the metabolic syndrome (insulin resistance syndrome or syndrome x)
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AuthorJames B Meigs, MD, MPH
Section EditorsDavid M Nathan, MDJoseph I Wolfsdorf, MB, BCh
Deputy EditorJean E Mulder, MD
The metabolic syndrome (insulin resistance syndrome or syndrome X)
All topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Aug 2012. | This topic last updated: Oct 6, 2011.
INTRODUCTION — Obesity, particularly abdominal obesity, is associated with resistance to the effects of insulin onperipheral glucose and fatty acid utilization, often leading to type 2 diabetes mellitus. Insulin resistance, theassociated hyperinsulinemia and hyperglycemia, and adipocyte cytokines (adipokines) may also lead to vascularendothelial dysfunction, an abnormal lipid profile, hypertension, and vascular inflammation, all of which promote thedevelopment of atherosclerotic cardiovascular disease (CVD) [1-4]. A similar profile can be seen in individuals withabdominal 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 tothis constellation of findings have included syndrome X, the insulin resistance syndrome, the deadly quartet, or theobesity dyslipidemia syndrome . Genetic predisposition, lack of exercise, and body fat distribution all affect thelikelihood that a given obese subject will become overtly diabetic or develop CVD.
It should be noted that questions have been raised as to whether the metabolic syndrome, as currently defined,captures any unique pathophysiology implied by calling it a "syndrome," and whether metabolic syndrome confersrisk beyond its individual components. These questions raise uncertainty about the value of diagnosing metabolicsyndrome in individual patients [13,14]. These arguments will be reviewed at the end of this discussion (see 'Acritical look at the metabolic syndrome' below). Regardless of whether the metabolic syndrome is considered aunique entity, the need is unquestioned to identify and manage its individual components to decrease morbidity andmortality associated with diabetes and cardiovascular disease [15,16].
The definition, prevalence, clinical implications, and therapy of the metabolic syndrome will be reviewed here,including the limited data in children and adolescents. The pathogenesis of the relationship between obesity and type2 diabetes and other causes of insulin resistance are discussed separately. (See "Pathogenesis of type 2 diabetesmellitus", section on 'Role of diet, obesity, and inflammation' and "Insulin resistance: Definition and clinicalspectrum".)
The metabolic syndrome should not be confused with another disorder called syndrome X in which angina pectorisoccurs in patients with normal coronary arteries. (See "Cardiac syndrome X: Angina pectoris with normal coronaryarteries".)
DEFINITION — Because metabolic syndrome traits co-occur, patients identified with one or just a few traits are likelyto have other traits, as well as insulin resistance . Whether it is valuable to assess insulin resistance in addition tomore readily measured traits of the syndrome is uncertain.
There are several definitions for the metabolic syndrome, leading to some difficulty in comparing data from studiesusing different criteria (table 1) [18-24]. The National Cholesterol Education Program (NCEP/ATP III) andInternational Diabetes Federation (IDF) definitions are the most widely used.
2001 National Cholesterol Education Program/ATP III — Guidelines developed by the 2001 National CholesterolEducation Program (Adult Treatment Panel [ATP] III) focused explicitly on the risk of cardiovascular disease and didnot require evidence of insulin or glucose abnormalities, although abnormal glycemia is one of the criteria . ATPIII metabolic syndrome criteria were updated in 2005 in a statement from the American Heart Association(AHA)/National Heart, Lung, and Blood Institute (NHLBI) [22,23]. Updates include the following:
Lowering the threshold for abnormal fasting glucose to 100 mg/dL, corresponding to the ADA criteria forimpaired fasting glucose (see "Diagnosis of diabetes mellitus")
Explicitly including diabetes in the hyperglycemia trait definition
Explicitly including use of drugs for lipid control or blood pressure control in the dyslipidemia and hypertensiontrait definitions, respectively
Current ATP III criteria define the metabolic syndrome as the presence of any three of the following five traits:
Abdominal obesity, defined as a waist circumference in men ≥102 cm (40 in) and in women ≥88 cm (35 in)
Serum triglycerides ≥150 mg/dL (1.7 mmol/L) or drug treatment for elevated triglycerides
Serum HDL cholesterol <40 mg/dL (1 mmol/L) in men and <50 mg/dL (1.3 mmol/L) in women or drugtreatment for low HDL-C
Blood pressure ≥130/85 mmHg or drug treatment for elevated blood pressure
Fasting plasma glucose (FPG) ≥100 mg/dL (5.6 mmol/L) or drug treatment for elevated blood glucose
International Diabetes Federation — The International Diabetes Federation (IDF) updated their metabolicsyndrome criteria in 2006 . Central obesity is an essential element in this definition, with different waistcircumference thresholds set for different race/ethnicity groups:
Increased waist circumference, with ethnic-specific waist circumference cut-points (table 2)
PLUS any two of the following:
Triglycerides >150 mg/dL (1.7 mmol/L) or treatment for elevated triglycerides
HDL cholesterol <40 mg/dL (1.03 mmol/L) in men or <50 mg/dL (1.29 mmol/L) in women, or treatment for lowHDL
Systolic blood pressure >130, diastolic blood pressure >85, or treatment for hypertension
Fasting plasma glucose >100 mg/dL (5.6 mmol/L) or previously diagnosed type 2 diabetes; an oral glucosetolerance test is recommended for patients with an elevated fasting plasma glucose, but not required
Comparing criteria in defining populations — Using data from the National Health and Nutrition ExaminationSurvey 1999 to 2002 database, 39 percent of US adult participants met IDF criteria for the metabolic syndrome,compared to 34.5 percent using the ATP III criteria . The two definitions overlapped for 93 percent of subjects indetermining presence or absence of the metabolic syndrome. When applied to an urban population in the US, theIDF criteria categorized 15 to 20 percent more adults with the metabolic syndrome than the ATP III criteria .
