Official reprint from UpToDate www.uptodate.

com 2012 UpToDate

The metabolic syndrome (insulin resistance syndrome or syndrome X) Author James B Meigs, MD, MPH Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Aug 2012. | This topic last updated: Oct 6, 2011. INTRODUCTION Obesity, particularly abdominal obesity, is associated with resistance to the effects of insulin on peripheral glucose and fatty acid utilization, often leading to type 2 diabetes mellitus. Insulin resistance, the associated hyperinsulinemia and hyperglycemia, and adipocyte cytokines (adipokines) may also lead to vascular endothelial dysfunction, an abnormal lipid profile, hypertension, and vascular inflammation, all of which promote the development of atherosclerotic cardiovascular disease (CVD) [1-4]. A similar profile can be seen in individuals with abdominal obesity who do not have an excess of total body weight [5-8]. The co-occurrence of metabolic risk factors for both type 2 diabetes and CVD (abdominal obesity, hyperglycemia, dyslipidemia, and hypertension) suggested the existence of a "metabolic syndrome" [1,9-11]. Other names applied to this constellation of findings have included syndrome X, the insulin resistance syndrome, the deadly quartet, or the obesity dyslipidemia syndrome [12]. Genetic predisposition, lack of exercise, and body fat distribution all affect the likelihood that a given obese subject will become overtly diabetic or develop CVD. It should be noted that questions have been raised as to whether the metabolic syndrome, as currently defined, captures any unique pathophysiology implied by calling it a "syndrome," and whether metabolic syndrome confers risk beyond its individual components. These questions raise uncertainty about the value of diagnosing metabolic syndrome in individual patients [13,14]. These arguments will be reviewed at the end of this discussion (see 'A critical look at the metabolic syndrome' below). Regardless of whether the metabolic syndrome is considered a unique entity, the need is unquestioned to identify and manage its individual components to decrease morbidity and mortality associated with diabetes and cardiovascular disease [15,16]. The definition, prevalence, clinical implications, and therapy of the metabolic syndrome will be reviewed here, including the limited data in children and adolescents. The pathogenesis of the relationship between obesity and type 2 diabetes and other causes of insulin resistance are discussed separately. (See "Pathogenesis of type 2 diabetes mellitus", section on 'Role of diet, obesity, and inflammation' and "Insulin resistance: Definition and clinical spectrum".) The metabolic syndrome should not be confused with another disorder called syndrome X in which angina pectoris occurs in patients with normal coronary arteries. (See "Cardiac syndrome X: Angina pectoris with normal coronary arteries".) DEFINITION Because metabolic syndrome traits co-occur, patients identified with one or just a few traits are likely to have other traits, as well as insulin resistance [17]. Whether it is valuable to assess insulin resistance in addition to more readily measured traits of the syndrome is uncertain. There are several definitions for the metabolic syndrome, leading to some difficulty in comparing data from studies using different criteria (table 1) [18-24]. The National Cholesterol Education Program (NCEP/ATP III) and International Diabetes Federation (IDF) definitions are the most widely used. 2001 National Cholesterol Education Program/ATP III Guidelines developed by the 2001 National Cholesterol Education Program (Adult Treatment Panel [ATP] III) focused explicitly on the risk of cardiovascular disease and did not require evidence of insulin or glucose abnormalities, although abnormal glycemia is one of the criteria [21]. ATP III metabolic syndrome criteria were updated in 2005 in a statement from the American Heart Association (AHA)/National Heart, Lung, and Blood Institute (NHLBI) [22,23]. Updates include the following: Section Editors David M Nathan, MD Joseph I Wolfsdorf, MB, BCh Deputy Editor Jean E Mulder, MD

Lowering the threshold for abnormal fasting glucose to 100 mg/dL, corresponding to the ADA criteria for impaired fasting glucose (see "Diagnosis of diabetes mellitus") Explicitly including diabetes in the hyperglycemia trait definition Explicitly including use of drugs for lipid control or blood pressure control in the dyslipidemia and hypertension trait definitions, respectively Current ATP III criteria define the metabolic syndrome as the presence of any three of the following five traits: Abdominal obesity, defined as a waist circumference in men 102 cm (40 in) and in women 88 cm (35 in) Serum triglycerides 150 mg/dL (1.7 mmol/L) or drug treatment for elevated triglycerides Serum HDL cholesterol <40 mg/dL (1 mmol/L) in men and <50 mg/dL (1.3 mmol/L) in women or drug treatment for low HDL-C Blood pressure 130/85 mmHg or drug treatment for elevated blood pressure Fasting plasma glucose (FPG) 100 mg/dL (5.6 mmol/L) or drug treatment for elevated blood glucose International Diabetes Federation The International Diabetes Federation (IDF) updated their metabolic syndrome criteria in 2006 [25]. Central obesity is an essential element in this definition, with different waist circumference thresholds set for different race/ethnicity groups: Increased waist circumference, with ethnic-specific waist circumference cut-points (table 2) PLUS any two of the following: Triglycerides >150 mg/dL (1.7 mmol/L) or treatment for elevated triglycerides HDL cholesterol <40 mg/dL (1.03 mmol/L) in men or <50 mg/dL (1.29 mmol/L) in women, or treatment for low HDL Systolic blood pressure >130, diastolic blood pressure >85, or treatment for hypertension Fasting plasma glucose >100 mg/dL (5.6 mmol/L) or previously diagnosed type 2 diabetes; an oral glucose tolerance test is recommended for patients with an elevated fasting plasma glucose, but not required Comparing criteria in defining populations Using data from the National Health and Nutrition Examination Survey 1999 to 2002 database, 39 percent of US adult participants met IDF criteria for the metabolic syndrome, compared to 34.5 percent using the ATP III criteria [26]. The two definitions overlapped for 93 percent of subjects in determining presence or absence of the metabolic syndrome. When applied to an urban population in the US, the IDF criteria categorized 15 to 20 percent more adults with the metabolic syndrome than the ATP III criteria [27]. The relative value of different metabolic syndrome definitions in terms of prognosis and management appears to be similar [28-30]. As examples: In a prospective cohort study of a random sample of British women (n = 3589) aged 60 to 79 years, who were free of coronary heart disease (CHD) at baseline, all three definitions of the metabolic syndrome were modestly and similarly associated with CHD risk [28]. The age-adjusted hazard ratios for IDF, WHO, and NCEP syndromes were 1.32 (95% CI 1.03-1.70), 1.45 (1.00-2.10), and 1.38 (1.00-1.93), respectively. Similarly, when data from the Framingham population are examined using ATPIII, IDF, and EGIR definitions of the metabolic syndrome, roughly equivalent associations for incident type 2 diabetes (HR 3.5, 95% CI 2.2 to 5.6; 4.6, 2.7 to 7.7; 3.3, 2.1 to 5.1, respectively) and for CVD (1.8, 1.4 to 2.3; 1.7, 1.3 to 2.3; 2.1, 1.6 to 2.7, respectively) are observed [29]. Thus, risk factor clustering defines increased risk for type 2 diabetes and CVD.

