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METABOLIC SYNDROME
A Resource from the American College of Preventive Medicine

CLINICAL REFERENCE
The following Clinical Reference Document provides the evidence to support the Metabolic Syndrome Time Tool. The following bookmarks are available to move around the Clinical Reference Document. You may also download a printable version for future reference.

 

 

  1. Description/Definitions
  2. Diagnostic Criteria
  3. Prevalence and Trends
  4. Impact on Health and Disease
  5. Etiology and Mechanisms
  6. Treating the Metabolic Syndrome
  7. Guidelines
  8. The Challenges
  9. Clinical Approach: The Initial Consult
  10. Practice Reorganization: The Chronic Care Model
  11. Bottom Line
  12. Resources
  13. References
1. DESCRIPTION / DEFINITION

The fattening of the human species and the emergence of the metabolic syndrome and Type 2 diabetes are among the major epidemiologic events of our time. [1]The National Cholesterol Education Program (NCEP) Adult Treatment Panel III, which provides the current diagnostic standard, describes the metabolic syndrome as a constellation of clinical characteristics associated with an increase in risk of developing type 2 diabetes and atherosclerotic cardiovascular disease.[2]A general definition: A collection of metabolic abnormalities associated with insulin resistance that predisposes affected individuals to accelerated atherosclerosis and consequently increased risk of cardiovascular events. [3]The metabolic abnormalities include:
  • carbohydrate intolerance,
  • a specific pattern of dyslipidemia - increased triglycerides, low HDL cholesterol, small dense LDL cholesterol, increased apolipoprotein B
  • hypertension
  • endothelial dysfunction
  • increased coagulation
  • decreased fibrinolysis, and
  • microalbuminuria [4]
Central, abdominal, or visceral obesity appears to be a major etiologic factor for the insulin resistance and other factors of the metabolic syndrome. [3]
  • It is commonly associated with pre-diabetic hyperinsulinemia, which contributes greatly to the metabolic dysfunction.
  • This combination of metabolic abnormalities, especially when occurring together, contributes to endothelial dysfunction, inflammation and an accelerated rate of atherosclerosis. [5]
It is part of the natural course of developing impaired glucose tolerance and Type 2 diabetes -- from insulin resistance to hyperinsulemia to impaired glucose tolerance to hyperglycemia to diabetes. [6,7]
  • It is progressive, with borderline risk factors worsening over time.
The metabolic syndrome is thought to be a driver of the modern day epidemics of diabetes and CVD; as such, it has become a major, and growing, public health challenge around the world. [9]
  • It has enormous clinical and public health implications by providing a simple way to identify individuals at greatly increased risk of suffering these devastating diseases.

History of the Metabolic Syndrome
The clustering of risk factors that has become the "Metabolic Syndrome" came primarily from the diabetes field. The pathology of Type 2 diabetes and the role of insulin resistance had been studied for years. But the concept of the syndrome was introduced in 1988 by Reaven in the "Banting" Lecture of the ADA Annual Meeting -- "Role of insulin resistance in human disease". He coined the initial name, "Syndrome X". [7]

He described insulin resistance as the dominant underlying risk factor that leads to progressively disrupted metabolism. This eventually led others in the diabetes field to later adopt the name, "Insulin Resistance Syndrome". [10-14]

They largely viewed obesity as an exacerbating factor but without the pathophysiological significance of insulin resistance. More recently, MetabolicSyndrome (or Dysmetabolic Syndrome) has become the more commonly used name, reflecting the broader scope of underlying factors in the development of the syndrome. [15-17]

The Cloud of Controversy
The American Diabetes Association (ADA) and the American Heart Association (AHA) disagree when it comes to the Metabolic Syndrome. [18]

  • The ADA emphasizes the association with diabetes, referring to the syndrome as "pre-diabetes.”
  • They discount its use in CVD risk prediction, claiming that it is merely a combination of risk factors that the AHA already includes without calling it the Metabolic Syndrome.
The AHA is actually more enthusiastic about the syndrome than the ADA. [18]
  • They emphasize its importance in CVD prevention and risk assessment – that the specific combination of disorders places these people at a much higher risk, and deserves the increased attention.
The controversy involves four aspects:
  • The varying definitions,
  • Evidence for and against its use in predicting cardiovascular disease risk,
  • Questions about the underlying pathophysiology, and
  • Whether it changes treatment over simply treating the individual conditions. [19]

For a concise summary of the controversial issues that surround the syndrome see the review article by Grundy: Grundy, Scott.Metabolic Syndrome: A Multiplex Cardiovascular Risk Factor. J Clin Endocrinology & Metabolism 92(2): 399-404, 2007.

Gaining Acceptance
The concept of the Metabolic Syndrome continues to gain acceptance as a condition that mandates treatment as a single entity rather than as individual conditions. [20]

  • An important value of the syndrome is the increasing attention to the important link between metabolic alterations and cardiovascular events.
  • Each risk factor of the syndrome (visceral obesity, atherogenetic dyslipidemia, elevated blood pressure, and dysglycemia) can be dealt with individually, but the optimal therapeutic approach is to focus on reversing its root causes of atherogenic diet, sedentary lifestyle, and overweight or obesity. [21]
The most important function of identifying the syndrome in an individual is the focus it places on lifestyle – the entire syndrome is best treated by adopting a healthy diet and becoming more active. [21]
  • The root causes are too little physical activity combined with an atherogenic diet – it results in weight gain and the metabolic syndrome in genetically susceptible people.
The metabolic syndrome provides an early warning of at risk subjects and emphasizes the need to treat more aggressively by lifestyle modification patients with multiple abnormalities even though the abnormalities might be slight.
  • The syndrome can be easily used in clinical practice and when assessed against the background of the age, sex and smoking habits, provides an evaluation of potential cardiovascular risk. [22]
Lack of Awareness
The Study to Help Improve Early evaluation and management of risk factors Leading to Diabetes (SHIELD), a longitudinal US population-based survey initiated in 2004, showed that less than 15% of respondents had even heard of the metabolic syndrome. [23]
  • The lack of knowledge about metabolic syndrome indicates limited penetration of this concept into public awareness.
2. DIAGNOSTIC CRITERIA

The NCEP-ATP III report included the definition of the metabolic syndrome that is now most widely used:
  • Any 3 of the 5 defining criteria:
    • abdominal obesity: waist circumference ≥ 40” in men, ≥ 35” in women,
    • elevated triglycerides: ≥ 150 mg/dL or on drug therapy for elevated triglycerides,
    • low HDL cholesterol: < 40 mg/dL in men or < 50 mg/dL in women or on drug therapy for low HDL,
    • borderline hypertension: ≥ 130/85 or on drug therapy for elevated blood pressure,
    • fasting hyperglycemia: ≥ 100 mg/dL or on drug therapy for elevated glucose. [2] http://circ.ahajournals.org/cgi/content/full/112/17/e285/TBL1

  • Lower waist circumference cut points (i.e., ≥ 35 inches in men and ≥ 31 inches in women) appear to be appropriate for Asian Americans. [2]
The defining criteria for the syndrome has been a source of controversy and the subject of many symposia around the world. The first published definition was from the World Health Organization (WHO) in 1998, along with its related European Group for the Study of Insulin Resistance (EGIR) guidelines. [24,25]In 2001, at the urging of the American Association of Clinical Endocrinologists (AACE), a new ICD-9 code (277.7) for the "dysmetabolic syndrome" was approved [26]
  • ICD-9 CODE 277.7 Dysmetabolic syndrome X
  • Use additional codes for associated manifestation, such as:
    • cardiovascular disease (414.00-414.07)
    • obesity (278.00-278.01

In the same year, the National Cholesterol Education Project Adult Treatment Panel (NCEP-ATP III) published its expert panel report and guidelines, using the name "Metabolic Syndrome" because it seemed to better describe the constellation of risk-factors and their underlying pathology. [2,27]

The American College of Endocrinology (ACE) subsequenly published a position statement in collaboration with American Association of Clinical Endocrinologists (AACE) on "insulin resistance" (their preferred term), which uses BMI rather than waist circumference to measure central obesity, introduces ethnicity as a risk factor, and emphasizes that diagnosis should be based on clinical judgment informed by the evaluation of risk factors. [28]

The most recent definition of the metabolic syndrome was released by the International Diabetes Federation (IDF) in 2005. [29]

  • It is the same as the NCEP definition, except that it requires meeting the waist circumference criteria first, then any two others; this reflects the growing recognition of the key role of central obesity.
  • It also uses a slightly lower waist circumference threshold, as well as ethnicity specific thresholds.
  • But, requiring abdominal adiposity means missing non-obese individuals who have increased CVD mortality. [30]
The NCEP-ATPIII is the simplest criteria and the most suitable for clinical practice. [31]
  • The IDF criteria are a little more complex and have not been as well evaluated.

The table below compares the definitions of the NCEP-ATP III and the IDF.

Table. Current Criteria for the Diagnosis of the Metabolic Syndrome*

 

NCEP-ATP III

IDF

Hypertension

Current antihypertensive therapy OR
SBP ≥ 130 OR DBP ≥ 85

Current antihypertensive therapy OR
BP ≥ 130/85

Dyslipidemia - Elevated Triglycerides

Plasma triglycerides ≥ 150 mg/dL

Plasma triglycerides ≥ 150 mg/dL or specific treatment for high triglycerides

Dyslipidemia - Depressed HDL

 

HDL < 40 mg/dL in men or < 50 mg/dL in women

HDL < 40 mg/dL in men or < 50 mg/dL in women or specific treatment for low HDL

Obesity

Waist circumference ≥ 40 inches in men or ≥ 35 inches in women

Waist circumference > 37 inches in men or > 31.5 inches in women

Glucose

Fasting blood glucose ≥ 100 mg/dL

Fasting glucose ≥ 100 mg/dL OR previously diagnosed type 2 diabetes

Requirements for diagnosis

Any 3 of the above criteria.

Waist circumference criteria PLUS any 2 of other criteria.

NCEP-ATP III = National Cholesterol Education Project Adult Treatment Panel; IDF = International Diabetes Federation; BP = blood pressure; HDL = high-density lipoprotein; BMI = body mass index; IGT = impaired glucose tolerance
*Adapted from: Kendall DM, Harmel AP. The metabolic syndrome, type 2 diabetes, and cardiovascular disease. Understanding the role of insulin resistance.
Am J Manag Care. 2002;8:S635-S653.

Improving the Diagnostic Capability -- Potential New Criteria
Insulin Resistance
Insulin resistance and the resulting compensatory hyperinsulinemia are clearly key pathophysiologic factors. Simple, valid and reliable measurements of each would be very helpful but such measures are not currently available (standardized fasting insulin assays), or practical (insulin resistance tests) in the clinical setting. [32,33]

  • The gold standard for insulin resistance is the euglycemic hyperinsulinemic clamp method, but it is too time consuming and expensive to use for screening
Adiponectin
The recently discovered adipokine, adiponectin, has been shown to reflect insulin resistance (lower level - greater resistance). Data from the Rancho Bernardo Study suggest that measurement of adiponectin levels could eventually become a useful way to test for early risk for the development of the metabolic syndrome.
  • Age-adjusted total adiponectin concentration at baseline was found to be lower in those who eventually developed the metabolic syndrome. [34]
C-Reactive Protein
Adding CRP, as a marker of inflammation, to the definition of the Metabolic Syndrome has been shown to improve the prediction of CVD, and may also be predictive of development of the metabolic syndrome. [35]
  • CRP is being used to improve vascular risk prediction in primary and secondary prevention trials across all levels of low-density lipoprotein-cholesterol (LDL-C), all levels of the Framingham Risk Score, and all levels of metabolic syndrome. [36]

Using the Triglyceride/HDL ratio
The triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio may be a clinically simple and useful indicator for hyperinsulinemia among nondiabetic adults regardless of race/ethnicity. [37]

Additional lipoprotein testing
The 2008 ADA/ACC consensus statement discusses the use of apolipoprotein B testing as well as LDL particle testing to differentiate MetS dyslipidemia. [See Resources, Consensus Statements]

3. PREVALENCE AND TRENDS

NHANES 1999-2000, using the NCEP definition, showed the prevalence of the metabolic syndrome to be 34.5% overall, 33.7% among men, and 35.4% among women. [38]
  • Using the IDF criteria (lower waist circumference), the prevalence increased to 39.0 % among all participants, 39.9% among men, and 38.1% among women. This primarily reflected an increased prevalence in Mexican-American men (lower waist threshold).
  • The two definitions correctly classified approximately 93% of the participants as having or not having the metabolic syndrome.
As the population ages, so does the prevalence of the Metabolic Syndrome. One analysis shows about 45% of the population over 60 to have the syndrome. [39]
  • Studies suggest that 1 of every 3 people born in the year 2000 will develop diabetes, and if present trends continue, for Latino and African Americans born in 2000, the risk approaches 1 in 2.
And it is being seen at younger and younger ages, in parallel with the rising incidence of obesity. [40]
  • NHANES data show that the prevalence of the metabolic syndrome in 12- to 19-year-olds increased from 9.2% in 1988-1994 to 12.7% in 1999-2000.
  • Even more alarming is the prevalence in overweight adolescents -- 38.6% vs 1.4% in normal-weight adolescents.
There are gender differences in the syndrome as well.
  • Prevalence has been increasing at a steeper rate in women during the last decade; this may be contributing to the increased rate of CVD in postmenopausal women who are more prone to central obesity. [41]
Of the individual components of the syndrome, fasting hyperglycemia is the last to develop, reflecting the natural course of the developmental process:
  • Insulin resistance -> Hyperinsulinemia -> Impaired glucose tolerance -> Fasting hyperglycemia -> Type 2 diabetes [7]

This is reflected in the prevalence of individual components of the MS reported in NHANES III:

 

Men

Women

Increased waist circumference

30%

46%

Triglycerides > 150

36%

25%

Low HDL

36%

40%

Hypertension

38%

29%

Fasting glucose > 110

16%

10%

NHANES III. Ford ES et al. JAMA 2002; 287: 356-9

The Mirror Image -- Rising Obesity
In 1980, 13% of men and 17% of women were obese; today 28% of men, 34% of women.
  • The same trend is seen in children, rates obesity increased from 6% to 15% in 6-11 yr olds and from 5% to 16% in 12-19 yr olds over the same 20 yr period, 1980-2000. [42]
From NHANES III (1988-94) to NHANES 1999-00, the prevalence of overweight increased from 56% to 65% of the population and the prevalence of obesity increased from 23% to 31%. [43]
  • Nearly 2 out of every 3 are overweight, 1 of 3 obese, a striking statistic that has an enormous impact on the health of the nation.
  • NHANES data from 1999-2004 shows that over half of people with hypertension are currently obese. [44]
An ominous trend is the rise in abdominal obesity – fat accumulated in the trunk as opposed to the lower body; fat that is closely associated with the metabolic syndrome.
  • NHANES data shows that the average waist circumference has steadily increased in both men and women over the last 40 years, but especially the last 10 years. [45]
  • NHANES 2003-4 showed that over half of U.S. adults (42% of men, 61% of women) had abdominal obesity. [46]

Waist Circumference (inches)

 

Men

Women

1960-1962

35

30.3

1988-1994

37.4

35

2003-2004

39.5

37


4. IMPACT ON HEALTH AND DISEASE

Despite the controversies, there is no question about the impact of this collection of risk factors on health and disease. Many researchers have shown that increased insulin resistance and the metabolic syndrome increase the risk for CVD and the development of type 2 diabetes. [44-53] [47-56]
  • People with the metabolic syndrome are at essentially twice the risk for cardiovascular disease compared with those without the syndrome. It further raises the risk for type 2 diabetes by about 5-fold. [2,57]

Data from more than 154,000 men and 90,000 women in the NIH-AARP Diet and Health Study showed that, after adjustment for BMI and other covariates, a large waist circumference alone was associated with a 25% increased mortality. Even with a normal BMI, a large waist circumference conveyed a 20% increase in mortality risk. [58]

NHANES data shows that adults with the metabolic syndrome experience poorer health-related quality of life than adults without this syndrome. [59]

CARDIOVASCULAR DISEASE
The Metabolic Syndrome is associated with about a two-fold increase in risk of cardiovascular events, independent of the presence of diabetes mellitus. [60]

  • The doubling of risk was confirmed in a meta-analysis of 9 primary studies published between 2002 and 2004 that was presented at the ADA annual meeting in 2005; it included more than 50,000 patients with a median follow-up of 5 years. [61]
More importantly, longitudinal studies have confirmed that atherosclerosis develops earlier and at a faster rate in people with the metabolic syndrome than those without the syndrome. [62]
  • The high risk for CVD that results from the MS generally precedes the diagnosis of diabetes by 10-20 years. [63]
An increased prevalence of early subclinical cardiovascular damage has been observed in several studies when the MS includes hypertension. [64]
  • Several studies have found an increased prevalence of left ventricular hypertrophy, diastolic dysfunction, early carotid atherosclerosis, impaired aortic distensibility, hypertensive retinopathy and microalbuminuria in hypertensive patients with MS compared to those without it.
  • May partially explain the association of the MS with a higher cardiovascular and renal risk.
The majority of patients without known diabetes or IGT who have a heart attack do, in fact, have diabetes or impaired glucose tolerance that was undetected prior to the infarction. [65]
  • Only one third of these heart attack surviviors actually had neither diabetes nor glucose intolerance.
Death from cardiovascular disease is significantly increased in patients with the metabolic syndrome at all levels of glucose tolerance. The combination of the Metabolic Syndrome with diabetes is particularly hazardous. [66,67]
  • NGT w Metab Syn -- 1.73 times risk of CHD than NGT wo metab syn
  • IGT w Metab Syn -- 1.82 times risk of CHD than IGT wo metab syn
  • DM w Metab Syn -- 2.23 times risk of CHD than DM wo metab syn
  • DM w Metab Syn -- 5 times risk of CHD than NGT wo metab syn
Other studies have confirmed these findings.
  • The Botnia study from Finland showed that cardiovascular mortality in people with metabolic syndrome is increased 6-fold compared with people without the syndrome over a 7-year period. [67]
  • The Kuopio Ischaemic Heart Disease Risk Factor Study reported the risk of death from heart or vascular disease to be about 3-4 fold higher in patients with the metabolic syndrome. [68]
In women, the Nurses' Health Study has shown that: [63]
  • Those with diabetes when the study began had the highest risk for a CV event during 20-year follow-up – 5 times that of those who remained non-diabetic.
  • Those diagnosed with diabetes during the study were 4 times as likely to have an event after the daignosis.
  • And those who eventually developed diabetes and thus likely had the metabolic syndrome, had 3 times the risk of having a CV event before they were diagnosed with diabetes.

