Metabolic Syndrome
Report of the National Heart, Lung, and Blood Institute/American
Heart Association Conference
Circulation. 2004;109:433-438.
"Metabolic Syndrome" (dysmetabolic syndrome, syndrome X,
insulin resistance syndrome, obesity syndrome, and Reaven’s
syndrome) describes a cluster of CVD risk factors and metabolic
alterations associated with excess fat weight.
The prevalence rate of metabolic syndrome based on data from Third National
Health and Nutrition Examination Survey (NHANES III):
There was a slightly greater prevalence among women.
24.7% of female vs. 21.7% of males (p=0.007)
Whites were at greater risk.
24.1% of whites, 19.3% of blacks, and 16.5% of “other races”
(p=0.003)
The National Heart, Lung, and Blood Institute/American Heart
Association Conference reviewed the scientific evidence related
to definition of metabolic syndrome from several perspectives:
(1) major clinical outcomes
(2) metabolic components
(3) pathogenesis
(4) clinical criteria for diagnosis
(5) risk for clinical outcomes
(6) therapeutic interventions
Major clinical outcomes
CVD
Type 2 Diabetes
Polycystic Ovary Syndrome
Fatty Liver
Cholesterol Gallstones
Asthma
Sleep Disturbances
Cancer
Coagulation abnormalities
Major clinical outcomes
Metabolic components
Pathogenesis
Clinical criteria for diagnosis
Risk for clinical outcomes
Therapeutic interventions
Components of metabolic syndrome
The National Cholesterol Education Program’s Adult
Treatment Panel III report (ATP III) identified 6 components
of the metabolic syndrome that relate to CVD:
1. Abdominal obesity
2. Atherogenic dyslipidemia
3. Raised blood pressure
4. Insulin resistance  glucose intolerance
5. Proinflammatory state
6. Prothrombotic state
Major clinical outcomes
Metabolic components
Pathogenesis
Clinical criteria for diagnosis
Risk for clinical outcomes
Therapeutic interventions
Abdominal obesity
The form of obesity most strongly associated with the metabolic syndrome. It
presents clinically as increased waist circumference.
Atherogenic dyslipidemia
triglycerides
HDL cholesterol
 remnant lipoproteins
 apolipoprotein B
Small LDL/HDL particles
Elevated blood pressure
Strongly associates with obesity and commonly occurs in insulin-resistant
persons. Although it is multifactorial and less “metabolic” than other metabolicsyndrome components.
Insulin resistance  glucose intolerance
Present in the majority of people with the metabolic syndrome.
It strongly associates with other metabolic risk factors and correlates with
CVD risk.
These associations, combined with belief in its priority, account for the term
insulin resistance syndrome.
Elevated glucose constitutes a major, independent risk factor for CVD.
Proinflammatory state
Recognized clinically by elevations of C-reactive protein (CRP), is commonly
present in persons with metabolic syndrome.
Adipose tissue  inflammatory cytokines  CRP levels.
Prothrombotic state
Characterized by increased plasma plasminogen activator inhibitor (PAI)-1 and
fibrinogen. Fibrinogen, an acute-phase reactant like CRP, rises in response to a
high-cytokine state.
Pathogenesis of metabolic syndrome
Major clinical outcomes
Metabolic components
Pathogenesis
Clinical criteria for diagnosis
Risk for clinical outcomes
Three etiological categories:
Therapeutic interventions
1. Obesity and abnormal body fat distribution
2. Insulin resistance
3. Other factors that mediate specific components of the
metabolic syndrome
Obesity and Abnormal Body Fat Distribution
The National Cholesterol Education Program’s ATP III considered the
“obesity epidemic” as mainly responsible for the rising prevalence of
metabolic syndrome.
Independent atherogenic risk factors :  triglycerides and  HDL cholesterol
 remnant lipoproteins,  apolipoprotein B, small LDL, HDL particles.
 Nonesterified fatty acids (NEFA): overloads muscle and liver with lipid,
which enhances insulin resistance.
 Cytokines, CRP levels: proinflammatory state
 PAI-1: prothrombotic state
 Adiponectin: worsen of metabolic risk factors
Insulin Resistance
Many investigators place a greater priority on insulin resistance than
on obesity in pathogenesis.
Insulin resistanceother metabolic risk factors. Yet a broad range of
insulin sensitivities exists at any given level of body fat.
Hyperinsulinemia:  very low density lipoprotein,  triglycerides.
 glucose: a major, independent risk factor for CVD.
Insulin resistance:  blood pressure by a variety of mechanisms.
Other Factors That Mediate Specific Components of the
Metabolic Syndrome
Genetic variation in lipoprotein metabolism, blood pressure regulation,
insulin-secretory capacity, insulin sensitivity.
Advancing age
Endocrine factors linked to abnormalities in body-fat distribution
Clinical criteria for diagnosis
Major clinical outcomes
Metabolic components
Pathogenesis
Clinical criteria for diagnosis
Risk for clinical outcomes
Therapeutic interventions
At least 3 organizations have recommended clinical criteria
for the diagnosis of the metabolic syndrome.
Their criteria are similar in many aspects, but they also reveal
fundamental differences in positioning of the predominant
causes of the syndrome.
The National Cholesterol Education Program’s Adult
Treatment Panel III report (ATP III)
(Diagnosis can be made if 3 out of 5 present)
Circulation. 2004;109:433-438.
The National Cholesterol Education Program’s Adult
Treatment Panel III report (ATP III)
The primary clinical outcome of metabolic syndrome was CHD/CVD.
