The Metabolic Syndrome (Insulin Resistance Syndrome or Syndrome X)

14/4/2014 The metabolic syndrome (insulin resistance syndrome or syndrome X)
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Official reprint from UpToDate
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Author
James B Meigs, MD, MPH
Section Editors
David M Nathan, MD
Joseph I Wolfsdorf, MB, BCh
Deputy Editor
Jean E Mulder, MD
The metabolic syndrome (insulin resistance syndrome or syndrome X)
Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Mar 2014. | This topic last updated: Jan 23, 2013.
INTRODUCTION Obesity, particularly abdominal obesity, is associated with resistance to the effects of
insulin on peripheral glucose and fatty acid utilization, often leading to type 2 diabetes mellitus. Insulin
resistance, the associated hyperinsulinemia and hyperglycemia, and adipocyte cytokines (adipokines) may
also lead to vascular endothelial dysfunction, an abnormal lipid profile, hypertension, and vascular inflammation,
all of which promote the development of atherosclerotic cardiovascular disease (CVD) [1-4]. A similar profile can
be seen in individuals with abdominal obesity who do not have an excess of total body weight [5-8].
The co-occurrence of metabolic risk factors for both type 2 diabetes and CVD (abdominal obesity,
hyperglycemia, dyslipidemia, and hypertension) suggested the existence of a "metabolic syndrome" [1,9-11].
Other names applied to this constellation of findings have included syndrome X, the insulin resistance
syndrome, the deadly quartet, or the obesity dyslipidemia syndrome [12]. Genetic predisposition, lack of
exercise, and body fat distribution all affect the likelihood that a given obese subject will become overtly diabetic
or develop CVD.
It should be noted that questions have been raised as to whether the metabolic syndrome, as currently defined,
captures any unique pathophysiology implied by calling it a "syndrome," and whether metabolic syndrome
confers risk beyond its individual components. These questions raise uncertainty about the value of diagnosing
metabolic syndrome in individual patients [13,14]. These arguments will be reviewed at the end of this
discussion (see 'A critical look at the metabolic syndrome' below). Regardless of whether the metabolic
syndrome is considered a unique entity, the need is unquestioned to identify and manage its individual
components to decrease morbidity and mortality associated with diabetes and cardiovascular disease [15,16].
The definition, prevalence, clinical implications, and therapy of the metabolic syndrome will be reviewed here,
including the limited data in children and adolescents. The pathogenesis of the relationship between obesity and
type 2 diabetes and other causes of insulin resistance are discussed separately. (See "Pathogenesis of type 2
diabetes mellitus", section on 'Role of diet, obesity, and inflammation' and "Insulin resistance: Definition and
clinical spectrum".)
The metabolic syndrome should not be confused with another disorder called syndrome X in which angina
pectoris occurs in patients with normal coronary arteries. (See "Cardiac syndrome X: Angina pectoris with
normal coronary arteries".)
DEFINITION Because metabolic syndrome traits co-occur, patients identified with one or just a few traits are
likely to have other traits, as well as insulin resistance [17]. Whether it is valuable to assess insulin resistance
in addition to more readily measured traits of the syndrome is uncertain.
There are several definitions for the metabolic syndrome, leading to some difficulty in comparing data from
studies using different criteria (table 1) [18-24]. The National Cholesterol Education Program (NCEP/ATP III) is
the most widely used [25].
2001 National Cholesterol Education Program/ATP III Guidelines developed by the 2001 National
Cholesterol Education Program (Adult Treatment Panel [ATP] III) focused explicitly on the risk of cardiovascular

disease and did not require evidence of insulin or glucose abnormalities, although abnormal glycemia is one of
the criteria [21]. ATP III metabolic syndrome criteria were updated in 2005 in a statement from the American
Heart Association (AHA)/National Heart, Lung, and Blood Institute (NHLBI) [22,23]. Updates include the
following:
Lowering the threshold for abnormal fasting glucose to 100 mg/dL, corresponding to the ADA criteria for
impaired fasting glucose (see "Clinical presentation and diagnosis 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
Current ATP III criteria define the metabolic syndrome as the presence of any three of the following five traits:
Abdominal obesity, defined as a waist circumference in men 102 cm (40 in) and in women 88 cm (35
in)
Serum triglycerides 150 mg/dL (1.7 mmol/L) or drug treatment for elevated triglycerides
Serum HDL cholesterol <40 mg/dL (1 mmol/L) in men and <50 mg/dL (1.3 mmol/L) in women or drug
treatment for low HDL-C
Blood pressure 130/85 mmHg or drug treatment for elevated blood pressure
Fasting plasma glucose (FPG) 100 mg/dL (5.6 mmol/L) or drug treatment for elevated blood glucose
International Diabetes Federation The International Diabetes Federation (IDF) updated their metabolic
syndrome criteria in 2006 [26]. Central obesity is an essential element in this definition, with different waist
circumference thresholds set for different race/ethnicity groups:
Increased waist circumference, with ethnic-specific waist circumference cut-points (table 2)
PLUS any two of the following:
Triglycerides >150 mg/dL (1.7 mmol/L) or treatment for elevated triglycerides
HDL cholesterol <40 mg/dL (1.03 mmol/L) in men or <50 mg/dL (1.29 mmol/L) in women, or treatment for
low HDL
Systolic blood pressure >130, diastolic blood pressure >85, or treatment for hypertension
Fasting plasma glucose >100 mg/dL (5.6 mmol/L) or previously diagnosed type 2 diabetes; an oral
glucose tolerance test is recommended for patients with an elevated fasting plasma glucose, but not
required
Comparing criteria in defining populations Using data from the National Health and Nutrition
Examination Survey 1999 to 2002 database, 39 percent of US adult participants met IDF criteria for the
metabolic syndrome, compared to 34.5 percent using the ATP III criteria [27]. The two definitions overlapped for
93 percent of subjects in determining presence or absence of the metabolic syndrome. When applied to an
urban population in the US, the IDF criteria categorized 15 to 20 percent more adults with the metabolic
syndrome than the ATP III criteria [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 women (n = 3589) aged 60 to 79 years, who
were free of coronary heart disease (CHD) at baseline, all three definitions of the metabolic syndrome
were modestly and similarly associated with CHD risk [29]. The age-adjusted hazard ratios for IDF,
WHO, and NCEP syndromes were 1.32 (95% CI 1.03-1.70), 1.45 (1.00-2.10), and 1.38 (1.00-1.93),
respectively.
