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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