The WHO, ATP III, and IDF definitions include type 2 diabetes as syndrome traits. Experts do not all agree that type 2 diabetes should be part of the definition, as the importance of the syndrome is that it identifies patients at increased risk for the development of diabetes. Most patients with type 2 diabetes have features of the metabolic syndrome, in which it identifies those at greater risk of macrovascular but not microvascular complications [31]. Management of patients with type 2 diabetes should follow clinical guidelines, whether or not they also meet criteria for metabolic syndrome. (See "Overview of medical care in adults with diabetes mellitus".) Potential other markers The metabolic syndrome has been recognized as a proinflammatory, prothrombotic state, associated with elevated levels of C-reactive protein, interleukin (IL)-6, and plasminogen activator inhibitor (PAI)-1 [4,25,32-38]. Inflammatory and prothrombotic markers are associated with an increased risk for subsequent CVD and type 2 diabetes [34-37], although adipokines and inflammatory markers explained only a small part of the association between the metabolic syndrome and CHD mortality in one study [39]. Additionally, a causal association between elevated CRP and the metabolic syndrome was not demonstrated in a study of phenotype patterns associated with the metabolic syndrome and CRP levels [40]. The value of measurement or treatment of inflammatory or vascular function markers in the setting of metabolic syndrome is unknown. Use of these markers should be considered for clinical purposes only in the setting of CVD risk assessment and reduction. (See "C-reactive protein in cardiovascular disease" and "Screening for cardiovascular risk with C-reactive protein".) AHA/CDC guidelines emphasize that CRP testing still belongs in the category of optional, based on clinical judgment rather than recommended routinely because the magnitude of its independent predictive power remains uncertain [41]. PREVALENCE AND RISK FACTORS The prevalence of the metabolic syndrome, as defined by the 2001 ATP III criteria, was evaluated in 8814 adults in the United States participating in the third National Health and Nutrition Examination Survey (NHANES III, 1988 to 1994) [42]. The overall prevalence was 22 percent, with an agedependent increase (6.7, 43.5, and 42.0 percent for ages 20 to 29, 60 to 69, and >70 years, respectively) (figure 1). Mexican-Americans had the highest age-adjusted prevalence (31.9 percent). Among African-Americans and Mexican-Americans, the prevalence was higher in women than in men (57 and 26 percent higher, respectively) (figure 2). Data from NHANES 1999 to 2000 demonstrate that the prevalence has continued to increase, particularly in women [43]. The metabolic syndrome is becoming increasingly common. Using data from the National Health and Nutrition Examination Survey 1999 to 2002 database, 34.5 percent of participants met ATP III criteria for the metabolic syndrome compared with 22 percent in NHANES III (1988 to 1994) [26,42]. In addition, metabolic syndrome, defined by the 2005 revised ATP III criteria, was assessed in 3323 Framingham Heart Study participants, ages 22 to 81, who did not have diabetes or cardiovascular disease at a baseline examination in the early 1990s [44]. At baseline, the prevalence of the metabolic syndrome was 26.8 percent in men and 16.6 percent in women. After eight years of follow-up, there was an age-adjusted 56 percent increase in prevalence among men and a 47 percent increase among women. Increased weight Increased body weight is a major risk factor for the metabolic syndrome. In NHANES III, the metabolic syndrome was present in 5 percent of those at normal weight, 22 percent of those who were overweight, and 60 percent of those who were obese [45]. (See "Screening for and clinical evaluation of obesity in adults".) In the Framingham Heart Study cohort, an increase in weight of 2.25 kg or more over 16 years was associated with a 21 to 45 percent increase in the risk for developing the syndrome [46]. A large waist circumference alone identifies up to 46 percent of individuals who will develop the metabolic syndrome within five years [47]. The rapidly increasing prevalence of obesity among adults in the United States is likely to lead to even higher rates of the metabolic syndrome in the near future [48], highlighting the importance of obesity prevention and improving physical activity levels [49,50]. (See "Etiology and natural history of obesity" and "Health hazards associated with obesity in adults".) Other factors In addition to age, race, and weight, other factors associated with an increased risk of metabolic syndrome in NHANES III included postmenopausal status, smoking, low household income, high carbohydrate diet, no alcohol consumption, and physical inactivity [45]. In the Framingham Heart Study, soft drink consumption was also associated with an increased risk of developing adverse metabolic traits and the metabolic syndrome [51]. Use

of atypical antipsychotic medications, especially clozapine, significantly increases risk for the metabolic syndrome [52]. In addition, poor cardiorespiratory fitness is an independent and strong predictor of metabolic syndrome in both men and women [53]. (See "Exercise and fitness in the prevention of cardiovascular disease".) A parental history of metabolic syndrome increases risk, and genetic factors may account for as much as 50 percent of the variation in levels of metabolic syndrome traits in the offspring [54-57]. CLINICAL IMPLICATIONS The metabolic syndrome is an important risk factor for subsequent development of type 2 diabetes and/or CVD. Thus, the key clinical implication of a diagnosis of metabolic syndrome is identification of a patient who needs aggressive lifestyle modification focused on weight reduction and increased physical activity (table 3) [11,49,58]. Identification of patients at high metabolic risk Health care providers should assess individuals for metabolic risk at routine clinic visits. The Endocrine Society clinical guidelines suggest evaluation at three-year intervals in individuals with one or more risk factors [59]. The assessment should include measurement of blood pressure, waist circumference, fasting lipid profile, and fasting glucose. In patients identified as having the metabolic syndrome (table 1), aggressive lifestyle intervention (weight reduction, physical activity) is warranted to reduce the risks of type 2 diabetes and cardiovascular disease. Assessment of 10year risk for cardiovascular disease, using a risk assessment algorithm, such as the Framingham Risk Score or SCORE, is useful in targeting individuals for medical intervention to lower blood pressure and cholesterol. (See "Estimation of cardiovascular risk in an individual patient without known cardiovascular disease", section on 'Multivariate risk models' and "Estimation of cardiovascular risk in an individual patient without known cardiovascular disease", section on 'Clinical use of risk assessment'.) Risk of type 2 diabetes Prospective observational studies demonstrate a strong association between the metabolic syndrome and the risk for subsequent development of type 2 diabetes [60-64]. In a meta-analysis of 16 multi-ethnic cohort studies, the relative risk of developing diabetes ranged from 3.53 to 5.17, depending upon the definition of metabolic syndrome and the population studied [65]. As an example, in an analysis of 890 nondiabetic Pima Indians, 144 developed diabetes over four years of follow-up [60]. The metabolic syndrome increased the relative risk (RR) for incident diabetes by 2.1-fold with the ATP III definition and 3.6-fold using the WHO definition. This difference highlights the importance of insulin resistance (a required characteristic of the WHO definition) in the pathogenesis of type 2 diabetes. In several cohorts, the risk of diabetes increased with increasing number of components of the metabolic syndrome [44,58,62]. While the metabolic syndrome predicts increased risk for diabetes, it is not clear whether this adds additional important information [65,66]. In a prospective cohort study of 5842 Australian adults, metabolic syndrome (defined by WHO, ATP III, EGIR, or IDF) was not superior to fasting plasma glucose or a published diabetes prediction model (including age, gender, ethnicity, fasting plasma glucose, systolic blood pressure, HDL cholesterol, BMI, and family history) in identifying individuals who developed diabetes [67]. (See 'A critical look at the metabolic syndrome' below.) Risk of CVD Three meta-analyses, which included many of the same studies, found that the metabolic syndrome increases the risk for incident cardiovascular disease (CVD) (RRs ranging from 1.53 to 2.18) and all cause mortality (RRs 1.27 to 1.60) [68-70]. The increased risk appears to be related to the risk factor clustering or insulin resistance associated with the metabolic syndrome rather than simply to obesity. This was illustrated by the following studies: In a study of the Framingham population, obese people without metabolic syndrome did not have a significantly increased risk of diabetes or CVD [71]. Obese people with the metabolic syndrome had a 10-fold increased risk for diabetes and a twofold increased risk for CVD relative to normal weight people without the metabolic syndrome. Normal weight people meeting revised 2005 ATP III criteria for the metabolic syndrome had a fourfold increased risk for diabetes and a threefold increased risk for CVD. In a study of 211 moderately obese (BMI 30 to 35) men and women, insulin sensitivity varied sixfold, and those with the greatest degree of insulin resistance had the highest blood pressure, triglyceride concentrations, fasting and two-hour post oral glucose blood sugar levels, and the lowest HDL concentrations,

