The Metabolic Syndrome: Concepts and Controversy

  1. Lewis W. Johnson, MD and
  2. Ruth S. Weinstock, MD, PhD
  1. From the Division of Endocrinology, Diabetes and Metabolism, SUNY Upstate Medical University, Syracuse, NY (L.W.J., R.S.W.) and Veterans Affairs Medical Center, Syracuse, NY (R.S.W.)
  1. Address reprint requests and correspondence to Ruth S. Weinstock, MD, PhD, Division of Endocrinology, Diabetes and Metabolism, SUNY Upstate Medical University, 750 E Adams St, CWB 353, Syracuse, NY 13210 (e-mail: weinstor{at}upstate.edu).
 
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Abstract

The metabolic syndrome is an insulin-resistant state characterized by a cluster of cardiovascular risk factors, including various combinations of abdominal obesity, glucose intolerance, hypertension, and atherogenic dyslipidemia (elevated triglyceride values, low high-density lipoprotein cholesterol levels, and small dense low-density lipoprotein cholesterol particles). The current epidemic of obesity and physical inactivity has led to an increased prevalence of this disorder. In this review, we discuss the history and pathogenesis of the metabolic syndrome, the controversy regarding the appropriateness of considering it a distinct diagnosis, and the importance of lifestyle modification in its prevention and treatment. The need for all cardiovascular risk factors to be treated, whether or not they are components of the metabolic syndrome, is emphasized. Recent discussions in the literature regarding the continued use of the term metabolic syndrome should be considered a healthy academic debate that hopefully will stimulate ideas and innovative research to improve patient care.

ACE = American College of Endocrinology/American Association of Clinical Endocrinologists; ADA = American Diabetes Association; BMI = body mass index; CVD = cardiovascular disease; DM = diabetes mellitus; EASD = European Association for the Study of Diabetes; FRS = Framingham Risk Score; HDL = high-density lipoprotein; LDL = low-density lipoprotein; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III; UKPDS = United Kingdom Prospective Diabetes Study; WC = waist circumference; WHO = World Health Organization

The metabolic syndrome describes a group of modifiable risk factors occurring in the same individual and associated with an increased risk of developing cardiovascular disease (CVD) and type 2 diabetes mellitus (DM). Reports of clustering of metabolic risk factors are not new and date back to the early 1920s.1 However, there was little interest in this phenomenon until 1988, when Reaven2 coined the term syndrome X to describe a disorder consisting of insulin resistance, glucose intolerance, increased triglyceride and decreased high-density lipoprotein (HDL) cholesterol levels, and hypertension. He postulated that the common feature was insulin resistance and that all the other changes were likely to be secondary to this basic abnormality. Additionally, he noted that the more obese and sedentary an individual, the greater the degree of insulin resistance.

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DEFINITIONS

The World Health Organization (WHO) first defined the syndrome in 19983 and called it the metabolic syndrome, a term that had been used by Zimmet4 in 1991 to describe this cluster of findings. The WHO criteria for the metabolic syndrome required the presence of diabetes mellitus (DM), impaired fasting glucose, impaired glucose tolerance, or insulin resistance (assessed by the euglycemic insulin clamp technique) plus 2 additional factors. In 1999, the European Group for the Study of Insulin Resistance5 suggested that a more appropriate term would be the insulin resistance syndrome and modified the criteria to require fasting hyperinsulinemia plus 2 other factors using different cutpoints than those used by the WHO. One of the criteria was an increased waist circumference (WC) to reflect abdominal obesity. In 2001, the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III)6 simplified the definition to make it user-friendly for practitioners (Table 1). The NCEP ATP III required any 3 of 5 risk factors: abnormal WC, high triglyceride level, low HDL cholesterol level, high blood pressure, and high fasting plasma glucose concentration (Table 1). The NCEP ATP III criteria were updated in 2005 to correspond with the new American Diabetes Association (ADA) standard of a normal fasting glucose level of less than 100 mg/dL.7 In 2003, the American College of Endocrinology/American Association of Clinical Endocrinologists (ACE) published a position statement9 recommending that the appropriate term should be the insulin resistance syndrome and stressing that it places the individual at increased risk for not only type 2 DM and CVD but also other disease states associated with insulin resistance (essential hypertension, polycystic ovary syndrome, nonalcoholic fatty liver disease, certain forms of cancer, and sleep apnea). The ACE statement was meant to be more an explanation of the mechanisms of the syndrome, rather than another competing definition. The latest criteria were proposed by the International Diabetes Federation8 and are similar to the more commonly used NCEP ATP III definition but require measurement of abdominal girth, which has different cutoff values based on ethnicity and is seldom completed in a busy office setting. The WHO, NCEP ATP III, and International Diabetes Federation criteria for metabolic syndrome are summarized in Table 1, and ethnicity-specific WC cut points are shown in Table 2. The rationale for using different WC values is that Asians have a