The relative value of different metabolic syndrome definitions in terms of prognosis and management appears to besimilar [28-30]. As examples:
In a prospective cohort study of a random sample of British women (n = 3589) aged 60 to 79 years, who werefree of coronary heart disease (CHD) at baseline, all three definitions of the metabolic syndrome weremodestly and similarly associated with CHD risk . The age-adjusted hazard ratios for IDF, WHO, andNCEP syndromes were 1.32 (95% CI 1.03-1.70), 1.45 (1.00-2.10), and 1.38 (1.00-1.93), respectively.
Similarly, when data from the Framingham population are examined using ATPIII, IDF, and EGIR definitionsof the metabolic syndrome, roughly equivalent associations for incident type 2 diabetes (HR 3.5, 95% CI 2.2to 5.6; 4.6, 2.7 to 7.7; 3.3, 2.1 to 5.1, respectively) and for CVD (1.8, 1.4 to 2.3; 1.7, 1.3 to 2.3; 2.1, 1.6 to 2.7,respectively) are observed . Thus, risk factor clustering defines increased risk for type 2 diabetes andCVD.
The WHO, ATP III, and IDF definitions include type 2 diabetes as syndrome traits. Experts do not all agree that type2 diabetes should be part of the definition, as the importance of the syndrome is that it identifies patients at increasedrisk for the development of diabetes. Most patients with type 2 diabetes have features of the metabolic syndrome, inwhich it identifies those at greater risk of macrovascular but not microvascular complications . Management ofpatients with type 2 diabetes should follow clinical guidelines, whether or not they also meet criteria for metabolicsyndrome. (See "Overview of medical care in adults with diabetes mellitus".)
Potential other markers — The metabolic syndrome has been recognized as a proinflammatory, prothromboticstate, associated with elevated levels of C-reactive protein, interleukin (IL)-6, and plasminogen activator inhibitor(PAI)-1 [4,25,32-38]. Inflammatory and prothrombotic markers are associated with an increased risk for subsequentCVD and type 2 diabetes [34-37], although adipokines and inflammatory markers explained only a small part of theassociation between the metabolic syndrome and CHD mortality in one study . Additionally, a causal associationbetween elevated CRP and the metabolic syndrome was not demonstrated in a study of phenotype patternsassociated with the metabolic syndrome and CRP levels .
The value of measurement or treatment of inflammatory or vascular function markers in the setting of metabolicsyndrome is unknown. Use of these markers should be considered for clinical purposes only in the setting of CVDrisk assessment and reduction. (See "C-reactive protein in cardiovascular disease" and "Screening forcardiovascular risk with C-reactive protein".) AHA/CDC guidelines emphasize that CRP testing still belongs in thecategory of optional, based on clinical judgment rather than recommended routinely because the magnitude of itsindependent predictive power remains uncertain .
PREVALENCE AND RISK FACTORS — The prevalence of the metabolic syndrome, as defined by the 2001 ATP IIIcriteria, was evaluated in 8814 adults in the United States participating in the third National Health and NutritionExamination Survey (NHANES III, 1988 to 1994) . 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).Mexican-Americans had the highest age-adjusted prevalence (31.9 percent). Among African-Americans andMexican-Americans, the prevalence was higher in women than in men (57 and 26 percent higher, respectively)(figure 2). Data from NHANES 1999 to 2000 demonstrate that the prevalence has continued to increase, particularlyin women .
The metabolic syndrome is becoming increasingly common. Using data from the National Health and NutritionExamination Survey 1999 to 2002 database, 34.5 percent of participants met ATP III criteria for the metabolicsyndrome compared with 22 percent in NHANES III (1988 to 1994) [26,42]. In addition, metabolic syndrome, definedby the 2005 revised ATP III criteria, was assessed in 3323 Framingham Heart Study participants, ages 22 to 81, whodid not have diabetes or cardiovascular disease at a baseline examination in the early 1990s . At baseline, theprevalence of the metabolic syndrome was 26.8 percent in men and 16.6 percent in women. After eight years offollow-up, there was an age-adjusted 56 percent increase in prevalence among men and a 47 percent increaseamong women.
Increased weight — Increased body weight is a major risk factor for the metabolic syndrome. In NHANES III, themetabolic syndrome was present in 5 percent of those at normal weight, 22 percent of those who were overweight,and 60 percent of those who were obese . (See "Screening for and clinical evaluation of obesity in adults".)
In the Framingham Heart Study cohort, an increase in weight of 2.25 kg or more over 16 years was associated with a21 to 45 percent increase in the risk for developing the syndrome . A large waist circumference alone identifiesup to 46 percent of individuals who will develop the metabolic syndrome within five years .
The rapidly increasing prevalence of obesity among adults in the United States is likely to lead to even higher ratesof the metabolic syndrome in the near future , highlighting the importance of obesity prevention and improvingphysical activity levels [49,50]. (See "Etiology and natural history of obesity" and "Health hazards associated withobesity in adults".)