The associated risk factors have a continuous, progressive impact on total CV risk, with higher levels and numbers of factors translating into greater risk. [69]

Risk for stroke also increased Meta-analysis of 13 cohorts with the metabolic syndrome showed that they had a 1.6-fold increased risk of stroke. [70]

Is risk from the Metabolic Syndrome greater than expected from traditional risk factors?
Controversy exists as to whether the metabolic syndrome adds anything to cardiovascular risk prediction beyond the individual risk factors that define it. [71]

Data from the San Antonio Heart Study suggests that it does.

  • Excess risk was associated with increasing insulin resistance after adjusting for traditional risk factors -- age, ethnicity, LDL cholesterol, triglyceride, HDL cholesterol, systolic blood pressure, smoking, alcohol consumption, leisure time exercise, and waist circumference. [72]
Nontraditional risk factors
Conventional risk formulas underestimate actual CVD risk in patients with the metabolic syndrome because of the influence of nontraditional risk factors. [73]
  • As the syndrome evolves, a number of coexisting metabolic abnormalities contribute additional risk.
  • This likely explains the disproportionate increase in CVD risk in people with Type 2 diabetes [74]
An increased prevalence of non-traditional risk factors has been observed in patients with diabetes, IGT, IFG and the metabolic syndrome. [75]
  • After adjustments for traditional risk factors, the metabolic syndrome is associated with an increased likelihood of abnormal levels of:
    • low apolipoprotein A1 -- 2.27 times as likely as those without the syndrome,
    • high apolipoprotein-B -- 2.97 times as likely,
    • higher HOMA insulin resistance index -- 5.25 times as likely,
    • chronic kidney disease -- 2.27 times as likely, and
    • elevated markers of inflammation [high white blood cell count (1.55 times), and elevated C-reactive protein (1.46 times)].
There is accumulating evidence of the deleterious impact on several of these nontraditional risk factors when the metabolic syndrome is present.
  • Inflammation is one --the inflammatory marker, C reactive protein (CRP), appears to modify risk at all levels of the metabolic syndrome. [76]
  • Abdominal obesity increases risk even in the absence of traditional risk factors due to the effects of increased adipokines (reduced adiponectin). [77]
  • Diabetes is clearly a major risk factor, but accumulating evidence also suggests that prediabetes (either IGT or impaired fasting glucose) increases risk long before diabetes is diagnosed. [78]
Accumulating evidence suggests that several emerging biomarkers may prove useful in defining prognosis for CVD in patients with the MS.
  • CRP is one of these, a marker of chronic mild inflammation -- now commonly used in clinical practice to improve vascular risk prediction across all levels of LDL cholesterol, all levels of the Framingham Risk Score, and all levels of metabolic syndrome. [79]
  • Others include markers of:
    • increased oxidant stress (oxidized LDL),
    • thrombophilia (e.g. plasminogen activator inhibitor-1, PAI-1),
    • endothelial dysfunction (e.g. E-selectin), and
    • other lipoprotein abnormalities -- lipoprotein-associated phospholipase A2, myeloperoxidase, lipoprotein (a), isoprostanes, and small, dense LDL. [80]

Greater impact on women
The Metabolic risk factors of the syndrome have been suggested to portend a greater CHD risk in women than men, especially postmenopausal women. There are parallel epidemics occurring in postmenopausal women -- cardiovascular disease and the metabolic syndrome. [81]

The Nurses' Health Study has followed almost 120,000 women for over 20 years.

  • Women who subsequently developed diabetes, and therefore were most likely to have the metabolic syndrome, had almost 3 times the risk of having an event before they were diagnosed with diabetes.
  • Women were almost 4 times as likely to have an event after the diagnosis of diabetes, and women who entered the study with pre-existing diabetes were the most likely to have an event, with 5 times the relative risk. [63]

RISK FOR TYPE 2 DIABETES
Type 2 diabetes mellitus is a public health problem of epidemic proportions and its prevalence is on the rise. The metabolic syndrome is a powerful risk factor for Type 2 diabetes, stronger than for CVD. [82]

A meta-analysis of 16 cohorts showed that the presence of the MS increases the risk of developing diabetes by about 5 times. [83]

  • Framingham Heart Study -- nearly 7 times the risk over 8 years [84]
  • San Antonio Heart Study -- 3.3 times the risk over 7 to 8 years [85]
  • Insulin Resistance Atherosclerosis Study -- 3.4 to 5.4 times the risk over 5-6 years. [86]
  • Prospective study of general practices in 24 British towns -- 3.6 times the risk over 20 years. [87]
  • Community-based study, normal-weight subjects with the Metabolic Syndrome had 4 times the risk of developing Type 2 diabetes; obese with the syndrome had 10 times the risk of obese without the syndrome over 11 years. [88]
  • Hypertensive patients with the syndrome -- nearly 8 times risk of developing Type 2 diabetes over 4 years, and hypertensive patients who developed the syndrome over the 4 year study period were 4 times as likely to develop Type 2 diabetes[89]
  • In samples from the general population, the presence of the metabolic syndrome increased the risk for Type 2 diabetes by 3 times. [90]
The greater the number of components of the syndrome present, the greater the risk of developing Type 2 diabetes compared with the subjects without the MetS.
  • Insulin Resistance Atherosclerosis Study (IRAS), the 5-year probability of developing Type 2 diabetes by number of components of the MetS was: no components = 5%; one = 11%; two = 18%; three = 37%; four = 45%; and all five = 50% [91]
  • 1.58 times the risk for one component, 2.48 times the risk for two components, 3.10 times the risk for three components (diagnosis), and 5.22 times the risk for those with four components. [92]
  • The probability of developing CVD or DM2 over 20 years increased from 11.9% in those with no abnormalities to 31.2% in those with 3 abnormalities to 40.8% in those with 4 or 5 abnormalities. [93]
  • The relative risks of incidence of type 2 diabetes for the presence of 1,2,3, and > or =4 components, were, respectively, 1.92, 4.36, 6.44, and 15.08. [94]

This data suggests that the metabolic syndrome accounts for approximately half of new cases of Type 2 diabetes. [90,95]

Chronic Kidney Disease is another important effect of the MS
The metabolic syndrome is associated with an increased risk for CKD and albuminuria. [96]

  • An analysis from the NHANES database showed that chronic kidney disease increases with number of components of the metabolic syndrome.
5. ETIOLOGY - MECHANISMS

The 2 major underlying risk factors for the metabolic syndrome are obesity and insulin resistance. [97]
  • Exacerbating factors are physical inactivity, advancing age, and endocrine and genetic factors.
  • Associated hyperinsulinemia, hyperglycemia, and elevated adipokine levels (adipose cytokines) lead to vascular endothelial dysfunction, an abnormal lipid profile, hypertension, and vascular inflammation, all of which promote the development of atherosclerotic cardiovascular disease.
The simple fact that over 90% of cases of metabolic syndrome in obese people are reversed after weight reduction surgery suggests that obesity is the driving force. [21]
  • There is agreement that full expression of the syndrome depends on complex interactions between multiple possible genetic determinants (still largely unknown) and lifestyle habits.
Chronic energy imbalance seems to be the underlying problem. But the resulting pathophysiology is complex and not well understood. Adipocyte hypertrophy and hyperplasia, endoplasmic reticulum stress, and mitochondrial dysfunction are involved. [98]
  • lead to increased intracellular and systemic release of adipokines, free fatty acids, and inflammatory mediators that cause adipocyte dysfunction and induce adverse effects in the liver, pancreatic β-cells, and skeletal muscle as well as the heart and vascular beds.
Insulin resistance is a generalized metabolic disorder characterized by inefficient insulin action in its primary targets -- skeletal muscle, liver and adipocytes.[99]
  • It has long been recognized as an important metabolic link between the components of metabolic syndrome. [100]
  • Adipose tissue is exquisitely insulin sensitive in the healthy state, switches rapidly between fat uptake and fat release; it becomes dysregulated, and unresponsive in hyperinsulemic state.
Skeletal muscle is the primary tissue of insulin stimulated glucose uptake, disposal, and storage. [101]
  • Consequently it has a significant role in insulin sensitivity, as well as energy balance. Caloric excess, obesity and physical inactivity lead to skeletal muscle insulin resistance.
  • Recently, many nuclear receptors expressed in skeletal muscle have been shown to improve glucose tolerance, insulin resistance, and dyslipidemia.
The mechanisms that underlie the development of insulin resistance may not be completely understood, but the causes of the syndrome are -- obesity and too little physical activity, coupled with genetic factors. [102]
  • Obesity and inactivity both cause insulin resistance, and reduced utilization of glucose.
  • A 600% difference in glucose uptake between the most insulin-sensitive and the most insulin-resistant persons has been reported
  • Approximately 25% of this variability has been attributed to differences in adiposity, another 25% to differences in fitness, and the remaining 50% to genetic differences. [103]

Studies show that lifestyle factors are generally more important than genetic factors. Japanese-American men show a more rapid and intense progression of atherosclerosis than native Japanese in Japan, and they have three times the prevalence of the MS. Differences are not as pronounced in women. [104]

The Crucial Role of Abdominal Obesity
Increasing evidence points to visceral, or abdominal, obesity as the key link between genes and insulin resistance and the development of the syndrome. [97-101] [105-109]

  • How fat is distributed, i.e., the apple shape vs the pear shape, is largely genetically determined; risk is much higher with the apple shape (hence, the importance of waist circumference as a primary criteria). [106]
  • Visceral, or abdominal, adipocytes are different than peripheral adipocytes in important ways:
    • As they expand they become more and more metabolically active,
    • They produce numerous proteins, called adipokines, that have wide ranging biological activity, including key roles in the regulation of energy balance, lipid and glucose metabolism, angiogenesis, vascular and blood pressure regulation and insulin resistance. [106,107]
    • Production and release of adipokines becomes dysregulated as the adipocytes expand; they all increase except one -- adiponectin. [108]
    • Lipolytic activity increases -- more free fatty acids are released into the blood (see below).
    • Increased levels of adipokines contributes to systemic inflammation, hence, atherogenesis.
  • These adipocytes have changed the view of adipose tissue -- from passive energy storage cells to a metabolically active endocrine organ. [106,107]
  • Mounting evidence suggests that the repertoire of actions and reactions of adipocytes contributes to whole-body glucose and energy homeostasis, the control of blood pressure, immune-system function, haemostasis and atherosclerosis. [109]
Adipokines
The list of substances that are produced and released by fat cells continues to grow. [107]
  • Leptin was the first to be recognized and remains the most recognizeable; it is involved in regulating appetite, satiety, and fuel metabolism. Leptin was once thought to offer a cure for obesity, based on animal studies, but results have been far less impressive in studies with humans. [110]
  • Adiponectin is the new hope, differs from other adipokines in that its production and concentrations are actually decreased in insulin resistant subjects; increasing levels improve insulin sensitivity; is increasingly considered a major factor in obesity-related insulin resistance and atherosclerosis. [111]
  • Resistin increases insulin resistance and may stimulate glucose output from the liver. [110]
Other adipokines include TNF-a, IL-6, IL-1beta (interleukin 1beta), angiotensinogen, plasminogen activator inhibitor-1, acylation stimulating protein, tissue factor, monocyte chemoattractant protein-1, macrophage migration inhibitory factor, nerve growth factor, vascular endothelial growth factor, transforming factor b, adipsin, visfatin and haptoglobin. [110,111]
  • They are all increasingly produced by fat cells when they expand and become more active metabolically.
  • A number of these are linked to inflammation and the inflammatory response.

Data from the Framingham Offspring Study shows that adverse levels of adipokines (lower adiponectin, and higher resistin and TNF alpha) are associated with insulin resistance in individuals at low or high diabetes risk. [112]

Increased FFA Flux Increased plasma levels of free fatty acids (FFA) occur in states of insulin resistance such as the metabolic syndrome. [113]

  • High levels of plasma FFA seem to play an important role for the development of insulin resistance but the mechanisms involved are not clearly understood. One effect is that insulin-stimulated glucose uptake and metabolism is impaired in skeletal muscle.
  • FFA compete with glucose for substrate utilization in skeletal muscle and block insulin signalling pathways; this reduces insulin sensitivity and glucose disposal in muscle and liver, causing an increase in blood glucose; insulin secretion is stimulated, resulting in hyperinsulinaemia -- a key feature of the insulin-resistance syndrome.
  • Leads to accumulation of triglyceride in muscle and liver, which further depresses insulin action in these tissues and increases the output of apo B-containing lipoproteins. [114]
The Metabolic Syndrome is progressive
Glucose metabolism becomes progressively disrupted as insulin resistance develops; hyperinsulinemia gives way to fasting hyperglycemia, then IGT and finally Type 2 diabetes.
  • Borderline risk factors progress to categorical risk factors. [115]
Several facets of the metabolic syndrome -- hypertension, hyperglycemia, and dyslipidemia -- stimulate the generation of free radicals, which impair the activity of nitric oxide, causing reduced endothelial-derived vasorelaxation (endothelial dysfunction). [116,117]
  • Abnormalities in the vasculature begin early in the process, along with subtle abnormalities in glucose metabolism.
  • The degree of endothelial dysfunction increases progressively from normal to first-degree relatives of diabetic persons to people with impaired glucose tolerance to those with type 2 diabetes. [118]
Visceral fat is also a key regulator of inflammation.
  • Abdominal obesity is characterized by a state of chronic mild inflammation.
  • Large clinical studies have shown that CRP, as a marker of inflammation, increases with the number of components of the MS, as well as Type 2 diabetes. [109]
  • Adipocytes directly promote the inflammatory state through the secretion of a growing list of cytokines (adipokines) that promote inflammation. [119]
  • This inflammation appears to be a crucial step in the emergence of insulin resistance, and is increasingly considered to be important in the development of diseases linked to obesity, particularly Type 2 diabetes and the metabolic syndrome. [119-121]
  • There is increasing evidence from nearly every internal medicine subspecialty that adipocytes and adipokines are involved in primary inflammatory processes and diseases. [122]
Effects of inflammation
  • interferes with normal insulin signalling. [109]
  • promotes thrombosis, a process that underlies acute coronary event and stroke. [123]
  • renders HDL proinflammatory instead of anti-inflammatory. [124]