View this table:
TABLE 1.

Comparison of WHO, NCEP ATP III, and IDF Definitions of the Metabolic Syndrome*

higher incidence of insulin resistance and DM at a lower body mass index (BMI) (calculated as weight in kilograms divided by the square of height in meters) and WC than Europeans.10 All 3 versions allow the inclusion of patients with DM and share the common goal of identifying individuals at increased risk for developing CVD. Of note, the presence of DM is generally considered a CVD risk equivalent.6,11

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CLINICAL IMPORTANCE

The pandemic of obesity, metabolic syndrome, and diabetes has sparked a tremendous interest in the medical literature. A MEDLINE search limited to English-language articles with the terms metabolic syndrome, insulin resistance syndrome, or syndrome X in the title returned 4024 articles published during the past 5 years, 1408 of which were published in the 12 months ending in March 2006.

View this table:
TABLE 2.

Ethnicity-Specific Values for Waist Circumference

Using measured heights and weights, results from the National Health and Nutrition Examination Survey indicate that in US adults aged 20 to 74 years, the age-adjusted prevalence of being either overweight or obese (BMI, ≥25 kg/m2) increased from 47% in 1976-1980 to 65% in 1999-2002. During the same period, obesity (BMI, ≥30 kg/m2) doubled from 15% to 31%.12 Overweight and obesity are independent risk factors for CVD, the leading cause of death and disability in US adults. The prevalence of CVD in people 25 years or older who have normal weight (BMI, 18.5-24.9 kg/m2) or are overweight (BMI, 25.0-29.9 kg/m2) or obese (BMI, ≥30 kg/m2) is 20%, 28%, and 39%, respectively.13 In association with increasing obesity, the age-adjusted prevalence of the metabolic syndrome in the US population aged 25 years or older has increased from 24% in 1988-1994 to 27% in 1999-2000, and in those older than 60 years, the prevalence is more than 40%.14 Depending on the definition used and the population studied, the risk of an individual with the metabolic syndrome developing type 2 DM or CVD has varied. In a recent review by Grundy,15 the risk of type 2 DM developing was estimated to be 5 times greater in persons with the metabolic syndrome without DM than in those not meeting 3 of the 5 NCEP ATP III criteria, and the relative risk of CVD was doubled. Obesity and metabolic syndrome have also been increasing at an alarming rate in children and adolescents.16 An estimated 1 million US adolescents meet the criteria for the metabolic syndrome.17 In the Bogalusa Heart Study,18 autopsies of young people who had died of trauma showed that the extent of atherosclerosis in the aorta and coronary arteries correlated with the number of metabolic risk factors.

Overweight/obesity and a sedentary lifestyle are becoming the norm in the United States, and physicians are seeing increasing numbers of persons with this cluster of factors. This group of risk factors, as well as the individual risk factors, place patients at increased risk of developing type 2 DM and CVD and contribute to the development of other potentially devastating conditions such as infertility, malignancy, steatohepatitis, and degenerative arthritis. On the basis of these trends, concern that a subsequent major increase in CVD will occur over the next 2 decades is reasonable.

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PATHOGENESIS

The prevailing theory is that in most people with the metabolic syndrome, the development of obesity and physical inactivity leads to insulin resistance and compensatory hyperinsulinemia. Most insulin-resistant individuals are able to maintain the degree of hyperinsulinemia required to prevent decompensation of glucose homeostasis. If pancreatic insulin secretion fails to increase adequately, impaired glucose tolerance or DM develops. Genetic factors probably play a role in the varied clinical manifestations seen in individual patients.