Other factors — In addition to age, race, and weight, other factors associated with an increased risk of metabolicsyndrome in NHANES III included postmenopausal status, smoking, low household income, high carbohydrate diet,no alcohol consumption, and physical inactivity . In the Framingham Heart Study, soft drink consumption wasalso associated with an increased risk of developing adverse metabolic traits and the metabolic syndrome . Use
of atypical antipsychotic medications, especially clozapine, significantly increases risk for the metabolic syndrome. In addition, poor cardiorespiratory fitness is an independent and strong predictor of metabolic syndrome in bothmen and women . (See "Exercise and fitness in the prevention of cardiovascular disease".)
A parental history of metabolic syndrome increases risk, and genetic factors may account for as much as 50 percentof the variation in levels of metabolic syndrome traits in the offspring [54-57].
CLINICAL IMPLICATIONS — The metabolic syndrome is an important risk factor for subsequent development oftype 2 diabetes and/or CVD. Thus, the key clinical implication of a diagnosis of metabolic syndrome is identificationof a patient who needs aggressive lifestyle modification focused on weight reduction and increased physical activity(table 3) [11,49,58].
Identification of patients at high metabolic risk — Health care providers should assess individuals for metabolicrisk at routine clinic visits. The Endocrine Society clinical guidelines suggest evaluation at three-year intervals inindividuals with one or more risk factors . The assessment should include measurement of blood pressure, waistcircumference, fasting lipid profile, and fasting glucose.
In patients identified as having the metabolic syndrome (table 1), aggressive lifestyle intervention (weight reduction,physical activity) is warranted to reduce the risks of type 2 diabetes and cardiovascular disease. Assessment of 10-year risk for cardiovascular disease, using a risk assessment algorithm, such as the Framingham Risk Score orSCORE, is useful in targeting individuals for medical intervention to lower blood pressure and cholesterol. (See"Estimation of cardiovascular risk in an individual patient without known cardiovascular disease", section on'Multivariate risk models' and "Estimation of cardiovascular risk in an individual patient without known cardiovasculardisease", section on 'Clinical use of risk assessment'.)
Risk of type 2 diabetes — Prospective observational studies demonstrate a strong association between themetabolic syndrome and the risk for subsequent development of type 2 diabetes [60-64]. In a meta-analysis of 16multi-ethnic cohort studies, the relative risk of developing diabetes ranged from 3.53 to 5.17, depending upon thedefinition of metabolic syndrome and the population studied . As an example, in an analysis of 890 nondiabeticPima Indians, 144 developed diabetes over four years of follow-up . The metabolic syndrome increased therelative risk (RR) for incident diabetes by 2.1-fold with the ATP III definition and 3.6-fold using the WHO definition.This difference highlights the importance of insulin resistance (a required characteristic of the WHO definition) in thepathogenesis of type 2 diabetes.
In several cohorts, the risk of diabetes increased with increasing number of components of the metabolic syndrome[44,58,62]. While the metabolic syndrome predicts increased risk for diabetes, it is not clear whether this addsadditional important information [65,66]. In a prospective cohort study of 5842 Australian adults, metabolic syndrome(defined by WHO, ATP III, EGIR, or IDF) was not superior to fasting plasma glucose or a published diabetesprediction model (including age, gender, ethnicity, fasting plasma glucose, systolic blood pressure, HDL cholesterol,BMI, and family history) in identifying individuals who developed diabetes . (See 'A critical look at the metabolicsyndrome' below.)
Risk of CVD — Three meta-analyses, which included many of the same studies, found that the metabolic syndromeincreases the risk for incident cardiovascular disease (CVD) (RRs ranging from 1.53 to 2.18) and all cause mortality(RRs 1.27 to 1.60) [68-70].
The increased risk appears to be related to the risk factor clustering or insulin resistance associated with themetabolic syndrome rather than simply to obesity. This was illustrated by the following studies:
In a study of the Framingham population, obese people without metabolic syndrome did not have asignificantly increased risk of diabetes or CVD . Obese people with the metabolic syndrome had a 10-foldincreased risk for diabetes and a twofold increased risk for CVD relative to normal weight people without themetabolic syndrome. Normal weight people meeting revised 2005 ATP III criteria for the metabolic syndromehad a fourfold increased risk for diabetes and a threefold increased risk for CVD.
In a study of 211 moderately obese (BMI 30 to 35) men and women, insulin sensitivity varied sixfold, andthose with the greatest degree of insulin resistance had the highest blood pressure, triglycerideconcentrations, fasting and two-hour post oral glucose blood sugar levels, and the lowest HDL concentrations,
despite equal levels of obesity .
Thus, not all moderately obese individuals have the same risk for developing cardiovascular disease or diabetes;risks differ as a function of insulin sensitivity, with insulin-resistant, obese individuals at highest risk.
The risk also may be related to underlying subclinical CVD (as measured by ECG, echocardiography, carotidultrasound, and ankle-brachial blood pressure) in individuals with metabolic syndrome . In the FraminghamOffspring study, 51 percent of 581 participants with metabolic syndrome had subclinical CVD, and the risk of overtCVD in these individuals was greater than in individuals with metabolic syndrome without subclinical CVD (HR 2.67versus 1.59). Subclinical CVD was also predictive of overt CVD in subjects without metabolic syndrome (HR 1.93,95% CI 1.15-3.24).
While the metabolic syndrome predicts increased risk for CVD, it is not clear whether this adds additional importantinformation [66,68,74]. As examples:
Elevated triglyceride and low HDL cholesterol levels were as strong of a predictor of vascular events as thepresence of metabolic syndrome (by ATP III criteria) in a prospective study of a population of patients withangiographically-determined coronary artery disease .
