ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Metabolic syndrome (insulin resistance syndrome or syndrome X)

Metabolic syndrome (insulin resistance syndrome or syndrome X)
Literature review current through: Jan 2024.
This topic last updated: Aug 23, 2023.

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]. Body fat distribution, a sedentary lifestyle, and genetic predisposition all affect the likelihood that an individual with obesity will develop diabetes or CVD.

It should be noted that questions have been raised as to whether metabolic syndrome 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 metabolic syndrome is considered a unique entity, individual components need to be identified and managed to decrease the associated morbidity and mortality [15,16].

The definition, prevalence, clinical implications, and therapy of 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".)

Metabolic syndrome should not be confused with another disorder called syndrome X in which angina pectoris occurs in patients with normal coronary arteries. (See "Microvascular angina: Angina pectoris with normal coronary arteries".)

DEFINITION — There are several definitions for metabolic syndrome, leading to some difficulty in comparing data from studies using different criteria (table 1) [17-23]. The National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) is the most widely used [24]. Although abdominal obesity may be central to the pathophysiology of metabolic syndrome, it is not a prerequisite for diagnosis; the presence of any three of the five criteria listed constitutes a diagnosis of metabolic syndrome. (See 'National Cholesterol Education Program ATP III' below.)

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 [25]. Whether it is necessary or helpful to assess insulin resistance in addition to more readily measured traits of the syndrome is uncertain. In addition, although formal definitions of metabolic syndrome do not specifically include glycated hemoglobin (A1C), an abnormal A1C (5.7 to 6.4 percent) is increasingly accepted and used to define impaired glycemia in patients with metabolic syndrome. (See "Clinical presentation, diagnosis, and initial evaluation of diabetes mellitus in adults", section on 'Diagnostic criteria'.)

National Cholesterol Education Program ATP III — The 2005 ATP III criteria define the metabolic syndrome as the presence of any three of the following traits:

Abdominal obesity, defined as a waist circumference ≥102 cm (40 in) in males and ≥88 cm (35 in) in females

Serum triglycerides ≥150 mg/dL (1.7 mmol/L) or drug treatment for elevated triglycerides

Serum high-density lipoprotein (HDL) cholesterol <40 mg/dL (1 mmol/L) in males and <50 mg/dL (1.3 mmol/L) in females or drug treatment for low HDL cholesterol

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; central obesity was an essential element in this definition, with different waist circumference thresholds set for different race/ethnicity groups (table 2) [26]. In 2009, in an attempt to harmonize the criteria used to define metabolic syndrome, the IDF along with several organizations (including the AHA, the NHLBI, the World Heart Federation, the International Association for the Study of Obesity, and the International Atherosclerosis Society) eliminated an increased waist circumference as a diagnostic requirement. They now recommend using the following five criteria, with the presence of any of three qualifying for the diagnosis of metabolic syndrome (table 1):

Increased waist circumference, with ethnic-specific waist circumference cut-points (table 2)

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 females, or treatment for low HDL

Systolic blood pressure ≥130, diastolic blood pressure ≥85, or treatment for hypertension

FPG ≥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 FPG, but it is not required

Comparing criteria in defining populations — Using data from the National Health and Nutrition Examination Survey (NHANES) 1999 to 2002 database, 39 percent of United States adult participants met IDF criteria for metabolic syndrome, compared with 34.5 percent using the ATP III criteria [27]. The two definitions overlapped for 93 percent of subjects in determining presence or absence of metabolic syndrome. When applied to an urban population in the United States, the IDF criteria categorized 15 to 20 percent more adults with metabolic syndrome than the ATP III criteria [28].

The value of different metabolic syndrome definitions in terms of prognosis and management appears to be similar [29-31]. As examples:

In a prospective cohort study of a random sample of British females (n = 3589) aged 60 to 79 years, who were free of coronary heart disease (CHD) at baseline, all three definitions of metabolic syndrome were modestly and similarly associated with CHD risk [29]. The age-adjusted hazard ratios (HRs) for the IDF, World Health Organization (WHO), and NCEP syndromes were 1.32 (95% CI 1.03-1.70), 1.45 (95% CI 1.00-2.10), and 1.38 (95% CI 1.00-1.93), respectively.

Similarly, when data from the Framingham population are examined using ATP III, IDF, and European Group for the Study of Insulin Resistance (EGIR) definitions of metabolic syndrome, roughly equivalent associations for incident type 2 diabetes (HR 3.5, 95% CI 2.2-5.6; HR 4.6, 95% CI 2.7-7.7; HR 3.3, 95% CI 2.1-5.1, respectively) and for CVD (HR 1.8, 95% CI 1.4-2.3; HR 1.7, 95% CI 1.3-2.3; HR 2.1, 95% CI 1.6-2.7, respectively) are observed [30]. Thus, risk-factor clustering defines increased risk for type 2 diabetes and CVD.

Whether to include type 2 diabetes in the definition of metabolic syndrome is controversial. Although type 2 diabetes is a component of the WHO, ATP III, and IDF definitions, some experts disagree with its inclusion because the value of diagnosing metabolic syndrome is to identify those at higher risk for developing type 2 diabetes and, ideally, prevent it. Furthermore, among patients with known type 2 diabetes, making a diagnosis of metabolic syndrome has uncertain value. It can identify those with a higher rates of macrovascular but not microvascular complications and, ultimately, has a poor predictive value for cardiovascular outcomes in that population [32]. The management of patients with type 2 diabetes thus does not depend on whether they meet criteria for metabolic syndrome and is discussed in detail elsewhere. (See "Overview of general medical care in nonpregnant adults with diabetes mellitus".)