The metabolic syndrome is a proinflammatory and prothrombotic state, with glucotoxicity and lipotoxicity contributing to the metabolic and vascular abnormalities. Adipose tissue not only stores fat but also is an active endocrine organ with receptors that respond to signals from many sources, including the central nervous system. Adipose tissue is a source of metabolically active substances including elevated levels of free fatty acids, which affect parallel insulin-signaling pathways in the liver, skeletal muscle, and blood vessels, leading to hyperglycemia and endothelial dysfunction. Abnormalities include increased gluconeogenesis, decreased glucose uptake in skeletal muscle, loss of vasodilation, platelet aggregation, increased oxidative stress, and the formation of advanced glycation end products. Insulin resistance also affects the production of inflammatory cytokines (tumor necrosis factor α, interleukin 6), prothrombotic substances (fibrinogen, plasminogen activator inhibitor 1), and other molecules such as resistin, adiponectin (anti-inflammatory), and leptin.

Persons with the metabolic syndrome tend to have central or abdominal obesity in contrast to lower-body obesity. Central obesity is associated with a greater amount of visceral fat than is lower-body obesity, which is associated with more subcutaneous fat. Visceral fat is metabolically active, producing free fatty acids and inflammatory cytokines that drain directly into the liver via the portal circulation. Fat deposits in the liver are associated with overproduction of very-low-density lipoprotein, predisposing the patient to atherogenic dyslipidemia (elevated tri-glycerides, low HDL cholesterol levels, and small dense low-density lipoprotein [LDL] cholesterol particles). Although LDL cholesterol levels may not be elevated, the number of particles may be increased, and the small dense particles more readily enter the arterial wall and are oxidized, leading to atherosclerosis.

In addition to impaired glucose tolerance and atherogenic dyslipidemia, the insulin-resistant state, in at least some individuals, promotes development of hypertension. Endothelial dysfunction causes vascular changes and affects blood flow. Even with no detectable abnormality in glucose metabolism, other manifestations of insulin resistance can be present, including increased production of inflammatory cytokines. It is now well known that inflammation and oxidation play key roles in the etiology and progression of CVD.19 Factors responsible for the initiation of the insulin-resistant state and the basis for individual variation in its manifestations are being actively investigated.

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RECENT CONTROVERSY

The ADA and the European Association for the Study of Diabetes (EASD) recently published a joint statement questioning the clinical value of the metabolic syndrome.20 Their concerns were as follows: (1) the criteria for the diagnosis of metabolic syndrome are ambiguous, and the rationale for thresholds is ill defined; (2) the value of including DM in the definition of metabolic syndrome is questionable; (3) the validity of using insulin resistance as the unifying etiology is uncertain; (4) there is no clear basis for including/excluding other CVD risk factors; (5) the CVD risk value varies and depends on the specific risk factors present; (6) the CVD risk associated with the syndrome appears to be no greater than the sum of its parts; (7) treatment of the syndrome is no different than the treatment of its components; and (8) the medical value of diagnosing the syndrome is unclear. The authors of the ADA/EASD joint statement suggest a research agenda to critically analyze how the syndrome is defined and to determine its usefulness in predicting CVD risk over and above that of the individual components.

The ADA/EASD statement resulted in the publication of articles in the lay press, including USA TODAY,21 The New York Times, and The Washington Post. The National Heart, Lung, and Blood Institute and the American Heart Association7 continue to support the use of the term metabolic syndrome to describe an entity that increases the risk of developing CVD and type 2 DM and its use as a secondary target for reducing CVD events after the primary targets of smoking cessation, lowering LDL cholesterol levels, and blood pressure control. They agree that further research is needed to refine the most appropriate therapies for patients with the metabolic syndrome.