Similarly, when data from the Framingham population are examined using ATPIII, IDF, and EGIR
definitions of the metabolic syndrome, roughly equivalent associations for incident type 2 diabetes (HR
3.5, 95% CI 2.2 to 5.6; 4.6, 2.7 to 7.7; 3.3, 2.1 to 5.1, respectively) and for CVD (1.8, 1.4 to 2.3; 1.7, 1.3
to 2.3; 2.1, 1.6 to 2.7, respectively) are observed [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 the
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 medical care in adults with diabetes
mellitus".)
Potential other markers The metabolic syndrome has been recognized as a proinflammatory,
prothrombotic state, associated with elevated levels of C-reactive protein, interleukin (IL)-6, and plasminogen
activator inhibitor (PAI)-1 [4,26,33-39]. 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 the metabolic syndrome and CHD mortality in one study
[40]. Additionally, a causal association between elevated CRP and the metabolic syndrome was not
demonstrated in a study of phenotype patterns associated with the metabolic syndrome and CRP levels [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" and "Screening for
cardiovascular risk with C-reactive protein".) AHA/CDC guidelines emphasize that CRP testing still belongs in
the category of optional, based on clinical judgment rather than recommended routinely because the magnitude
of its independent predictive power remains uncertain [42].
PREVALENCE AND RISK FACTORS The prevalence of the metabolic syndrome, as defined by the 2001
ATP III criteria, was evaluated in 8814 adults in the United States participating in the third National Health and
Nutrition Examination Survey (NHANES III, 1988 to 1994) [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). Mexican-Americans had the highest age-adjusted prevalence (31.9 percent). Among African-
Americans and Mexican-Americans, the prevalence was higher in women than in men (57 and 26 percent
higher, respectively) (figure 2). Data from NHANES 1999 to 2000 demonstrate that the prevalence has continued
to increase, particularly in women [44].
The metabolic syndrome is becoming increasingly common. Using data from the National Health and Nutrition
Examination Survey 1999 to 2002 database, 34.5 percent of participants met ATP III criteria for the metabolic
syndrome compared with 22 percent in NHANES III (1988 to 1994) [27,43]. In addition, metabolic syndrome,
defined by the 2005 revised ATP III criteria, was assessed in 3323 Framingham Heart Study participants, ages
22 to 81, who did not have diabetes or cardiovascular disease at a baseline examination in the early 1990s [45].
At baseline, the prevalence of the metabolic syndrome was 26.8 percent in men and 16.6 percent in women.
After eight years of follow-up, there was an age-adjusted 56 percent increase in prevalence among men and a 47
percent increase among women.
Increased weight Increased body weight is a major risk factor for the metabolic syndrome. In NHANES III,
the metabolic syndrome was present in 5 percent of those at normal weight, 22 percent of those who were
overweight, and 60 percent of those who were obese [46]. (See "Screening for and clinical evaluation of obesity
in adults".)
In the Framingham Heart Study cohort, an increase in weight of 2.25 kg or more over 16 years was associated
with a 21 to 45 percent increase in the risk for developing the syndrome [47]. A large waist circumference alone
identifies up to 46 percent of individuals who will develop the 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 the metabolic syndrome in the near future [49], highlighting the importance of obesity prevention and
improving physical activity levels [50,51]. (See "Etiology and natural history of obesity" and "Health hazards
associated with obesity in adults".)
Other factors In addition to age, race, and weight, other factors associated with an increased risk of
metabolic syndrome in NHANES III included postmenopausal status, smoking, low household income, high
carbohydrate diet, no alcohol consumption, and physical inactivity [46]. In the Framingham Heart Study, soft
drink consumption was also associated with an increased risk of developing adverse metabolic traits and the
metabolic syndrome [52]. Use of atypical antipsychotic medications, especially clozapine, significantly
increases risk for the metabolic syndrome [53]. In addition, poor cardiorespiratory fitness is an independent and
strong predictor of metabolic syndrome in both men and women [54]. (See "Exercise and fitness in the
prevention of cardiovascular disease".)