Relation to disease
Many epidemiologic studies have shown associations between inflammation markers and diabetes, the most consistent being for leukocytes, the strongest being for CRP. [125]

Consistent with this relation, inflammation markers have also been shown to predict conditions present in the prediabetes state such as weight gain, hypertension, gestational diabetes, and declining insulin sensitivity and the Metabolic Syndrome. [126]

  • Elevated levels of CRP are also associated with increased risk for CVD and diabetes. [126]
  • Increasing severity of metabolic syndrome is also associated with increasing CRP. [127]
Importance of using waist circumference to assess obesity risk
Waist circumference is a key marker for the metabolic syndrome because it is a measure of visceral adiposity -- the type of body fat that is very metabolically active and that contributes to health risks. [128]
  • Visceral abdominal fat is the most significant predictor of the presence of metabolic syndrome, particularly in normal-weight individuals. [128]
  • For a given WC, overweight, obese and normal-weight persons have been shown to have comparable health risks. [129]
It is a simple measure for identifying insulin resistance. [130]
  • At any BMI, greater waist circumference predicts increased risk of the presence of the MS. [131]
  • In young men it is independently associated with insulin resistance; helps identify sub-groups of overweight or obese young men at higher metabolic risk. [132]
It has the strongest relation to inflammation (increased CRP levels) of the five Metabolic Syndrome criteria. [133]
  • And, it is superior to BMI for predicting future myocardial infarctions. [134]
Impact of Sedentary LifestyleCross-sectional and prospective studies generally support that levels of physical activity and fitness are inversely related to the prevalence of this syndrome. [135]
  • Sedentary behaviors, such as excessive time spent watching television or using a computer, are significantly associated with an increased risk for this syndrome.
  • Compared to subjects who viewed TV < 14 hr/week, those who viewed TV > 20 hr/week had a 1.5-fold risk for men and a 1.9-fold risk for women of having metabolic syndrome, after adjusting for physical activity and other covariates. [136]
Some suggest that low cardiorespiratory fitness should be considered a feature of metabolic syndrome.
  • Vo(2max) has a strong, inverse, and graded association with the risk of metabolic syndrome. Men and women in the lowest third of Vo(2max) had 10- and 11-fold higher risks and those in the middle third had 3- and 5-fold higher risks (P < 0.001 all) of metabolic syndrome than those with the highest Vo(2max) after multivariable adjustments. [137]
6. TREATING THE METABOLIC SYNDROME

People with the Metabolic Syndrome require attention to risk factors for both atherosclerotic cardiovascular disease and type 2 diabetes. There are two objectives in managing the syndrome:
  1. to reduce the underlying causes (i.e., obesity and physical inactivity), and
  2. to treat associated risk factors, including separate drug therapy when appropriate. [138]
The first line treatment is lifestyle therapy because it can improve all aspects of the syndrome. But, as it progresses, drug therapy directed at individual risk factors may be needed. [139] According to the NCEP ATP III – the presence of the syndrome is an indication for intensive lifestyle modification. [NCEP]
  • Weight loss, increased physical activity, and an anti-atherogenic diet can improve all of the metabolic abnormalities without pharmaceutical intervention. [140]
There are currently no drugs specifically for the Metabolic Syndrome. [140]
  • Drugs for insulin resistance and the MS are being studied.
  • Some show promise (e.g., thiazolidinediones) but await additional research.

But drug therapy is often needed to control risk factors when lifestyle change alone is not enough. [140]

Weight loss has a huge impact in improving the risk factors of the metabolic syndrome. Several studies have shown that losing just 7% to 10% of initial body weight is sufficient to improve waist circumference, elevated triglycerides and low HDL-choelsterol, trunk fat, and plasma glucose. [141]

Importance of a Multi-Faceted Approach
There is growing consensus of the importance of a multifaceted approach, tailored to the patient's unique risk profile -- treating all risk factors together, early and aggressively. [117]

  • Includes global cardiovascular risk assessment.
  • Weight reduction and increased physical activity are always the foundation. [142]
  • With drug therapy, attention to the varying effects that agents of different therapeutic classes have on other cardiovascular and metabolic parameters.
A CME program summarizes the key aspects of treatment for the prevention of cardiovascular and renal disease in patients with the metabolic syndrome: [143]
  • Quit smoking, if a smoker -- obviously extremely important in view of already heightened risk
  • A diet that replaces bad fats and carbs with good ones, with increased fiber; in other words, more of a Mediterranean diet, or the DASH diet from the NIH.
  • Increased exercise -- such as walking 30 minutes every day.
  • Aspirin therapy, and perhaps other platelet antagonists, for the pro-thrombotic effects.
  • Lipid control -- focuses on reducing triglycerides and apo B, raising HDL and lowering LDL; the LDL goal has become more stringent in the presence of the Metabolic Syndrome -- < 70 mg/dL vs < 100 mg/dL without it; often requires a combination approach.
  • Blood pressure control -- also often requires a combination medication approach, and
  • Good control of glycated hemoglobin, < 7% by ADA standards; < 6.5% by AACE standards; the lower the better, in view of the early appearance of atherosclerotic changes with the syndrome.

Simultaneous management of multiple risk factors has the potential to greatly reduce the incidence of CVD in individuals with the metabolic syndrome. [144]

Lifestyle Therapy -- The Cornerstone of Treatment
The most indisputable fact about the Metabolic Syndrome is the importance of lifestyle changes in managing it. This is:

  • "the most effective therapeutic intervention for patients with the metabolic syndrome". [145]
  • "the best available option for treating the metabolic syndrome". [146]
There is abundant evidence that this approach can reduce the likelihood of developing type 2 diabetes.
  • In a meta-analysis, lifestyle interventions reduced diabetes by approximately one-half and pharmacologic interventions by approximately one-third. [147]
  • Major lifestyle studies included the Finnish Diabetes Prevention Study (DPS) [148] and the U.S. Diabetes Prevention Program (DPP) [149], both with reductions in development of diabetes by 58%.
  • Diabetes Prevention Program evaluated effectiveness of lifestyle approach to prevent Type 2 diabetes in obese -- was stopped early because results were indisputable:
  • 2 years -- 5% of lifestyle group vs 22% of control developed diabetes,
  • 4 years -- 20% (lifestyle) vs 37% (control) developed diabetes. [149]
  • Finnish Diabetes Prevention Study evaluated diet and exercise intervention in people with impaired glucose tolerance
    • After 6 years, fewer than 20% of diet/exercise group vs greater than 40% of control developed type 2 diabetes [148]
There is also growing evidence on improving the clinical status of patients with the syndrome.
  • A significant reduction in the prevalence of metabolic syndrome (OR 0.6) and abdominal obesity (0.5) was observed in the previously mentioned Finnish Diabetes Prevention Study.[150]
  • A general recommendation-based program of lifestyle intervention carried out by trained professionals was compared to standard unstructured information given by family physicians. The result: after one year, the lifestyle intervention significantly reduced the metabolic syndrome (OR = 0.3), as well as central obesity (OR = 0.3), hypertriglyceridemia (OR = 0.5), and diabetes (OR = 0.2) [151]
  • The combination of diet and exercise interventions was significantly more effective than either diet or exercise alone in the treatment of the metabolic syndrome after a one year study. Two out three cases were reversed with the combination vs only about 1 in 3 in each of the other groups. [152]

Exercise
Exercise has many positive effects in people with metabolic syndrome – improving insulin action, glucose metabolism, aerobic metabolism, mitochondrial density, and respiratory chain proteins. [153]

Randomized controlled trial evidence shows that exercise training in people with the MS or IGT: [154,155]

  • Increases insulin sensitivity,
  • Decreases blood pressure, if elevated,
  • Reduces triglycerides, increases HDL,
  • Reduces inflammation,
  • Improves endothelial function [155]
Almost all physical activity has a positive effect on insulin action, but moderate intensity, daily activity seems best. A significant part of the positive effect comes from the last bout of activity, hence the need for daily activity. [156]
  • 30 minutes brisk walking 3-7 times per week over 6 months reversed insulin resistance in sedentary insulin resistant individuals with no change in diet or weight. [157]
  • Small increases in activity and fitness improved clustered metabolic risk in the ProActive cohort of at-risk individuals. [158]
  • Both an increase in overall physical activity and an increase in cardiorespiratory fitness improve the entire cluster of metabolic abnormalities. [154]
  • Adding some resistance exercise to aerobic exercise can provide additional benefits. [159]
  • A modest amount of moderate-intensity exercise, with no change in diet, significantly improved MS and supported the recommendation of 30 minutes of moderate-intensity exercise every day. [160]
    • Increasing the volume of exercise, i.e., more than 30 minutes per day, had greater benefits than increasing the intensity of exercise.

A physician should be consulted before beginning a new physical activity program for people with chronic diseases, such as cardiovascular disease and diabetes mellitus, or for those who are at high risk for these diseases. Experts also advise men over age 40 and women over age 50 to consult a physician before they begin a vigorous activity program. [AHA/ACSM Guidelines, see Resources]

Just becoming less sedentary has a positive effect on the syndrome.

  • The Australian Diabetes, Obesity and Lifestyle study has shown that avoiding prolonged uninterrupted periods of sedentary time, especially sitting, has a favorable effect on waist circumference, BMI, triglycerides, and 2-h plasma glucose. [161]
  • The Nurses' Health Study has shown the importance of both reducing sedentary activity and increasing physical activity. Sedentary behaviors, especially TV watching, were associated with significantly elevated risk of obesity and type 2 diabetes, whereas even light to moderate activity was associated with substantially lower risk. [162]
Exercise can be as simple as brisk walking for 30 minutes a day, or as complicated as a combination of aerobic and resistance training with a professional trainer. [163]
  • First goal is to just become more active -- look for ways to stand more, walk more, just be more active
  • Then, begin light exercise, such as walking a mile in about for 20-30 minutes; build up to doing this most days of the week,
  • Then, begin to walk a little faster; moderate exercise is considered the equivalent of walking 2 miles in 30 minutes most days of the week,
  • Then, begin adding a few longer walks, such as 45 minutes, a couple of times a week,
  • Then, add some calisthenics, stretching or light exercises with weights, such as machines or dumbbells.
  • Each step builds on the one before it; as the patient gets stronger, he or she will naturally become more active.
Diet Changes
The epidemic of the Metabolic Syndrome has been seen by some as the unwanted result of the dietary low fat crusade that has dominated the past 50 years. [164]
  • Fat intake has dropped but obesity and the metabolic syndrome have risen.
  • The problem is that low fat diets tend to be high in carbohydrates, and there is evidence that such diets may increase triglycerides and reduce HDL in susceptible people. [165]
  • The 2006 AHA scientific statement on diet and lifestyle recommendations recommends a moderate fat intake for the metabolic syndrome. [166]
There is no single diet currently recommended for people with the Metabolic Syndrome, BUT there is evidence to support a Mediterranean style diet as the best approach. [21]
  • A systematic review of 35 studies of the effects of the Mediterranean diet showed favorable effects on lipoprotein levels, endothelial vasodilatation, insulin resistance, metabolic syndrome, antioxidant capacity, myocardial and cardiovascular mortality, and cancer incidence in obese patients and in those with previous myocardial infarction. [167]
  • Analyses from the Nurses' Health Study suggest that over 80% of coronary heart disease, 70% of stroke, and 90% of type 2 diabetes can be avoided by healthy food choices that are consistent with the traditional Mediterranean diet, along with regular physical activity and not smoking. [168]
  • A Mediterranean style diet reduced the prevalence of the syndrome by nearly 50% over a low fat diet. [169]
  • The Dietary Approach to Stop Hypertension (DASH) diet, which is similar to a Mediterranean diet, reduced the prevalence of the metabolic syndrome by 35% compared with a control diet. [170]
  • A dietary pattern that included frequent intake of vegetables, fruits, fish, pasta and rice and low intake of fried foods, sausages, fried fish, and potatoes was associated with a better metabolic profile. [171]
Translated the Mediterranean diet means:
  • Eating more good fats (olive oil, nuts, fish oils) and fewer poor fats (saturated and trans -- fast foods, packaged baked goods) and,
  • More good carbohydrates (whole grains, vegetables, fruits -- high in fiber and antioxidants) and fewer bad carbohydrates (refined sugars, candy, soft drinks, processed and packaged foods),
  • Choosing leaner sources of proteins and low fat dairy.
The importance of good fats and whole grains:
There is growing evidence that the type of fat in the diet plays an important role in the development of insulin resistance. [172]
  • Higher levels of saturated fats impair the action of insulin, while polyunsaturated fatty acids, especially omega-3 and -6, improve insulin sensitivity, hence the beneficial effects of adding a fish oil supplement.
  • Omega-3 fatty acids in fish oils help reduce triglycerides and increasing HDL, and have the added benefit of antioxidant properties.
  • Fatty acids have also been shown to alter gene expression in cells, in particular the peroxisome proliferator-activated receptor-gamma2 gene, adding to this multifaceted connection.
Substituting whole grains for refined grains in the same hypocaloric diet in people with metabolic syndrome resulted in a significantly greater decrease in percentage body fat in the abdominal region, and a significantly greater reduction in inflammation. [173]
  • Increased whole grain and cereal fiber intake was also associated with a reduced risk of developing the metabolic syndrome in the Framingham Offspring Study. [174]
In middle-aged adults, soft drink consumption is associated with a higher prevalence and incidence of multiple metabolic risk factors. Consumption of ≥1 soft drink per day was associated with nearly 1.5 times the risk of developing metabolic syndrome. [175]
  • Emerging evidence also suggests that increased consumption of fructose may also be a factor in the growing rates of obesity and the metabolic syndrome. [176]
The Glycemic Index and Glycemic Load have received attention in relation to the Metabolic Syndrome.
  • The GI of a food is a value based on the average increase in blood glucose levels occurring when a 50 g carbohydrate portion of that food is consumed. The GL accounts for the amount of carbohydrate per serving.
  • However, evidence suggests that the importance of low GI or GL diets in relation to the metabolic syndrome has yet to be established. One of the reasons is that the diets used in the intervention studies frequently not only differed in GI or GL, but also in fiber, protein and/or fat content.
  • In some prospective cohort studies, effects of GI or GL disappeared after correcting for fiber intake. [177]
The Atherosclerosis Risk in Communities (ARIC) study found that long term consumption of a Western dietary pattern, especially including meat, fried foods, and diet soda, increased the risk of developing the Metabolic Syndrome. [178]
  • The Whitehall II study confirmed this -- a dietary pattern with high consumption of diet soft drinks, onions, sugar-sweetened beverages, burgers and sausages, crisps and other snacks, and white bread and low consumption of high-fiber breakfast cereals, jam, French dressing/vinaigrette, and whole wheat bread was associated with the development of insulin resistance and type 2 diabetes. [179]
Pharmacologic Therapy
The goal is to prevent, or at least slow, the development of cardiovascular disease and type 2 diabetes.
  • In view of the difficulties of long term weight loss and adherence to diet and exercise regimens, drug therapy is often needed. [180]
  • There are currently no specific drugs to treat insulin resistance or the Metabolic Syndrome in general, but there likely will be in the not too distant future. [181]
    • Keep abreast of this line of research (see drugs in the pipeline below).
There are, obviously, effective drug therapies to treat the individual conditions, including:
  • Prevention of type 2 diabetes, hyperglycemia
  • Dyslipidemia
  • Hypertension
  • Increased coagulation
  • Decreased fibrinolysis

Pharmacologic therapy for lipids and blood pressure, at minimum, will eventually be needed for most people with the Metabolic Syndrome. [182]

Drugs for the Prevention of Type 2 diabetes
This is a primary goal because of widespread and devastating complications that result, along with the fact that the Metabolic Syndrome increases risk for diabetes so much.