Other potential markers — Metabolic syndrome has been recognized as a proinflammatory, prothrombotic state, associated with elevated levels of C-reactive protein (CRP), interleukin (IL)-6, and plasminogen activator inhibitor (PAI)-1 [4,26,33-39]. Inflammatory and prothrombotic markers are associated with an increased risk for subsequent CVD and type 2 diabetes [35-38]; adipokines and inflammatory markers, however, explained only a small part of the association between metabolic syndrome and CHD mortality in one study [40]. Additionally, a causal association between elevated CRP and metabolic syndrome was not demonstrated in a study of phenotype patterns associated with metabolic syndrome and CRP levels [41].

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"). AHA/US Centers for Disease Control and Prevention (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 [42].

EPIDEMIOLOGY AND RISK FACTORS

Epidemiology — The prevalence of metabolic syndrome, as defined by the 2001 Adult Treatment Panel III (ATP III) criteria, was evaluated in 8800 United States adults participating in the third National Health and Nutrition Examination Survey (NHANES III, 1988 to 1994) [43]. The overall prevalence was 22 percent, with an age-dependent increase (6.7, 43.5, and 42.0 percent for ages 20 to 29, 60 to 69, and >70 years, respectively) (figure 1). Among this cohort, Mexican Americans had the highest age-adjusted prevalence (31.9 percent). Among Black Americans and Mexican Americans, the prevalence was higher in females than in males (57 and 26 percent higher, respectively) (figure 2).

Metabolic syndrome has become increasingly prevalent. Using data from the NHANES 2011 to 2016 database, 34.7 percent of participants met ATP III criteria for metabolic syndrome compared with 22 percent in NHANES III (1988 to 1994) [43,44]. In the 2011 to 2016 cohort, the prevalence was lowest among those identifying as non-Hispanic Asian and highest among those identifying as Hispanic and "other"; among all groups, the prevalence increased with advancing age [44].

In addition, metabolic syndrome, defined by the 2005 revised ATP III criteria, was assessed in 3300 adult Framingham Heart Study participants without diabetes or cardiovascular disease (CVD) [45]. At baseline, the prevalence of metabolic syndrome was 26.8 percent in males and 16.6 percent in females. After eight years of follow-up, there was an age-adjusted 56 percent increase in prevalence among males and a 47 percent increase among females.

Weight as a risk factor — Increased body weight is a major risk factor for metabolic syndrome. In NHANES III, metabolic syndrome was present in 5 percent of those at normal weight, 22 percent of those with overweight, and 60 percent of those with obesity [46]. (See "Obesity in adults: Prevalence, screening, and evaluation".)

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 [47]. A large waist circumference alone identifies up to 46 percent of individuals who will develop metabolic syndrome within five years [48].

The rapidly increasing prevalence of obesity among adults in the United States is likely to lead to even higher rates of metabolic syndrome in the near future [49], highlighting the importance of obesity prevention and improving physical activity levels [50,51]. (See "Obesity in adults: Etiologies and risk factors" and "Overweight and obesity in adults: Health consequences".)

Some normal-weight individuals are at increased risk of hypertension, CVD, and diabetes [46,52]. It is unknown if these individuals represent a distinct subphenotype of metabolic syndrome (ie, "normal weight, metabolically obese"). In a genome-wide association study evaluating 19 common genetic variants associated with insulin resistance (defined by elevated fasting insulin concentrations), a metabolic profile consistent with a genetically common, subtle form of lipodystrophy in the general population was identified [53]. These genetic variants were associated with increased levels of metabolic risk traits, liver markers, type 2 diabetes, and coronary artery disease but lower body mass index (BMI) and increased visceral-to-subcutaneous adipose tissue ratio.

Other risk factors — In addition to age, race, and weight, other factors associated with an increased risk of metabolic syndrome in NHANES included postmenopausal status, smoking, low household income, high carbohydrate diet, no alcohol consumption, and physical inactivity [46,54]. In the Framingham Heart Study, soft drink and sugar-sweetened beverage consumption was also associated with an increased risk of developing adverse metabolic traits and metabolic syndrome [55,56]. Use of atypical antipsychotic medications, especially clozapine, significantly increases risk for metabolic syndrome [57]. In addition, poor cardiorespiratory fitness is an independent and strong predictor of metabolic syndrome [58]. (See "Exercise and fitness in the prevention of atherosclerotic 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 [59-62].

CLINICAL EVALUATION AND IMPLICATIONS OF DIAGNOSIS

Clinical evaluation — 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 at least one risk factor [63]. The assessment should include measurement of blood pressure, waist circumference, fasting lipid profile, and fasting glucose concentration.

Implications of a diagnosis of metabolic syndrome — Patients with metabolic syndrome are at elevated risk of developing cardiovascular disease and other obesity-related disorders. The key clinical implication of a diagnosis of metabolic syndrome is to identify patients who will benefit from aggressive lifestyle modification focused on weight reduction and increased physical activity and, ideally, prevent the future development of these clinical outcomes [11,50,64]. (See 'Goals and rationale of therapy' below.)

Risk of cardiovascular disease — Three meta-analyses, which included many of the same studies, found that 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) [65-67].

The increased risk appears to be related to the risk-factor clustering or insulin resistance associated with metabolic syndrome rather than simply to obesity. Specifically, not all individuals with obesity have the same risk of developing CVD or diabetes; risks differ as a function of insulin sensitivity, with insulin-resistant individuals at greatest risk. This was illustrated by the following studies:

In a study of the Framingham population, people with obesity but without metabolic syndrome did not have a significantly increased risk of diabetes or CVD [52]. However, individuals with obesity and metabolic syndrome had a 10-fold increased risk for diabetes and a twofold increased risk for CVD relative to normal-weight people without metabolic syndrome. Normal-weight people meeting revised 2005 ATP III criteria for metabolic syndrome had a fourfold increased risk for diabetes and a threefold increased risk for CVD.

