metabolism PPARs Glucose Metabolism PPARs

Regulate Lipid andRegulate Lipid and GlucoseGlucose

PPAR Agonists Interrupt the PPAR Agonists Interrupt the Inflammatory CycleInflammatory Cycle

PPAR

PPAR Agonists May Block Inflammatory Atherogenesis at Several Steps

CONCLUSIONCONCLUSION Metabolic Syndrome is a clustering of Metabolic Syndrome is a clustering of

cardiovascular risk factorscardiovascular risk factors Metabolic Syndrome is a global epidemicMetabolic Syndrome is a global epidemic Insulin Resistance is the core of Insulin Resistance is the core of

Metabolic Syndrome modified by obesity, Metabolic Syndrome modified by obesity, inflammation, genetics and inflammation, genetics and environmental factorsenvironmental factors

Management of MS include lifestyle Management of MS include lifestyle modifcation and drug treatment of the modifcation and drug treatment of the individual componentsindividual components