  • Beyond diet and exercise, several oral anti-diabetic agents have been shown to reduce the development of diabetes in patients with IGT, when the syndrome has progressed to that point.
  • These include metformin, acarbose and troglitazone. [183]
      • Metformin decreases the amount of glucose made by the liver while increasing glucose uptake by target tissues. HbA1c reduction of 1% to 2% can be expected.
      • Acarbose (an Alpha-Glucosidase Inhibitor) and Troglitazone (a thiazolidinedione) are still being investigated for use with the MS
    • More interestingly, multiple large prospective studies have also reported a reduction in the development of type 2 diabetes with anti-hypertensive therapy using ACE inhibitors and angiotensin receptor blockers (ARBs). [184]
    • A meta-analysis of 12 randomized controlled clinical trials showed that ACE inhibitors and ARBs reduced the incidence of newly diagnosed diabetes by 27% and 23%, respectively. [184]
Drugs for Dyslipidemia
The first priority is to reduce LDL cholesterol to the new lower limit of below 70 mg/dL, owing to the highly increased risk of CVD.
  • Management should allow for statins in virtually all cases. [182]
Next priority is to address the more typical lipid abnormalities seen in patients with the metabolic syndrome -- higher triglyceride and apolipoprotein B levels, lower HDL cholesterol and apolipoprotein A-I levels, and smaller, denser, more numerous LDL cholesterol particles. [182,185]
  • Many will still have elevated TGs, low HDL, and many will still have elevated levels of small, dense LDL, even after statin therapy.

Therefore, combination therapy is often necessary.

A recent European Consensus Panel recommends the combination of nicotinic acid and a statin, with lifestyle modification, as a useful strategy to lower CHD risk in patients with metabolic syndrome. [186]

  • Nicotinic acid can raise HDL-C (by up to 29% at clinically recommended doses). It also substantially reduces triglycerides and LDL-C, and promotes a shift from small, dense LDL to larger, more buoyant LDL particles.
  • Preliminary clinical data suggest that combining nicotinic acid with a statin will produce a greater reduction in cardiovascular risk in patients with diabetes and metabolic syndrome than statin monotherapy alone.
  • Prolonged-release nicotinic acid with improved tolerability compared with previous formulations may have obvious advantages for use in this setting.
Fibrates, such as gemfibrozil and fenofibrate, lower triglyceride and raise HDL cholesterol levels. [182]
  • The mechanisms are not completely understood, but one is the upregulation of the enzyme, lipoprotein lipase, which hydrolyzes TGs and VLDLs; the result is that there is more efficient conversion of VLDL to remnant particles, a reduction in TGs and improved removal of these remnant lipoproteins.
  • Gemfibrozil is not recommended in combination with statins because of an increased risk of rhabdomyolysis.
Niacin derivatives, especially extended-release niacin, may also be effective in lowering LDL cholesterol and triglycerides and increasing HDL cholesterol. [182]
  • Niacin essentially puts the brakes on adipocytes, reducing the flux of fatty acids, one of the primary drivers for hyperlipidemia in insulin-resistant patients.
  • The dose needs to be titrated slowly and should be given with immediate-release aspirin to prevent flushing reactions. At higher doses, they may cause deterioration in glucose control.
Statins
Drugs of choice when LDL cholesterol is elevated (above the new aggressive goal of 70 mg/dL). [187]
  • Can improve other aspects of dyslipidemia as well
  • In patients with the metabolic syndrome, rosuvastatin 10 mg improved LDL cholesterol (-47%), non-HDL cholesterol (-43%), non-HDL cholesterol/HDL cholesterol ratio (-47%), apolipoprotein B (-37%), apolipoprotein B/apolipoprotein A-I ratio (-40%), triglycerides (-23%), apolipoprotein A-I (+7%), and HDL cholesterol (+10%) in a manner similar to that in hypercholesterolemic patients who did not meet these criteria. [188]
Data from the Heart Protection Study (HPS) and the Collaborative Atorvastatin Diabetes Study (CARDS) have clearly shown that statins reduce the risk of cardiovascular events in diabetics (by 24% and 37%); has led to the wide spread belief that most diabetics as well as others at high risk for vascular events could benefit from statins regardless of age or initial serum lipids. [189]
  • Cholesterol absorption inhibitors, such as ezemtimide, have been recently shown in the SANDS Trial to reduce carotid atherosclerosis is patients with diabetes [239].
  • Ezemtimide is also indicated to lower apo B.
Drugs for Hypertension
Hypertension should be managed aggressively, with a target of 130/80 mm Hg or below.
  • Multiple agents are usually required. [182]
  • ACE inhibitors and ARBs have the additional advantage of preventing the deterioration of glucose tolerance. [182,183]

Anti-thrombotic
Aspirin therapy should be administered if the cardiovascular risk is high. [187]

Drugs in the Pipeline for the Metabolic Syndrome
The thiazolidinedione class of "insulin-sensitizing" agents appears to show great promise for the future. [190]

  • These drugs directly target insulin resistance.
  • Rosiglitazone (Avandia) and Pioglitazone (Actos) are examples.
  • Pioglitazone, alone and with metformin, has been shown to improve glycaemic control and lipid profiles in patients with the metabolic syndrome in combined data from four worldwide randomized, multicenter, double-blind studies.
  • A reduction in HbA1c of 1-2% can be expected.
  • Close monitoring of liver function tests is advised since hepatotoxicity is the main serious adverse effect. These drugs may take a few weeks before they affect blood glucose levels.
Another class of drugs being intensively studied is the Alpha-Glucosidase Inhibitor group. [191]
  • These drugs block the alpha-glucosidase enzymes in the intestines that are responsible for the breakdown and absorption of carbohydrates during digestion; blocking the enzymes thus slows absorption of glucose into the blood.
  • Acarbose (Precose) and Miglitol (Glyset) are examples
  • HbA1c reduction in the range of 0.5-1% can be expected. Side effects are typically limited to upset stomach.
  • The STOP-NIDDM study (study to prevent non-insulin-dependent diabetes mellitus) showed a 49% reduction of cardiovascular events in patients with IGT treated with acarbose, compared with placebo.
  • Furthermore, a retrospective meta-analysis of seven placebo-controlled long-term-studies of acarbose in patients with Type 2 diabetes showed a reduction of cardiovascular events of 41%.
7. GUIDELINES

Diagnosis and Management of the Metabolic Syndrome -- from the American Heart Association/ National Heart, Lung, and Blood Institute, 2005
[4]

RECOMMENDATIONS:

Diagnosis: Use the NCEP ATP III criteria

Lifestyle Modification:

Weight loss:

  • Goal: Reduce body weight by 7%–10% during first year of therapy. Continue weight loss with goal to ultimately achieve desirable weight (BMI <25 kg/m2)
  • Approach: Encourage weight maintenance/reduction through balance of physical activity, caloric intake, and formal behavioral programs to maintain/achieve waist circumference of <40 inches in men and <35 inches in women. Aim initially at slow reduction of &7%–10% from baseline weight. Even small amounts of weight loss are associated with significant health benefits.
Physical activity:
  • Goal: Regular moderate-intensity physical activity; at least 30 min of continuous/intermittent (preferably 60 min) 5 d/wk, but preferably daily
  • Approach: If established CVD, assess risk with detailed physical activity history and/or exercise test, to guide prescription. Encourage 30–60 min moderate-intensity aerobic activity (eg, brisk walking), preferably daily, supplemented by increase in daily lifestyle activities (eg, pedometer step tracking, walking breaks at work, gardening, household work). Higher exercise times achieved by accumulating exercise throughout day. Encourage resistance training 2 d/wk. Advise medically supervised programs for high-risk patients.
Diet:
  • Goal: Reduced intakes of saturated fat, transfat, cholesterol
  • Approach: Saturated fat <7% of total calories; reduce trans fat; dietary cholesterol <200 mg/d; total fat 25%–35% of total calories. Most dietary fat should be unsaturated, simple sugars should be limited.

Therapy for specific risk factors:
Atherogenic dyslipidemia:

  • Primary target: LDL-C Reduce LDL-C levels to ATP III goals
    • For elevated LDL-C: Give priority to reduction of LDL-C over other lipid parameters.
    • Achieve LDL-C goals based on patient’s risk category:
    • High risk: <100 mg/dL (optional <70 mg/dL for high-risk patients)
    • Moderately high risk: <130 mg/dL (optional <100 mg/dL)
    • Moderate risk: <130 mg/dL
    • Lower risk: <160 mg/dL
  • Secondary target: Non-HDL-C If TG ≥200 mg/dL, reduce non-HDL-C to ATP III goals (after attaining LDL-C goals)
    • If TG ≥200 mg/dL, goal for non–HDL-C for each risk category is 30 mg/dL higher than for LDL-C.
    • If TG ≥200 mg/dL after achieving LDL-C goal, consider additional therapies to attain non-HDL-C goal.
  • Tertiary target: HDL-C if low, after attaining non-HDL-C goal, raise HDL-C to extent possible with standard therapies for atherogenic dyslipidemia
    • If HDL-C is low after achieving non–HDL-C, either lifestyle therapy can be intensified or drug therapy can be used for raising HDL-C levels, depending on patient’s risk category.
Elevated BP:
  • Goal: Reduce BP to <140/90 mm Hg (or <130/80 mm Hg if diabetes is present).
    • For BP ≥120/80 mm Hg: Initiate or maintain lifestyle modification via weight control, increased physical activity, alcohol moderation, sodium reduction, and emphasis on increased consumption of fresh fruits, vegetables, and low-fat dairy products in all patients with metabolic syndrome.
    • For BP ≥140/90 mm Hg (or ≥130/80 mm Hg if diabetes is present), add BP medication as needed to achieve goal BP.
Elevated glucose:
  • Goal: For impaired fasting glucose (IFG), delay progression to type 2 diabetes mellitus. For diabetes, hemoglobin A1C <7.0%.
    • For IFG, encourage weight reduction and increased physical activity.
    • For type 2 diabetes, lifestyle therapy and pharmacotherapy, if necessary, should be used to achieve near-normal HbA1C (<7%). Modify other risk factors and behaviors (eg, abdominal obesity, physical inactivity, elevated BP, lipid abnormalities).
Prothrombotic state:
  • Goal: Reduce thrombotic and fibrinolytic risk factors
    • For high-risk, initiate and continue low-dose aspirin therapy; with CVD, consider clopidogrel if aspirin is contraindicated.
    • For moderately high-risk patients, consider low-dose aspirin prophylaxis.
Proinflammatory state:
  • No specific therapies beyond lifestyle therapies
Physical Activity – from the American College of Sports Medicine and the American Heart Association, 2007 [192]
The minimum physical activity recommendations to promote and maintain health in adults 18-65 include:
  • At least 30 minutes of moderate-intensity aerobic activity five days a week. Moderate activity is equivalent to a brisk walk that causes the heart to beat faster. Can be all at once or in segments of at least 10 minutes, OR
  • At least 20 minutes of vigorous activity three days a week. Vigorous activity, such as jogging or running quickly, raises the heart rate and causes you to breathe quickly, AND
  • At least two non-consecutive days of muscle-strengthening exercise each week. Eight to 10 exercises per session with a weight that allows 8 -12 repetitions of each exercise. May include a progressive-weight training program, exercises or calisthenics that involve weight-bearing activity or activities such as stair climbing.

To lose weight or further reduce the risk for premature chronic health conditions and mortality requires exceeding these minimum amounts.

Diet – U.S. Preventive Services Task Force, 2003 [193]
Intensive behavioral dietary counseling is recommended for adult patients with hyperlipidemia and other known risk factors for cardiovascular and diet-related chronic disease.

  • Two approaches appear promising in primary care settings:
    • (1) medium-intensity face-to-face dietary counseling (two to three group or individual sessions) delivered by a dietitian or nutritionist or by a specially trained primary care physician or nurse practitioner, and
    • (2) lower-intensity interventions that involve 5 minutes or less of primary care provider counseling supplemented by patient self-help materials, telephone counseling, or other interactive health communications.
  • The largest effect of dietary counseling has been observed with more intensive interventions (multiple sessions lasting 30 minutes or longer) among patients with hyperlipidemia or hypertension, and among others at increased risk for diet-related chronic disease.
  • The 5-A behavioral counseling framework is supported:
    • Assess dietary practices and related risk factors,
    • Advise to change dietary practices,
    • Agree on individual diet change goals,
    • Assist to change dietary practices or address motivational barriers, and
    • Arrange regular follow-up and support or refer to more intensive behavioral nutritional counseling (e.g., medical nutrition therapy) if needed.
  • Examples of behavior counseling interventions include teaching self-monitoring, training to overcome common barriers to selecting a healthy diet, helping patients to set their own goals, providing guidance in shopping and food preparation, role playing, and arranging for intra-treatment social support.
  • Office-level systems supports (prompts, reminders, and counseling algorithms) have been found to significantly improve the delivery of appropriate dietary counseling by primary care clinicians.
  • The USPSTF concluded that such counseling is likely to improve important health outcomes.
Treatment of the Metabolic Syndrome – Finnish Medical Society, 2007 [194] Treatment of the Metabolic Syndrome (MS) is principally non-pharmacological and based on lifestyle changes. This approach has been shown to have an excellent effect, for example in the prevention of diabetes (DPS Study) (Tuomilehto et al., 2001; Knowler et al., 2002) [A].
  • Lifestyle changes are the only treatment form which have an effect on all the components of the syndrome, and not employing this treatment should be considered ethically wrong.
Non-Pharmacological Treatment includes:
  • Increasing physical activity
  • Weight reduction
  • Dietary changes: increased intake of fiber and decreased intake of fat (particularly saturated fat) and rapidly metabolized carbohydrates (highly refined); salt restriction
  • Cessation of smoking
  • Limit alcohol intake to a moderate level
Drug Treatment:
  • Drug treatment for the entire syndrome does not exist; treatment consists of managing the individual components.
  • Unless contraindicated, all patients with MS should be prescribed low dose aspirin.
  • The treatment of hypertension should not contain drugs that worsen insulin resistance, such as non-selective beta-blockers and high-dose diuretics, unless other reasons (secondary prevention of myocardial infarction) warrant their use. The first-line drugs for the treatment of hypertension are:
    • Angiotensin-converting enzyme (ACE) inhibitors
    • Angiotensin-II receptor antagonists (losartan, valsartan, eprosartan, candesartan)
    • Alpha1 receptor blockers
    • Calcium-channel blockers
    • Highly selective beta-blockers
  • Dyslipidemia should principally be treated with statins bearing in mind that the patient has a high risk of coronary artery disease.
  • Hypertriglyceridemia should be treated with fibrates if, in spite of non-pharmacological treatment, the triglyceride values are persistently >5.0 mmol/L. Hypertriglyceridemia in a patient with MS should be treated medically (statin or fibrate) if the level of triglycerides is >2.30 mmol/L and total-cholesterol/HDL-cholesterol ratio is higher than 5 or if HDL-cholesterol is lower than 0.9 mmol/L.
  • Dysglycemia in a patient with MS should be treated with metformin or thiazolidine derivatives (pioglitazone or rosiglitazone) since these will not only improve the dysglycemia but will also have an effect on the other components of the MS. Insulin may also be used for the treatment of dysglycemia in a MS patient to achieve good diabetic control.
  • Biguanides, acarbose, and guar gum may correct insulin resistance and are thus feasible as a first-line drug for an obese patient with type 2 diabetes.
  • Orlistat or sibutramine may be indicated in MS if the BMI is >30 kg/m2. These are anti-obesity drugs that also reduce the amount of visceral fat, in particular. However, the new endocannabinoid-receptor blockers are likely to provide the best benefit among pharmacotherapeutic alternatives. Rimonabant is an example of these drugs, and it has a positive effect on almost all the components of MS.
    • Rimonabant should not be prescribed if the patient is concurrently in severe depression. It should be prescribed with caution and the patient should be carefully followed up if he/she has a history of depression.
Follow-up:
  • Motivation and monitoring of lifestyle changes is of the utmost importance.
  • The monitoring of a patient who requires drug treatment is the responsibility of a doctor. Regular appointments may often act as an important motivator.
  • Monitoring of patients not on drug therapy may be carried out by a practice nurse. The following should be included in the follow-up: motivation of lifestyle changes, weight and waist circumference measurements, blood pressure readings, and checking of blood lipids and fasting blood glucose. A doctor should be consulted if:
    • Blood pressure repeatedly >140 mmHg and/or >90 mmHg
    • Total cholesterol: HDL-cholesterol ratio >5
    • Triglyceride values repeatedly >2.30 mmol/L
    • Plasma glucose is >7.8 mmol/L (fasting plasma glucose is >6.7 mmol/L
    • The patient develops symptoms of another illness (gout, etc.)
Screening for metabolic syndrome in adults-- University of Texas at Austin, Family Nurse Practitioner Program [195] Objectives:
  • Provides a dietary and nonpharmacologic treatment guideline for the management of metabolic syndrome
  • To guide practice decisions that integrate medical, nutritional, and behavioral elements
  • To promote self-management education that empowers the patient to take responsibility for day-to-day management

This guideline provides detailed step by step guidelines for the initial and follow-up encounters – assessment, clinical data, intervention (education, training, communication, etc), monitoring.