A parental history of metabolic syndrome increases risk, and genetic factors may account for as much as 50
percent of the variation in levels of metabolic syndrome traits in the offspring [55-58].
CLINICAL IMPLICATIONS The metabolic syndrome is an important risk factor for subsequent development
of type 2 diabetes and/or CVD. Thus, the key clinical implication of a diagnosis of metabolic syndrome is
identification of a patient who needs aggressive lifestyle modification focused on weight reduction and increased
physical activity (table 3) [11,50,59].
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 [60]. The assessment should include measurement of blood
pressure, waist circumference, fasting lipid profile, and fasting glucose.
In patients identified as having the metabolic syndrome (table 1), aggressive lifestyle intervention (weight
reduction, physical activity) is warranted to reduce the risks of type 2 diabetes and cardiovascular disease.
Assessment of 10-year risk for cardiovascular disease, using a risk assessment algorithm, such as the
Framingham Risk Score or SCORE, is useful in targeting individuals for medical intervention to lower blood
pressure and cholesterol. (See "Estimation of cardiovascular risk in an individual patient without known
cardiovascular disease".)
Risk of type 2 diabetes Prospective observational studies demonstrate a strong association between the
metabolic syndrome and the risk for subsequent development of type 2 diabetes [61-65]. In a meta-analysis of
16 multi-ethnic cohort studies, the relative risk of developing diabetes ranged from 3.53 to 5.17, depending upon
the definition of metabolic syndrome and the population studied [66]. As an example, in an analysis of 890
nondiabetic Pima Indians, 144 developed diabetes over four years of follow-up [61]. The metabolic syndrome
increased the relative risk (RR) for incident diabetes by 2.1-fold with the ATP III definition and 3.6-fold using the
WHO definition. This difference highlights the importance of insulin resistance (a required characteristic of the
WHO definition) in the pathogenesis of type 2 diabetes.
In several cohorts, the risk of diabetes increased with increasing number of components of the metabolic
syndrome [45,59,63]. While the metabolic syndrome predicts increased risk for diabetes, it is not clear whether
this adds additional important information [66,67]. In a prospective cohort study of 5842 Australian adults,
metabolic syndrome (defined by WHO, ATP III, EGIR, or IDF) was not superior to fasting plasma glucose or a
published diabetes prediction model (including age, gender, ethnicity, fasting plasma glucose, systolic blood
pressure, HDL cholesterol, BMI, and family history) in identifying individuals who developed diabetes [68]. (See
'A critical look at the metabolic syndrome' below.)
Risk of CVD Three meta-analyses, which included many of the same studies, found that the metabolic
syndrome increases the risk for incident cardiovascular disease (CVD) (RRs ranging from 1.53 to 2.18) and all
cause mortality (RRs 1.27 to 1.60) [69-71].
The increased risk appears to be related to the risk factor clustering or insulin resistance associated with the
metabolic syndrome rather than simply to obesity. This was illustrated by the following studies:
In a study of the Framingham population, obese people without metabolic syndrome did not have a
significantly increased risk of diabetes or CVD [72]. Obese people with the metabolic syndrome had a
10-fold increased risk for diabetes and a twofold increased risk for CVD relative to normal weight people
without the metabolic syndrome. Normal weight people meeting revised 2005 ATP III criteria for the
metabolic syndrome had a fourfold increased risk for diabetes and a threefold increased risk for CVD.
In a study of 211 moderately obese (BMI 30 to 35) men and women, insulin sensitivity varied sixfold, and
those with the greatest degree of insulin resistance had the highest blood pressure, triglyceride
concentrations, fasting and two-hour post oral glucose blood sugar levels, and the lowest HDL
concentrations, despite equal levels of obesity [73].
Thus, not all moderately obese individuals have the same risk for developing cardiovascular disease or diabetes;
risks differ as a function of insulin sensitivity, with insulin-resistant, obese individuals at highest risk.
The risk also may be related to underlying subclinical CVD (as measured by ECG, echocardiography, carotid
ultrasound, and ankle-brachial blood pressure) in individuals with metabolic syndrome [74]. In the Framingham
Offspring study, 51 percent of 581 participants with metabolic syndrome had subclinical CVD, and the risk of
overt CVD in these individuals was greater than in individuals with metabolic syndrome without subclinical CVD
(HR 2.67 versus 1.59). Subclinical CVD was also predictive of overt CVD in subjects without metabolic
syndrome (HR 1.93, 95% CI 1.15-3.24).
While the metabolic syndrome predicts increased risk for CVD, it is not clear whether this adds additional
important information [67,69,75]. 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 [76].