despite equal levels of obesity [72]. Thus, not all moderately obese individuals have the same risk for developing cardiovascular disease or diabetes; risks differ as a function of insulin sensitivity, with insulin-resistant, obese individuals at highest risk. The risk also may be related to underlying subclinical CVD (as measured by ECG, echocardiography, carotid ultrasound, and ankle-brachial blood pressure) in individuals with metabolic syndrome [73]. In the Framingham Offspring study, 51 percent of 581 participants with metabolic syndrome had subclinical CVD, and the risk of overt CVD in these individuals was greater than in individuals with metabolic syndrome without subclinical CVD (HR 2.67 versus 1.59). Subclinical CVD was also predictive of overt CVD in subjects without metabolic syndrome (HR 1.93, 95% CI 1.15-3.24). While the metabolic syndrome predicts increased risk for CVD, it is not clear whether this adds additional important information [66,68,74]. As examples: Elevated triglyceride and low HDL cholesterol levels were as strong of a predictor of vascular events as the presence of metabolic syndrome (by ATP III criteria) in a prospective study of a population of patients with angiographically-determined coronary artery disease [75]. The Framingham Risk Score was a better predictor of CHD and stroke than metabolic syndrome (ATP III criteria with obesity defined by an elevated BMI rather than waist circumference) in a prospective study of 5128 British men aged 40 to 59 years followed for 20 years [76]. Low HDL cholesterol and high blood pressure were better predictors of CHD than the metabolic syndrome in a prospective study of 2737 men from the same cohort [64]. Other associations The metabolic syndrome has also been associated with several obesity-related disorders including: Fatty liver disease with steatosis, fibrosis, and cirrhosis [77-79]. (See "Epidemiology, clinical features, and diagnosis of nonalcoholic steatohepatitis".) Hepatocellular and intrahepatic cholangiocarcinoma. (See "Epidemiology and etiologic associations of hepatocellular carcinoma", section on 'Diabetes mellitus' and "Epidemiology, pathogenesis, and classification of cholangiocarcinoma", section on 'Metabolic syndrome'.) Chronic kidney disease (CKD; defined as a glomerular filtration rate less than 60 mL/min per 1.73 m2) and microalbuminuria [80,81]. In a report from NHANES III, the metabolic syndrome in multivariate analysis significantly increased the risk of both chronic kidney disease and microalbuminuria (adjusted odds ratio 2.6 and 1.9, respectively) [80]. The risk of both complications increased with the number of components of the metabolic syndrome. In a prospective cohort study, 10 percent of individuals with the metabolic syndrome at baseline subsequently developed CKD compared with 6 percent among those without the metabolic syndrome [82]. Polycystic ovary syndrome [83]. (See "Clinical manifestations of polycystic ovary syndrome in adults".) Sleep-disordered breathing, including obstructive sleep apnea [84,85]. (See "Overview of obstructive sleep apnea in adults".) Hyperuricemia and gout [86,87]. (See "Asymptomatic hyperuricemia", section on 'Potential consequences of hyperuricemia'.) Several components of the metabolic syndrome, including hyperlipidemia, hypertension, and diabetes have been associated with an increased risk of cognitive decline and dementia. The metabolic syndrome (when associated with a high level of inflammation) may also be associated with cognitive decline in the elderly. (See "Risk factors for dementia".) THERAPY In 2001, ATP III recommended two major therapeutic goals in patients with the metabolic syndrome

[21]. These goals were reinforced by a report from the American Heart Association and the National Institutes of Health (table 3) and by clinical guidelines from The Endocrine Society [23,58,59]: Treat underlying causes (overweight/obesity and physical inactivity) by intensifying weight management and increasing physical activity. Treat cardiovascular risk factors if they persist despite lifestyle modification. There is no direct evidence that attempting to prevent type 2 diabetes and CVD by treating the metabolic syndrome is as effective as attaining the above goals. It is possible to treat insulin resistance with drugs that enhance insulin action (eg, thiazolidinediones and metformin). However, the ability of such an approach to improve outcomes compared to weight reduction and exercise alone is not yet well supported by clinical trials [88,89]. (See "Metformin in the treatment of diabetes mellitus" and "Thiazolidinediones in the treatment of diabetes mellitus" and "Prediction and prevention of type 2 diabetes mellitus" and 'Prevention of type 2 diabetes' below.) Lifestyle modification Prevention or reduction of obesity, particularly abdominal obesity, is the main therapeutic goal in patients with the metabolic syndrome [49,90]. The importance of weight management in preventing progression of metabolic syndrome components is illustrated by The Coronary Artery Risk Development in Young Adults (CARDIA) study [91]. In this observational study of 5115 young adults (ages 18 to 30 years), increasing BMI over 15 years was associated with adverse progression of metabolic syndrome components compared with young adults who maintained stable BMI over the study period, regardless of baseline BMI. Weight reduction is optimally achieved with a multimodality approach including diet, exercise, and possible pharmacologic therapy, as with orlistat [92,93]. Diet Several dietary approaches have been advocated for treatment of the metabolic syndrome. Most patients with the metabolic syndrome are overweight, and weight reduction, which improves insulin sensitivity, is an important outcome goal of any diet. (See "Overview of therapy for obesity in adults" and "Alpha-glucosidase inhibitors and lipase inhibitors for treatment of diabetes mellitus".) The following specific diet approaches have been recommended: The Mediterranean diet may be beneficial [94-97]. In a study comparing the Mediterranean diet (high in fruits, vegetables, nuts, whole grains, and olive oil) with a low-fat prudent diet, subjects in the Mediterranean diet group had greater weight loss, lower blood pressure, improved lipid profiles, improved insulin resistance, and lower levels of markers of inflammation and endothelial function [94]. (See "Dietary fat" and "Endothelial dysfunction".) The DASH diet (daily sodium intake limited to 2400 mg, and higher in dairy intake than the Mediterranean diet), compared to a weight reducing diet emphasizing healthy food choices, resulted in greater improvements in triglycerides, diastolic blood pressure, and fasting glucose, even after controlling for weight loss [98]. Foods with low glycemic index may improve glycemia and dyslipidemia [99]. A diet that is low in glycemic index/glycemic load, replacing refined grains with whole grains, fruits and vegetables, and eliminating highglycemic beverages, may be particularly beneficial for patients with the metabolic syndrome. The impact of the glycemic index itself versus the increase in high fiber foods that accompanies a lower glycemic index diet is uncertain [100]. (See "Dietary carbohydrates".) Exercise Exercise may be beneficial beyond its effect on weight loss by more selectively removing abdominal fat, at least in women [101]. Current physical activity guidelines recommend practical, regular, and moderate regimens for exercise. The standard exercise recommendation is a daily minimum of 30 minutes of moderateintensity (such as brisk walking) physical activity. Increasing the level of physical activity appears to further enhance the beneficial effect [102]. (See "Role of physical activity and exercise in obesity" and "Exercise and fitness in the prevention of cardiovascular disease".) Removal of abdominal adipose tissue with liposuction does not improve insulin sensitivity or risk factors for coronary heart disease, suggesting that the negative energy balance induced by diet and exercise are necessary for achieving the metabolic benefits of weight loss [103]. (See "Overview of therapy for obesity in adults", section on 'Liposuction'.) Prevention of type 2 diabetes Although not strictly addressing the metabolic syndrome, clinical trials have

shown that lifestyle modifications can substantially reduce the risk of development of type 2 diabetes and the levels of risk factors for CVD in patients at increased risk. Prevention of type 2 diabetes is discussed in detail elsewhere. (See "Prediction and prevention of type 2 diabetes mellitus", section on 'Prevention'.) In the Diabetes Prevention Program (DPP), 3234 obese subjects with impaired fasting glucose or impaired glucose tolerance were randomly assigned to one of the following groups [89]: Intensive lifestyle changes with the aim of reducing weight by 7 percent through a low-fat diet and exercise for 150 minutes per week Treatment with metformin (850 mg twice daily) plus information on diet and exercise Placebo plus information on diet and exercise At an average follow-up of three years, fewer patients in the intensive lifestyle group developed diabetes (14 versus 22 and 29 percent in the metformin and placebo groups, respectively). The metabolic syndrome (using ATP III criteria) was present in 53 percent of DPP participants at baseline [104]. In the remaining subjects (n = 1523), both intensive lifestyle intervention and metformin therapy reduced the risk of developing the metabolic syndrome (threeyear cumulative incidences of 51, 45, and 34 percent in the placebo, metformin, and lifestyle groups, respectively). Oral hypoglycemic agents Among the oral hypoglycemic agents used to treat type 2 diabetes, metformin and the thiazolidinediones (rosiglitazone and pioglitazone) improve glucose tolerance in part by enhancing insulin sensitivity. The role of these agents in patients with metabolic syndrome, to prevent diabetes, has not been definitively established, and furthermore, rosiglitazone has been removed from the market. (See "Prediction and prevention of type 2 diabetes mellitus", section on 'Pharmacologic therapy'.) As examples: Metformin may prevent or delay the development of diabetes in subjects with impaired glucose tolerance. In the Diabetes Prevention Program (DPP) trial described above, metformin therapy plus instructions on diet and exercise was associated with a 31 percent reduction in the risk of developing diabetes compared to placebo (at three years, diabetes developed in 22 versus 29 percent); however, metformin was less effective than intensive lifestyle modification (diabetes developed in 22 versus 14 percent) [89]. Both intensive lifestyle intervention and metformin therapy were effective for prevention of the metabolic syndrome in patients who did not have the syndrome at baseline [104]. Metformin may reduce the incidence of diabetes-related end points. In a subgroup analysis from the United Kingdom Prospective Diabetes Study (UKPDS), metformin was associated with significant reductions in any diabetes-related end point (sudden death, hypo- or hyperglycemia causing death, MI, angina, heart failure, stroke, renal failure, amputation, retinopathy, monocular blindness or cataract extraction) and all cause mortality compared to conventional therapy with diet [105]. There are no data on glycemic control goals in patients with the metabolic syndrome who are not diabetic. Current recommendations are to treat impaired fasting glucose and impaired glucose tolerance with weight loss of about 5 to 10 percent of the baseline weight; at least 30 minutes per day of moderately intense physical activity; and dietary therapy with a low intake of saturated fats, trans fats, cholesterol, and simple sugars, and increased intake of fruits, vegetables, and whole grains. Routine pharmacoprevention for diabetes with any agent is not recommended. However, metformin could be considered in certain individuals with both IFG and IGT. (See "Prediction and prevention of type 2 diabetes mellitus", section on 'Metformin'.) In addition, when patients cross the diabetic diagnostic threshold, immediate therapy with metformin is recommended [106]. (See "Initial management of blood glucose in type 2 diabetes mellitus".) Cardiovascular risk reduction Reduction of risk factors for cardiovascular disease includes treatment of hypertension, cessation of smoking, glycemic control in patients with diabetes, and lowering of serum cholesterol according to recommended guidelines [107,108]. Lipid-lowering ATP III recommended a goal serum LDL cholesterol of less than 100 mg/dL (2.6 mmol/L) for secondary prevention in patients with type 2 diabetes [21], and subsequent studies have suggested a more aggressive goal of less than 80 mg/dL (2.1 mmol/L) with a regimen that includes administration of a statin. (See