8. THE CHALLENGES

Under-recognition

This increasingly important pro-inflammatory condition remains both under-recognized and under-treated.
  • Growing evidence supports early intervention, but many physicians do not recognize the risk associated with it and fail to initiate early treatment. [196]
Improving lifestyle change counseling rates
Assisting patients to improve health-related behaviors is an important responsibility of caregivers, including physicians, nurses, health educators, and counselors. From 1992 to 2000, diet and physical activity counseling took place in < 45 and 30%, respectively, of primary care physician visits by adults with CVD risk factors. [197]
  • Physicians in primary care seldom have time to engage in such discussions and may be unsure how to discuss behavior change with their patients; [197-199]
  • Non-physicians are generally the appropriate caregivers to assist patients in adopting healthy behaviors.
9. CLINICAL APPROACH - THE INITIAL CONSULT

Suspecting the Metabolic Syndrome
Early recognition of the metabolic syndrome is vital because of its progressive nature. The earlier in the process that intervention occurs, the less intensive the treatment required and the greater the likelihood of success. [200]

The presence of obesity or hypertension in any patient warrants screening for the metabolic syndrome and diabetes because of the vascular risk.

  • The syndrome is common in patients with hypertension, present in over half in an analysis of a cohort of nearly 13,000 subjects with diagnosed hypertension. [201]
  • But primary care providers overlooked the Metabolic Syndrome in over half of those who had it. [201]
  • Abnormal glucose metabolism, including previously undiagnosed impaired fasting glucose and diabetes, are often already present in patients with serious heart conditions. [202]
A number of other conditions also increase the risk of developing the MS; hence, they should stimulate assessment of it. These include:
  • prior gestational diabetes,
  • elevated uric acid levels,
  • familial hypercholesterolemia,
  • nonalcoholic fatty liver, or
  • polycystic ovary syndrome in women of reproductive age [203,204]
Measuring Waist Circumference
More and more experts advocate the including waist circumference as a vital sign in clinic visits to document the presence of central obesity. [205]
To measure waist circumference: [4,206]
  1. Locate upper edge of hip bone, the iliac crest, on each side
  2. Place cloth measuring tape in a horizontal plane (parallel to the floor) around the abdomen at this level
  3. Make sure the tape is snug but not so snug that it compresses skin
  4. Take the measurement at the end of a normal exhalation. Patient should be cautioned not to pull in stomach. A wall chart is helpful to compare patient with standards.
There are other methods of measuring waist circumference – the narrowest or widest point, the umbilicus, midpoint between lowest rib and iliac crest, but a systematic review found that the site of measurement did not influence clinical outcomes. [207]
  • More important is that the same method be used consistently so changes can be accurately documented.

Evaluate the Primary Criteria
The NCEP criteria for the metabolic syndrome was designed for use in clinical practice. The only lab work required is a standard fasting blood test. [2,4]The criteria and thresholds for diagnosis include:

Waist circumference

≥ 35 inches for women or ≥ 40 inches for men

Blood pressure

Systolic pressure ≥ 130 OR Diastolic pressure ≥ 85

Fasting triglycerides

≥ 150 mg/dL

Fasting HDL cholesterol

< 50 mg/dL for women or < 40 mg/dL for men

Fasting glucose

≥ 100 mg/dL

  • Currently taking medication for blood pressure, triglycerides, HDL or hyperglycemia counts as a criteria met.
Diagnosis and Coding
If 3 or more criteria are met, the diagnosis is confirmed: ICD-9 CODE 277.7 "Dysmetabolic syndrome X" [26]
  • Record the diagnosis in the medical record
Assess Cardiovascular Risk
The gold standard for CVD risk assessment is the Framingham Risk Score: http://hp2010.nhlbihin.net/atpiii/calculator.asp?usertype=prof
  • It estimates the probability of a cardiovascular event in the next 10 years.
  • Need to know total and HDL cholesterol, systolic BP, smoking status, age, gender
  • Determine risk level:
    • Low risk: 5% or less
    • Intermediate risk: 6% to 20%
    • High risk: > 20% [196]
  • Some recommend use of 10% as lower end of intermediate range. [4]
Outline Treatment Needs
ABCDE: A Practical Approach to the Metabolic Syndrome in Primary Care
This strategy aimed at primary prevention of cardiovascular events in people with the Metabolic Syndrome was developed at the Johns Hopkins Ciccarone Center for the Prevention of Heart Disease. [196]
  • "A" for assessment of cardiovascular risk and aspirin therapy, "B" for blood pressure control, "C" for cholesterol management, "D" for diabetes prevention and diet therapy, and "E" for exercise therapy.

ABCDE Approach for Treating the Metabolic Syndrome

A

Aspirin

All patients with ≥ 6% 10-yr risk (without contraindications)

B

Blood Pressure Control

Goal is < 130/80 if intermediate risk (≥ 6% 10-yr risk)

 

First line pharmacotherapy: ACEI or ACE

 

B-blockers, diuretics may inc risk of diabetes

C

Cholesterol Management

 

LDL-C

First line pharmacotherapy: Statins

 

Goal is < 130 mg/dL if intermediate risk

 

Goal is < 100 mg/dL if high risk

Non-HDL-C

Statin intensification, Fenofibrate

 

Goal is < 160 mg/dL if intermediate risk

 

Goal is < 130 mg/dL if high risk

 

Consider omega-3 fatty acid supplement

HDL-C

Long acting niacin, with concern for risk of inc in glucose intolerance

D

Diabetes Prevention

First line: Intensive lifestyle modification for all

 

Second line pharmacotherapy: Metformin, consider pioglitazone

Diet

Weight loss

 

Mediterranean diet: increase omega-3 fatty acids, fruits, vegetables, fiber, nuts

 

Low glycemic load

E

Exercise

Daily moderate to vigorous activity

 

Recommend use of pedometer with goal of > 10,000 steps/day

Counseling for Lifestyle Change
Lifestyle change strategies—including setting reasonable goals, raising awareness, confronting barriers to change, managing stress, cognitive restructuring, preventing relapse, and providing support--are the keys to long-term success in managing the Metabolic Syndrome. [208]

The Practical Guide to the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults developed by the North American Association for the Study of Obesity in conjunction with the National Heart, Lung, and Blood Institute suggests that the clinical consultation involve: [209]

  • "Patient-centered counseling," -- encourage patient to set goals and express their own ideas for therapy, with input from the healthcare professional.
  • A treatment plan that takes into account the patient's readiness for therapy and the patient's ability to comply with the plan.
  • Realistic goals established; frequent follow-up visits scheduled to monitor progress; modify the treatment plan as needed, and provide encouragement.
  • Effective therapy requires a long-term structured approach with continued support from the physician and other caregivers, particularly during periods of patient recidivism.
Attitude is important
  • Patients at high risk for metabolic syndrome were stratified into attitude-behavior categories of 'Already Doing It', 'I Know I Should' and 'Don't Bother Me' and over half (54%) were in the 'Don't Bother Me' group. These are more difficult to treat with lifestyle modification approaches. [210]
Type of interventions
  • A number of behavior modification strategies have shown good efficacy. These strategies include:a tailored problem-solving intervention, involving goal-setting, self-monitoring, stimulus control, cognitive restructuring, stress management, relapse prevention, social support, and contracting. [211]
  • Frequent self-monitoring is especially important for continued success.
The counseling process:
  • The process begins after the physician has diagnosed and explained the syndrome, discussed the associated risks and explained the treatment options, especially the need for lifestyle modification.
  • It is usually carried out by a nurse or allied health professional trained in motivational interviewing and "coaching.”
  • Goal setting with action planning is a useful technique for engaging patients in the process. Some evidence suggests that it is effective in improving healthy behaviors, especially eating behaviors. [212]
  • The American Diabetes Association, the American Association of Diabetes Educators, and the American Heart Association all recommend goal setting for cardiovascular disease risk reduction.
It is a collaborative process -- patients choose a behavior-change goal. To initiate a discussion about goal setting, ask:
  • "Is there anything you would like to do this week to improve your health?"
  • This question allows patients to choose a behavior they are motivated to change and forms the basis for setting a behavior-change goal. [213]
After a patient has agreed on a general goal, the patient and caregivers negotiate a specific action plan to assist in goal attainment. [214,215]
  • General goals occur over a longer period of time; short-term goals can be used to identify steps toward the general goal; action plans focus on achieving specific short-term goals.
  • Patients should have a high level of confidence that they can carry out their action plan; success increases self-efficacy (a person's confidence that he or she can make positive life changes).
  • Ask patients to estimate, on a 0-10 scale, how confident they are that they can carry out their action plan. Action plans can be adjusted so that patients have a confidence level of at least 7 on the 10-point scale that they can succeed. Action plans can be agreed on orally or using a written form, as shown
Specific goals lead to higher performance than either no goal or vague goals.
  • Specific short-term goals are associated with better performance than long-term and general goals.
  • Increased self-efficacy results in people setting and achieving goals, whereas reduced self-efficacy—from failing to achieve a goal—may lead to goal abandonment. [216]
  • In health-related behavior change, self-efficacy is also associated with healthier behaviors. [217]
Many studies find that regular and sustained follow-up is a necessary component of this method. Follow-up can be conducted by telephone, by e-mail, through Internet-based interactive programs, individually, or in groups. Follow-up includes problem solving related to barriers to success in carrying out action plans. [218]
  • Lack of success is translated into "lessons learned" instead of failure.
  • A great advantage to doing action planning in groups, as occurs in the well-established Chronic Disease Self-Management Program, is that patients can "buddy up" and do follow-up and problem solving with each other by telephone. [219]

A training program for behavior change counseling, using goal setting and action planning has been described. [220]

10. PRACTICE REORGANIZATION - USING THE CHRONIC CARE MODEL

The management of a chronic condition, like the Metabolic Syndrome, requires a partnership between the healthcare team and the patient living with the chronic condition.
  • It is something that most practices and reimbursement systems are not set up to provide.
  • And, it is perhaps the greatest challenge confronting primary care physicians. [221-224]
The Chronic Care Model [225] recognizes the changes needed to organize health services for people with chronic conditions, and offers a guide for improving practice performance. The model has been endorsed by the AAFP, along with health care organizations all over the world. [226]
  • It emphasizes office redesign and the use of nonphysician staff to accomplish disease management tasks. [227-230]
  • The goal of the model is the development of prepared, proactive teams that prepare and partner with informed, activated patients.
  • Due to time constraints, physicians have no choice but to create teams, either within the practice or using community resources, along with well written educational materials to help patients modify certain behaviors.

The model focuses on improving performance in six interrelated components: [226,231]

1) Self management support – the key to effective chronic care

  • To assist patients in becoming better informed and activated self managers
  • Includes providing encouragement and information, teaching specific skills, promoting healthy behaviors, teaching problem solving skills, assisting with emotional support, maintaining regular and sustained follow-up
2) Practice re-design – two elements required to provide self management support:
  • Planned visits – using a pre-determined agenda; can include individual or group visits, phone calls or emails, internet programs
  • Care teams – identify roles, provide needed training; includes clinicians, nurses, dietitians, social workers, behavioral health professionals, health coaches, exercise therapists, community health workers
3) Decision support -- using evidence-based recommendations and guidelines
  • Chart reminders for recommended services and
  • Electronic record protocols for referrals to specialists
4) Clinical Information Systems – to track care
  • Develop registry – patient list with preventive and chronic care needs and relevant clinical information
  • Team member designated to periodically review, update, identify needed services, reminders to send out
  • Separate registries can be created for patients with the Metabolic Syndrome, or other chronic conditions, or other specific criteria
5) Health care organization – two key elements required to redesign the practice:
  • Leadership – understand and embrace the Chronic Care Model
  • Financing – comprehensive per-patient payments rather than fee for service financing, which usually does not reimburse axillary services
6) Community Resources
  • Primary care practices can rarely provide all of the services needed for patients with chronic conditions – need to know and encompass local resources to fill the gaps in promoting healthy lifestyles
A practical way to pay for and target chronic care activities is to reimburse physicians for units of service delivered by their team. California’s well-established Comprehensive Perinatal Services Program (CPSP) is a good example of a payment mechanism that supports health education and case menagement services through payments to physician employers. [232,233]
  • The Future of Family Medicine report predicted that implementation of the Chronic Care Model would have a positive impact on office costs after making assumptions regarding time required and reimbursement for providing high-quality care. [234]

The AMA Roadmap for Clinical Practice for the Assessment and Management of Adult Obesity is very helpful also for managing the Metabolic Syndrome. It contains 10 booklets of which numbers 4 (Dietary management), 5 (Physical activity management) and 9 (Setting up the office environment) are particularly useful. [See Resources]

11. BOTTOM LINE

Questions have been raised about the scientific basis of the metabolic syndrome, but this is a research issue; the controversy in no way negates the value of using the syndrome to describe a common phenotype of patients encountered in clinical practice that have a very high risk for developing diabetes and CVD.
  • There is no ambiguity that physicians should aggressively treat the entire cardiovascular risk factor profile concurrently in individuals with metabolic syndrome. [235
There is also some confusion about the use of the MS to predict cardiovascular events.
  • The dichotomous nature of diagnosis, the lack of age, LDL cholesterol, family history and smoking are part of this. [236]
  • As such it is not meant to be a substitute for, but rather an addition to, standard cardiovascular risk assessments. As Yusuf says in a CME program about the syndrome, "it is a useful construct because it gets us to think about multiple risk factors". [237]
  • And, the syndrome is better at predicting the development of Type 2 diabetes. This alone gives it a very important role in clinical practice.
Most importantly, with the Metabolic Syndrome, is doing something about it.
  • Whether the underlying cause is insulin resistance, inflammation or simply environmental changes, the best treatment is increasing physical activity and changing eating habits.
  • As Haffner says, "one of the important things potentially is that the metabolic syndrome encourages providers to look for other risk factors, and in particular it encourages behavioral therapy rather than just treating the risk factors individually with pharmacologic therapy." [238]
  • Clinicians know what patients need to do, but getting them to do it is a different matter.
  • If it was easy to help patients lose fat and become more active, obesity and the metabolic syndrome, Type 2 diabetes and cardiovascular disease, would not all be epidemics.
  • Fortunately, clinical strategies are evolving on both the lifestyle and the pharmaceutical sides of the treatment paradigm.
    • Behavior change strategies are becoming more systematic, and the keys to success at the different motivational stages are being developed, and
    • New drugs that will treat the underlying insulin resistance and obesity are on the horizon for those who need them.
12. RESOURCES

GUIDELINES:

Diagnosis and Management of the Metabolic Syndrome. An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement: Executive Summary
Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Bethesda, Md: National Institutes of Health, National Heart, Lung, and Blood Institute; 2001. NIH Publication 01-3095.Physical Activity Guidelines – American College of Sports Medicine and the American Heart Association, 2007
  • Includes the minimum physical activity recommendations for managing chronic conditions and enhancing health in adults 18-65
  • Haskell WL, Lee IM, Pate RR et al. Physical activity and public health: updated recommendation for adults from the American College of Sports Medicine and the American Heart Association. Circulation. 2007 Aug 28;116(9):1081-93
Diet Counseling Guideline – U.S. Preventive Services Task Force, 2003
  • Guideline to effective approaches to behavioral dietary counseling in primary care
  • Includes the 5-A behavioral counseling framework and office level system changes to support counseling
U.S. Preventive Services Task Force. Behavioral counseling in primary care to promote a healthy diet: recommendations and rationale. Am J Prev Med. 2003 Jan;24(1):93-100.
Treatment of the Metabolic Syndrome – Finnish Medical Society, 2007 Preventing cancer, cardiovascular disease, and diabetes. A common agenda for the American Cancer Society, the American Diabetes Association, and the American Heart Association.
  • Available from the AHA website: http://circ.ahajournals.org/cgi/content/full/109/25/3244
  • Eyre H, Kahn R, Robertson RM et al. Preventing cancer, cardiovascular disease, and diabetes: a common agenda for the American Cancer Society, the American Diabetes Association, and the American Heart Association. Circulation 2004 Jun 29;109(25):3244-55.
Screening for metabolic syndrome in adults -- University of Texas at Austin, School of Nursing, Family Nurse Practitioner Program