The Framingham Risk Score was a better predictor of CHD and stroke than metabolic syndrome (ATP III
criteria with obesity defined by an elevated BMI rather than waist circumference) in a prospective study of
5128 British men aged 40 to 59 years followed for 20 years [77].
Low HDL cholesterol and high blood pressure were better predictors of CHD than the metabolic
syndrome in a prospective study of 2737 men from the same cohort [65].
Other associations The metabolic syndrome has also been associated with several obesity-related
disorders including:
Fatty liver disease with steatosis, fibrosis, and cirrhosis [78-80]. (See "Epidemiology, clinical features,
and diagnosis of nonalcoholic fatty liver disease in adults", section on 'Associated disorders'.)
Hepatocellular and intrahepatic cholangiocarcinoma. (See "Epidemiology and etiologic associations of
hepatocellular carcinoma", section on 'Diabetes mellitus' and "Epidemiology, pathogenesis, and
classification of cholangiocarcinoma", section on 'Metabolic syndrome'.)
Chronic kidney disease (CKD; defined as a glomerular filtration rate less than 60 mL/min per 1.73 m2)
and microalbuminuria [81,82]. In a report from NHANES III, the metabolic syndrome in multivariate
analysis significantly increased the risk of both chronic kidney disease and microalbuminuria (adjusted
odds ratio 2.6 and 1.9, respectively) [81]. The risk of both complications increased with the number of
components of the metabolic syndrome. In a prospective cohort study, 10 percent of individuals with the
metabolic syndrome at baseline subsequently developed CKD compared with 6 percent among those
without the metabolic syndrome [83].
Polycystic ovary syndrome [84]. (See "Clinical manifestations of polycystic ovary syndrome in adults".)
Sleep-disordered breathing, including obstructive sleep apnea [85,86]. (See "Overview of obstructive sleep
apnea in adults".)
Hyperuricemia and gout [87,88]. (See "Asymptomatic hyperuricemia", section on 'Potential
consequences of hyperuricemia'.)
Several components of the metabolic syndrome, including hyperlipidemia, hypertension, and diabetes have been
associated with an increased risk of cognitive decline and dementia. The metabolic syndrome (when associated
with a high level of inflammation) may also be associated with cognitive decline in the elderly. (See "Risk factors
for dementia".)
THERAPY In 2001, ATP III recommended two major therapeutic goals in patients with the metabolic
syndrome [21]. These goals were reinforced by a report from the American Heart Association and the National
Institutes of Health (table 3) and by clinical guidelines from The Endocrine Society [23,59,60]:
Treat underlying causes (overweight/obesity and physical inactivity) by intensifying weight management
and increasing physical activity.
Treat cardiovascular risk factors if they persist despite lifestyle modification.
There is no direct evidence that attempting to prevent type 2 diabetes and CVD by treating the metabolic
syndrome is as effective as attaining the above goals. It is possible to treat insulin resistance with drugs that
enhance insulin action (eg, thiazolidinediones and metformin). However, the ability of such an approach to
improve outcomes compared to weight reduction and exercise alone is not yet well supported by clinical trials
[89,90]. (See "Metformin in the treatment of adults with type 2 diabetes mellitus" and "Thiazolidinediones in the
treatment of diabetes mellitus" and "Prevention of type 2 diabetes mellitus" and 'Prevention of type 2 diabetes'
below.)
Lifestyle modification Prevention or reduction of obesity, particularly abdominal obesity, is the main
therapeutic goal in patients with the metabolic syndrome [50,91]. 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 [92]. In this observational study of 5115 young adults (ages 18 to
30 years), increasing BMI over 15 years was associated with adverse progression of metabolic syndrome
components compared with young adults who maintained stable BMI over the study period, regardless of
baseline BMI.
Weight reduction is optimally achieved with a multimodality approach including diet, exercise, and possible
pharmacologic therapy, as with orlistat [93,94].
Diet Several dietary approaches have been advocated for treatment of the metabolic syndrome. Most
patients with the metabolic syndrome are overweight, and weight reduction, which improves insulin sensitivity, is
an important outcome goal of any diet. (See "Overview of therapy for obesity in adults" and "Alpha-glucosidase
inhibitors and lipase inhibitors for treatment of diabetes mellitus".) The following specific diet approaches have
been recommended:
The Mediterranean diet may be beneficial [95-98]. In a study comparing the Mediterranean diet (high in
fruits, vegetables, nuts, whole grains, and olive oil) with a low-fat prudent diet, subjects in the
Mediterranean diet group had greater weight loss, lower blood pressure, improved lipid profiles, improved
insulin resistance, and lower levels of markers of inflammation and endothelial function [95]. (See
"Dietary fat" and "Endothelial dysfunction".)
The DASH diet (daily sodium intake limited to 2400 mg, and higher in dairy intake than the
Mediterranean diet), compared to a weight reducing diet emphasizing healthy food choices, resulted in
greater improvements in triglycerides, diastolic blood pressure, and fasting glucose, even after controlling
for weight loss [99].
Foods with low glycemic index may improve glycemia and dyslipidemia [100]. 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 the metabolic
syndrome. The impact of the glycemic index itself versus the increase in high fiber foods that
accompanies a lower glycemic index diet is uncertain [101]. (See "Dietary carbohydrates".)