In a study of 211 people with moderate obesity (BMI 30 to 35), insulin sensitivity varied sixfold, and those with the greatest degree of insulin resistance had the highest blood pressure, triglyceride concentrations, and fasting and two-hour post oral glucose blood sugar levels, and the lowest HDL concentrations, despite equal levels of obesity [68].

The risk also may be related to underlying subclinical CVD (as measured by electrocardiography [ECG], echocardiography, carotid ultrasound, and ankle-brachial blood pressure) in individuals with metabolic syndrome [69]. 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 (hazard ratio [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).

Although metabolic syndrome predicts increased risk for CVD, it is not clear whether this adds clinically meaningful prognostic information [65,70,71]. 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 [72].

The Framingham Risk Score was a better predictor of coronary heart disease (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 males aged 40 to 59 years followed for 20 years [73].

Low HDL cholesterol and high blood pressure were better predictors of CHD than metabolic syndrome in a prospective study of 2737 males from the same cohort [74].

Risk of type 2 diabetes — Prospective observational studies demonstrate a strong association between metabolic syndrome and the risk for subsequent development of type 2 diabetes [74-78]. In a meta-analysis of 16 multiethnic cohort studies, the relative risk (RR) of developing diabetes ranged from 3.53 to 5.17, depending upon the definition of metabolic syndrome and the population studied [79]. As an example, in an analysis of 890 nondiabetic Pima Indians, 144 developed diabetes over four years of follow-up [75]. Metabolic syndrome increased the RR for incident diabetes by 2.1-fold with the Adult Treatment Panel III (ATP III) definition and 3.6-fold using the World Health Organization (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 metabolic syndrome [45,64,77]. While metabolic syndrome predicts increased risk for diabetes, it is not clear whether this adds additional important information [70,79]. In a prospective cohort study of 5842 Australian adults, metabolic syndrome (defined by WHO, ATP III, the European Group for the Study of Insulin Resistance [EGIR], or the International Diabetes Federation [IDF]) was not superior to fasting plasma glucose or a published diabetes prediction model (including age, sex, ethnicity, fasting plasma glucose, systolic blood pressure, high-density lipoprotein [HDL] cholesterol, body mass index [BMI], and family history) in identifying individuals who developed diabetes [80]. (See 'A critical look at the metabolic syndrome' below.)

Other associations — Metabolic syndrome has also been associated with several obesity-related disorders including:

Fatty liver disease with steatosis, fibrosis, and cirrhosis [81-83]. (See "Epidemiology, clinical features, and diagnosis of nonalcoholic fatty liver disease in adults", section on 'Associated disorders'.)

Hepatocellular carcinoma and intrahepatic cholangiocarcinoma. (See "Epidemiology and risk factors for hepatocellular carcinoma", section on 'Diabetes mellitus' and "Epidemiology, risk factors, anatomy, and pathology 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 [84,85]. In a report from National Health and Nutrition Examination Survey (NHANES III), metabolic syndrome in multivariate analysis significantly increased the risk of both CKD and microalbuminuria (adjusted odds ratio [OR] 2.6 and 1.9, respectively) [84]. The risk of both complications increased with the number of components of metabolic syndrome. In a prospective cohort study, 10 percent of individuals with metabolic syndrome at baseline subsequently developed CKD compared with 6 percent among those without metabolic syndrome [86].

Polycystic ovary syndrome [87]. (See "Clinical manifestations of polycystic ovary syndrome in adults".)

Sleep-disordered breathing, including obstructive sleep apnea [88,89]. (See "Clinical presentation and diagnosis of obstructive sleep apnea in adults".)

Hyperuricemia and gout [90,91]. (See "Asymptomatic hyperuricemia", section on 'Potential clinical consequences' and "Pathophysiology of gout", section on 'Hyperuricemia and gout'.)

Several components of metabolic syndrome, including hyperlipidemia, hypertension, and diabetes, have been associated with an increased risk of cognitive decline and dementia. Metabolic syndrome (when associated with a high level of inflammation) may also be associated with cognitive decline in older adults. (See "Risk factors for cognitive decline and dementia".)

THERAPY

Goals and rationale of therapy — The therapeutic goals for individuals with metabolic syndrome are:

Treat underlying causes by reducing weight and increasing physical activity

Treat cardiovascular risk factors if they persist despite lifestyle modification

These goals are consistent with recommendations from the Adult Treatment Panel III (ATP III) [20], American Heart Association (AHA), National Institutes of Health (NIH), and Endocrine Society [22,63,64].

Intensive lifestyle interventions can decrease mortality and may be associated with a reduced risk of cardiovascular events [92,93]. Improving components of cardiovascular risk (eg, waist circumference, high triglycerides, low HDL, measures of hyperglycemia, and insulin sensitivity) and thereby reversing metabolic syndrome presumably drives changes in clinical endpoints [93-98]. As an example, a network meta-analysis of randomized clinical trials studying interventions for metabolic syndrome reported that groups randomized to lifestyle interventions were more likely to resolve metabolic syndrome than those in the control groups (OR [odds ratio] 2.61; 95% credible interval 1.0-5.47) [97]. Furthermore, a separate retrospective cohort study found that reversal of metabolic syndrome was associated with a reduced risk of developing a major cardiovascular event (RR [rate ratio] 0.85, 95% CI 0.83-0.87) [92]. Among the individual metabolic syndrome criteria, recovery from hypertension was most strongly associated with a reduction in cardiovascular risk.

Outcomes with specific types of lifestyle interventions are discussed below.