The Framingham Risk Score was a better predictor of CHD and stroke than metabolic syndrome (ATP IIIcriteria with obesity defined by an elevated BMI rather than waist circumference) in a prospective study of5128 British men aged 40 to 59 years followed for 20 years .
Low HDL cholesterol and high blood pressure were better predictors of CHD than the metabolic syndrome ina prospective study of 2737 men from the same cohort .
Other associations — The metabolic syndrome has also been associated with several obesity-related disordersincluding:
Fatty liver disease with steatosis, fibrosis, and cirrhosis [77-79]. (See "Epidemiology, clinical features, anddiagnosis of nonalcoholic steatohepatitis".)
Hepatocellular and intrahepatic cholangiocarcinoma. (See "Epidemiology and etiologic associations ofhepatocellular carcinoma", section on 'Diabetes mellitus' and "Epidemiology, pathogenesis, and classificationof cholangiocarcinoma", section on 'Metabolic syndrome'.)
Chronic kidney disease (CKD; defined as a glomerular filtration rate less than 60 mL/min per 1.73 m2) andmicroalbuminuria [80,81]. In a report from NHANES III, the metabolic syndrome in multivariate analysissignificantly increased the risk of both chronic kidney disease and microalbuminuria (adjusted odds ratio 2.6and 1.9, respectively) . The risk of both complications increased with the number of components of themetabolic syndrome. In a prospective cohort study, 10 percent of individuals with the metabolic syndrome atbaseline subsequently developed CKD compared with 6 percent among those without the metabolicsyndrome .
Polycystic ovary syndrome . (See "Clinical manifestations of polycystic ovary syndrome in adults".)
Sleep-disordered breathing, including obstructive sleep apnea [84,85]. (See "Overview of obstructive sleepapnea in adults".)
Hyperuricemia and gout [86,87]. (See "Asymptomatic hyperuricemia", section on 'Potential consequences ofhyperuricemia'.)
Several components of the metabolic syndrome, including hyperlipidemia, hypertension, and diabetes have beenassociated with an increased risk of cognitive decline and dementia. The metabolic syndrome (when associated witha high level of inflammation) may also be associated with cognitive decline in the elderly. (See "Risk factors fordementia".)
THERAPY — In 2001, ATP III recommended two major therapeutic goals in patients with the metabolic syndrome
. These goals were reinforced by a report from the American Heart Association and the National Institutes ofHealth (table 3) and by clinical guidelines from The Endocrine Society [23,58,59]:
Treat underlying causes (overweight/obesity and physical inactivity) by intensifying weight management andincreasing physical activity.
Treat cardiovascular risk factors if they persist despite lifestyle modification.
There is no direct evidence that attempting to prevent type 2 diabetes and CVD by treating the metabolic syndromeis as effective as attaining the above goals. It is possible to treat insulin resistance with drugs that enhance insulinaction (eg, thiazolidinediones and metformin). However, the ability of such an approach to improve outcomescompared to weight reduction and exercise alone is not yet well supported by clinical trials [88,89]. (See "Metforminin the treatment of diabetes mellitus" and "Thiazolidinediones in the treatment of diabetes mellitus" and "Predictionand prevention of type 2 diabetes mellitus" and 'Prevention of type 2 diabetes' below.)
Lifestyle modification — Prevention or reduction of obesity, particularly abdominal obesity, is the main therapeuticgoal in patients with the metabolic syndrome [49,90]. The importance of weight management in preventingprogression of metabolic syndrome components is illustrated by The Coronary Artery Risk Development in YoungAdults (CARDIA) study . In this observational study of 5115 young adults (ages 18 to 30 years), increasing BMIover 15 years was associated with adverse progression of metabolic syndrome components compared with youngadults 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 possiblepharmacologic therapy, as with orlistat [92,93].
Diet — Several dietary approaches have been advocated for treatment of the metabolic syndrome. Most patientswith the metabolic syndrome are overweight, and weight reduction, which improves insulin sensitivity, is an importantoutcome goal of any diet. (See "Overview of therapy for obesity in adults" and "Alpha-glucosidase inhibitors andlipase inhibitors for treatment of diabetes mellitus".) The following specific diet approaches have been recommended:
The Mediterranean diet may be beneficial [94-97]. In a study comparing the Mediterranean diet (high in fruits,vegetables, nuts, whole grains, and olive oil) with a low-fat prudent diet, subjects in the Mediterranean dietgroup had greater weight loss, lower blood pressure, improved lipid profiles, improved insulin resistance, andlower levels of markers of inflammation and endothelial function . (See "Dietary fat" and "Endothelialdysfunction".)
The DASH diet (daily sodium intake limited to 2400 mg, and higher in dairy intake than the Mediterraneandiet), compared to a weight reducing diet emphasizing healthy food choices, resulted in greater improvementsin triglycerides, diastolic blood pressure, and fasting glucose, even after controlling for weight loss .
Foods with low glycemic index may improve glycemia and dyslipidemia . A diet that is low in glycemicindex/glycemic load, replacing refined grains with whole grains, fruits and vegetables, and eliminating high-glycemic beverages, may be particularly beneficial for patients with the metabolic syndrome. The impact ofthe glycemic index itself versus the increase in high fiber foods that accompanies a lower glycemic index dietis uncertain . (See "Dietary carbohydrates".)
Exercise — Exercise may be beneficial beyond its effect on weight loss by more selectively removing abdominalfat, at least in women . Current physical activity guidelines recommend practical, regular, and moderateregimens 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 enhancethe beneficial effect . (See "Role of physical activity and exercise in obesity" and "Exercise and fitness in theprevention of cardiovascular disease".)