Exercise Exercise may be beneficial beyond its effect on weight loss by more selectively removing
abdominal fat, at least in women [102]. Current 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 [103]. (See "Role of physical activity and exercise in obese adults" and
"Exercise and fitness in the prevention of cardiovascular disease".)
Removal of abdominal adipose tissue with liposuction does not improve insulin sensitivity or risk factors for
coronary heart disease, suggesting that the negative energy balance induced by diet and exercise are
necessary for achieving the metabolic benefits of weight loss [104]. (See "Overview of therapy for obesity in
adults", section on 'Liposuction'.)
Prevention of type 2 diabetes Although not strictly addressing the metabolic syndrome, clinical trials have
shown that lifestyle modifications can substantially reduce the risk of development of type 2 diabetes and the
levels of risk factors for CVD in patients at increased risk. Prevention of type 2 diabetes is discussed in detail
elsewhere. (See "Prevention of type 2 diabetes mellitus", section on 'Our approach'.)
In the Diabetes Prevention Program (DPP), 3234 obese subjects with impaired fasting glucose or impaired
glucose tolerance were randomly assigned to one of the following groups [90]:
Intensive lifestyle changes with the aim of reducing weight by 7 percent through a low-fat diet and
exercise for 150 minutes per week
Treatment with metformin (850 mg twice daily) plus information on diet and exercise
Placebo plus information on diet and exercise
At an average follow-up of three years, fewer patients in the intensive lifestyle group developed diabetes (14
versus 22 and 29 percent in the metformin and placebo groups, respectively). The metabolic syndrome (using
ATP III criteria) was present in 53 percent of DPP participants at baseline [105]. In the remaining subjects (n =
1523), both intensive 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
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 Diabetes Prevention Program (DPP) trial described above, metformin therapy plus instructions on
diet and exercise was associated with a 31 percent reduction in the risk of developing diabetes compared
to placebo (at three years, diabetes developed in 22 versus 29 percent); however, metformin was less
effective than intensive lifestyle modification (diabetes developed in 22 versus 14 percent) [90]. Both
intensive lifestyle intervention and metformin therapy were effective for prevention of the metabolic
syndrome in patients who did not have the syndrome at baseline [105].
Metformin may reduce the incidence of diabetes-related end points. In a subgroup analysis from the
United Kingdom Prospective Diabetes Study (UKPDS), metformin was associated with significant
reductions in any diabetes-related end point (sudden death, hypo- or hyperglycemia causing death, MI,
angina, heart failure, stroke, renal failure, amputation, retinopathy, monocular blindness or cataract
extraction) and all cause mortality compared to conventional therapy with diet [106].
There are no data on glycemic control goals in patients with the metabolic syndrome who are not diabetic.
Current recommendations are to treat impaired fasting glucose and impaired glucose tolerance with weight loss
of about 5 to 10 percent of the baseline weight; at least 30 minutes per day of moderately intense physical
activity; and dietary therapy with a low intake of saturated fats, trans fats, cholesterol, and simple sugars, and
increased intake of fruits, vegetables, and whole grains.
Routine pharmacoprevention for diabetes with any agent is not recommended. However, metformin could be
considered in certain individuals with both IFG and IGT. (See "Prevention of type 2 diabetes mellitus", section on
'Metformin'.) In addition, when patients cross the diabetic diagnostic threshold, immediate therapy with
metformin is recommended [107]. (See "Initial management of blood glucose in adults with type 2 diabetes
mellitus".)
Cardiovascular risk reduction Reduction of risk factors for cardiovascular disease includes treatment of
hypertension, cessation of smoking, glycemic control in patients with diabetes, and lowering of serum
cholesterol according to recommended guidelines [108,109].
Lipid-lowering ATP III recommended a goal serum LDL cholesterol of less than 100 mg/dL (2.6 mmol/L)
for secondary prevention in patients with type 2 diabetes [21], and subsequent studies have suggested a more
aggressive goal of less than 80 mg/dL (2.1 mmol/L) with a regimen that includes administration of a statin. (See
"Intensity of lipid lowering therapy in secondary prevention of cardiovascular disease", section on 'Summary and
recommendations'.)
Current evidence does not support the metabolic syndrome as a coronary risk equivalent in terms of goals for
lipid management [110]. However, among patients with elevated serum LDL-cholesterol and established
coronary disease in the 4S trial of lipid lowering with simvastatin, those with characteristics of the metabolic
syndrome (lowest quartile for HDL cholesterol and highest quartile for triglycerides) had both the highest risk of
major coronary events and the greatest benefit (48 percent risk reduction) from statin therapy [111,112].
Treatment of patients with known coronary disease and the metabolic syndrome with atorvastatin 80 mg,
compared to atorvastatin 10 mg, decreased the rate of major cardiovascular events at five years (9.5 versus 13
percent, HR 0.71, 95% CI 0.61-0.84) [113].
Antihypertensive therapy There are conflicting data on whether angiotensin converting enzyme (ACE)
inhibitors or angiotensin II receptor blockers (ARB) used to treat hypertension in type 2 diabetes may also help
to reduce insulin resistance. (See "Prevention of type 2 diabetes mellitus".)
