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 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]. Abdominal obesity 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 valuable to assess insulin resistance in addition to more readily measured traits of the syndrome is uncertain. In addition, although no formal definitions of metabolic syndrome include glycated hemoglobin (A1C), 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 — Guidelines developed by the 2001 NCEP ATP III focused explicitly on the risk of cardiovascular disease (CVD) and did not require evidence of insulin or glucose abnormalities, although abnormal glycemia is one of the criteria [20]. 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) [21,22]. Updates include the following:
●Lowering the threshold for abnormal fasting glucose to 100 mg/dL, corresponding to the American Diabetes Association (ADA) criteria for impaired fasting glucose (IFG) (see "Clinical presentation, diagnosis, and initial evaluation of diabetes mellitus in adults")
●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
ATP III criteria define metabolic syndrome as the presence of any three of the following five traits:
●Abdominal obesity, defined as a waist circumference ≥102 cm (40 in) in men 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 relative 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.
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 metabolic syndrome, in which it identifies those at greater risk of macrovascular but not microvascular complications [32]. Management of patients with type 2 diabetes should follow clinical guidelines, whether or not they also meet criteria for metabolic syndrome. (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], although adipokines and inflammatory markers 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 11 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. These data suggest reduced subcutaneous adiposity as a mechanism linking the components of metabolic syndrome.
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 IMPLICATIONS — Metabolic syndrome is an important risk factor for subsequent development of type 2 diabetes and/or cardiovascular disease (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) [11,50,63].
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 [64]. The assessment should include measurement of blood pressure, waist circumference, fasting lipid profile, and fasting glucose.
In patients identified as having metabolic syndrome (table 1), aggressive lifestyle intervention (weight reduction, physical activity) is warranted to reduce the risks of type 2 diabetes and CVD. Assessment of 10-year risk for CVD, using a risk assessment algorithm, such as the Framingham Risk Score or Systematic Coronary Risk Evaluation (SCORE), is useful in targeting individuals for medical intervention to lower blood pressure and cholesterol. (See "Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults: Our approach".)
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 [65-69]. 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 [70]. As an example, in an analysis of 890 nondiabetic Pima Indians, 144 developed diabetes over four years of follow-up [65]. 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 [45,63,67]. While metabolic syndrome predicts increased risk for diabetes, it is not clear whether this adds additional important information [70,71]. 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 [72]. (See 'A critical look at the metabolic syndrome' below.)
Risk of cardiovascular disease — Three meta-analyses, which included many of the same studies, found that metabolic syndrome increases the risk for incident CVD (RRs ranging from 1.53 to 2.18) and all-cause mortality (RRs 1.27 to 1.60) [73-75].
The increased risk appears to be related to the risk-factor clustering or insulin resistance associated with metabolic syndrome rather than simply to obesity. 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 [76].
Thus, not all individuals with moderate obesity have the same risk for developing CVD or diabetes; risks differ as a function of insulin sensitivity, with insulin-resistant, individuals at highest risk.
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 [77]. 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).
While metabolic syndrome predicts increased risk for CVD, it is not clear whether this adds additional important information [71,73,78]. 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 [79].
●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 [80].
●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 [69].
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, 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 [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 — In 2001, the Adult Treatment Panel III (ATP III) recommended two major therapeutic goals in patients with metabolic syndrome [20]. These goals were reinforced by a report from the American Heart Association (AHA) and the National Institutes of Health (NIH) (table 3) and by clinical guidelines from the Endocrine Society [22,63,64]:
●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 cardiovascular disease (CVD) by treating 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 with weight reduction and exercise alone is not yet well supported by clinical trials [92,93]. (See "Metformin in the treatment of adults with type 2 diabetes mellitus" and "Thiazolidinediones in the treatment of type 2 diabetes mellitus" and "Prevention of type 2 diabetes mellitus" and 'Prevention of type 2 diabetes' below.)
Lifestyle modification — Aggressive lifestyle modification focused on weight reduction and increased physical activity is the primary therapy for the management of metabolic syndrome [94-96]. 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 [97]. In this observational study of 5115 young adults (ages 18 to 30 years), increasing body mass index (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 [98,99].
Diet — Several dietary approaches have been advocated for treatment of metabolic syndrome. Most patients with metabolic syndrome are overweight, and weight reduction, which improves insulin sensitivity, is an important outcome goal of any diet (see "Obesity in adults: Overview of management" and "Alpha-glucosidase inhibitors for treatment of diabetes mellitus"). The following specific diet approaches have been recommended:
●The Mediterranean diet may be beneficial [100-103]. 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 dysfunction [100]. (See "Dietary fat" and "Coronary endothelial dysfunction: Clinical aspects".)
●The Dietary Approaches to Stop Hypertension (DASH) diet (daily sodium intake limited to 2400 mg, and higher in dairy intake than the Mediterranean diet), compared with 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 [104].
●Foods with low glycemic index may improve glycemia and dyslipidemia [105]. A diet that is low in glycemic index/glycemic load, replacing refined grains with whole grains, fruits, and vegetables, and eliminating high-glycemic beverages, may be particularly beneficial for patients with 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 [106].