"Intensity of lipid lowering therapy in secondary prevention of coronary heart disease", section on 'Summary and recommendations'.) Current evidence does not support the metabolic syndrome as a coronary risk equivalent in terms of goals for lipid management [109]. However, among patients with elevated serum LDL-cholesterol and established coronary disease in the 4S trial of lipid lowering with simvastatin, those with characteristics of the metabolic syndrome (lowest quartile for HDL cholesterol and highest quartile for triglycerides) had both the highest risk of major coronary events and the greatest benefit (48 percent risk reduction) from statin therapy [110,111]. Treatment of patients with known coronary disease and the metabolic syndrome with atorvastatin 80 mg, compared to atorvastatin 10 mg, decreased the rate of major cardiovascular events at five years (9.5 versus 13 percent, HR 0.71, 95% CI 0.61-0.84) [112]. Antihypertensive therapy There are conflicting data on whether angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARB) used to treat hypertension in type 2 diabetes may also help to reduce insulin resistance. (See "Prediction and prevention of type 2 diabetes mellitus".) Hypertension control is important in patients with diabetes mellitus. The goal blood pressure may be somewhat lower than that in the general population and varies with the presence or absence of diabetic nephropathy with proteinuria. It is not clear if the lower goal applies to patients with metabolic syndrome, but it may be reasonable to aim for such a goal. (See "Treatment of hypertension in patients with diabetes mellitus", section on 'Goal blood pressure'.) The value of ACE inhibitors and ARBs in hypertensive patients with the metabolic syndrome who do not have CVD or diabetes is not known. (See "Choice of therapy in essential hypertension: Recommendations".) CHILDREN AND ADOLESCENTS Definition The metabolic syndrome also occurs in children and adolescents but there is no consensus on the definition (table 4) [113-117]. As in adults, this lack of consensus makes it difficult to compare studies that use different diagnostic criteria and leaves the clinician without any clear parameters for assessing the long-term clinical implications of the metabolic syndrome in children or for tracking the effectiveness of lifestyle interventions. (See 'Clinical implications' above.) The International Diabetes Federation (IDF) definition of metabolic syndrome in children 10 to 16 years old is similar to that used by the IDF for adults, except that the definition for adolescents uses ethnic-specific waist circumference percentiles and one cutoff level for HDL rather than a sex-specific cutoff [117,118]. For children 16 years and older, the adult criteria can be used. For children younger than 10 years of age, metabolic syndrome cannot be diagnosed, but vigilance is recommended if the waist circumference is 90 percentile. Prevalence and risk factors When clinically applied, these pediatric definitions result in varying prevalence rates [119-122]. The US prevalence of metabolic syndrome (defined by the modified ATP III criteria) is estimated to be about 9 percent based upon a NHANES III survey of 1960 children >12 years of age [123]. However, pubertal growth and development is characterized by changes in metabolic traits that characterize the syndrome, resulting in significant individual variability in the categorical diagnosis. In one study of 1098 adolescents, as many as half of the adolescents initially classified as having metabolic syndrome lost the diagnosis during the three-year observation period, while others acquired the diagnosis [120]. The racial and ethnic distribution of metabolic syndrome is similar to that seen in adults, with the highest prevalence in Mexican-Americans, followed by non-Hispanic whites, and non-Hispanic blacks (12.9, 10.9, and 2.9 percent, respectively). Native Americans may be the ethnic group at greatest risk for metabolic syndrome as illustrated by a population-based study of Canadian Native (Oji-Cree) children and adolescents (10 to 19 years) that reported a 19 percent prevalence rate (defined by ATP III criteria) [124]. Among obese children, the prevalence of the metabolic syndrome is high and increases with worsening obesity [114,115]. This was illustrated in a study of 439 obese, 31 overweight, and 20 normal-weight children and adolescents who underwent a comprehensive metabolic assessment [114]. The metabolic syndrome was present in 39 and 50 percent of the moderately and severely obese subjects, respectively. In contrast, no overweight or normalweight children met the criteria for the metabolic syndrome. Risk factors in childhood that could predict emergence of metabolic syndrome were identified in a longitudinal study of a cohort from the National Heart, Lung, and Blood Institute Growth and Health Study (NGHS) [125]. Girls aged 9

and 10 years (n = 1192) were followed for 10 years. Metabolic syndrome (defined by ATP III criteria) was present in 0.2 percent at baseline and in 3.5 percent of black and 2.4 percent of white girls at ages 18 and 19. Waist circumference and serum triglycerides at baseline were predictive of subsequent metabolic syndrome. For every increase of 1 cm in waist circumference at year two, the risk of developing metabolic syndrome increased by 7.4 percent; for every increase of 1 mg/dL in triglyceride level at baseline, the risk of metabolic syndrome increased 1.3 percent. Race was not a significant independent factor in this study. In summary, the prevalence of the metabolic syndrome is high among obese children and adolescents and increases with the severity of the obesity, and with central adiposity in particular. However, there is instability in the diagnosis of metabolic syndrome during pubertal development, making prevalence estimates less reliable [120,126]. Consistency in the clinical diagnosis is required to better define the natural history of the syndrome in children and adolescents and to assess the long-term clinical implications. Clinical implications There are few longitudinal studies in children and adolescents with metabolic syndrome. In contrast to the data from adults, therefore, long-term cardiovascular and diabetes risks are not well defined. In one cohort study of 771 adults (mean age 38) who had participated in the Lipid Research Clinics study as children and adolescents 22 to 31 years previously, the incidence of self-reported CVD was more common in adults who exhibited metabolic syndrome traits as children than in those who did not (19.4 versus 1.5 percent, odds ratio 14.6, 95% CI 4.8-45.3) [127]. Of 31 children who had metabolic syndrome traits in the initial study, 21 (68 percent) had adult metabolic syndrome. Increasing BMI was strongly associated with risk of adult metabolic syndrome. Thus, the definition of metabolic syndrome may be clinically useful for risk stratification and therapeutic intervention in pediatrics. However, lifestyle modification that emphasizes reduction of established risk factors, such as promotion of exercise, weight loss, and smoking cessation, is the main therapeutic goal in obese children and adolescents, regardless of a metabolic syndrome diagnosis. (See 'Lifestyle modification' above.) A CRITICAL LOOK AT THE METABOLIC SYNDROME The American Diabetes Association and the European Association for the Study of Diabetes published a joint statement raising questions about whether the components of the metabolic syndrome, as defined above, warrant classification as a true "syndrome" [13]. The arguments raised include: Lack of clarity of definition, with criteria differing between the ATP, WHO, and other definitions; many published studies use further modifications to classify subjects with the metabolic syndrome. Multiple different phenotypes included within the metabolic syndrome, with indications for differing treatment strategies. As an example, a patient with a large waist circumference, high triglycerides, and high fasting glucose would need to be managed differently than a patient with high blood pressure, low HDL, and high triglycerides. Lack of a consistent evidence-base for setting the thresholds for the various components in the definitions. Inclusion of patients with clinical CVD or diabetes as part of the syndrome which is intended to define risk for these diseases. Unclear pathogenesis uniting the components of the syndrome; insulin resistance may not underlie all factors, and is not a consistent finding in some definitions. Other risk factors for CVD that are not components of the metabolic syndrome, such as inflammatory markers, may have equal or greater bearing on risk. The CVD risk associated with the metabolic syndrome has not been shown to be greater than the sum of its individual components [23,128,129]. The critical weakness of the current metabolic syndrome construct is that treatment of the syndrome is no different than treatment for each of its components. Virtually all agree clustering of risk factors for diabetes and cardiovascular disease is a real phenomenon. All agree that the presence of one component of the metabolic syndrome should lead to evaluation for other risk factors. Whether patient benefit is gained from diagnosing patients with a syndrome of such uncertain characteristics or predictive value remains an open question. The advice remains to treat individual