Hypertension control is important in patients with diabetes mellitus. The goal blood pressure may be somewhat
lower than that in the general population and varies with the presence or absence of diabetic nephropathy with
proteinuria. It is not clear if the lower goal applies to patients with metabolic syndrome, but it may be reasonable
to aim for such a goal. (See "Treatment of hypertension in patients with diabetes mellitus", section on 'Goal
blood pressure'.)
The value of ACE inhibitors and ARBs in hypertensive patients with the metabolic syndrome who do not have
CVD or diabetes is not known. (See "Choice of therapy in primary (essential) hypertension:
Recommendations".)
CHILDREN AND ADOLESCENTS
Definition The metabolic syndrome also occurs in children and adolescents but there is no consensus on
the definition (table 4) [114-118]. As in adults, this lack of consensus makes it difficult to compare studies that
use different diagnostic criteria and leaves the clinician without any clear parameters for assessing the long-term
clinical implications of the metabolic syndrome in children or for tracking the effectiveness of lifestyle
interventions. (See 'Clinical implications' above.)
The International Diabetes Federation (IDF) definition of metabolic syndrome in children 10 to 16 years old is
similar to that used by the IDF for adults, except that the definition for adolescents uses ethnic-specific waist
circumference percentiles and one cutoff level for HDL rather than a sex-specific cutoff [118,119]. 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 [120-123]. The US prevalence of metabolic syndrome (defined by the modified ATP III criteria) is estimated
to be about 9 percent based upon a NHANES III survey of 1960 children >12 years of age [124]. However,
pubertal growth and development is characterized by changes in metabolic traits that characterize the
syndrome, resulting in significant individual variability in the categorical diagnosis. In one study of 1098
adolescents, as many as half of the adolescents initially classified as having metabolic syndrome lost the
diagnosis during the three-year observation period, while others acquired the diagnosis [121].
The racial and ethnic distribution of metabolic syndrome is similar to that seen in adults, with the highest
prevalence in Mexican-Americans, followed by non-Hispanic whites, and non-Hispanic blacks (12.9, 10.9, and
2.9 percent, respectively). Native Americans may be the ethnic group at greatest risk for metabolic syndrome as
illustrated by a population-based study of Canadian Native (Oji-Cree) children and adolescents (10 to 19 years)
that reported a 19 percent prevalence rate (defined by ATP III criteria) [125].
Among obese children, the prevalence of the metabolic syndrome is high and increases with worsening obesity
[115,116]. This was illustrated in a study of 439 obese, 31 overweight, and 20 normal-weight children and
adolescents who underwent a comprehensive metabolic assessment [115]. The metabolic syndrome was
present in 39 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
study of a cohort from the National Heart, Lung, and Blood Institute Growth and Health Study (NGHS) [126].
Girls aged 9 and 10 years (n = 1192) were followed for 10 years. Metabolic syndrome (defined by ATP III criteria)
was present in 0.2 percent at baseline and in 3.5 percent of black and 2.4 percent of white girls at ages 18 and
19. Waist circumference and serum triglycerides at baseline were predictive of subsequent metabolic syndrome.
For every increase of 1 cm in waist circumference at year two, the risk of developing metabolic syndrome
increased by 7.4 percent; for every increase of 1 mg/dL in triglyceride level at baseline, the risk of metabolic
syndrome increased 1.3 percent. Race was not a significant independent factor in this study.
In summary, the prevalence of the metabolic syndrome is high among obese children and adolescents and
increases with the severity of the obesity, and with central adiposity in particular. However, there is instability in
the diagnosis of metabolic syndrome during pubertal development, making prevalence estimates less reliable
[121,127]. Consistency in the clinical diagnosis is required to better define the natural history of the syndrome in
children and adolescents and to assess the long-term clinical implications.
Clinical implications There are few longitudinal studies in children and adolescents with metabolic
syndrome. In contrast to the data from adults, therefore, long-term cardiovascular and diabetes risks are not well
defined. In one cohort study of 771 adults (mean age 38) who had participated in the Lipid Research Clinics
study as children and adolescents 22 to 31 years previously, the incidence of self-reported CVD was more
common in adults who exhibited metabolic syndrome traits as children than in those who did not (19.4 versus
1.5 percent, odds ratio 14.6, 95% CI 4.8-45.3) [128]. Of 31 children who had metabolic syndrome traits in the
initial study, 21 (68 percent) had adult metabolic syndrome. Increasing BMI was strongly associated with risk of
adult metabolic syndrome.
Thus, the definition of metabolic syndrome may be clinically useful for risk stratification and therapeutic
intervention in pediatrics. However, lifestyle modification that emphasizes reduction of established risk factors,
such as promotion of exercise, weight loss, and smoking cessation, is the main therapeutic goal in obese
children and adolescents, regardless of a metabolic syndrome diagnosis. (See 'Lifestyle modification' above.)