Lifestyle modification and weight reduction — Aggressive lifestyle modification focused on weight reduction and increased physical activity is the primary therapy for metabolic syndrome [99-101]. These are generally similar to approaches for individuals with overweight/obesity or prediabetes. Multicomponent interventions that include behavioral changes with individualized goal-setting, environmental modification, and attention to adherence over time are most likely to be effective. (See "Obesity in adults: Behavioral therapy".)

Weight reduction is optimally achieved with a multimodality approach that includes diet, exercise and, for selected patients, pharmacologic therapy or surgical intervention.

Diet — Weight reduction, which improves insulin sensitivity, is the cornerstone of lifestyle modification. We suggest the Mediterranean diet (high in fruits, vegetables, nuts, whole grains, and olive oil) or a low-fat diet for weight reduction because these have also been associated with reductions in all-cause mortality [93].

Specifically, in a network meta-analysis of randomized trials of diet interventions among patients at increased risk of cardiovascular disease, Mediterranean and low-fat diets reduced overall mortality and non-fatal myocardial infarction whereas others did not [93]. Observational and randomized trials of patients with overweight and obesity also document an association between weight loss and reductions in mortality. The Mediterranean diet has also been associated with greater weight loss, lower blood pressure, improved lipid profiles, improved insulin resistance, and lower levels of markers of inflammation and endothelial dysfunction than a low-fat, prudent diet, although the clinical impact of these differences in surrogate outcomes is uncertain [102]. Components of these diets and their impact on general health and in patients with overweight or obesity are discussed elsewhere. (See "Healthy diet in adults" and "Obesity in adults: Dietary therapy".)

Diets other than the Mediterranean diet that can improve components of the metabolic syndrome include the following:

The Dietary Approaches to Stop Hypertension (DASH) diet (daily sodium intake limited to 2400 mg and higher in dairy intake than the Mediterranean diet) – This resulted in greater improvements in triglycerides, diastolic blood pressure, and fasting glucose than did a weight-reducing diet emphasizing healthy food choices, even after controlling for weight loss [103].

A diet that is low in glycemic index/glycemic load (replacing refined grains with whole grains, fruits, and vegetables and eliminating high-glycemic beverages) – Foods with low glycemic index may improve glycemia and dyslipidemia [104] and may be particularly beneficial for patients with metabolic syndrome. The positive impact of this approach may derive from the glycemic index itself or the increase in high-fiber foods that accompanies a lower glycemic index diet [105].

A high-fiber diet (≥30 g/day) – One trial randomized 240 individuals with metabolic syndrome (mean BMI 35 kg/m2) to a high-fiber diet (≥30 g/day) or a more complex diet recommended by the AHA (fruits, vegetables, whole grain, high fiber, lean animal and vegetable proteins, reduction in sugar-sweetened beverages, moderate to no alcohol intake) [106]. After 12 months, equivalent weight loss (-2.1 versus -2.7 kg, respectively) and reductions in blood pressure occurred in both groups.

An eight-hour time-restricted eating schedule (with or without consumption of a low-carbohydrate diet) - This intervention reduced all components of metabolic syndrome in a trial of individuals with metabolic syndrome treated for three months [107].

Exercise — For individuals with metabolic syndrome, we recommend regular exercise. Exercise can augment weight loss from diet changes, improve metabolic outcomes, and may help to maintain weight loss over time [108]. Exercise may also be beneficial beyond its effect on weight loss by more selectively removing abdominal fat, at least in females [109].

Preferred regimens In general, we suggest that patients choose a regimen they enjoy and can practically incorporate into their daily routines. We also advise patients to combine aerobic and resistance training, if possible. The standard exercise recommendation is a daily minimum of 30 minutes of moderate-intensity (such as brisk walking) physical activity. Increasing the level of physical activity appears further to enhance the beneficial effect [110]. However, programs that combine aerobic and resistance training may be more effective than either component alone for improving cardiovascular risk parameters [111]. As an example, a network meta-analysis suggested that adding resistance training to aerobic exercise exerts a larger effect on metabolic parameters (weight, waist circumference, hyperglycemia, and hypertriglyceridemia) than aerobic exercise alone [112]. The role of exercise in managing obesity and preventing cardiovascular disease is discussed elsewhere. (See "Obesity in adults: Role of physical activity and exercise" and "Exercise and fitness in the prevention of atherosclerotic cardiovascular disease".)

Regimens for patients with activity limitations – We encourage patients to engage in any level of activity that their physical limitations allow. Those who are unable to exercise still benefit by reducing sedentary behavior. As an example, in a trial among 64 sedentary middle-aged adults with metabolic syndrome, an intervention to reduce sedentary behavior by one hour a day compared with the individual's baseline or control (usual behavior), improved insulin resistance, HbA1c, and liver enzymes after three months of treatment [113].

Pharmacotherapy or bariatric surgery in selected patents — Many patients with metabolic syndrome and obesity cannot sustain weight loss with intensive lifestyle modification or engage in diet and exercise. Additional options for such patients include pharmacotherapy or bariatric surgery. These options are discussed elsewhere. (See "Obesity in adults: Drug therapy" and "Obesity in adults: Overview of management", section on 'Bariatric surgery' and "Outcomes of bariatric surgery".)

Manage modifiable cardiovascular risk factors — The cardiovascular risk associated with metabolic syndrome has not been shown to be greater than the sum of its individual components [22,114-116]. Consequently, clinicians should encourage similar risk factor modification as in the general population. This includes addressing component CVD risk factors: treatment of hypertension, prevention of diabetes, and lowering of serum cholesterol [117,118].

Prevention of type 2 diabetes

Impact of lifestyle modifications – Measures to prevent diabetes in patients with metabolic syndrome mirror those for the general population. Clinicians should first focus on helping patients reduce weight and increase activity since these measures have been shown to reduce the likelihood of developing diabetes in individuals with metabolic syndrome. (See "Prevention of type 2 diabetes mellitus", section on 'Lifestyle intervention'.)