Removal of abdominal adipose tissue with liposuction does not improve insulin sensitivity or risk factors for coronaryheart disease, suggesting that the negative energy balance induced by diet and exercise are necessary for achievingthe metabolic benefits of weight loss . (See "Overview of therapy for obesity in adults", section on 'Liposuction'.)
Prevention of type 2 diabetes — Although not strictly addressing the metabolic syndrome, clinical trials have
shown that lifestyle modifications can substantially reduce the risk of development of type 2 diabetes and the levelsof risk factors for CVD in patients at increased risk. Prevention of type 2 diabetes is discussed in detail elsewhere.(See "Prediction and prevention of type 2 diabetes mellitus", section on 'Prevention'.)
In the Diabetes Prevention Program (DPP), 3234 obese subjects with impaired fasting glucose or impaired glucosetolerance were randomly assigned to one of the following groups :
Intensive lifestyle changes with the aim of reducing weight by 7 percent through a low-fat diet and exercise for150 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 versus22 and 29 percent in the metformin and placebo groups, respectively). The metabolic syndrome (using ATP IIIcriteria) was present in 53 percent of DPP participants at baseline . In the remaining subjects (n = 1523), bothintensive lifestyle intervention and metformin therapy reduced the risk of developing the 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 enhancinginsulin sensitivity. The role of these agents in patients with metabolic syndrome, to prevent diabetes, has not beendefinitively established, and furthermore, rosiglitazone has been removed from the market. (See "Prediction andprevention 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. Inthe Diabetes Prevention Program (DPP) trial described above, metformin therapy plus instructions on diet andexercise was associated with a 31 percent reduction in the risk of developing diabetes compared to placebo(at three years, diabetes developed in 22 versus 29 percent); however, metformin was less effective thanintensive lifestyle modification (diabetes developed in 22 versus 14 percent) . Both intensive lifestyleintervention and metformin therapy were effective for prevention of the metabolic syndrome in patients whodid not have the syndrome at baseline .
Metformin may reduce the incidence of diabetes-related end points. In a subgroup analysis from the UnitedKingdom Prospective Diabetes Study (UKPDS), metformin was associated with significant reductions in anydiabetes-related end point (sudden death, hypo- or hyperglycemia causing death, MI, angina, heart failure,stroke, renal failure, amputation, retinopathy, monocular blindness or cataract extraction) and all causemortality compared to conventional therapy with diet .
There are no data on glycemic control goals in patients with the metabolic syndrome who are not diabetic. Currentrecommendations are to treat impaired fasting glucose and impaired glucose tolerance with weight loss of about 5 to10 percent of the baseline weight; at least 30 minutes per day of moderately intense physical activity; and dietarytherapy 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 beconsidered in certain individuals with both IFG and IGT. (See "Prediction and prevention of type 2 diabetes mellitus",section on 'Metformin'.) In addition, when patients cross the diabetic diagnostic threshold, immediate therapy withmetformin is recommended . (See "Initial management of blood glucose in type 2 diabetes mellitus".)
Cardiovascular risk reduction — Reduction of risk factors for cardiovascular disease includes treatment ofhypertension, cessation of smoking, glycemic control in patients with diabetes, and lowering of serum cholesterolaccording to recommended guidelines [107,108].
Lipid-lowering — ATP III recommended a goal serum LDL cholesterol of less than 100 mg/dL (2.6 mmol/L) forsecondary prevention in patients with type 2 diabetes , and subsequent studies have suggested a moreaggressive goal of less than 80 mg/dL (2.1 mmol/L) with a regimen that includes administration of a statin. (See
"Intensity of lipid lowering therapy in secondary prevention of coronary heart disease", section on 'Summary andrecommendations'.)
Current evidence does not support the metabolic syndrome as a coronary risk equivalent in terms of goals for lipidmanagement . However, among patients with elevated serum LDL-cholesterol and established coronarydisease in the 4S trial of lipid lowering with simvastatin, those with characteristics of the metabolic syndrome (lowestquartile for HDL cholesterol and highest quartile for triglycerides) had both the highest risk of major coronary eventsand the greatest benefit (48 percent risk reduction) from statin therapy [110,111]. Treatment of patients with knowncoronary disease and the metabolic syndrome with atorvastatin 80 mg, compared to atorvastatin 10 mg, decreasedthe rate of major cardiovascular events at five years (9.5 versus 13 percent, HR 0.71, 95% CI 0.61-0.84) .
Antihypertensive therapy — There are conflicting data on whether angiotensin converting enzyme (ACE)inhibitors or angiotensin II receptor blockers (ARB) used to treat hypertension in type 2 diabetes may also help toreduce insulin resistance. (See "Prediction and prevention of type 2 diabetes mellitus".)
Hypertension control is important in patients with diabetes mellitus. The goal blood pressure may be somewhat lowerthan 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 agoal. (See "Treatment of hypertension in patients with diabetes mellitus", section on 'Goal blood pressure'.)
The value of ACE inhibitors and ARBs in hypertensive patients with the metabolic syndrome who do not have CVDor diabetes is not known. (See "Choice of therapy in essential hypertension: Recommendations".)
CHILDREN AND ADOLESCENTS
Definition — The metabolic syndrome also occurs in children and adolescents but there is no consensus on thedefinition (table 4) [113-117]. As in adults, this lack of consensus makes it difficult to compare studies that usedifferent diagnostic criteria and leaves the clinician without any clear parameters for assessing the long-term clinicalimplications of the metabolic syndrome in children or for tracking the effectiveness of lifestyle interventions. (See'Clinical implications' above.)