risk factors when present and to prescribe therapeutic lifestyle changes and weight management for obese patients with multiple risk factors. INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Basics topic (see "Patient information: Metabolic syndrome (The Basics)") Beyond the Basics topic (see "Patient information: The metabolic syndrome (Beyond the Basics)") SUMMARY The metabolic syndrome is defined as the co-occurrence of metabolic risk factors for both type 2 diabetes and cardiovascular disease (abdominal obesity, hyperglycemia, dyslipidemia, and hypertension). There are several definitions for the metabolic syndrome (table 1). The National Cholesterol Education Program (NCEP/ATP III) and International Diabetes Federation (IDF) definitions are the most widely used. (See 'Definition' above.) The metabolic syndrome is an important risk factor for subsequent development of type 2 diabetes and/or CVD. Thus, the key clinical implication of a diagnosis of metabolic syndrome is identification of a patient who needs aggressive lifestyle modification focused on weight reduction and increased physical activity (table 3). (See 'Clinical implications' above and 'Lifestyle modification' above.) Prevention of type 2 diabetes is discussed in detail elsewhere. (See "Prediction and prevention of type 2 diabetes mellitus", section on 'Prevention'.) Reduction of risk factors for cardiovascular disease includes treatment of hypertension, cessation of smoking, glycemic control in patients with diabetes, and lowering of serum cholesterol according to recommended guidelines. (See "Hypertension: Who should be treated?" and "Treatment of hypertension in patients with diabetes mellitus", section on 'Goal blood pressure' and "Intensity of lipid lowering therapy in secondary prevention of coronary heart disease", section on 'Summary and recommendations'.) Questions have been raised as to whether the metabolic syndrome, as currently defined, captures any unique pathophysiology implied by calling it a "syndrome," and whether metabolic syndrome confers risk beyond its individual components. The critical weakness of the current metabolic syndrome construct is that treatment of the syndrome is no different than treatment for each of its components. (See 'A critical look at the metabolic syndrome' above.)

Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 1988; 37:1595. 2. DeFronzo RA, Ferrannini E. Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 1991; 14:173. 3. Lindsay RS, Howard BV. Cardiovascular risk associated with the metabolic syndrome. Curr Diab Rep 2004; 4:63.

4. Koh KK, Han SH, Quon MJ. Inflammatory markers and the metabolic syndrome: insights from therapeutic interventions. J Am Coll Cardiol 2005; 46:1978. 5. Richelsen B, Pedersen SB. Associations between different anthropometric measurements of fatness and metabolic risk parameters in non-obese, healthy, middle-aged men. Int J Obes Relat Metab Disord 1995; 19:169. 6. Ruderman N, Chisholm D, Pi-Sunyer X, Schneider S. The metabolically obese, normal-weight individual revisited. Diabetes 1998; 47:699. 7. Conus F, Allison DB, Rabasa-Lhoret R, et al. Metabolic and behavioral characteristics of metabolically obese but normal-weight women. J Clin Endocrinol Metab 2004; 89:5013. 8. St-Onge MP, Janssen I, Heymsfield SB. Metabolic syndrome in normal-weight Americans: new definition of the metabolically obese, normal-weight individual. Diabetes Care 2004; 27:2222. 9. Ferrannini E, Haffner SM, Mitchell BD, Stern MP. Hyperinsulinaemia: the key feature of a cardiovascular and metabolic syndrome. Diabetologia 1991; 34:416. 10. Haffner SM, Valdez RA, Hazuda HP, et al. Prospective analysis of the insulin-resistance syndrome (syndrome X). Diabetes 1992; 41:715. 11. Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet 2005; 365:1415. 12. Grundy SM, Brewer HB Jr, Cleeman JI, et al. Definition of metabolic syndrome: Report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation 2004; 109:433. 13. Kahn R, Buse J, Ferrannini E, et al. 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; 28:2289. 14. Ferrannini E. Metabolic syndrome: a solution in search of a problem. J Clin Endocrinol Metab 2007; 92:396. 15. Eckel RH, Kahn R, Robertson RM, Rizza RA. Preventing cardiovascular disease and diabetes: a call to action from the American Diabetes Association and the American Heart Association. Circulation 2006; 113:2943. 16. Grundy SM. Metabolic syndrome: a multiplex cardiovascular risk factor. J Clin Endocrinol Metab 2007; 92:399. 17. Meigs JB. Invited commentary: insulin resistance syndrome? Syndrome X? Multiple metabolic syndrome? A syndrome at all? Factor analysis reveals patterns in the fabric of correlated metabolic risk factors. Am J Epidemiol 2000; 152:908. 18. 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. 19. 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. 20. Matthews DR, Hosker JP, Rudenski AS, et al. Homeostasis model assessment: insulin resistance and betacell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28:412. 21. 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. 22. Genuth S, Alberti KG, Bennett P, et al. Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care 2003; 26:3160. 23. Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005; 112:2735. 24. Alberti KG, Zimmet P, Shaw J, IDF Epidemiology Task Force Consensus Group. The metabolic syndrome--a new worldwide definition. Lancet 2005; 366:1059. 25. International Diabetes Federation. The IDF consensus worldwide definition of the metabolic syndrome, 2006. http://www.idf.org/webdata/docs/MetS_def_update2006.pdf (Accessed on September 30, 2011). 26. Ford ES. Prevalence of the metabolic syndrome defined by the International Diabetes Federation among adults in the U.S. Diabetes Care 2005; 28:2745. 27. Adams RJ, Appleton S, Wilson DH, et al. Population comparison of two clinical approaches to the metabolic syndrome: implications of the new International Diabetes Federation consensus definition. Diabetes Care 2005; 28:2777. 28. Lawlor DA, Smith GD, Ebrahim S. Does the new International Diabetes Federation definition of the metabolic

syndrome predict CHD any more strongly than older definitions? Findings from the British Women's Heart and Health Study. Diabetologia 2006; 49:41. 29. Meigs JB, Rutter MK, Sullivan LM, et al. Impact of insulin resistance on risk of type 2 diabetes and cardiovascular disease in people with metabolic syndrome. Diabetes Care 2007; 30:1219. 30. Lorenzo C, Williams K, Hunt KJ, Haffner SM. The National Cholesterol Education Program - Adult Treatment Panel III, International Diabetes Federation, and World Health Organization definitions of the metabolic syndrome as predictors of incident cardiovascular disease and diabetes. Diabetes Care 2007; 30:8. 31. Cull CA, Jensen CC, Retnakaran R, Holman RR. Impact of the metabolic syndrome on macrovascular and microvascular outcomes in type 2 diabetes mellitus: United Kingdom Prospective Diabetes Study 78. Circulation 2007; 116:2119. 32. Ridker PM, Buring JE, Cook NR, Rifai N. C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14 719 initially healthy American women. Circulation 2003; 107:391. 33. Festa A, D'Agostino R Jr, Howard G, et al. Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS). Circulation 2000; 102:42. 34. Ridker PM. Clinical application of C-reactive protein for cardiovascular disease detection and prevention. Circulation 2003; 107:363. 35. Festa A, D'Agostino R Jr, Tracy RP, et al. Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of type 2 diabetes: the insulin resistance atherosclerosis study. Diabetes 2002; 51:1131. 36. Pradhan AD, Manson JE, Rifai N, et al. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 2001; 286:327. 37. Hu FB, Meigs JB, Li TY, et al. Inflammatory markers and risk of developing type 2 diabetes in women. Diabetes 2004; 53:693. 38. Rutter MK, Meigs JB, Sullivan LM, et al. C-reactive protein, the metabolic syndrome, and prediction of cardiovascular events in the Framingham Offspring Study. Circulation 2004; 110:380. 39. Langenberg C, Bergstrom J, Scheidt-Nave C, et al. Cardiovascular death and the metabolic syndrome: role of adiposity-signaling hormones and inflammatory markers. Diabetes Care 2006; 29:1363. 40. Timpson NJ, Lawlor DA, Harbord RM, et al. C-reactive protein and its role in metabolic syndrome: mendelian randomisation study. Lancet 2005; 366:1954. 41. Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J Clin Invest 2003; 111:1805. 42. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 2002; 287:356. 43. Ford ES, Giles WH, Mokdad AH. Increasing prevalence of the metabolic syndrome among u.s. Adults. Diabetes Care 2004; 27:2444. 44. Wilson PW, D'Agostino RB, Parise H, et al. Metabolic syndrome as a precursor of cardiovascular disease and type 2 diabetes mellitus. Circulation 2005; 112:3066. 45. Park YW, Zhu S, Palaniappan L, et al. The metabolic syndrome: prevalence and associated risk factor findings in the US population from the Third National Health and Nutrition Examination Survey, 1988-1994. Arch Intern Med 2003; 163:427. 46. Wilson PW, Kannel WB, Silbershatz H, D'Agostino RB. Clustering of metabolic factors and coronary heart disease. Arch Intern Med 1999; 159:1104. 47. Palaniappan L, Carnethon MR, Wang Y, et al. Predictors of the incident metabolic syndrome in adults: the Insulin Resistance Atherosclerosis Study. Diabetes Care 2004; 27:788. 48. Mokdad AH, Serdula MK, Dietz WH, et al. The spread of the obesity epidemic in the United States, 1991-1998. JAMA 1999; 282:1519. 49. Manson JE, Skerrett PJ, Greenland P, VanItallie TB. The escalating pandemics of obesity and sedentary lifestyle. A call to action for clinicians. Arch Intern Med 2004; 164:249. 50. Ferreira I, Twisk JW, van Mechelen W, et al. Development of fatness, fitness, and lifestyle from adolescence to the age of 36 years: determinants of the metabolic syndrome in young adults: the amsterdam growth and health longitudinal study. Arch Intern Med 2005; 165:42. 51. 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; 116:480. 52. Lamberti JS, Olson D, Crilly JF, et al. Prevalence of the metabolic syndrome among patients receiving clozapine. Am J Psychiatry 2006; 163:1273.