CONSENSUS STATEMENTS:
Lipoprotein Management in Patients with Cardiometabolic Risk. Consensus statement from the American Diabetes Association and the American College of Cardiology Foundation
Diabetes Care 31:811-822, 2008
http://care.diabetesjournals.org/cgi/content/full/31/4/811

MEASURING WAIST CIRCUMFERENCE:
A short video showing how to take the measurement
http://media.metabolicsyndromeinstitute.com/fichiers-site-mets/waist_circumference.mpg

CARDIOVASCULAR RISK ASSESSMENT TOOLS:
Framingham Risk Assessment Tool

PROCAM Risk Calculator OFFICE SYSTEMS AND PRACTICE ORGANIZATION:
Roadmap for Clinical Practice series: Assessment and Management of Adult Obesity:
  • This is a key resource for enhancing any aspect of obesity management. It consists of 10 booklets that offer practical recommendations for the primary care setting.
Booklet 1 - Introduction and clinical considerations
Booklet 2 - Evaluating your patients for overweight or obesity
Booklet 3 - Assessing readiness and making treatment decisions
Booklet 4 - Dietary management
Booklet 5 - Physical activity management
Booklet 6 - Pharmacological management
Booklet 7 - Surgical management
Booklet 8 - Communication and counseling strategies
Booklet 9 - Setting up the office environment
Booklet 10 - Resources for physicians and patients
http://www.ama-assn.org/ama/pub/category/10931.html
ORGANIZATIONS:
The Metabolic Syndrome Institute
  • Created in 2003, an independent and nonprofit association; members are international experts in lipid metabolism, diabetes, heart disease, endocrinology obesity, genetics, epidemiology, basic research and health economics.
  • First association totally devoted to the dissemination of knowledge about the metabolic syndrome. http://metabolic-syndrome-institute.com/
American Heart Association

ON-LINE PRESENTATIONS
http://www.niddk.nih.gov/fund/other/FDA-NIH/Eckel.pdf
Powerpoint presentation on the Metabolic Syndrome

CME PROGRAMS:
Fighting the Clinical "Battle of the Bulge"
http://www.medscape.com/viewarticle/577385
http://www.medscape.com/viewprogram/15622_pnt

Obesity, Insulin Resistance, and Atherosclerosis: Can the Cycle Be Broken?
http://www.medscape.com/viewarticle/577798

Cardiometabolic Risk Reduction in Patients With Type 2 Diabetes: Evolving Science and
Emerging Strategies
http://www.medscape.com/viewprogram/15708

Targeting the Interplay of Obesity, Insulin Resistance and Mixed Dyslipidemia: An Integrative Approach to Reducing Cardiometabolic Risk
http://www.medscape.com/viewprogram/14920

PATIENT INFO

13. REFERENCES

1. Duncan BB, Schmidt MI. The epidemiology of low-grade chronic systemic inflammation and type 2 diabetes. Diabetes Technol Ther. 2006 Feb;8(1):7-17.

2. NCEP. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) JAMA 2001;285:2486-2497.

3. Haffner SM, Ruilope L, Dahlof B, Abadie E, Kupfer S, Zannad F. Metabolic syndrome, new onset diabetes, and new end points in cardiovascular trials. J Cardiovasc Pharmacol. 2006 Mar; 47(3):469-75.

4. Grundy SM, Cleeman JI, Daniels SR et al. Diagnosis and management of the metabolic syndrome: an AHA/NHLBI scientific statement. Circulation 2005; 112: 2735-2752

5. Hutley L, Prins JB. Fat as an endocrine organ: relationship to the metabolic syndrome. Am J Med Sci. 2005 Dec;330(6):280-9.

6. Ramlo-Halsted BA & Edelman SV. The natural history of type 2 diabetes. Implications for practice. Primary Care 1999; 26(4): 771-89.

7. Reaven GM. Banting Lecture 1988. Role of insulin resistance in human disease. Diabetes 1988; 37(12): 1595-1607

8. Cortez-Dias N, Martins S, Fiuza M. Metabolic syndrome: an evolving concept. Rev Port Cardiol. 2007 Dec;26(12):1409-21.

9. Boden-Albala B. Current understanding of multiple risk factors as the metabolic syndrome: distillation or deconstruction. Semin Neurol. 2006 Feb;26(1):108-16.

10. Reaven GM. Role of insulin resistance in human disease (syndrome X): an expanded definition Annu Rev Med 1993;44:121-131.

11. Ferrannini E, Haffner SM, Mitchell BD, Stern MP. Hyperinsulinemia: the key feature of a cardiovascular and metabolic syndrome Diabetologia 1991;34:416-422.

12. DeFronzo RA, Ferrannini E. Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidaemia, and atherosclerotic cardiovascular disease. Diabetes Care 1991;14:173-194.

13. Balkau B, Charles MA. Comment on the provisional report from the WHO consultation. European Group for the Study of Insulin Resistance (EGIR). Diabet Med 1999;16:442-443.

14. Einhorn D. ACE position statement on insulin resistance syndrome Endocr Pract 2003;9:237-252.

15. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1:diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 1998;15:539-553.

16. Porte Jr. D. Mechanisms for hyperglycemia in the metabolic syndrome. The key role of beta-cell dysfunction. Ann N Y Acad Sci 1999;892:73-83.

17. Groop L. Genetics of the metabolic syndrome. Br J Nutr 2000;83(Suppl 1):S39-S48.

18. Kahn R, Buse J, Ferrannini E, Stern M. The metabolic syndrome: time for a critical appraisal. Joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia. 2005 Sep;48(9):1684-99.

19. Brietzke SA. Controversy in diagnosis and management of the metabolic syndrome. Med Clin North Am. 2007 Nov;91(6):1041-61, vii-viii.

20. Grundy SM. Drug therapy of the metabolic syndrome: minimizing the emerging crisis in polypharmacy. Nat Rev Drug Discov 2006; 5: 295-309

21. Giugliano D, Ceriello A, Esposito K. Are there specific treatments for the metabolic syndrome? Am J Clin Nutr. 2008 Jan;87(1):8-11

22. Balkau B, Valensi P, Eschwège E, Slama G. A review of the metabolic syndrome. Diabetes Metab. 2007 Dec;33(6):405-13.

23. Lewis SJ, Rodbard HW, Fox KM, Grandy S; SHIELD Study Group. Self-reported prevalence and awareness of metabolic syndrome: findings from SHIELD. Int J Clin Pract. 2008 Aug;62(8):1168-76

24. Alberti KGMM, Zimmet PZ; WHO Consultation. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus. Provisional report of a WHO consultation. Diabet Med. 1998;15:539-553.

25. Balkau B, Charles MA. Comments on the provisional report from the WHO consultation. European Group for the Study of Insulin Resistance. Diabet Med. 1999;16:442-443.

26. http://icd9.chrisendres.com/index.php?action=child&recordid=1974

27. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report Circulation 2002;106:3143-3421

28. ACE Position Statement. Insulin resistance. Endocr Pract. 2003;9:240-252.

29. Barclay L. Medscape Medical News. New definition of the metabolic syndrome: a newsmaker interview with Sir George Alberti, MA, DPhil, BMBCh. Available at: http://www.medscape.com/viewarticle/504382

30. Gao W; DECODE Study Group. Does the constellation of risk factors with and without abdominal adiposity associate with different cardiovascular mortality risk? Int J Obes (Lond). 2008 May;32(5):757-62.

31. Mule G, Cottone S, Nardi E, Andronico G, Cerasola G. Metabolic syndrome in subjects with essential hypertension: relationships with subclinical cardiovascular and renal damage. Minerva Cardioangiol. 2006 Apr;54(2):173-94.

32. Cohn GS, Kittleson MM, Blumenthal RS. Toward an improved diagnosis of the metabolic syndrome other clues to the presence of insulin resistance. Am J Hypertens. 2005 Aug;18(8):1099-103

33. Sattar N. Insulin resistance and the metabolic syndrome as predictors of cardiovascular risk: where are we now? Minerva Endocrinol. 2005 Sep;30(3):121-38.

34. Krentz AJ, Araneta MRG, Barrett-Connor E. Low adiponectin levels predict the metabolic syndrome in older men and women: the Rancho Bernardo Study. Program and abstracts of the 65th Scientific Sessions of the American Diabetes Association; June 10-14, 2005; San Diego, California. Abstract 2435-PO.

35. Haffner SM. The metabolic syndrome: inflammation, diabetes mellitus, and cardiovascular disease. Am J Cardiol. 2006 Jan 16;97(2A):3A-11A.

36. Tsimikas S, Willerson JT, Ridker PM. C-reactive protein and other emerging blood biomarkers to optimize risk stratification of vulnerable patients. J Am Coll Cardiol. 2006 Apr 18;47(8 Suppl):C19-31.

37. Li C, Ford ES, Meng YX, Mokdad AH, Reaven GM. Does the association of the triglyceride to high-density lipoprotein cholesterol ratio with fasting serum insulin differ by race/ethnicity? Cardiovasc Diabetol. 2008 Feb 28;7:4.

38. Ford ES. Prevalence of the metabolic syndrome defined by the International Diabetes Federation among adults in the U.S. Diabetes Care. 2005 Nov;28(11):2745-9.

39. Ford ES, Giles WH, Mokdad AH. Increasing prevalence of the metabolic syndrome among u.s. Adults. Diabetes Care. 2004 Oct;27(10):2444-9.

40. de Ferranti SD, Gauvreau K, Ludwig DS, Newburger JW, Rifai N. Inflammation and changes in metabolic syndrome abnormalities in US adolescents: findings from the 1988-1994 and 1999-2000 National Health and Nutrition Examination Surveys. Clin Chem. 2006 Jul;52(7):1325-30.

41. Regitz-Zagrosek V, Lehmkuhl E, Weickert MO. Gender differences in the metabolic syndrome and their role for cardiovascular disease. Clin Res Cardiol. 2006 Mar;95(3):136-47.

42. Ogden CL, Flegal KM, Carroll MD, Johnson CL. Prevalence and trends in overweight among US children and adolescents, 1999-2000. JAMA. 2002 Oct 9;288(14):1728-32.

43. Flegal KM, Carroll MD, Ogden CL, Johnson CL. Prevalence and trends in obesity among US adults, 1999-2000. JAMA. 2002 Oct 9;288(14):1723-7.

44. Ford ES, Zhao G, Li C, Pearson WS, Mokdad AH. Trends in obesity and abdominal obesity among hypertensive and non-hypertensive adults in the United States. Am J Hypertens. 2008 Oct;21(10):1124-8.

45. Okosun IS, Chandra KM, Boev A, Boltri JM, Choi ST, Parish DC, Dever GE. Abdominal obesity in U.S. adults: prevalence and trends, 1960-2000. Prev Med 2004 Jul; 39(1): 197-206

46. Li C, Ford ES, McGuire LC, Mokdad AH. Increasing trends in waist circumference and abdominal obesity among US adults. Obesity (Silver Spring). 2007 Jan;15(1):216-24.

47. Hu FB, Stampfer MJ, Haffner SM, Solomon CG, Willett WC, Manson JE. Elevated risk of cardiovascular disease prior to clinical diagnosis of type 2 diabetes. Diabetes Care. 2002;25:1129-1134.

48. Haffner SM, Valdez RA, Hazuda HP, Mitchell BD, Morales PA, Stern MP. Prosepctive analysis of the insulin resistance syndrome (syndrome X). Diabetes. 1992;41:715-722.

49. Haffner SM, Stern MP, Hazuda HP, Mitchell BD, Patterson JK. Cardiovascular risk factors in confirmed prediabetic individuals. Does the clock for coronary heart disease start ticking before the onset of clinical diabetes? JAMA. 1990;263:2893-2898.

50. Haffner SM, Mykkanen L, Festa A, Burke JP, Stern MP. Insulin-resistant prediabetic subjects have more atherogenic risk factors than insulin-sensitive prediabetic subjects: implications for preventing coronary heart disease during the prediabetic state. Circulation. 2000;101:975-980.

51. Lakka H-M, Laaksonen DE, Lakka TA, et al. The metabolic syndrome and total cardiovascular disease mortality in middle-aged men. JAMA. 2002;288:2709-2716.

52. Isomaa B, Almgren P, Tuomi T, et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care. 2001;24:683-689.

53. Yip P, Facchini FS, Reaven GM. Resistance to insulin mediated glucose disposal as a predictor of cardiovascular disease J Clin Endocrinol Metab. 1998;83:2773-2776.

54. Festa A, D'Agostino RJ, Howard G, Mykkanen L, Tracy RP, Haffner SM. Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS). Circulation. 2000;102:42-47.

55. Kahn R, Buse J, Ferrannini E, Stern M; American Diabetes Association; European Association for the Study of Diabetes. The metabolic syndrome: time for a critical appraisal: joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2005 Sep;28(9):2289-304.

56. Pollex RL, Hegele RA. Genetic determinants of the metabolic syndrome. Nat Clin Pract Cardiovasc Med. 2006 Sep;3(9):482-9

57. Grundy SM. Metabolic syndrome pandemic. Arterioscler Thromb Vasc Biol. 2008 Apr;28(4):629-36.

58. Koster A, Leitzman MF, Schatzkin A, et al. Waist circumference and mortality. Am J Epidemiol. 2008;167:1465-1475

59. Ford ES, Li C. Metabolic syndrome and health-related quality of life among U.S. adults. Ann Epidemiol. 2008 Mar;18(3):165-71.

60. Zarich SW. Metabolic syndrome, diabetes and cardiovascular events: current controversies and recommendations. Minerva Cardioangiol. 2006 Apr;54(2):195-214.

61. Blonde L, Ray S, Carson W, L'italien GJ. Metabolic syndrome predicts cardiovascular disease and new onset diabetes -- a systematic review of the literature. Program and abstracts of the 65th Scientific Sessions of the American Diabetes Association; June 10-14, 2005; San Diego, California. Abstract 2449-PO.

62. Bonora E. The metabolic syndrome and cardiovascular disease. Ann Med. 2006;38(1):64-80.

63. Hu FB, Stampfer MJ, Haffner SM, Solomon CG, Willett WC, Manson JE. Elevated risk of cardiovascular disease prior to clinical diagnosis of type 2 diabetes. Diabetes Care. 2002;25:1129-1134

64. Mule G, Cottone S, Nardi E, Andronico G, Cerasola G. Metabolic syndrome in subjects with essential hypertension: relationships with subclinical cardiovascular and renal damage. Minerva Cardioangiol. 2006 Apr;54(2):173-94.

65. Norhammar A, Tenerz A, Nilsson G, Hamsten A, Efendic S, Ryden L, Malmberg K. Glucose metabolism in patients with acute myocardial infarction and no previous diagnosis of diabetes mellitus: a prospective study. Lancet. 2002 Jun 22;359(9324):2140-4.

66. Haffner SM, Ruilope L, Dahlof B et al. Metabolic syndrome, new onset diabetes, and new end points in cardiovascular trials. J Cardiovasc Pharmacol. 2006 Mar;47(3):469-75.

67. Isomaa B, Almgren P, Tuomi T et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care. 2001 Apr;24(4):683-9.

68. Lakka HM, Laaksonen DE, Lakka TA et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA. 2002 Dec 4;288(21):2709-16.

69. Erhardt LR. Rationale for multiple risk intervention: the need to move from theory to
practice. Vasc Health Risk Manag. 2007;3(6):985-97.

70. Li W, Ma D, Liu M et al. Association between metabolic syndrome and risk of stroke: a meta-analysis of cohort studies. Cerebrovasc Dis. 2008;25(6):539-47.

71. Zarich SW. Metabolic syndrome, diabetes and cardiovascular events: current controversies and recommendations. Minerva Cardioangiol. 2006 Apr;54(2):195-214.

72. Hanley AJ, Williams K, Stern MP, Haffner SM. Homeostasis model assessment of insulin resistance in relation to the incidence of cardiovascular disease: the San Antonio Heart Study. Diabetes Care. 2002 Jul;25(7):1177-84.

73. Zieve FJ. The metabolic syndrome: diagnosis and treatment. Clin Cornerstone. 2004;6 Suppl 3:S5-13.

74. Fonseca V, Desouza C, Asnani S, Jialal I. Nontraditional risk factors for cardiovascular disease in diabetes. Endocr Rev. 2004 Feb;25(1):153-75.