The International Diabetes Federation (IDF) definition of metabolic syndrome in children 10 to 16 years old is similarto that used by the IDF for adults, except that the definition for adolescents uses ethnic-specific waist circumferencepercentiles and one cutoff level for HDL rather than a sex-specific cutoff [117,118]. For children 16 years and older,the adult criteria can be used. For children younger than 10 years of age, metabolic syndrome cannot be diagnosed,but vigilance is recommended if the waist circumference is ≥90 percentile.
Prevalence and risk factors — When clinically applied, these pediatric definitions result in varying prevalence rates[119-122]. The US prevalence of metabolic syndrome (defined by the modified ATP III criteria) is estimated to beabout 9 percent based upon a NHANES III survey of 1960 children >12 years of age . However, pubertal growthand development is characterized by changes in metabolic traits that characterize the syndrome, resulting insignificant individual variability in the categorical diagnosis. In one study of 1098 adolescents, as many as half of theadolescents initially classified as having metabolic syndrome lost the diagnosis during the three-year observationperiod, while others acquired the diagnosis .
The racial and ethnic distribution of metabolic syndrome is similar to that seen in adults, with the highest prevalencein Mexican-Americans, followed by non-Hispanic whites, and non-Hispanic blacks (12.9, 10.9, and 2.9 percent,respectively). Native Americans may be the ethnic group at greatest risk for metabolic syndrome as illustrated by apopulation-based study of Canadian Native (Oji-Cree) children and adolescents (10 to 19 years) that reported a 19percent prevalence rate (defined by ATP III criteria) .
Among obese children, the prevalence of the metabolic syndrome is high and increases with worsening obesity[114,115]. This was illustrated in a study of 439 obese, 31 overweight, and 20 normal-weight children andadolescents who underwent a comprehensive metabolic assessment . The metabolic syndrome was present in39 and 50 percent of the moderately and severely obese subjects, respectively. In contrast, no overweight or normal-weight children met the criteria for the metabolic syndrome.
Risk factors in childhood that could predict emergence of metabolic syndrome were identified in a longitudinal studyof a cohort from the National Heart, Lung, and Blood Institute Growth and Health Study (NGHS) . Girls aged 9
and 10 years (n = 1192) were followed for 10 years. Metabolic syndrome (defined by ATP III criteria) was present in0.2 percent at baseline and in 3.5 percent of black and 2.4 percent of white girls at ages 18 and 19. Waistcircumference and serum triglycerides at baseline were predictive of subsequent metabolic syndrome. For everyincrease of 1 cm in waist circumference at year two, the risk of developing metabolic syndrome increased by 7.4percent; for every increase of 1 mg/dL in triglyceride level at baseline, the risk of metabolic syndrome increased 1.3percent. Race was not a significant independent factor in this study.
In summary, the prevalence of the metabolic syndrome is high among obese children and adolescents and increaseswith the severity of the obesity, and with central adiposity in particular. However, there is instability in the diagnosis ofmetabolic syndrome during pubertal development, making prevalence estimates less reliable [120,126]. Consistencyin the clinical diagnosis is required to better define the natural history of the syndrome in children and adolescentsand to assess the long-term clinical implications.
Clinical implications — There are few longitudinal studies in children and adolescents with metabolic syndrome. Incontrast to the data from adults, therefore, long-term cardiovascular and diabetes risks are not well defined. In onecohort study of 771 adults (mean age 38) who had participated in the Lipid Research Clinics study as children andadolescents 22 to 31 years previously, the incidence of self-reported CVD was more common in adults who exhibitedmetabolic syndrome traits as children than in those who did not (19.4 versus 1.5 percent, odds ratio 14.6, 95% CI4.8-45.3) . Of 31 children who had metabolic syndrome traits in the initial study, 21 (68 percent) had adultmetabolic syndrome. Increasing BMI was strongly associated with risk of adult metabolic syndrome.
Thus, the definition of metabolic syndrome may be clinically useful for risk stratification and therapeutic interventionin pediatrics. However, lifestyle modification that emphasizes reduction of established risk factors, such as promotionof exercise, weight loss, and smoking cessation, is the main therapeutic goal in obese children and adolescents,regardless of a metabolic syndrome diagnosis. (See 'Lifestyle modification' above.)
A CRITICAL LOOK AT THE METABOLIC SYNDROME — The American Diabetes Association and the EuropeanAssociation for the Study of Diabetes published a joint statement raising questions about whether the components ofthe metabolic syndrome, as defined above, warrant classification as a true "syndrome" . The arguments raisedinclude:
Lack of clarity of definition, with criteria differing between the ATP, WHO, and other definitions; manypublished studies use further modifications to classify subjects with the metabolic syndrome.
Multiple different phenotypes included within the metabolic syndrome, with indications for differing treatmentstrategies. As an example, a patient with a large waist circumference, high triglycerides, and high fastingglucose would need to be managed differently than a patient with high blood pressure, low HDL, and hightriglycerides.
Lack of a consistent evidence-base for setting the thresholds for the various components in the definitions.
Inclusion of patients with clinical CVD or diabetes as part of the syndrome which is intended to define risk forthese diseases.
Unclear pathogenesis uniting the components of the syndrome; insulin resistance may not underlie all factors,and is not a consistent finding in some definitions.
Other risk factors for CVD that are not components of the metabolic syndrome, such as inflammatory markers,may have equal or greater bearing on risk.
The CVD risk associated with the metabolic syndrome has not been shown to be greater than the sum of itsindividual components [23,128,129].