Although not strictly addressing metabolic syndrome, clinical trials have investigated the impact of lifestyle modification on preventing diabetes in individuals with impaired glucose regulation (eg impaired glucose tolerance [IGT], impaired fasting glucose [IFG], or hemoglobin A1C of 5.7 to 6.4 percent) [96,119]. They have shown that lifestyle modifications can substantially reduce the risk of developing type 2 diabetes, with risk reductions that persist for up to 15 years [120].

Drugs to prevent diabetes for selected patients – Patients who have persistent insulin resistance despite attempts at lifestyle changes may benefit from metformin. This is similar to recommendations for patients with prediabetes, based on the Diabetes Prevention Program [120] and consistent with guideline recommendations from the American Diabetes Association. Alternatively, clinicians may offer weight-lowering medications to those who meet criteria for obesity pharmacotherapy. The rationale for and details of drug therapy for the prevention and treatment of type 2 diabetes are discussed elsewhere. (See "Prevention of type 2 diabetes mellitus", section on 'Pharmacologic therapy' and "Initial management of hyperglycemia in adults with type 2 diabetes mellitus", section on 'Initial pharmacologic therapy'.)

Lipid lowering

Assessment of atherosclerotic cardiovascular disease risk – Clinicians should assess each patient's risk of future atherosclerotic cardiovascular disease (ASCVD) and counsel patients about dietary changes to improve lipid profiles. Risk assessment is discussed in detail elsewhere. (See "Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults: Our approach", section on 'How to assess ASCVD risk' and "Lipid management with diet or dietary supplements".)

Threshold for statin therapy – As in the general population, the decision to start statin therapy depends on the ASCVD risk. Evidence does not support metabolic syndrome as a coronary risk equivalent that would prompt statin initiation [121]. Nevertheless, metabolic syndrome is a "risk enhancing factor" that may warrant statin therapy even in individuals whose ASCVD risk would not otherwise meet the threshold for treatment [118] (table 3). Patients who initiate statins should receive evidence-based doses of moderate to high intensity statins. Detailed discussions of pharmacotherapy for patients with dyslipidemia are found elsewhere. (See "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease", section on 'Indications for statin therapy'.)

Patients with metabolic syndrome and elevated low-density lipoprotein (LDL) cholesterol may benefit more than those without metabolic syndrome from high-intensity statin therapy. For example, among patients with elevated serum LDL cholesterol and established coronary disease in the Scandinavian Simvastatin Survival Study (4S) trial, those with characteristics of metabolic syndrome (lowest quartile for high-density lipoprotein [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 [122,123].

Management of hypertriglyceridemia – Clinicians should manage hypertriglyceridemia similarly to the management of patients without metabolic syndrome. (See "Hypertriglyceridemia in adults: Management".)

Antihypertensive therapy

Target blood pressure – We recommend aggressive blood pressure control for patients who have hypertension as part of their metabolic syndrome, with specific blood pressure targets based on patients' comorbidities and cardiovascular risk. Patients with metabolic syndrome who have a high risk of future cardiovascular events would benefit from a lower blood pressure target than that used for lower risk populations. Goal blood pressures are discussed elsewhere. (See "Goal blood pressure in adults with hypertension", section on 'Patients with multiple cardiovascular risk factors'.)

The presence of metabolic syndrome in patients with hypertension has been associated with an increased risk of poorly controlled hypertension [124], end-organ damage (eg, left ventricular hypertrophy, hypertensive retinopathy) [125-127], and all-cause mortality [128].

Current guidelines in the United States and Europe do not specify distinct blood pressure targets for patients with metabolic syndrome.

Lifestyle modification – All patients with hypertension should engage in total lifestyle changes that include reducing weight, restricting salt, and limiting alcohol intake. (See "Overview of hypertension in adults", section on 'Nonpharmacologic therapy'.)

Drug therapy – In patients whose blood pressure is uncontrolled with lifestyle measures, our approach is the same as that in the general population (see "Choice of drug therapy in primary (essential) hypertension"). Given the potential of thiazide diuretics to exacerbate hyperglycemia, albeit modestly, and adversely affect lipid profiles, it would be reasonable to reserve this class of anti-hypertensives for patients who have an inadequate blood pressure response to the aforementioned agents [129]. Alternatively, clinicians can initiate thiazide diuretics in combination with ACE inhibitors or ARB agents as these medications may counteract the hyperglycemia-inducing effects of thiazides [127,130].

CHILDREN AND ADOLESCENTS

Definition — Metabolic syndrome also occurs in children and adolescents but there is no consensus on the definition (table 4) [131-135]. 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 metabolic syndrome in children or for tracking the effectiveness of lifestyle interventions. (See 'Clinical evaluation and implications of diagnosis' 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 high-density lipoprotein (HDL) rather than a sex-specific cutoff [135,136]. 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 ≥90th percentile.

Prevalence and risk factors — When clinically applied, these pediatric definitions result in varying prevalence rates [137-140]. The United States prevalence of metabolic syndrome (defined by the modified Adult Treatment Panel III [ATP III] criteria) is estimated to be approximately 9 percent based upon a National Health and Nutrition Examination Survey (NHANES III) survey of 1960 children >12 years of age [141]. 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 [138,142]. 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 [138].

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 White Americans and non-Hispanic Black Americans (12.9, 10.9, and 2.9 percent, respectively). The Native North American population may be the group at greatest risk for metabolic syndrome as illustrated by a population-based study of Canadian First Nation (Oji-Cree) children and adolescents (10 to 19 years) that reported a 19 percent prevalence rate (defined by ATP III criteria) [143].