53. LaMonte MJ, Barlow CE, Jurca R, et al. Cardiorespiratory fitness is inversely associated with the incidence of metabolic syndrome: a prospective study of men and women. Circulation 2005; 112:505. 54. Pankow JS, Jacobs DR Jr, Steinberger J, et al. Insulin resistance and cardiovascular disease risk factors in children of parents with the insulin resistance (metabolic) syndrome. Diabetes Care 2004; 27:775. 55. Mills GW, Avery PJ, McCarthy MI, et al. Heritability estimates for beta cell function and features of the insulin resistance syndrome in UK families with an increased susceptibility to type 2 diabetes. Diabetologia 2004; 47:732. 56. Meigs JB, Panhuysen CI, Myers RH, et al. A genome-wide scan for loci linked to plasma levels of glucose and HbA(1c) in a community-based sample of Caucasian pedigrees: The Framingham Offspring Study. Diabetes 2002; 51:833. 57. Panhuysen CI, Cupples LA, Wilson PW, et al. A genome scan for loci linked to quantitative insulin traits in persons without diabetes: the Framingham Offspring Study. Diabetologia 2003; 46:579. 58. Grundy SM, Hansen B, Smith SC Jr, et al. Clinical management of metabolic syndrome: report of the American Heart Association/National Heart, Lung, and Blood Institute/American Diabetes Association conference on scientific issues related to management. Circulation 2004; 109:551. 59. Rosenzweig JL, Ferrannini E, Grundy SM, et al. Primary prevention of cardiovascular disease and type 2 diabetes in patients at metabolic risk: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2008; 93:3671. 60. Hanson RL, Imperatore G, Bennett PH, Knowler WC. Components of the "metabolic syndrome" and incidence of type 2 diabetes. Diabetes 2002; 51:3120. 61. Resnick HE, Jones K, Ruotolo G, et al. Insulin resistance, the metabolic syndrome, and risk of incident cardiovascular disease in nondiabetic american indians: the Strong Heart Study. Diabetes Care 2003; 26:861. 62. Klein BE, Klein R, Lee KE. Components of the metabolic syndrome and risk of cardiovascular disease and diabetes in Beaver Dam. Diabetes Care 2002; 25:1790. 63. Sattar N, Gaw A, Scherbakova O, et al. Metabolic syndrome with and without C-reactive protein as a predictor of coronary heart disease and diabetes in the West of Scotland Coronary Prevention Study. Circulation 2003; 108:414. 64. Sattar N, McConnachie A, Shaper AG, et al. Can metabolic syndrome usefully predict cardiovascular disease and diabetes? Outcome data from two prospective studies. Lancet 2008; 371:1927. 65. Ford ES, Li C, Sattar N. Metabolic syndrome and incident diabetes: current state of the evidence. Diabetes Care 2008; 31:1898. 66. Stern MP, Williams K, Gonzlez-Villalpando C, et al. Does the metabolic syndrome improve identification of individuals at risk of type 2 diabetes and/or cardiovascular disease? Diabetes Care 2004; 27:2676. 67. Cameron AJ, Magliano DJ, Zimmet PZ, et al. The metabolic syndrome as a tool for predicting future diabetes: the AusDiab study. J Intern Med 2008; 264:177. 68. Ford ES. Risks for all-cause mortality, cardiovascular disease, and diabetes associated with the metabolic syndrome: a summary of the evidence. Diabetes Care 2005; 28:1769. 69. Galassi A, Reynolds K, He J. Metabolic syndrome and risk of cardiovascular disease: a meta-analysis. Am J Med 2006; 119:812. 70. Gami AS, Witt BJ, Howard DE, et al. Metabolic syndrome and risk of incident cardiovascular events and death: a systematic review and meta-analysis of longitudinal studies. J Am Coll Cardiol 2007; 49:403. 71. Meigs JB, Wilson PW, Fox CS, et al. Body mass index, metabolic syndrome, and risk of type 2 diabetes or cardiovascular disease. J Clin Endocrinol Metab 2006; 91:2906. 72. McLaughlin T, Abbasi F, Lamendola C, Reaven G. Heterogeneity in the prevalence of risk factors for cardiovascular disease and type 2 diabetes mellitus in obese individuals: effect of differences in insulin sensitivity. Arch Intern Med 2007; 167:642. 73. Ingelsson E, Sullivan LM, Murabito JM, et al. Prevalence and prognostic impact of subclinical cardiovascular disease in individuals with the metabolic syndrome and diabetes. Diabetes 2007; 56:1718. 74. Kohli P, Greenland P. Role of the metabolic syndrome in risk assessment for coronary heart disease. JAMA 2006; 295:819. 75. Saely CH, Koch L, Schmid F, et al. Adult Treatment Panel III 2001 but not International Diabetes Federation 2005 criteria of the metabolic syndrome predict clinical cardiovascular events in subjects who underwent coronary angiography. Diabetes Care 2006; 29:901. 76. 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; 165:2644.