The critical weakness of the current metabolic syndrome construct is that treatment of the syndrome is no differentthan treatment for each of its components. Virtually all agree clustering of risk factors for diabetes and cardiovasculardisease is a real phenomenon. All agree that the presence of one component of the metabolic syndrome should leadto evaluation for other risk factors. Whether patient benefit is gained from diagnosing patients with a syndrome ofsuch uncertain characteristics or predictive value remains an open question. The advice remains to treat individual
risk factors when present and to prescribe therapeutic lifestyle changes and weight management for obese patientswith multiple risk factors.
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“Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th gradereading level, and they answer the four or five key questions a patient might have about a given condition. Thesearticles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond theBasics 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 withsome medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail thesetopics to your patients. (You can also locate patient education articles on a variety of subjects by searching on“patient info” and the keyword(s) of interest.)
Basics topic (see "Patient information: Metabolic syndrome (The Basics)")
Beyond the Basics topic (see "Patient information: The metabolic syndrome (Beyond the Basics)")
The metabolic syndrome is defined as the co-occurrence of metabolic risk factors for both type 2 diabetes andcardiovascular disease (abdominal obesity, hyperglycemia, dyslipidemia, and hypertension). There areseveral definitions for the metabolic syndrome (table 1). The National Cholesterol Education Program(NCEP/ATP III) and International Diabetes Federation (IDF) definitions are the most widely used. (See'Definition' above.)
The metabolic syndrome is an important risk factor for subsequent development of type 2 diabetes and/orCVD. Thus, the key clinical implication of a diagnosis of metabolic syndrome is identification of a patient whoneeds aggressive lifestyle modification focused on weight reduction and increased physical activity (table 3).(See 'Clinical implications' above and 'Lifestyle modification' above.)
Prevention of type 2 diabetes is discussed in detail elsewhere. (See "Prediction and prevention of type 2diabetes mellitus", section on 'Prevention'.)
Reduction of risk factors for cardiovascular disease includes treatment of hypertension, cessation of smoking,glycemic control in patients with diabetes, and lowering of serum cholesterol according to recommendedguidelines. (See "Hypertension: Who should be treated?" and "Treatment of hypertension in patients withdiabetes mellitus", section on 'Goal blood pressure' and "Intensity of lipid lowering therapy in secondaryprevention of coronary heart disease", section on 'Summary and recommendations'.)
Questions have been raised as to whether the metabolic syndrome, as currently defined, captures any uniquepathophysiology implied by calling it a "syndrome," and whether metabolic syndrome confers risk beyond itsindividual components. The critical weakness of the current metabolic syndrome construct is that treatment ofthe syndrome is no different than treatment for each of its components. (See 'A critical look at the metabolicsyndrome' above.)
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Topic 1784 Version 12.0
Five current definitions of the metabolic syndrome
Parameters NCEP ATP32005 IDF 2006 EGIR 1999 WHO
Required Waist ≥94 cm(men) or ≥80cm (women)*
Insulinresistance orfastinghyperinsulinemiain top 25percent
Insulinresistancein top 25percent•;glucose≥6.1mmol/L(110mg/dL); 2-hourglucose≥7.8mmol/L(140mg/dL)
High riskof insulinresistanceΔor BMI≥25 kg/m2
or waist≥102 cm(men) or≥88 cm(women)
≥3 of: And ≥2 of: And ≥2 of: And ≥2 of: And ≥2 of:
Glucose ≥5.6 mmol/L(100 mg/dL)or drugtreatment forelevated bloodglucose
≥5.6 mmol/L(100 mg/dL)or diagnoseddiabetes
<1.0 mmol/L(40 mg/dL)(men); <1.3mmol/L (50mg/dL)(women) ordrugtreatment forlow HDL-C◊
<1.0 mmol/L(40 mg/dL)(men); <1.3mmol/L (50mg/dL)(women) ordrugtreatment forlow HDL-C
<1.0 mmol/L(40 mg/dL)
<0.9mmol/L (35mg/dL)(men);<1.0mmol/L (40mg/dL)(women)
Triglycerides ≥1.7 mmol/L(150 mg/dL)or drugtreatment forelevatedtriglycerides◊
≥1.7 mmol/L(150 mg/dL)or drugtreatment forhightriglycerides
or ≥2.0 mmol/L(180 mg/dL) ordrug treatmentfor dyslipidemia
Obesity Waist ≥102cm (men) or≥88 cm(women)§
Waist ≥94 cm(men) or ≥80cm (women)
Waist/hipratio >0.9(men) or>0.85(women) orBMI ≥30kg/m2
Hypertension ≥130/85 ≥130/85 ≥140/90 mmHg ≥140/90 ≥130/85
mmHg or drugtreatment forhypertension
mmHg ordrugtreatment forhypertension
or drugtreatment forhypertension
NCEP: National Cholesterol Education Program; IDF: International Diabetes Federation; EGIR: Groupfor the Study of Insulin Resistance; WHO: World Health Organization; AACE: American Association ofClinical Endocrinologists; HDL: high density lipoprotein; BMI: body mass index.* For South Asia and Chinese patients, waist ≥90 cm (men) or ≥80 cm (women); for Japanesepatients, waist ≥90 cm (men) or ≥80 cm (women).• Insulin resistance measured using insulin clamp.Δ High risk of being insulin resistant is indicated by the presence of at least one of the following:diagnosis of CVD, hypertension, polycystic ovary syndrome, non-alcoholic fatty liver disease oracanthosis nigricans; family history of type 2 diabetes, hypertension of CVD; history of gestationaldiabetes or glucose intolerance; nonwhite ethnicity; sedentary lifestyle; BMI 25 kb/m2 or waistcircumference 94 cm for men and 80 cm for women; and age 40 years.◊ Treatment with one or more of fibrates or niacin.§ In Asian patients, waist ≥90 cm (men) or ≥80 cm (women). Meigs James. Metabolic syndrome andthe risk for type 2 diabetes. Expert Rev Endocrin Metab 2006; 1:57. Table 1. Updated data fromthe International Diabetes Federation, 2006. Available at:http://www.idf.org/webdata/docs/MetS_def_update2006.pdf.