A CRITICAL LOOK AT THE METABOLIC SYNDROME The American Diabetes Association and the
European Association for the Study of Diabetes published a joint statement raising questions about whether the
components of the metabolic syndrome, as defined above, warrant classification as a true "syndrome" [13]. The
arguments raised include:
Lack of clarity of definition, with criteria differing between the ATP, WHO, and other definitions; many
published studies use further modifications to classify subjects with the metabolic syndrome.
http://www.uptodate.com/contents/the-metabolic-syndrome-insulin-resistance-syndrome-or-syndrome-x?topicKey=ENDO%2F1784&elapsedTimeMs=1&s 10/24
Multiple different phenotypes included within the metabolic syndrome, with indications for differing
treatment strategies. As an example, a patient with a large waist circumference, high triglycerides, and
high fasting glucose would need to be managed differently than a patient with high blood pressure, low
HDL, and high triglycerides.
Lack of a consistent evidence-base for setting the thresholds for the various components in the
definitions.
Inclusion of patients with clinical CVD or diabetes as part of the syndrome which is intended to define
risk for these diseases.
Unclear pathogenesis uniting the components of the syndrome; insulin resistance may not underlie all
factors, and is not a consistent finding in some definitions.
Other risk factors for CVD that are not components of the metabolic syndrome, such as inflammatory
markers, may have equal or greater bearing on risk.
The CVD risk associated with the metabolic syndrome has not been shown to be greater than the sum of
its individual components [23,129,130].
The critical weakness of the current metabolic syndrome construct is that treatment of the syndrome is no
different than treatment for each of its components. Virtually all agree clustering of risk factors for diabetes and
cardiovascular disease is a real phenomenon. All agree that the presence of one component of the metabolic
syndrome should lead to evaluation for other risk factors. Whether patient benefit is gained from diagnosing
patients with a syndrome of such uncertain characteristics or predictive value remains an open question. The
advice remains to treat individual risk factors when present and to prescribe therapeutic lifestyle changes and
weight management for obese patients with multiple risk factors.
INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and
Beyond the Basics. The Basics patient education pieces are written in plain language, at the 5 to 6 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 10 to 12 grade reading level and are best for patients who want in-depth information and are
comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these
topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on
patient info and the keyword(s) of interest.)
Basics topic (see "Patient information: Metabolic syndrome (The Basics)")
Beyond the Basics topic (see "Patient information: The metabolic syndrome (Beyond the Basics)")
SUMMARY
The metabolic syndrome is defined as the co-occurrence of metabolic risk factors for both type 2
diabetes and cardiovascular disease (abdominal obesity, hyperglycemia, dyslipidemia, and
hypertension). There are several definitions for the metabolic syndrome (table 1). The National
Cholesterol Education Program (NCEP/ATP III) is the most widely used. (See 'Definition' above.)
The metabolic syndrome is an important risk factor for subsequent development of type 2 diabetes and/or
CVD. Thus, the key clinical implication of a diagnosis of metabolic syndrome is identification of a patient
who needs aggressive lifestyle modification focused on weight reduction and increased physical activity
(table 3). (See 'Clinical implications' above and 'Lifestyle modification' above.)
Prevention of type 2 diabetes is discussed in detail elsewhere. (See "Prevention of type 2 diabetes
th th
th th
mellitus", section on 'Our approach'.)
Reduction of risk factors for cardiovascular disease includes treatment of hypertension, cessation of
smoking, glycemic control in patients with diabetes, and lowering of serum cholesterol according to
recommended guidelines. (See "Hypertension: Who should be treated?" and "Treatment of hypertension
in patients with diabetes mellitus", section on 'Goal blood pressure' and "Intensity of lipid lowering
therapy in secondary prevention of cardiovascular disease", section on 'Summary and
recommendations'.)
Questions have been raised as to whether the metabolic syndrome, as currently defined, captures any
unique pathophysiology implied by calling it a "syndrome," and whether metabolic syndrome confers risk
beyond its individual components. The critical weakness of the current metabolic syndrome construct is
that treatment of the syndrome is no different than treatment for each of its components. (See 'A critical
look at the metabolic syndrome' above.)
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127. Gustafson JK, Yanoff LB, Easter BD, et al. The stability of metabolic syndrome in children and
adolescents. J Clin Endocrinol Metab 2009; 94:4828.
128. Morrison JA, Friedman LA, Gray-McGuire C. Metabolic syndrome in childhood predicts adult
cardiovascular disease 25 years later: the Princeton Lipid Research Clinics Follow-up Study. Pediatrics
2007; 120:340.
129. Sundstrm J, Vallhagen E, Risrus U, et al. Risk associated with the metabolic syndrome versus the
sum of its individual components. Diabetes Care 2006; 29:1673.
130. Bayturan O, Tuzcu EM, Lavoie A, et al. The metabolic syndrome, its component risk factors, and
progression of coronary atherosclerosis. Arch Intern Med 2010; 170:478.