77. Marceau P, Biron S, Hould FS, et al. Liver pathology and the metabolic syndrome X in severe obesity. J Clin Endocrinol Metab 1999; 84:1513. 78. Hamaguchi M, Kojima T, Takeda N, et al. The metabolic syndrome as a predictor of nonalcoholic fatty liver disease. Ann Intern Med 2005; 143:722. 79. Hanley AJ, Williams K, Festa A, et al. Liver markers and development of the metabolic syndrome: the insulin resistance atherosclerosis study. Diabetes 2005; 54:3140. 80. Chen J, Muntner P, Hamm LL, et al. The metabolic syndrome and chronic kidney disease in U.S. adults. Ann Intern Med 2004; 140:167. 81. Zhang L, Zuo L, Wang F, et al. Metabolic syndrome and chronic kidney disease in a Chinese population aged 40 years and older. Mayo Clin Proc 2007; 82:822. 82. Kurella M, Lo JC, Chertow GM. Metabolic syndrome and the risk for chronic kidney disease among nondiabetic adults. J Am Soc Nephrol 2005; 16:2134. 83. Pasquali R, Gambineri A, Anconetani B, et al. The natural history of the metabolic syndrome in young women with the polycystic ovary syndrome and the effect of long-term oestrogen-progestagen treatment. Clin Endocrinol (Oxf) 1999; 50:517. 84. Vgontzas AN, Papanicolaou DA, Bixler EO, et al. Sleep apnea and daytime sleepiness and fatigue: relation to visceral obesity, insulin resistance, and hypercytokinemia. J Clin Endocrinol Metab 2000; 85:1151. 85. Ip MS, Lam B, Ng MM, et al. Obstructive sleep apnea is independently associated with insulin resistance. Am J Respir Crit Care Med 2002; 165:670. 86. Choi HK, Ford ES. Prevalence of the metabolic syndrome in individuals with hyperuricemia. Am J Med 2007; 120:442. 87. Choi HK, Ford ES, Li C, Curhan G. Prevalence of the metabolic syndrome in patients with gout: the Third National Health and Nutrition Examination Survey. Arthritis Rheum 2007; 57:109. 88. Meigs JB. The metabolic syndrome. BMJ 2003; 327:61. 89. 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 2002; 346:393. 90. Magkos F, Yannakoulia M, Chan JL, Mantzoros CS. Management of the metabolic syndrome and type 2 diabetes through lifestyle modification. Annu Rev Nutr 2009; 29:223. 91. Lloyd-Jones DM, Liu K, Colangelo LA, et al. Consistently stable or decreased body mass index in young adulthood and longitudinal changes in metabolic syndrome components: the Coronary Artery Risk Development in Young Adults Study. Circulation 2007; 115:1004. 92. Reaven G, Segal K, Hauptman J, et al. Effect of orlistat-assisted weight loss in decreasing coronary heart disease risk in patients with syndrome X. Am J Cardiol 2001; 87:827. 93. Heymsfield SB, Segal KR, Hauptman J, et al. Effects of weight loss with orlistat on glucose tolerance and progression to type 2 diabetes in obese adults. Arch Intern Med 2000; 160:1321. 94. Esposito K, Marfella R, Ciotola M, et al. Effect of a mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: a randomized trial. JAMA 2004; 292:1440. 95. Tortosa A, Bes-Rastrollo M, Sanchez-Villegas A, et al. Mediterranean diet inversely associated with the incidence of metabolic syndrome: the SUN prospective cohort. Diabetes Care 2007; 30:2957. 96. Salas-Salvad J, Fernndez-Ballart J, Ros E, et al. Effect of a Mediterranean diet supplemented with nuts on metabolic syndrome status: one-year results of the PREDIMED randomized trial. Arch Intern Med 2008; 168:2449. 97. Kastorini CM, Milionis HJ, Esposito K, et al. The effect of Mediterranean diet on metabolic syndrome and its components: a meta-analysis of 50 studies and 534,906 individuals. J Am Coll Cardiol 2011; 57:1299. 98. 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. 99. Brand-Miller J, Hayne S, Petocz P, Colagiuri S. Low-glycemic index diets in the management of diabetes: a meta-analysis of randomized controlled trials. Diabetes Care 2003; 26:2261. 100. 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. 101. Desprs JP, Pouliot MC, Moorjani S, et al. Loss of abdominal fat and metabolic response to exercise training in obese women. Am J Physiol 1991; 261:E159. 102. Thompson PD, Buchner D, Pina IL, et al. Exercise and physical activity in the prevention and treatment of atherosclerotic cardiovascular disease: a statement from the Council on Clinical Cardiology (Subcommittee on Exercise, Rehabilitation, and Prevention) and the Council on Nutrition, Physical Activity, and Metabolism

(Subcommittee on Physical Activity). Circulation 2003; 107:3109. 103. Klein S, Fontana L, Young VL, et al. Absence of an effect of liposuction on insulin action and risk factors for coronary heart disease. N Engl J Med 2004; 350:2549. 104. Orchard TJ, Temprosa M, Goldberg R, et al. The effect of metformin and intensive lifestyle intervention on the metabolic syndrome: the Diabetes Prevention Program randomized trial. Ann Intern Med 2005; 142:611. 105. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352:854. 106. Nathan DM, Buse JB, Davidson MB, et al. Management of hyperglycemia in type 2 diabetes: A consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2006; 29:1963. 107. Pearson TA, Blair SN, Daniels SR, et al. AHA Guidelines for Primary Prevention of Cardiovascular Disease and Stroke: 2002 Update: Consensus Panel Guide to Comprehensive Risk Reduction for Adult Patients Without Coronary or Other Atherosclerotic Vascular Diseases. American Heart Association Science Advisory and Coordinating Committee. Circulation 2002; 106:388. 108. Eberly LE, Prineas R, Cohen JD, et al. Metabolic syndrome: risk factor distribution and 18-year mortality in the multiple risk factor intervention trial. Diabetes Care 2006; 29:123. 109. Marroquin OC, Kip KE, Kelley DE, et al. Metabolic syndrome modifies the cardiovascular risk associated with angiographic coronary artery disease in women: a report from the Women's Ischemia Syndrome Evaluation. Circulation 2004; 109:714. 110. Ballantyne CM, Olsson AG, Cook TJ, et al. Influence of low high-density lipoprotein cholesterol and elevated triglyceride on coronary heart disease events and response to simvastatin therapy in 4S. Circulation 2001; 104:3046. 111. Pyrl K, Ballantyne CM, Gumbiner B, et al. Reduction of cardiovascular events by simvastatin in nondiabetic coronary heart disease patients with and without the metabolic syndrome: subgroup analyses of the Scandinavian Simvastatin Survival Study (4S). Diabetes Care 2004; 27:1735. 112. Deedwania P, Barter P, Carmena R, et al. Reduction of low-density lipoprotein cholesterol in patients with coronary heart disease and metabolic syndrome: analysis of the Treating to New Targets study. Lancet 2006; 368:919. 113. Goodman E. Pediatric metabolic syndrome: smoke and mirrors or true magic? J Pediatr 2006; 148:149. 114. Weiss R, Dziura J, Burgert TS, et al. Obesity and the metabolic syndrome in children and adolescents. N Engl J Med 2004; 350:2362. 115. Cook S, Weitzman M, Auinger P, et al. Prevalence of a metabolic syndrome phenotype in adolescents: findings from the third National Health and Nutrition Examination Survey, 1988-1994. Arch Pediatr Adolesc Med 2003; 157:821. 116. Jolliffe CJ, Janssen I. Development of age-specific adolescent metabolic syndrome criteria that are linked to the Adult Treatment Panel III and International Diabetes Federation criteria. J Am Coll Cardiol 2007; 49:891. 117. Zimmet P, Alberti G, Kaufman F, et al. The metabolic syndrome in children and adolescents. Lancet 2007; 369:2059. 118. Fernndez JR, Redden DT, Pietrobelli A, Allison DB. Waist circumference percentiles in nationally representative samples of African-American, European-American, and Mexican-American children and adolescents. J Pediatr 2004; 145:439. 119. Chi CH, Wang Y, Wilson DM, Robinson TN. Definition of metabolic syndrome in preadolescent girls. J Pediatr 2006; 148:788. 120. Goodman E, Daniels SR, Meigs JB, Dolan LM. Instability in the diagnosis of metabolic syndrome in adolescents. Circulation 2007; 115:2316. 121. DuBose KD, Stewart EE, Charbonneau SR, et al. Prevalence of the metabolic syndrome in elementary school children. Acta Paediatr 2006; 95:1005. 122. Reinehr T, de Sousa G, Toschke AM, Andler W. Comparison of metabolic syndrome prevalence using eight different definitions: a critical approach. Arch Dis Child 2007; 92:1067. 123. de Ferranti SD, Gauvreau K, Ludwig DS, et al. Prevalence of the metabolic syndrome in American adolescents: findings from the Third National Health and Nutrition Examination Survey. Circulation 2004; 110:2494. 124. Retnakaran R, Zinman B, Connelly PW, et al. Nontraditional cardiovascular risk factors in pediatric metabolic syndrome. J Pediatr 2006; 148:176. 125. Morrison JA, Friedman LA, Harlan WR, et al. Development of the metabolic syndrome in black and white adolescent girls: a longitudinal assessment. Pediatrics 2005; 116:1178.