75. Muntner P, He J, Chen J, Fonseca V, Whelton PK. Prevalence of non-traditional cardiovascular disease risk factors among persons with impaired fasting glucose, impaired glucose tolerance, diabetes, and themetabolic syndrome: analysis of the Third National Health and Nutrition Examination Survey (NHANES III). Ann Epidemiol. 2004 Oct;14(9):686-95.

76. Alexander J, Clearfield M. Cardiovascular disease after menopause: a growing epidemic. Minerva Ginecol. 2006 Feb;58(1):35-40.

77. Despres JP. Is visceral obesity the cause of the metabolic syndrome? Ann Med. 2006;38(1):52-63.

78. Segura J, Campo C, Ruilope LM, Rodicio JL. Do we need to target 'prediabetic' hypertensive patients? J Hypertens. 2005 Dec;23(12):2119-25.

79. Tsimikas S, Willerson JT, Ridker PM. C-reactive protein and other emerging blood biomarkers to optimize risk stratification of vulnerable patients. J Am Coll Cardiol. 2006 Apr 18;47(8 Suppl):C19-31.

80. Bonora E. The metabolic syndrome and cardiovascular disease. Ann Med. 2006;38(1):64-80.

81. Alexander J, Clearfield M. Cardiovascular disease after menopause: a growing epidemic. Minerva Ginecol. 2006 Feb;58(1):35-40.

82. Abuissa H, Bel DS, O'keefe JH Jr. Strategies to prevent type 2 diabetes. Curr Med Res Opin. 2005 Jul;21(7):1107-14.

83. Ford ES, Li C, Sattar N. Metabolic syndrome and incident diabetes: current state of the evidence. Diabetes Care.2008 Sep;31(9):1898-904.

84. Wilson PW, D'Agostino RB, Parise H, Sullivan L, Meigs JB. Metabolic syndrome as a precursor of cardiovascular disease and type 2 diabetes mellitus. Circulation. 2005 Nov 15;112(20):3066-72.

85. Lorenzo C, Okoloise M, Williams K et al. The metabolic syndrome as predictor of type 2 diabetes: the San Antonio heart study. Diabetes Care. 2003 Nov;26(11):3153-9.

86. Hanley AJ, Karter AJ, Williams K et al. Prediction of type 2 diabetes mellitus with alternative definitions of the metabolic syndrome: the Insulin Resistance Atherosclerosis Study. Circulation. 2005 Dec 13;112(24):3713-21.

87. Wannamethee SG, Shaper AG, Lennon L, Morris RW. Metabolic syndrome vs Framingham Risk Score for prediction of coronary heart disease, stroke, and type 2 diabetes mellitus. Arch Intern Med. 2005 Dec 12-26;165(22):2644-50.

88. Meigs JB, Wilson PW, Fox CS, Vasan RS, Nathan DM, Sullivan LM, D'Agostino RB. Body mass index, metabolic syndrome, and risk of type 2 diabetes or cardiovascular disease. J Clin Endocrinol Metab. 2006 Aug;91(8):2906-12.

89. Lim HS, Lip GY, Beevers DG, Blann AD. Factors predicting the development of metabolic syndrome and type II diabetes against a background of hypertension. Eur J Clin Invest. 2005 May;35(5):324-9.

90. Ford ES. Risks for all-cause mortality, cardiovascular disease, and diabetes associated with the metabolic syndrome: a summary of the evidence. Diabetes Care. 2005 Jul;28(7):1769-78.

91. D'Agostino RB Jr, Hamman RF, Karter AJ et al. Cardiovascular disease risk factors predict the development of type 2 diabetes: the insulin resistance atherosclerosis study. Diabetes Care. 2004 Sep;27(9):2234-40.

92. Nakanishi N, Nishina K, Okamoto M et al. Clustering of components of the metabolic syndrome and risk for development of type 2 diabetes in Japanese male office workers. Diabetes Res Clin Pract. 2004 Mar;63(3):185-94

93. Wannamethee SG, Shaper AG, Lennon L, Morris RW. Metabolic syndrome vs Framingham Risk Score for prediction of coronary heart disease, stroke, and type 2 diabetes mellitus. Arch Intern Med. 2005 Dec 12-26;165(22):2644-50.

94. Nakanishi N, Takatorige T, Fukuda H et al. Components of the metabolic syndrome as predictors of cardiovascular disease and type 2 diabetes in middle-aged Japanese men. Diabetes Res Clin Pract. 2004 Apr;64(1):59-70.

95. Wilson PW, D'Agostino RB, Parise H, Sullivan L, Meigs JB. Metabolic syndrome as a precursor of cardiovascular disease and type 2 diabetes mellitus. Circulation. 2005 Nov 15;112(20):3066-72.

96. Chen J, Muntner P, Hamm LL, Jones DW, Batuman V, Fonseca V, Whelton PK, He J. The metabolic syndrome and chronic kidney disease in U.S. adults. Ann Intern Med. 2004 Feb 3;140(3):167-74.

97. Jiamsripong P, Mookadam M, Honda T et al. The metabolic syndrome and cardiovascular disease: Part I. Prev Cardiol. 2008 Summer;11(3):155-61.

98. Ferranti S & Mozaffarian D. The Perfect Storm: Obesity, Adipocyte Dysfunction, and Metabolic Consequences. Clinical Chemistry. 2008;54:945-955.

99. Haag M, Dippenaar NG. Dietary fats, fatty acids and insulin resistance: short review of a multifaceted connection. Med Sci Monit. 2005 Dec;11(12):RA359-67

100. Meerarani P, Badimon JJ, Zias E, Fuster V, Moreno PR. Metabolic syndrome and diabetic atherothrombosis: implications in vascular complications. Curr Mol Med. 2006 Aug;6(5):501-14.

101. Smith AG, Muscat GE. Skeletal muscle and nuclear hormone receptors: implications for cardiovascular and metabolic disease. Int J Biochem Cell Biol. 2005 Oct;37(10):2047-63.

102. Kakafika AI, Liberopoulos EN, Karagiannis A et al. Dyslipidaemia, hypercoagulability and the metabolic syndrome. Curr Vasc Pharmacol. 2006 Jul;4(3):175-83.

103. Reaven GM. The metabolic syndrome: is this diagnosis necessary? Am J Clin Nutr. 2006 Jun;83(6):1237-47.

104. Yoneda M, Yamane K, Jitsuiki K et al. Prevalence of metabolic syndrome compared between native Japanese and Japanese-Americans. Diabetes Res Clin Pract. 2008 Mar;79(3):518-22.

105. Klein J, Perwitz N, Kraus D, Fasshauer M. Adipose tissue as source and target for novel therapies. Trends Endocrinol Metab. 2006 Jan-Feb;17(1):26-32.

106. Despres JP. Is visceral obesity the cause of the metabolic syndrome? Ann Med. 2006;38(1):52-63.

107. Hutley L, Prins JB. Fat as an endocrine organ: relationship to the metabolic syndrome. Am J Med Sci. 2005 Dec;330(6):280-9.

108. Mendez-Sanchez N, Chavez-Tapia NC, Zamora-Valdes D, Uribe M. Adiponectin, structure, function and pathophysiological implications in non-alcoholic fatty liver disease. Mini Rev Med Chem. 2006 Jun;6(6):651-6.

109. Fulop T, Tessier D, Carpentier A. The metabolic syndrome. Pathol Biol (Paris). 2006 Sep;54(7):375-86.

110. Ahima RS. Central actions of adipocyte hormones. Trends in Endocrinol and Metabolism, 2005; 16: 307-13

111. Mendez-Sanchez N, Chavez-Tapia NC, Zamora-Valdes D, Uribe M. Adiponectin, structure, function andpathophysiological implications in non-alcoholic fatty liver disease. Mini Rev Med Chem. 2006 Jun;6(6):651-6.

112. Hivert MF, Sullivan LM, Fox CS et al. Associations of adiponectin, resistin, and tumor necrosis factor-alpha with insulin resistance. J Clin Endocrinol Metab. 2008 Aug;93(8):3165-72.

113. Hirabara SM, Silveira LR, Abdulkader F et al. Time-dependent effects of fatty acids on skeletal muscle metabolism. J Cell Physiol. 2007 Jan;210(1):7-15.

114. Karpe F, Tan GD. Adipose tissue function in the insulin-resistance syndrome. Biochem Soc Trans. 2005 Nov;33(Pt 5):1045-8.

115. Grundy SM. Metabolic syndrome: connecting and reconciling cardiovascular and diabetes worlds. J Am Coll Cardiol. 2006 Mar 21;47(6):1093-100.

116. Sowers JR. Hypertension, angiotensin II, and oxidative stress. N Engl J Med. 2002 Jun 20;346(25):1999-2001.

117. Grundy SM. Atherogenic dyslipidemia associated with metabolic syndrome and insulin resistance. Clin Cornerstone. 2006;8 Suppl 1:S21-7.

118. Caballero AE, Arora S, Saouaf R et al. Microvascular and macrovascular reactivity is reduced in subjects at risk for type 2 diabetes. Diabetes. 1999; 48(9):1856-62.

119. Giles TD, Sander GE. Pathophysiologic, diagnostic, and therapeutic aspects of the metabolic syndrome. J Clin Hypertens (Greenwich). 2005 Nov;7(11):669-78.

120. Trayhurn P, Wood IS. Signalling role of adipose tissue: adipokines and inflammation in obesity. Biochem Soc Trans. 2005 Nov;33(Pt 5):1078-81.

121. Vettor R, Milan G, Rossato M, Federspil G. Review article: adipocytokines and insulin resistance. Aliment Pharmacol Ther. 2005 Nov;22 Suppl 2:3-10.

122. Schaffler A, Muller-Ladner U, Scholmerich J, Buchler C. Role of adipose tissue as an inflammatory organ in human diseases. Endocr Rev. 2006 Aug;27(5):449-67.

123. Meerarani P, Badimon JJ, Zias E, Fuster V, Moreno PR. Metabolic syndrome and diabetic atherothrombosis: implications in vascular complications. Curr Mol Med. 2006 Aug;6(5):501-14.

124. Ansell BJ, Watson KE, Fogelman AM, Navab M, Fonarow GC. High-density lipoprotein function recent advances. J Am Coll Cardiol. 2005 Nov 15;46(10):1792-8.

125. Duncan BB, Schmidt MI. The epidemiology of low-grade chronic systemic inflammation and type 2 diabetes. Diabetes Technol Ther. 2006 Feb;8(1):7-17.

126. Haffner SM. The metabolic syndrome: inflammation, diabetes mellitus, and cardiovascular disease. Am J Cardiol. 2006 Jan 16;97(2A):3A-11A.

127. Santos AC, Lopes C, Guimaraes JT, Barros H. Central obesity as a major determinant of increased high-sensitivity C-reactive protein in metabolic syndrome. Int J Obes (Lond). 2005 Dec;29(12):1452-6.

128. Goodpaster BH, Krishnaswami S, Harris TB, et al. Obesity, regional body fat distribution, and the metabolic syndrome in older men and women. Arch Intern Med. 2005;165:777-783.

129. Janssen I, Katzmarzyk PT, Ross R. Waist circumference and not body mass index explains obesity-related health risk. Am J Clin Nutr. 2004 Mar;79(3):379-84.

130. Sierra-Johnson J, Johnson BD, Allison TG, Bailey KR, Schwartz GL, Turner ST. Correspondence between the adult treatment panel III criteria for metabolic syndrome and insulin resistance. Diabetes Care. 2006 Mar;29(3):668-72.

131. Janssen I, Katzmarzyk PT, Ross R. Body mass index, waist circumference, and health risk: evidence in support of current National Institutes of Health guidelines. Arch Intern Med. 2002 Oct 14;162(18):2074-9.

132. Santi MJ, Carrozas MA, Barba A, Astola A, Jimenez A, Mangas A. [Waist circumference as a predictor of insulin resistance in young men]. Med Clin (Barc). 2005 Jun 11;125(2):46-50.

133. Florez H, Castillo-Florez S, Mendez A, Casanova-Romero P, Larreal-Urdaneta C, Lee D, Goldberg R. C-reactive protein is elevated in obese patients with the metabolic syndrome. Diabetes Res Clin Pract. 2006 Jan;71(1):92-100.

134. Yusuf S, Hawken S, Ounpuu S, et al. Obesity and the risk of myocardial infarction in 27,000 participants from 52 countries: a case-control study. Lancet. 2005;366:1640-1649.

135. Ford ES, Li C. Physical activity or fitness and the metabolic syndrome. Expert Rev Cardiovasc Ther. 2006 Nov;4(6):897-915.

136. Chang PC, Li TC, Wu MT et al. Association between television viewing and the risk of metabolic syndrome in a community-based population. BMC Public Health. 2008 Jun 3;8:193.

137. Hassinen M, Lakka TA, Savonen K et al. Cardiorespiratory fitness as a feature of metabolic syndrome in older men and women: the Dose-Responses to Exercise Training study (DR's EXTRA). Diabetes Care. 2008 Jun;31(6):1242-7.

138. Grundy SM, Cleeman JI, Merz CN et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004 Jul 13;110(2):227-39.

139. Cortez-Dias N, Martins S, Fiuza M. Metabolic syndrome: an evolving concept. Rev Port Cardiol. 2007 Dec;26(12):1409-21.

140. Grundy SM. Metabolic syndrome: therapeutic considerations. Handb Exp Pharmacol. 2005;(170):107-33.

141. Fernandez ML. The metabolic syndrome. Nutr Rev. 2007 Jun;65(6 Pt 2):S30-4.

142. Hall WD, Watkins LO, Wright JT Jr et al. The metabolic syndrome: recognition and management. Dis Manag. 2006 Feb;9(1):16-33.

143. Toto RD, Sowers JR & Jamerson KA. A Debate on the Metabolic Syndrome: Evolving Challenges and Controversies: http://www.medscape.com/viewprogram/4479_pnt

144. Zieve FJ. The metabolic syndrome: diagnosis and treatment. Clin Cornerstone. 2004;6 Suppl 3:S5-13.

145. Luchsinger JA. A work in progress: the metabolic syndrome. Sci Aging Knowledge Environ. 2006 Jun 28;2006(10):pe19.

146. Liberopoulos EN, Mikhailidis DP, Elisaf MS. Diagnosis and management of the metabolic syndrome in obesity. Obes Rev. 2005 Nov;6(4):283-96

147. Gillies CL, Abrams KR, Lambert PC et al. Pharmacological and lifestyle interventions to prevent or delay type 2 diabetes in people with impaired glucose tolerance: systematic review and meta-analysis. BMJ 334:299, 2007

148. Tuomilehto J, Lindström J, Eriksson JG et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 344:1343–1350, 2001

149. Knowler WC, Barrett-Connor E, Fowler SE et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 346:393–403, 2002

150. Ilanne-Parikka P, Eriksson JG, Lindström J et al. Effect of lifestyle intervention on the occurrence of metabolic syndrome and its components in the Finnish Diabetes Prevention Study. Diabetes Care. 2008 Apr;31(4):805-7.

151. Bo S, Ciccone G, Baldi C et al. Effectiveness of a lifestyle intervention on metabolic syndrome. A randomized controlled trial. J Gen Intern Med. 2007 Dec;22(12):1695-703.

152. Anderssen SA, Carroll S, Urdal P, Holme I. Combined diet and exercise intervention reverses the metabolic syndrome in middle-aged males: results from the Oslo Diet and Exercise Study. Scand J Med Sci Sports. 2007Dec;17(6):687-95.

153. Wells GD, Noseworthy MD, Hamilton J, Tarnopolski M, Tein I. Skeletal muscle metabolic dysfunction in obesity and metabolic syndrome. Can J Neurol Sci. 2008 Mar;35(1):31-40.

154. Carroll S, Dudfield M. What is the relationship between exercise and metabolic abnormalities? A review of the metabolic syndrome. Sports Med. 2004;34(6):371-418.

155. Hamdy O, Ledbury S, Mullooly C et al. Lifestyle modification improves endothelial function in obese subjects with the insulin resistance syndrome. Diabetes Care. 2003 Jul;26(7):2119-25.

156. Sigal RJ, Kenny GP, Wasserman DH et al. Physical activity/exercise and type 2 diabetes: a consensus statement from the American Diabetes Association. Diab Care 2006; 29(6): 1433-38

157. Duncan GE, Perri MG, Threiaque DW et al. Exercise training without weight loss, increases insulin sensitivity and postheparin plasmalipase activity in previously sedentary adults. Diabetes Care 2003; 26(3): 557-62

158. Simmons RK, Griffin SJ, Steele R et al. Increasing overall physical activity and aerobic fitness is associated with improvements in metabolic risk: cohort analysis of the ProActive trial. Diabetologia. 2008 May;51(5):787-94.