In a recent statement,22 the ACE restated their original opinion8 that the term insulin resistance syndrome more clearly describes the pathophysiology of this syndrome and that it is a major driver of atherosclerosis and DM and may play a role in disorders as diverse as infertility, malignancy, and abnormalities of liver function (fatty liver). The ACE specifically distinguished insulin resistance syndrome from type 2 DM and CVD because one of the most important goals was to identify individuals at risk before such consequences occurred. They believe it has been helpful to recognize the clustering of factors that increase the risk of an individual being insulin resistant as a syndrome. Furthermore, they assert that the concept is clinically useful and has led physicians to search for related risk factors and associated illnesses. Several recognized authorities have also voiced their opinions regarding the clinical utility of the continued use of the concept of the metabolic syndrome.23-25

In July 2006, a joint statement from the ADA and the American Heart Association regarding this recent controversy was published simultaneously in Diabetes Care26 and Circulation.27 The associations stated that they remain committed to CVD risk factor recognition and treatment. The ADA prefers assessing and treating “cardiometabolic risk.” The joint statement stresses the importance of lifestyle modification, including weight loss and increased physical activity.

Questioning of the concept of the metabolic syndrome is not new. In the 1998 report,3 the WHO noted that persons with central obesity, hypertension, and dyslipidemia, with or without hyperglycemia, present a major classification, diagnostic, and therapeutic challenge. They called for a clear description of the essential components of the syndrome and data to support the relative importance of each component. They also noted that internationally acknowledged criteria for central obesity, insulin resistance, and hyperinsulinemia would be of assistance. Unfortunately, 8 years later, we have not satisfactorily answered these questions.

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DISCUSSION

The NCEP ATP III criteria have definite flaws. First, the 5 criteria and the cutoffs appear to be arbitrary and not evidence based. Second, the risk factor values are continuous and must be considered as such, not just as present or absent. The fact that CVD risk increases with increasing blood glucose levels, systolic blood pressure, and LDL cholesterol values has been well documented. Third, important risk factors such as LDL cholesterol, cigarette smoking, family history, and age are not included, limiting the usefulness of the metabolic syndrome in predicting CVD risk. Finally, the inclusion of individuals with the diagnosis of DM is confusing because the metabolic syndrome is considered useful in predicting CVD risk, but DM alone is considered a CVD equivalent that requires aggressive treatment. The metabolic syndrome has been defined in several ways and thus cannot be considered a precise diagnosis. Rather, its presence should alert health care professionals to assess for all CVD risk factors and serve as a reminder that an individual is at increased risk of developing DM or CVD.

The diagnosis of metabolic syndrome is an indicator of long-term cardiovascular risk, but for short-term risk assessment, the Framingham Risk Score (FRS)28 is superior. The NCEP ATP III modification of the FRS includes age, sex, total cholesterol, LDL cholesterol, HDL cholesterol, systolic blood pressure, family history of early coronary heart disease, and smoking status and provides the 10-year risk of having a coronary event. The calculator can be downloaded to a desktop or handheld computer, and a table for manual calculation is also available (www.nhlbi.nih.gov). For patients with type 2 DM, the FRS is inaccurate, and the United Kingdom Prospective Diabetes Study (UKPDS) risk engine29 can be used. The UKPDS risk engine provides risk estimates and 95% confidence intervals in individuals with type 2 DM for nonfatal and fatal coronary heart disease and stroke. In addition to age, sex, ethnicity, total cholesterol, HDL cholesterol, systolic blood pressure, and smoking status, the UKPDS risk engine includes duration of DM and hemoglobin A1c. This calculator can be downloaded to a desktop or handheld computer (www.dtu.ox.ac.uk/index.html). A new pen-and-paper 10-year risk estimator for type 2 DM based on the UKPDS risk engine has been developed for use in situations in which a computer is not readily available.30 Because age is heavily weighted in both the FRS and the UKPDS risk evaluators, the 10-year risk of developing CVD may be calculated to be relatively low in younger individuals, yet they are at high long-term risk. Recently, the ADA made available the Diabetes PHD (Personal Health Decisions) cardiometabolic risk calculator that is based on the Archimedes model (Archimedes Inc, San Francisco, Calif) and incorporates age, race/ethnicity, sex, weight, family history, smoking, physical activity, and medications in addition to fasting blood sugar (hemoglobin A1c if diabetic), serum lipids, and blood pressure to estimate the risk of developing diabetes and CVD. This calculator can be accessed by both health care professionals and patients at www.diabetes.org/diabetesphd.