Among children with obesity, the prevalence of metabolic syndrome is high and increases with worsening obesity [132,133]. This was illustrated in a study of children and adolescents who underwent a comprehensive metabolic assessment including 439 with obesity, 31 with overweight, and 20 with a normal BMI [132]. Metabolic syndrome was present in 39 and 50 percent of subjects with moderate and severe obesity, respectively. By contrast, no overweight or normal-weight children met the criteria for 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 (NHLBI) Growth and Health Study (NGHS) [144]. 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 2, 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 metabolic syndrome is high among children and adolescents with obesity 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 [138,145]. 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 cardiovascular disease (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 [OR] 14.6, 95% CI 4.8-45.3) [146]. Of 31 children who had metabolic syndrome traits in the initial study, 21 (68 percent) had adult metabolic syndrome. Increasing body mass index (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.

Lifestyle modification that emphasizes reduction of established risk factors, such as promotion of a healthy diet, exercise, weight loss, and smoking cessation, is the main therapeutic goal in children and adolescents with obesity, regardless of a metabolic syndrome diagnosis. This topic is reviewed in detail separately. (See "Pediatric prevention of adult cardiovascular disease: Promoting a healthy lifestyle and identifying at-risk children", section on 'Promoting a heart-healthy lifestyle'.)

A CRITICAL LOOK AT THE METABOLIC SYNDROME — The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) published a joint statement raising questions about whether the components of 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 Adult Treatment Panel III (ATP III), World Health Organization (WHO), and other definitions; many published studies use further modifications to classify subjects with metabolic syndrome.

Multiple different phenotypes included within 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 high-density lipoprotein (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 cardiovascular disease (CVD) or diabetes as part of the syndrome that 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 metabolic syndrome, such as inflammatory markers, may have equal or greater bearing on risk.

The CVD risk associated with metabolic syndrome has not been shown to be greater than the sum of its individual components [22,114-116].

The critical weakness of the metabolic syndrome construct is that treatment of the syndrome is no different than treatment for each of its components. Virtually all agree that the clustering of risk factors for diabetes and CVD is a real phenomenon. All agree that the presence of one component of 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 patients with obesity and multiple risk factors.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Prevention of type 2 diabetes mellitus".)

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 education: Metabolic syndrome (The Basics)")

Beyond the Basics topic (see "Patient education: Metabolic syndrome (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Definition of metabolic syndrome Metabolic syndrome is defined as the co-occurrence of metabolic risk factors for type 2 diabetes and cardiovascular disease (CVD), specifically abdominal obesity, hyperglycemia, dyslipidemia, and hypertension. There are several definitions for metabolic syndrome (table 1). The National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) is the most widely used. (See 'Definition' above.)

Controversy regarding the utility of diagnosing metabolic syndrome The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) have questioned whether metabolic syndrome, as defined above, warrants classification as a true "syndrome". (See 'A critical look at the metabolic syndrome' above.)

Reasons not to classify metabolic syndrome as a separate entity include: 1) the risks of developing cardiovascular disease and diabetes in these individuals are equivalent to the sum risk of each component and 2) treatment of those with metabolic syndrome resembles that of patients with each component risk factor.

Reasons to classify metabolic syndrome as a separate entity include: 1) The increased risk of incident CVD and all-cause mortality conferred by metabolic syndrome seems related to risk-factor clustering rather than to obesity specifically and 2) diagnosing metabolic syndrome identifies patients who warrant aggressive intervention. (See 'Clinical evaluation and implications of diagnosis' above.)

Importance of lifestyle modification Aggressive lifestyle modification via weight reduction and increased physical activity is cornerstone of management. These measures can reduce the risk of all-cause mortality, cardiovascular events, and type 2 diabetes. (See 'Lifestyle modification and weight reduction' above.)

For patients with metabolic syndrome, we suggest a Mediterranean or low-fat diet rather than other diets (Grade 2B). These diets have been associated with reductions in all-cause mortality in individuals with elevated cardiovascular risk. (See 'Diet' above and "Healthy diet in adults" and "Obesity in adults: Dietary therapy".)

Exercise programs that combine aerobic exercise and resistance training may be most beneficial for improving metabolic parameters. (See 'Exercise' above and "Obesity in adults: Role of physical activity and exercise" and "Exercise and fitness in the prevention of atherosclerotic cardiovascular disease".)

Prevention of type 2 diabetes – Prevention of type 2 diabetes centers on lifestyle modification and, for some individuals, pharmacotherapy. These interventions are discussed in detail elsewhere. (See "Prevention of type 2 diabetes mellitus", section on 'Our approach'.)

Treatment of dyslipidemia Lipid lowering strategies resemble those recommended for the general population; however, metabolic syndrome is a risk-enhancing factor that may warrant initiation of pharmacotherapy at lower levels of cardiovascular risk. (See 'Lipid lowering' above and "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease".)

Treatment of hypertension As in the general population, blood pressure targets depend on cardiovascular risk. Many patients with metabolic syndrome have a high enough risk that would benefit from a lower blood pressure target than that used for lower risk populations. Specific target blood pressures are discussed elsewhere. (See "Goal blood pressure in adults with hypertension", section on 'Patients with multiple cardiovascular risk factors'.)

Antihypertensive selection is largely the same as in the general population. Thiazide diuretics have a small adverse effect on lipids and insulin resistance. (See 'Antihypertensive therapy' above and "Goal blood pressure in adults with hypertension" and "Choice of drug therapy in primary (essential) hypertension" and "Treatment of hypertension in patients with diabetes mellitus".)