159. Maiorana A, O’Driscoll G, Goodman C et al. Combined aerobic and resistance exercise improves glycemic control and fitness in type 2 diabetes. Diab Res Clin Pract 2002; 56(2): 115-23

160. Johnson JL, Slentz CA, Houmard JA et al. Exercise training amount and intensity effects on metabolic syndrome (from Studies of a Targeted Risk Reduction Intervention through Defined Exercise). Am J Cardiol. 2007 Dec 15;100(12):1759-66.

161. Healy GN, Dunstan DW, Salmon J et al. Breaks in sedentary time: beneficial associations with metabolic risk. Diabetes Care. 2008 Apr;31(4):661-6.

162. Hu FB, Li TY, Colditz GA, Willett WC, Manson JE. Television watching and other sedentary behaviors in relation to risk of obesity and type 2 diabetes mellitus in women.

163. CDC. National Center for Chronic Disease Prevention and Health Promotion. Surgeon General's Report on Physical Activity and Health
http://www.cdc.gov/nccdphp/sgr/chapcon.htm

164. Weinberg SL. The diet-heart hypothesis: a critique. J Am Coll Cardiol 2004; 43: 731-3

165. Giugliano D, Esposito K. Mediterranean diet and metabolic diseases. Curr Opin Lipidol. 2008 Feb;19(1):63-8.

166. Lichtenstein AH, Appel LJ, Brands M et al. Diet and lifestyle recommendations revision 2006. A scientific statement from the American Heart Association Nutrition Committee. Circulation 2006; 114:82-96

167. Serra-Majem L, Roman B, Estruch R. Scientific evidence of interventions using the Mediterranean diet: asystematic review. Nutr Rev. 2006 Feb;64(2 Pt 2):S27-47.

168. Willett WC. The Mediterranean diet: science and practice. Public Health Nutr. 2006 Feb;9(1A):105-10.

169. Esposito K, Marfella R, Ciotola M et al. Effect of a Mediterranean style diet on endothelial function and markers of vascular inflammation in the metabolic syndrome: a randomized trial. JAMA 2004; 292: 1440-6

170. Azadbakht L, Mirmiran P, Esmaillzadeh A et al. Beneficial effects of a dietary approaches to stop hypertension eating plan on features of the metabolic syndrome. Diabetes Care 2005; 28: 2823-31

171. Williams DE, Prevost AT, Whichelow MJ et al. A cross-sectional study of dietary patterns with glucose intolerance and other features of the metabolic syndrome. Br J Nutr 2000; 83: 257-66

172. Haag M, Dippenaar NG. Dietary fats, fatty acids and insulin resistance: short review of a multifaceted connection. Med Sci Monit. 2005 Dec;11(12):RA359-67

173. Katcher HI, Legro RS, Kunselman AR, Gillies PJ et al. The effects of a whole grain-enriched hypocaloric diet on cardiovascular disease risk factors in men and women with metabolic syndrome. Am J Clin Nutr. 2008 Jan;87(1):79-90.

174. McKeown NM, Meigs JB, Liu S et al. Carbohydrate nutrition, insulin resistance, and the prevalence of the metabolic syndrome in the Framingham Offspring Cohort. Diabetes Care 2004; 27: 538-46

175. Dhingra R, Sullivan L, Jacques PF et al. Soft drink consumption and risk of developing cardiometabolic risk factors and the metabolic syndrome in middle-aged adults in the community. Circulation. 2007 Jul 31;116(5):480-8.

176. Rutledge AC, Adeli K. Fructose and the metabolic syndrome: pathophysiology and molecular mechanisms. Nutr Rev. 2007 Jun;65(6 Pt 2):S13-23.

177. Vrolix R, van Meijl LE, Mensink RP. The metabolic syndrome in relation with the glycemic index and the glycemic load. Physiol Behav. 2008 May 23;94(2):293-9.

178. Lutsey PL, Steffen LM, Stevens J. Dietary intake and the development of the metabolic syndrome: the Atherosclerosis Risk in Communities study. Circulation. 2008 Feb 12;117(6):754-61.

179. McNaughton SA, Mishra GD, Brunner EJ. Dietary Patterns, Insulin Resistance, and Incidence of Type 2 Diabetes in the Whitehall II Study. Diabetes Care 2008; 31:1343-1348

180. Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA 2002 May 15;287(19):2570-81.

181. Klein S, Burke LE, Bray GA, Blair S, Allison DB, Pi-Sunyer X, Hong Y, Eckel RH. Clinical implications of obesity with specific focus on cardiovascular disease: a statement for professionals from the American Heart Association Council on Nutrition, Physical Activity, and Metabolism: endorsed by the American College of Cardiology. Circulation 2004 Nov 2;110(18):2952-67.

182. Zieve FJ. The metabolic syndrome: diagnosis and treatment. Clin Cornerstone. 2004;6 Suppl 3:S5-13.

183. Abuissa H, Bel DS, O'keefe JH Jr. Strategies to prevent type 2 diabetes. Curr Med Res Opin. 2005 Jul;21(7):1107-14.

184. Abuissa H, Jones PG, Marso SP, O'Keefe JH Jr. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for prevention of type 2 diabetes: a meta-analysis of randomized clinical trials. J Am Coll Cardiol. 2005 Sep 6;46(5):821-6.

185. Watts GF, Barrett PH. High-density lipoprotein metabolism in familial hypercholesterolaemia: significance, mechanisms, therapy. Nutr Metab Cardiovasc Dis. 2002 Feb;12(1):36-41.

186. Shepherd J, Betteridge J, Van Gaal L; European Consensus Panel. Nicotinic acid in the management of dyslipidaemia associated with diabetes and metabolic syndrome: a position paper developed by a European Consensus Panel. Curr Med Res Opin. 2005 May;21(5):665-82.

187. Liberopoulos EN, Mikhailidis DP, Elisaf MS. Diagnosis and management of the metabolic syndrome in obesity. Obes Rev. 2005 Nov;6(4):283-96

188. Ballantyne CM, Stein EA, Paoletti R, Southworth H, Blasetto JW. Efficacy of rosuvastatin 10 mg in patients with the metabolic syndrome. Am J Cardiol. 2003 Mar 6;91(5A):25C-28C.

189. Aronow WS. Hypercholesterolemia. The evidence supports use of statins. Geriatrics. 2003 Aug;58(8):18-20, 26-8, 31-2.

190. Lester JW, Fernandes AW. Pioglitazone in a subgroup of patients with type 2 diabetes meeting the criteria for metabolic syndrome. Int J Clin Pract. 2005 Feb;59(2):134-42.

191. Leschke M. [Does targeted therapy of type 2 diabetes prevent cardiovascular incidents?] Med Klin (Munich). 2003 Oct 15;98 Suppl 1:12-6.

192. Haskell WL, Lee IM, Pate RR et al. Physical activity and public health: updated recommendation for adults from the American College of Sports Medicine and the American Heart Association. Circulation. 2007 Aug 28;116(9):1081-93.

193. U.S. Preventive Services Task Force. Behavioral counseling in primary care to promote a healthy diet: recommendations and rationale. Am J Prev Med. 2003 Jan;24(1):93-100.

194. Finnish Medical Society Duodecim. Metabolic syndrome. In: EBM Guidelines. Evidence-Based Medicine [Internet]. Helsinki, Finland: Wiley Interscience. John Wiley & Sons; 2007 Dec 13

195. University of Texas at Austin, School of Nursing, Family Nurse Practitioner Program. Screening for metabolic syndrome in adults. Austin (TX): University of Texas at Austin, School of Nursing; 2004 May. 24 p

196. Blaha MJ, Bansal S, Rouf R et al. A practical "ABCDE" approach to the metabolic syndrome. Mayo Clin Proc. 2008 Aug;83(8):932-41.

197. Ma J, Urizar GG Jr, Alehegn T, Stafford RS. Diet and physical activity counseling during ambulatory care visits in the United States. Prev Med 2004; 39 : 815-224.

198. Rosal MC, Ockene JK, Luckmann R et al. Coronary heart disease multiple risk factor reduction: providers' perspectives. Am J Prev Med 2004; 27 (Suppl. 2): 54-60.

199. Yarnell KS, Pollak KI, Ostbye T, Krause KM, Michener JL. Primary care: is there enough time for prevention? Am J Public Health 2003; 93:635-641.

200. Zarich SW. Metabolic syndrome, diabetes and cardiovascular events: current controversies and recommendations. Minerva Cardioangiol. 2006 Apr;54(2):195-214.

201. Calderon A, Barrios V, Llisterri JL, et al. Metabolic syndrome: an entity frequently misdiagnosed in primary care. Data from the PRESCOT Study. Program and abstracts of the 65th Scientific Sessions of the American Diabetes Association; June 10-14, 2005; San Diego, California. Abstract 2429-PO.

202. Conaway DG, O'Keefe JH. Frequency of undiagnosed and untreated diabetes mellitus in patients with acute coronary syndromes. Expert Rev Cardiovasc Ther. 2006 Jul;4(4):503-7.

203. Pervanidou P, Kanaka-Gantenbein C, Chrousos GP. Assessment of metabolic profile in a clinical setting. Curr Opin Clin Nutr Metab Care. 2006 Sep;9(5):589-95.

204. Watts GF, Barrett PH. High-density lipoprotein metabolism in familial hypercholesterolaemia: significance, mechanisms, therapy. Nutr Metab Cardiovasc Dis. 2002 Feb;12(1):36-41.

205. Pervanidou P, Kanaka-Gantenbein C, Chrousos GP. Assessment of metabolic profile in a clinical setting. Curr Opin Clin Nutr Metab Care. 2006 Sep;9(5):589-95.

206. http://www.ama-assn.org/ama1/pub/upload/mm/433/booklet2.pdf

207. Ness-Abramof R, Apovian CM. Waist circumference measurement in clinical practice. Nutr Clin Pract 2008; 23: 397-404

208. Foreyt JP. Need for lifestyle intervention: how to begin. Am J Cardiol. 2005 Aug 22;96(4A):11E-14E.

209. Klein S, Burke LE, Bray GA, Blair S, Allison DB, Pi-Sunyer X, Hong Y, Eckel RH. Clinical implications of obesity with specific focus on cardiovascular disease: a statement for professionals from the American Heart Association Council on Nutrition, Physical Activity, and Metabolism: endorsed by the American College of Cardiology. Circulation 2004 Nov 2;110(18):2952-67.

210. Lewis SJ, Rodbard HW, Fox KM, Grandy S; SHIELD Study Group. Self-reported prevalence and awareness of metabolic syndrome: findings from SHIELD. Int J Clin Pract. 2008 Aug;62(8):1168-76

211. Foreyt JP. The role of lifestyle modification in dysmetabolic syndrome management.
Nestle Nutr Workshop Ser Clin Perform Programme. 2006;11:197-206

212. Ammerman AS, Lindquist CH, Lohr KN, Hersey J: The efficacy of behavioral interventions to modify dietary fat and fruit and vegetable intake: a review of the evidence. Prev Med 35:25 -41, 2002

213 Bodenheimer T, Davis C, Holman H. Helping Patients Adopt Healthier Behaviors. Clinical Diabetes 25:66-70, 2007

214. MacGregor K, Handley M, Wong S, Sharifi C, Gjeltema K, Schillinger D, Bodenheimer T: Behavior-change action plans in primary care: a feasibility study of clinicians. J Am Board Fam Med19 : 215-223,2006

215. Handley M, MacGregor K, Schillinger D, Sharifi C, Wong S, Bodenheimer T: Using action plans to help primary care patients adopt healthy behaviors: a descriptive study. J Am Board Fam Med 19:224 -231, 2006

216. Locke EA, Latham GP: Building a practically useful theory of goal setting and task motivation. Am Psychologist 57:705 -717, 2002

217. Marks R, Allegrante JP, Lorig K: A review and synthesis of research evidence for self-efficacy-enhancing interventions for reducing chronic disability. Health Promot Pract 6:37 -43,148-156, 2005

218. Goldberg HI, Lessler MS, Mertens K, Eytan TA, Cheadle AD: Self-management support in a web-based medical record. Joint Comm J Qual Safety30 : 629-635,2004

219. Lorig KR, Ritter P, Stewart AL, Sobel DS, Brown BW, Bandura A, Gonzalez VM, Laurent DD, Holman HR: Chronic disease self-management program: 2-year health status and health care utilization outcomes. Med Care39 : 1217-1223,2001

220. Bodenheimer T, Davis C, Holman H. Helping Patients Adopt Healthier Behaviors. Clinical Diabetes 25:66-70, 2007

221. Starfield B, Lemke KW, Bernhardt T, Foldes SS, Forrest CB, Weiner JP. Comorbidity: implications for the importance of primary care in ‘case’ management. Ann Fam Med. 2003;1(1):8–14.

222. Fortin M, Bravo G, Hudon C, Vanasse A, Lapointe L. Prevalence of multimorbidity among adults seen in family practice. Ann Fam Med. 2005;3(3):223–228.

223. Schoen C, Davis K, How SK, Schoenbaum SC. U.S. health system performance: a national scorecard. Health Aff (Millwood). 2006;25(6):w457–w475.

224. McGlynn EA, Asch SM, Adams J, et al. The quality of health care delivered to adults in the United States. N Engl J Med. 2003;348(26):2635–2645.

225. Wagner EH. The role of patient care teams in chronic disease management. BMJ. 2000;320(7234):569–572.

226. Chen E & Bodenheimer T. Applying the chronic care model to the management of obesity. Obesity Management 2008 Oct: 227-231.

227. Grumbach K, Bodenheimer T. Can health care teams improve primary care practice? JAMA. 2004;291(10):1246–1251.

228. Hroscikoski MC, Solberg LI, Sperl-Hillen JM, Harper PG, McGrail MP, Crabtree BF. Challenges of change: a qualitative study of chronic care model implementation. Ann Fam Med. 2006;4(4):317–326.

229. Nutting PA, Dickinson WP, Dickinson LM, et al. Use of chronic care model elements is associated with higher-quality care for diabetes. Ann Fam Med. 2007;5(1):14–20.

230. Solberg LI, Crain AL, Sperl-Hillen JM, Hroscikoski MC, Engebretson KI, O’Connor PJ. Care quality and implementation of the chronic care model: a quantitative study. Ann Fam Med. 2006;4(4):310–316.

231. Bodenheimer T, Wagner EH, Grumbach K. Improving primary care for patients with chronic illness. Parts 1 and 2. JAMA 2002; 288: 1775-1779, 1909-1914.

232. Korenbrot CC, Gill A, Clayson Z, Patterson E. Evaluation of California’s statewide implementation of enhanced perinatal services as Medicaid benefits. Public Health Rep. 1995;110(2):125–133.

233. Perkocha VA, Novotny TE, Bradley JC, Swanson J. The efficacy of two comprehensive perinatal programs on reducing adverse perinatal outcomes. Am J Prev Med. 1995;11(3 Suppl):21–29.

234. Martin JC, Avant RF, Bowman MA, et al. The future of family medicine: a collaborative project of the family medicine community. Ann Fam Med. 2004;2(Suppl 1):S3–S32.

235. Gotto AM Jr, Blackburn GL, Dailey GE 3rd et al. The metabolic syndrome: a call to action. Coron Artery Dis. 2006 Feb;17(1):77-80.

236. Sattar N. The metabolic syndrome: should current criteria influence clinical practice? Curr Opin Lipidol. 2006 Aug;17(4):404-11.

237. Yusuf S. The Epidemics of Type 2 Diabetes, Obesity, and the Metabolic Syndrome
http://www.medscape.com/viewprogram/4915_pnt

238. Haffner S. Cardiovascular Disease Risk and the Metabolic Syndrome
http://www.medscape.com/viewprogram/4915_pnt

239. Fleg JL, Mete M, Howard BV et al. Effect of statins alone versus statins plus ezetimide on carotid atherosclerosis in Type 2 diabetes, The SANDS (Stop Atherosclerosis in Native Diabetics Study) Trial. J Am Coll Cardiol published online Dec 3, 2008 [http://content.onlinejacc.org/cgi/content/full/j.jacc.2008.10.031.v1

 

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