126. Gustafson JK, Yanoff LB, Easter BD, et al. The stability of metabolic syndrome in children and adolescents. J Clin Endocrinol Metab 2009; 94:4828. 127. Morrison JA, Friedman LA, Gray-McGuire C. Metabolic syndrome in childhood predicts adult cardiovascular disease 25 years later: the Princeton Lipid Research Clinics Follow-up Study. Pediatrics 2007; 120:340. 128. Sundstrm J, Vallhagen E, Risrus U, et al. Risk associated with the metabolic syndrome versus the sum of its individual components. Diabetes Care 2006; 29:1673. 129. Bayturan O, Tuzcu EM, Lavoie A, et al. The metabolic syndrome, its component risk factors, and progression of coronary atherosclerosis. Arch Intern Med 2010; 170:478. Topic 1784 Version 12.0

GRAPHICS
Five current definitions of the metabolic syndrome
Parameters
Required

NCEP ATP3 2005

IDF 2006
Waist 94 cm (men) or 80 cm (women)*

EGIR 1999
Insulin resistance or fasting hyperinsulinemia in top 25 percent

WHO 1999
Insulin resistance in top 25 percent; glucose 6.1 mmol/L (110 mg/dL); 2hour glucose 7.8 mmol/L (140 mg/dL) And 2 of:

AACE 2003
High risk of insulin resistance or BMI 25 kg/m2 or waist 102 cm (men) or 88 cm (women)

Number of abnormalities Glucose

3 of: 5.6 mmol/L (100 mg/dL) or drug treatment for elevated blood glucose

And 2 of: 5.6 mmol/L (100 mg/dL) or diagnosed diabetes

And 2 of: 6.1-6.9 mmol/ (110-125 mg/dL)

And 2 of: 6.1 mmol/L (110 mg/dL); 2-hour glucose 7.8 mmol/L (140 mg/dL)

HDL cholesterol

<1.0 mmol/L (40 mg/dL) (men); <1.3 mmol/L (50 mg/dL) (women) or drug treatment for low HDL-C 1.7 mmol/L (150 mg/dL) or drug treatment for elevated triglycerides Waist 102 cm (men) or 88 cm (women)

<1.0 mmol/L (40 mg/dL) (men); <1.3 mmol/L (50 mg/dL) (women) or drug treatment for low HDL-C 1.7 mmol/L (150 mg/dL) or drug treatment for high triglycerides

<1.0 mmol/L (40 mg/dL)

<0.9 mmol/L (35 mg/dL) (men); <1.0 mmol/L (40 mg/dL) (women)

<1.0 mmol/L (40 mg/dL) (men); <1.3 mmol/L (50 mg/dL) (women) 1.7 mmol/L (150 mg/dL)

Triglycerides

or 2.0 mmol/L (180 mg/dL) or drug treatment for dyslipidemia

or 1.7 mmol/L (150 mg/dL)

Obesity

Waist 94 cm (men) or 80 cm (women)

Waist/hip ratio >0.9 (men) or >0.85 (women) or BMI 30 kg/m2 140/90 130/85

Hypertension

130/85

130/85

140/90 mmHg

mmHg or drug treatment for hypertension

mmHg or drug treatment for hypertension

or drug treatment for hypertension

mmHg

mmHg

NCEP: National Cholesterol Education Program; IDF: International Diabetes Federation; EGIR: Group for the Study of Insulin Resistance; WHO: World Health Organization; AACE: American Association of Clinical Endocrinologists; HDL: high density lipoprotein; BMI: body mass index. * For South Asia and Chinese patients, waist 90 cm (men) or 80 cm (women); for Japanese patients, waist 90 cm (men) or 80 cm (women). Insulin resistance measured using insulin clamp. High risk of being insulin resistant is indicated by the presence of at least one of the following: diagnosis of CVD, hypertension, polycystic ovary syndrome, non-alcoholic fatty liver disease or acanthosis nigricans; family history of type 2 diabetes, hypertension of CVD; history of gestational diabetes or glucose intolerance; nonwhite ethnicity; sedentary lifestyle; BMI 25 kb/m2 or waist circumference 94 cm for men and 80 cm for women; and age 40 years. Treatment with one or more of fibrates or niacin. In Asian patients, waist 90 cm (men) or 80 cm (women). Meigs James. Metabolic syndrome and the risk for type 2 diabetes. Expert Rev Endocrin Metab 2006; 1:57. Table 1. Updated data from the International Diabetes Federation, 2006. Available at: http://www.idf.org/webdata/docs/MetS_def_update2006.pdf.

Ethnic specific values for waist circumference

Ethnic group
Europids*
Men Women 94 cm 80 cm

Waist circumference (as measure of central obesity)

South Asians
Men Women 90 cm 80 cm

Chinese
Men Women 90 cm 80 cm

Japanese
Men Women 90 cm 80 cm

Ethnic South and Central Americans Sub-Saharan Africans Eastern Mediterranean and middle east (Arab) populations

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

Data are pragmatic cutoffs and better data are required to link them to risk. Ethnicity should be basis for classification, not country of residence. * In USA, Adult Treatment Panel
III values (102 cm male, 88 cm female) are likely to continue to be used for clinical purposes. In future epidemiological studies of populations of Europid origin (white people of European origin, regardless of where they live in the world), prevalence should be given, with both European and North American cutoffs to allow better comparisons. Reproduced with permission from: George K, Alberti MM, Zimmet P, et al. The metabolic syndrome - a new worldwide definition. Lancet 2005; 336:1059. Copyright 2005 Elsevier. Updated data from: the International Diabetes Federation, 2006. Available at: http://www.idf.org/webdata/docs/MetS_def_update2006.pdf.

Prevalence of NCEP ATP III metabolic syndrome among subjects in the NHANES III survey, by age

Adapted from Ford, ES, Giles, WH, Dietz, WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 2002; 287:356.

Prevalence of NCEP ATP III metabolic syndrome among subjects in the NHANES III survey by race/ethnicity and sex

Adapted from Ford, ES, Giles, WH, Dietz, WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 2002; 287:356.

Therapeutic goals for management of metabolic syndrome

Goals
Lifestyle risk factors Abdominal obesity Year 1: reduce body weight 7-10 percent. Continue weight loss thereafter with ultimate goal BMI <25 kg/m2 Physical inactivity Atherogenic diet Metabolic risk factors Dyslipidemia
Primary target elevated LDL-C High risk*: <100 mg/dL (2.6 mmol/>L); optional <70 mg/dL Moderate risk: <130 mg/dL (3.4 mmol/L) Lower risk: <160 mg/dL (4.9 mmol/L) Secondary target elevated non-HDLC High risk*: <130 mg/dL (3.4 mmol/L); optional <100 mg/dL (2.6 mmol/L) very high risk Moderate risk: <160 mg/dL (4.1 mmol/L) Lower risk: <190 mg/dL (4.9 mmol/L) Tertiary target reduced HDL-C Raise to extent possible w/weight reduction and exercise

At least 30 min (and preferably 60 min) continuous or intermittent moderate intensity exercise 5X/wk, but preferably daily Reduced intake saturate fat, trans fat, cholesterol

Elevated bp Elevated glucose

Reduce to at least <140/90 (<130/80 if diabetic) For IFG, encourage weight reduction and exercise For type 2 DM, target A1C <7 percent

Prothrombotic state Proinflammatory state

Low dose aspirin for high risk patients Lifestyle therapies; no specific interventions

DM: diabetes mellitus; IFG: impaired fasting glucose; bp: blood pressure. * High risk: diabetes, known coronary artery disease. Data from: Grundy, S, Cleeman, J, Daniels, S, et al. Diagnosis and management of the metabolic syndrome. An American Heart Association/National Heart, Lung, and Blood Institute scientific statement. Circulation 2005; 112:2735.

Definitions of metabolic syndrome in children and adolescents

Parameters
Required Waist circumference Number of abnormalities Triglyceride HDL BP Systolic Diastolic Glucose 3 >95th percentile <5th percentile Either >95th percentile >95th percentile Impaired glucose tolerance 90th percentile* 2 150 mg/dL (1.7 mmol/L) <40 mg/dL (1.03 mmol/L) Either >130 mmHg 85 mmHg 100 mg/dL (5.6 mmol/L) Fasting 110 mg/dL (6.1 mmol/L) 90th percentile All 110 mg/dL (1.24 mmol/L) 40 mg/dL (1.03 mmol/L) 90th percentile

Modified ATP III

IDF (10 to 16 years)

NHANES III

ATP III: Adult Treatment Panel; IDF: International Diabetes Federation; NHANES: National Health and Nutrition Examination Survey; HDL: high-density lipoprotein; BP: blood pressure. * Ethnic-specific waist circumference (see Fernandez JR, Redden DT, Pietrobelli A, et al. Waist circumference percentiles in nationally representative samples of African-American, EuropeanAmerican, and Mexican-American children and adolescents. J Pediatr 2004; 145:439).

 2012 UpToDate, Inc. All rights reserved. | Subscription and License Agreement | Release: 20.8 - C20.23 Licensed to: Faculdade PUCRS | Support Tag: [ecapp0603p.utd.com-201.54.140.8-C3AFD64CA4-42844.14]