  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. 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.
  18. 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.
  19. Matthews DR, Hosker JP, Rudenski AS, et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28:412.
  20. 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.
  21. Genuth S, Alberti KG, Bennett P, et al. Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care 2003; 26:3160.
  22. 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.
  23. Alberti KG, Zimmet P, Shaw J, IDF Epidemiology Task Force Consensus Group. The metabolic syndrome--a new worldwide definition. Lancet 2005; 366:1059.
  24. Alberti KG, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009; 120:1640.
  25. 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.
  26. 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).
  27. Ford ES. Prevalence of the metabolic syndrome defined by the International Diabetes Federation among adults in the U.S. Diabetes Care 2005; 28:2745.
  28. 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.
  29. 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.
  30. 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.
  31. 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.
  32. 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.
  33. 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.
  34. 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.
  35. Ridker PM. Clinical application of C-reactive protein for cardiovascular disease detection and prevention. Circulation 2003; 107:363.
  36. 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.
  37. 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.
  38. Hu FB, Meigs JB, Li TY, et al. Inflammatory markers and risk of developing type 2 diabetes in women. Diabetes 2004; 53:693.
  39. 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.
  40. 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.
  41. Timpson NJ, Lawlor DA, Harbord RM, et al. C-reactive protein and its role in metabolic syndrome: mendelian randomisation study. Lancet 2005; 366:1954.
  42. Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J Clin Invest 2003; 111:1805.
  43. 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.
  44. Hirode G, Wong RJ. Trends in the Prevalence of Metabolic Syndrome in the United States, 2011-2016. JAMA 2020; 323:2526.
  45. 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.
  46. 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.
  47. Wilson PW, Kannel WB, Silbershatz H, D'Agostino RB. Clustering of metabolic factors and coronary heart disease. Arch Intern Med 1999; 159:1104.
  48. 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.
  49. Mokdad AH, Serdula MK, Dietz WH, et al. The spread of the obesity epidemic in the United States, 1991-1998. JAMA 1999; 282:1519.
  50. 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.
  51. 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.
  52. 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.
  53. Yaghootkar H, Scott RA, White CC, et al. Genetic evidence for a normal-weight "metabolically obese" phenotype linking insulin resistance, hypertension, coronary artery disease, and type 2 diabetes. Diabetes 2014; 63:4369.
  54. Gennuso KP, Gangnon RE, Thraen-Borowski KM, Colbert LH. Dose-response relationships between sedentary behaviour and the metabolic syndrome and its components. Diabetologia 2015; 58:485.
  55. 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.
  56. Green AK, Jacques PF, Rogers G, et al. Sugar-sweetened beverages and prevalence of the metabolically abnormal phenotype in the Framingham Heart Study. Obesity (Silver Spring) 2014; 22:E157.
  57. Lamberti JS, Olson D, Crilly JF, et al. Prevalence of the metabolic syndrome among patients receiving clozapine. Am J Psychiatry 2006; 163:1273.
  58. 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.
  59. 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.
  60. 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.
  61. 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.
  62. 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.
  63. 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.
  64. 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.
  65. 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.
  66. Galassi A, Reynolds K, He J. Metabolic syndrome and risk of cardiovascular disease: a meta-analysis. Am J Med 2006; 119:812.
  67. 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.
  68. 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.
  69. 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.
  70. Stern MP, Williams K, González-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.
  71. Kohli P, Greenland P. Role of the metabolic syndrome in risk assessment for coronary heart disease. JAMA 2006; 295:819.
  72. 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.
  73. 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.
  74. 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.
  75. Hanson RL, Imperatore G, Bennett PH, Knowler WC. Components of the "metabolic syndrome" and incidence of type 2 diabetes. Diabetes 2002; 51:3120.
  76. 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.
  77. 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.
  78. 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.
  79. Ford ES, Li C, Sattar N. Metabolic syndrome and incident diabetes: current state of the evidence. Diabetes Care 2008; 31:1898.
  80. 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.
  81. 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.
  82. 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.
  83. 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.
  84. 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.
  85. 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.
  86. 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.
  87. 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.
  88. 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.
  89. 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.
  90. Choi HK, Ford ES. Prevalence of the metabolic syndrome in individuals with hyperuricemia. Am J Med 2007; 120:442.
  91. 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.
  92. Park S, Lee S, Kim Y, et al. Altered Risk for Cardiovascular Events With Changes in the Metabolic Syndrome Status: A Nationwide Population-Based Study of Approximately 10 Million Persons. Ann Intern Med 2019; 171:875.
  93. Karam G, Agarwal A, Sadeghirad B, et al. Comparison of seven popular structured dietary programmes and risk of mortality and major cardiovascular events in patients at increased cardiovascular risk: systematic review and network meta-analysis. BMJ 2023; 380:e072003.
  94. Salas-Salvadó J, Díaz-López A, Ruiz-Canela M, et al. Effect of a Lifestyle Intervention Program With Energy-Restricted Mediterranean Diet and Exercise on Weight Loss and Cardiovascular Risk Factors: One-Year Results of the PREDIMED-Plus Trial. Diabetes Care 2019; 42:777.