In patients with impaired glucose tolerance, both the Diabetes Prevention Program31 and the Finnish Diabetes Prevention Study32 behavior modification interventions produced identical 58% reductions in progression to type 2 DM. A secondary analysis of the Diabetes Prevention Pro-gram showed that over 3.2 years, the prevalence of the metabolic syndrome decreased from 51% to 43% in the lifestyle intervention group and increased from 55% to 61% in the conventional care group, demonstrating that lifestyle modification is effective in delaying or preventing the development of both the metabolic syndrome and DM.33 A diet that produces a 7% to 10% weight loss combined with moderate exercise such as walking for 30 minutes on most days of the week is effective, and this message should be conveyed to patients. Weight-loss drugs and bariatric surgery can be used in appropriate, carefully selected patients, but discussion of these therapies is beyond the scope of this review.

Lifestyle modification, including weight loss, healthy diet, and increased physical activity, is the cornerstone of therapy for the metabolic syndrome as well as for its component risk factors. Almost all energy-restricted diets result in short-term weight loss, but the challenge is long-term weight maintenance. Including an exercise regimen in daily life appears to play a major beneficial role. Pharmacological therapy should be used to attain glycemic, blood pressure, and lipid goals. Guidelines for the management of hyperglycemia, hypertension, and dyslipidemia are available.6,34,35 Smoking assessment and the need for prophylactic aspirin are also important. Updated guidelines (2006) for the secondary prevention of CVD recommend aggressive treatment of all risk factors, emphasizing blood pressure and LDL cholesterol reduction, lifestyle change, and glycemic control.36

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CONCLUSION

Whether the constellation of vascular risk factors is called metabolic syndrome, insulin resistance syndrome, syndrome X, increased cardiometabolic risk, or another name is of limited clinical importance. The fact is that physicians are seeing increasing numbers of persons, including children, with obesity and varying combinations of glucose intolerance or DM, hypertension, and dyslipidemia. Simple solutions for the public health issue of obesity and lack of exercise are not available and will require the cooperation of local, state, and federal government agencies, corporate entities, and many disciplines of medicine. The public must be made aware that the relationship of obesity to DM and heart disease is analogous to that of smoking and lung cancer. Patients with DM or established CVD require aggressive management, and adding a diagnosis of metabolic syndrome adds little value to their care. Any risk factor requires attention, including lifestyle change and/or medications. Aggressive treatment of all major CVD risk factors, including the components of the metabolic syndrome, is critical for the health of the world's population.

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Questions About Metabolic Syndrome

  1. Which one of the following is the correct current estimated prevalence of obesity (BMI, ≥30 kg/m2) in US adults aged 20 to 74 years?

    1. 10%

    2. 20%

    3. 31%

    4. 65%

    5. 90%

  2. Which one of the following is not a NCEP ATP III criterion for diagnosis of the metabolic syndrome?

    1. Increased WC

    2. Blood pressure ≥130/85 mm Hg

    3. Elevated uric acid

    4. Triglycerides ≥150 mg/dL

    5. Fasting plasma glucose ≥100 mg/dL

  3. The lipid pattern observed in individuals with the metabolic syndrome is characterized by which one of the following?

    1. High triglyceride and low HDL cholesterol levels and small dense LDL cholesterol particles

    2. High total cholesterol and LDL cholesterol levels

    3. High triglyceride and normal HDL cholesterol levels

    4. High triglyceride and LDL cholesterol levels

    5. Low triglyceride, normal HDL cholesterol, and high LDL cholesterol levels

  4. Which one of the following statements about the metabolic syndrome is false?

    1. It is an excellent predictor of 10-year risk of a coronary event

    2. It is associated with an increased long-term risk of CVD and type 2 DM

    3. It occurs in about 27% of the US population

    4. Its incidence increases with increasing age

    5. Its incidence is increasing in children

  5. Which one of the following is not associated with insulin resistance?

    1. Nonalcoholic fatty liver disease

    2. Some cancers

    3. Polycystic ovary syndrome

    4. Type 2 DM

    5. Hyperthyroidism

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Correct answers: 1. c, 2. c, 3. a, 4. a, 5. e

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Footnotes

  • A question-and-answer section appears at the end of this article.

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