Ethnic specific values for waist circumference
Ethnic group Waist circumference (as measure ofcentral obesity)
Men ≥94 cm
Women ≥80 cm
Men ≥90 cm
Women ≥80 cm
Men ≥90 cm
Women ≥80 cm
Men ≥90 cm
Women ≥80 cm
Ethnic South and Central Americans Use South Asian recommendations until morespecific data are available
Sub-Saharan Africans Use European data until more specific data areavailable
Eastern Mediterranean and middle east(Arab) populations
Use European data until more specific data areavailable
Data are pragmatic cutoffs and better data are required to link them to risk. Ethnicityshould be basis for classification, not country of residence. * In USA, Adult Treatment PanelIII values (102 cm male, 88 cm female) are likely to continue to be used for clinical purposes. Infuture epidemiological studies of populations of Europid origin (white people of European origin,regardless of where they live in the world), prevalence should be given, with both European and NorthAmerican cutoffs to allow better comparisons. Reproduced with permission from: George K, AlbertiMM, Zimmet P, et al. The metabolic syndrome - a new worldwide definition. Lancet 2005; 336:1059.Copyright © 2005 Elsevier. Updated data from: the International Diabetes Federation, 2006. Availableat: http://www.idf.org/webdata/docs/MetS_def_update2006.pdf.
Prevalence of NCEP ATP III metabolic syndromeamong subjects in the NHANES III survey, by age
Adapted from Ford, ES, Giles, WH, Dietz, WH. Prevalence of the metabolicsyndrome among US adults: findings from the third National Health andNutrition Examination Survey. JAMA 2002; 287:356.
Prevalence of NCEP ATP III metabolic syndromeamong subjects in the NHANES III survey byrace/ethnicity and sex
Adapted from Ford, ES, Giles, WH, Dietz, WH. Prevalence of the metabolicsyndrome among US adults: findings from the third National Health andNutrition Examination Survey. JAMA 2002; 287:356.
Therapeutic goals for management of metabolic syndrome
Lifestyle risk factors
Abdominal obesity Year 1: reduce body weight 7-10 percent.
Continue weight loss thereafter with ultimate goal BMI <25 kg/m2
Physical inactivity At least 30 min (and preferably ≥60 min) continuous or intermittentmoderate intensity exercise 5X/wk, but preferably daily
Atherogenic diet Reduced intake saturate fat, trans fat, cholesterol
Metabolic risk factors
Primary targetelevated LDL-C
High risk*: <100 mg/dL (2.6 mmol/>L); optional <70 mg/dL
Moderate risk: <130 mg/dL (3.4 mmol/L)
Lower risk: <160 mg/dL (4.9 mmol/L)
Secondary targetelevated non-HDL-C
High risk*: <130 mg/dL (3.4 mmol/L); optional <100 mg/dL (2.6 mmol/L)very high risk
Moderate risk: <160 mg/dL (4.1 mmol/L)
Lower risk: <190 mg/dL (4.9 mmol/L)
Tertiary targetreduced HDL-C
Raise to extent possible w/weight reduction and exercise
Elevated bp Reduce to at least <140/90 (<130/80 if diabetic)
Elevated glucose For IFG, encourage weight reduction and exercise
For type 2 DM, target A1C <7 percent
Prothrombotic state Low dose aspirin for high risk patients
Lifestyle therapies; no specific interventions
DM: diabetes mellitus; IFG: impaired fasting glucose; bp: blood pressure.* High risk: diabetes, known coronary artery disease. Data from: Grundy, S, Cleeman, J, Daniels, S,et al. Diagnosis and management of the metabolic syndrome. An American Heart Association/NationalHeart, Lung, and Blood Institute scientific statement. Circulation 2005; 112:2735.
Definitions of metabolic syndrome in children and adolescents
Parameters Modified ATPIII
IDF (10 to 16years) NHANES III
≥90th percentile* ≥90th percentile
≥3 ≥2 All
Triglyceride >95th percentile ≥150 mg/dL (1.7mmol/L)
≥110 mg/dL (1.24mmol/L)
HDL <5th percentile <40 mg/dL (1.03mmol/L)
≤40 mg/dL (1.03 mmol/L)
BP Either Either ≥90th percentile
Systolic >95th percentile >130 mmHg
Diastolic >95th percentile ≥85 mmHg
Glucose Impaired glucosetolerance
≥100 mg/dL (5.6mmol/L)
Fasting ≥110 mg/dL (6.1mmol/L)
ATP III: Adult Treatment Panel; IDF: International Diabetes Federation; NHANES: National Health andNutrition Examination Survey; HDL: high-density lipoprotein; BP: blood pressure.* Ethnic-specific waist circumference (see Fernandez JR, Redden DT, Pietrobelli A, et al. Waistcircumference percentiles in nationally representative samples of African-American, European-American, and Mexican-American children and adolescents. J Pediatr 2004; 145:439).
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