Priority is given to abdominal obesity as a contributor to metabolic
syndrome.
Cutpoints for several of these are less stringent than usually required to
identify a categorical risk factor, because multiple marginal risk factors
can impart significantly increased risk for CVD.
Explicit demonstration of insulin resistance is not required for diagnosis.
World Health Organization
World Health Organization
The guideline group also recognized CVD as the primary outcome of the
metabolic syndrome.
However, it viewed insulin resistance as a required component for diagnosis.
In addition to insulin resistance, 2 other risk factors are sufficient for a
diagnosis of metabolic syndrome.
A higher blood pressure was required than in ATP III. BMI (or increased
waist:hip ratio) was used instead of waist circumference
Microalbuminuria was listed as one criterion
The requirement of objective evidence of insulin resistance should give more
power to predict diabetes than does ATP III, but less applicable.
American Association of Clinical Endocrinologists
American Association of Clinical Endocrinologists
These criteria appear to be a hybrid of those of ATP III and WHO
metabolic syndrome.
However, no defined number of risk factors is specified; diagnosis
is left to clinical judgment.
Finding abnormal 2-hour glucose will improve prediction of type 2
diabetes.
Risk for clinical outcomes
Major clinical outcomes
Metabolic components
Pathogenesis
Clinical criteria for diagnosis
Risk for clinical outcomes
Therapeutic interventions
Metabolic Syndrome as a Predictor of CVD
Metabolic Syndrome as a Predictor of Diabetes
Diabetes as a Predictor of CVD
Metabolic Syndrome as a Predictor of CVD
In Framingham, the metabolic syndrome alone predicted 25% of all newonset CVD.
In the absence of diabetes, the metabolic syndrome generally did not raise
10-year risk for CHD to >20%.
Most of the risk associated with the metabolic syndrome is age, blood
pressure, total cholesterol, diabetes, and HDL cholesterol.
Beyond these, obesity, triglycerides, and glucose levels (in the absence of
diabetes) provided little additional power of prediction.
Metabolic Syndrome as a Predictor of Diabetes
Metabolic syndrome  new-onset diabetes.
Framingham cohort, in both men and women, Almost half of the
population-attributable risk for diabetes could be explained by the
presence of ATP III metabolic syndrome.
Diabetes as a Predictor of CVD
Framingham data showed that most men with diabetes had a
10-year risk for CHD 20%; in contrast, women rarely
exceeded the 20% level.
Oxford investigators therefore have developed a risk engine based
on the large UK Prospective Diabetes Study (UKPDS) database,
which had 500 hard CHD events. It differs from the Framingham
algorithm in that it includes a measure of glycemia and duration of
diabetes.
Surveys of other diabetic populations by UKPDS investigators
found that Framingham equations considerably underestimate
risk for CHD and stroke, whereas the UKPDS Risk
Engine provides a more robust estimate.
Therapeutic interventions
Major clinical outcomes
Metabolic components
Pathogenesis
Clinical criteria for diagnosis
Risk for clinical outcomes
Therapeutic interventions
Obesity and Body Fat Distribution as Targets of Therapy
Insulin Resistance as Target of Therapy
Specific Metabolic Risk Factors as Targets of
Therapy
Obesity and Body Fat Distribution as Targets of Therapy
ATP III recommended that obesity be the primary target of
intervention for metabolic syndrome.
First-line therapy: Weight reduction, increased physical activity.
serum cholesterol, triglycerides, glucose, CRP, PAI-1, blood
pressure, insulin resistance
HDL cholesterol
Implementation is the challenge!
Insulin Resistance as Target of Therapy
Insulin resistance, whether primary or secondary to obesity, is an attractive
target.
Weight reduction and increased physical activity
Two classes of drugs treating type 2 diabetes: Metformin and thiazolidinediones
(TZDs).
In UKPDS, metformin apparently reduced newonset CHD in obese patients with
diabetes.
In the Diabetes Prevention Program, metformin therapy prevented (or delayed) onset of
type 2 diabetes in persons with IGT.
There are, however, no CVD end-point studies on metformin or TZDs-treated patients
with metabolic syndrome.
Specific Metabolic Risk Factors as Targets of
Therapy
Atherogenic Dyslipidemia
Statins:  all apolipoprotein B–containing lipoproteins.
Statin trials reveal that statins reduce risk for CVD events in patients with
metabolic syndrome.
Fibrates
Fibrate trials strongly suggests that they reduce CVD end points in patients
with atherogenic dyslipidemia and metabolic syndrome.
Elevated Blood Pressure
Lifestyle therapies
Antihypertensive drugs
No class of antihypertensive drugs has been identified as being uniquely
efficacious in patients with metabolic syndrome.
Prothrombotic State
No drugs are available that target PAI-1 and fibrinogen.
Antiplatelet therapy: low-dose aspirin reduces CVD events
Proinflammatory State
Several lipid-lowering drugs will reduce CRP levels, which could reflect an
anti-inflammatory action.
Hyperglycemia
Lifestyle therapies
Hypoglycemic agents
Conclusion
CVD is the primary clinical outcome of metabolic syndrome
Risk for type 2 diabetes is higher
Diabetes is a major risk factor for CVD
ATP III criteria provide a practical tool to identify patients at increased risk
for CVD
WHO and AACE criteria require further oral glucose testing if IFG and
diabetes are absent.
Full agreement that therapeutic lifestle change (weight reduction)
constitutes first-line therapy.