●A high-fiber diet (≥30 g/day) resulted in similar weight loss as compared with 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) [107]. In this trial, 240 patients with metabolic syndrome (mean BMI 35 kg/m2) were randomly assigned to one of the diets. After 12 months, weight loss occurred in both treatment groups (-2.1 versus -2.7 kg, respectively), and there were similar improvements in diastolic and systolic blood pressure.
Exercise — Exercise may be beneficial beyond its effect on weight loss by more selectively removing abdominal fat, at least in females [108]. Physical activity guidelines recommend practical, regular, and moderate regimens for exercise. 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 to further enhance the beneficial effect [109]. (See "Obesity in adults: Role of physical activity and exercise" and "Exercise and fitness in the prevention of atherosclerotic cardiovascular disease".)
Removal of abdominal adipose tissue with liposuction does not improve insulin sensitivity or risk factors for coronary heart disease (CHD), suggesting that the negative energy balance induced by diet and exercise are necessary for achieving the metabolic benefits of weight loss [110]. (See "Obesity in adults: Overview of management", section on 'Liposuction'.)
Prevention of type 2 diabetes — Although not strictly addressing 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 "Prevention of type 2 diabetes mellitus", section on 'Our approach'.)
In the Diabetes Prevention Program (DPP), 3234 subjects with obesity and impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) were randomly assigned to one of the following groups [93]:
●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). Metabolic syndrome (using ATP III criteria) was present in 53 percent of DPP participants at baseline [111]. In the remaining subjects (n = 1523), both intensive lifestyle intervention and metformin therapy reduced the risk of developing metabolic syndrome (three-year 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 "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 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 with 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) [93]. Both intensive lifestyle intervention and metformin therapy were effective for prevention of metabolic syndrome in patients who did not have the syndrome at baseline [111].
●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, myocardial infarction (MI), angina, heart failure, stroke, renal failure, amputation, retinopathy, monocular blindness or cataract extraction) and all-cause mortality compared with conventional therapy with diet [112].
There are no data on glycemic control goals in patients with metabolic syndrome who are not diabetic. Recommendations are to treat IFG and IGT with weight loss of approximately 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 "Prevention of type 2 diabetes mellitus", section on 'Metformin'). In addition, when patients cross the diabetic diagnostic threshold, immediate therapy with metformin is recommended [113]. (See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus".)
Cardiovascular risk reduction — Reversal of the metabolic syndrome may be associated with a reduction in the risk of cardiovascular disease. As an example, in a retrospective cohort study including over nine million Korean adults followed for 3.5 years, reversal of metabolic syndrome was associated with a reduction in the risk of developing a major cardiovascular event (rate ratio [RR] 0.85, 95% CI 0.83-0.87) [114]. Among the individual metabolic syndrome criteria, recovery from hypertension was most strongly associated with a reduction in cardiovascular risk.
Guidelines recommend reduction of component CVD risk factors that comprise metabolic syndrome including treatment of hypertension, improved glycemic control in patients with diabetes, and lowering of serum cholesterol [115,116].
Lipid lowering — ATP III recommended a goal serum low-density lipoprotein (LDL) cholesterol of less than 100 mg/dL (2.6 mmol/L) for secondary prevention in patients with type 2 diabetes [20], 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 "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease", section on 'Summary and recommendations'.)
Evidence does not support metabolic syndrome as a coronary risk equivalent in terms of goals for lipid management [117]. However, 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 [118,119]. Treatment of patients with known coronary disease and metabolic syndrome with atorvastatin 80 mg, compared with atorvastatin 10 mg, decreased the rate of major cardiovascular events at five years (9.5 versus 13 percent, hazard ratio [HR] 0.71, 95% CI 0.61-0.84) [120].
Antihypertensive therapy — There are conflicting data on whether angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) used to treat hypertension in type 2 diabetes may also help to reduce insulin resistance. (See "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".)
The value of ACE inhibitors and ARBs in hypertensive patients with metabolic syndrome who do not have CVD or diabetes is not known. (See "Choice of drug therapy in primary (essential) hypertension".)
CHILDREN AND ADOLESCENTS
Definition — Metabolic syndrome also occurs in children and adolescents but there is no consensus on the definition (table 4) [121-125]. 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 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 high-density lipoprotein (HDL) rather than a sex-specific cutoff [125,126]. 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 [127-130]. 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 [131]. 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 [128,132]. 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 [128].
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 American population may be the 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) [133].
Among children with obesity, the prevalence of metabolic syndrome is high and increases with worsening obesity [122,123]. 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 [122]. 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) [134]. 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 [128,135]. 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) [136]. 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 'Promotion of 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 [22,137-139].
The critical weakness of 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 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
●Metabolic syndrome is defined as the co-occurrence of metabolic risk factors for both type 2 diabetes and cardiovascular disease (CVD) (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.)
●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 "Prevention of type 2 diabetes mellitus", section on 'Our approach'.)
●Reduction of risk factors for CVD includes treatment of hypertension, glycemic control in patients with diabetes, and lowering of serum cholesterol according to recommended guidelines. (See "Goal blood pressure in adults with hypertension" and "Treatment of hypertension in patients with diabetes mellitus" and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease", section on 'Summary and recommendations'.)
●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. The critical weakness of 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.)