  95. Yamaoka K, Tango T. Effects of lifestyle modification on metabolic syndrome: a systematic review and meta-analysis. BMC Med 2012; 10:138.
  96. 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.
  97. Guzmán A, Navarro E, Obando L, et al. Effectiveness of interventions for the reversal of a metabolic syndrome diagnosis: An update of a meta-analysis of mixed treatment comparison studies. Biomedica 2019; 39:647.
  98. Nagy I, Ohno-Iwashita Y, Ohta M, et al. Effect of perfringolysin O on the lateral diffusion constant of membrane proteins of hepatocytes as revealed by fluorescence recovery after photobleaching. Biochim Biophys Acta 1988; 939:551.
  99. 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.
  100. Bassi N, Karagodin I, Wang S, et al. Lifestyle modification for metabolic syndrome: a systematic review. Am J Med 2014; 127:1242.e1.
  101. Bozkurt B, Aguilar D, Deswal A, et al. Contributory Risk and Management of Comorbidities of Hypertension, Obesity, Diabetes Mellitus, Hyperlipidemia, and Metabolic Syndrome in Chronic Heart Failure: A Scientific Statement From the American Heart Association. Circulation 2016; 134:e535.
  102. 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.
  103. 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.
  104. 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.
  105. 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.
  106. Ma Y, Olendzki BC, Wang J, et al. Single-component versus multicomponent dietary goals for the metabolic syndrome: a randomized trial. Ann Intern Med 2015; 162:248.
  107. He M, Wang J, Liang Q, et al. Time-restricted eating with or without low-carbohydrate diet reduces visceral fat and improves metabolic syndrome: A randomized trial. Cell Rep Med 2022; 3:100777.
  108. Ostman C, Smart NA, Morcos D, et al. The effect of exercise training on clinical outcomes in patients with the metabolic syndrome: a systematic review and meta-analysis. Cardiovasc Diabetol 2017; 16:110.
  109. Després 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.
  110. 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.
  111. Schroeder EC, Franke WD, Sharp RL, Lee DC. Comparative effectiveness of aerobic, resistance, and combined training on cardiovascular disease risk factors: A randomized controlled trial. PLoS One 2019; 14:e0210292.
  112. Liang M, Pan Y, Zhong T, et al. Effects of aerobic, resistance, and combined exercise on metabolic syndrome parameters and cardiovascular risk factors: a systematic review and network meta-analysis. Rev Cardiovasc Med 2021; 22:1523.
  113. Garthwaite T, Sjöros T, Laine S, et al. Effects of reduced sedentary time on cardiometabolic health in adults with metabolic syndrome: A three-month randomized controlled trial. J Sci Med Sport 2022; 25:579.
  114. Sundström J, Vallhagen E, Risérus U, et al. Risk associated with the metabolic syndrome versus the sum of its individual components. Diabetes Care 2006; 29:1673.
  115. 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.
  116. López-Suárez A, Bascuñana-Quirell A, Beltrán-Robles M, et al. Metabolic syndrome does not improve the prediction of 5-year cardiovascular disease and total mortality over standard risk markers. Prospective population based study. Medicine (Baltimore) 2014; 93:e212.
  117. 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.
  118. Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2019; 140:e596.
  119. 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.
  120. Diabetes Prevention Program Research Group. Long-term effects of lifestyle intervention or metformin on diabetes development and microvascular complications over 15-year follow-up: the Diabetes Prevention Program Outcomes Study. Lancet Diabetes Endocrinol 2015; 3:866.
  121. 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.
  122. 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.
  123. Pyörälä 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.
  124. Arcucci O, de Simone G, Izzo R, et al. Association of suboptimal blood pressure control with body size and metabolic abnormalities. J Hypertens 2007; 25:2296.
  125. Cuspidi C, Meani S, Fusi V, et al. Metabolic syndrome and target organ damage in untreated essential hypertensives. J Hypertens 2004; 22:1991.
  126. Mulè G, Nardi E, Cottone S, et al. Influence of metabolic syndrome on hypertension-related target organ damage. J Intern Med 2005; 257:503.
  127. Katsimardou A, Imprialos K, Stavropoulos K, et al. Hypertension in Metabolic Syndrome: Novel Insights. Curr Hypertens Rev 2020; 16:12.
  128. Mancia G, Bombelli M, Corrao G, et al. Metabolic syndrome in the Pressioni Arteriose Monitorate E Loro Associazioni (PAMELA) study: daily life blood pressure, cardiac damage, and prognosis. Hypertension 2007; 49:40.
  129. Elliott WJ, Meyer PM. Incident diabetes in clinical trials of antihypertensive drugs: a network meta-analysis. Lancet 2007; 369:201.
  130. Zillich AJ, Garg J, Basu S, et al. Thiazide diuretics, potassium, and the development of diabetes: a quantitative review. Hypertension 2006; 48:219.
  131. Goodman E. Pediatric metabolic syndrome: smoke and mirrors or true magic? J Pediatr 2006; 148:149.
  132. Weiss R, Dziura J, Burgert TS, et al. Obesity and the metabolic syndrome in children and adolescents. N Engl J Med 2004; 350:2362.
  133. 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.
  134. 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.
  135. Zimmet P, Alberti G, Kaufman F, et al. The metabolic syndrome in children and adolescents. Lancet 2007; 369:2059.
  136. Fernández 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.
  137. Chi CH, Wang Y, Wilson DM, Robinson TN. Definition of metabolic syndrome in preadolescent girls. J Pediatr 2006; 148:788.
  138. Goodman E, Daniels SR, Meigs JB, Dolan LM. Instability in the diagnosis of metabolic syndrome in adolescents. Circulation 2007; 115:2316.
  139. DuBose KD, Stewart EE, Charbonneau SR, et al. Prevalence of the metabolic syndrome in elementary school children. Acta Paediatr 2006; 95:1005.
  140. 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.
  141. 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.
  142. Stanley TL, Chen ML, Goodman E. The typology of metabolic syndrome in the transition to adulthood. J Clin Endocrinol Metab 2014; 99:1044.
  143. Retnakaran R, Zinman B, Connelly PW, et al. Nontraditional cardiovascular risk factors in pediatric metabolic syndrome. J Pediatr 2006; 148:176.
  144. 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.
  145. Gustafson JK, Yanoff LB, Easter BD, et al. The stability of metabolic syndrome in children and adolescents. J Clin Endocrinol Metab 2009; 94:4828.
  146. 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.
Topic 1784 Version 48.0

References

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