Topic 1784 Version 14.0
GRAPHICS
Five definitions of the metabolic syndrome
Parameters
NCEP
ATP3
2005*
IDF 2006 EGIR 1999
WHO
1999
AACE
2003
Required Waist 94
cm (men) or
80 cm
(women)
Insulin
resistance or
fasting
hyperinsulinemia
in top 25
percent
Insulin
resistance
in top 25
percent ;
glucose
6.1
mmol/L
(110
mg/dL);
2-hour
glucose
7.8
mmol/L
(140
mg/dL)
High risk of
insulin
resistance
or BMI 25
kg/m or
waist 102
cm (men) or
88 cm
(women)
Number of
abnormalities
3 of: And 2 of: And 2 of: And 2
of:
And 2 of:
Glucose 5.6 mmol/L
(100 mg/dL)
or drug
treatment for
elevated
blood
glucose
5.6 mmol/L
(100 mg/dL)
or diagnosed
diabetes
6.1-6.9 mmol/
(110-125 mg/dL)
6.1
mmol/L
(110
mg/dL); 2-
hour
glucose 7.8
mmol/L
(140
mg/dL)
HDL
cholesterol
<1.0 mmol/L
(40 mg/dL)
(men); <1.3
mmol/L (50
mg/dL)
(women) or
drug
treatment for
low HDL-C
<1.0 mmol/L
(40 mg/dL)
(men); <1.3
mmol/L (50
mg/dL)
(women) or
drug
treatment
for low HDL-
C
<1.0 mmol/L (40
mg/dL)
<0.9
mmol/L
(35
mg/dL)
(men);
<1.0
mmol/L
(40
mg/dL)
(women)
<1.0
mmol/L (40
mg/dL)
(men); <1.3
mmol/L (50
mg/dL)
(women)
Triglycerides 1.7 mmol/L
(150 mg/dL)
or drug
treatment for
elevated
triglycerides
1.7 mmol/L
(150 mg/dL)
or drug
treatment
for high
triglycerides
or 2.0 mmol/L
(180 mg/dL) or
drug treatment
for dyslipidemia
or 1.7
mmol/L
(150
mg/dL)
1.7
mmol/L
(150
mg/dL)
Obesity Waist 102
cm (men) or
Waist 94 cm
(men) or 80 cm
Waist/hip
ratio >0.9


88 cm
(women)
(women) (men) or
>0.85
(women)
or BMI
30
kg/m
Hypertension 130/85
mmHg or
drug
treatment for
hypertension
130/85
mmHg or
drug
treatment
for
hypertension
140/90 mmHg
or drug
treatment for
hypertension
140/90
mmHg
130/85
mmHg
NCEP: National Cholesterol Education Program; IDF: International Diabetes Federation; EGIR:
Group for the Study of Insulin Resistance; WHO: World Health Organization; AACE: American
Association of Clinical Endocrinologists; HDL: high density lipoprotein; BMI: body mass index.
* Most commonly agreed upon criteria for metabolic syndrome (any three of five risk factors).
For South Asia and Chinese patients, waist 90 cm (men) or 80 cm (women); for Japanese
patients, waist 90 cm (men) or 80 cm (women).
Insulin resistance measured using insulin clamp.
High risk of being insulin resistant is indicated by the presence of at least one of the following:
diagnosis of CVD, hypertension, polycystic ovary syndrome, non-alcoholic fatty liver disease or
acanthosis nigricans; family history of type 2 diabetes, hypertension of CVD; history of
gestational diabetes or glucose intolerance; nonwhite ethnicity; sedentary lifestyle; BMI 25
kb/m or waist circumference 94 cm for men and 80 cm for women; and age 40 years.
Treatment with one or more of fibrates or niacin.
In Asian patients, waist 90 cm (men) or 80 cm (women).
References:
1. Alberti KG, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome: a joint interim
statement of the International Diabetes Federation Task Force on Epidemiology and
Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World
Heart Federation; International Atherosclerosis Society; and International Association for the
Study of Obesity. Circulation 2009; 120:1640.
2. Meigs James. Metabolic syndrome and the risk for type 2 diabetes. Expert Rev Endocrin Metab
2006; 1:57. Table 1. Updated data from the International Diabetes Federation, 2006.
Available at: http://www.idf.org/webdata/docs/MetS_def_update2006.pdf.
Graphic 53446 Version 8.0
2
2
Ethnic specific values for waist circumference
Ethnic group
Waist circumference (as measure of
central obesity)
Europids*
Men 94 cm
Women 80 cm
South Asians
Men 90 cm
Women 80 cm
Chinese
Men 90 cm
Women 80 cm
Japanese
Men 90 cm
Women 80 cm
Ethnic South and Central Americans Use South Asian recommendations until more
specific data are available
Sub-Saharan Africans Use European data until more specific data are
available
Eastern Mediterranean and middle east
(Arab) populations
Use European data until more specific data are
available
Data are pragmatic cutoffs and better data are required to link them to risk. Ethnicity
should be basis for classification, not country of residence.
* In USA, Adult Treatment Panel III values (102 cm male, 88 cm female) are likely to continue to
be used for clinical purposes. In future epidemiological studies of populations of Europid origin
(white people of European origin, regardless of where they live in the world), prevalence should
be given, with both European and North American cutoffs to allow better comparisons.
Reproduced with permission from: George K, Alberti MM, Zimmet P, et al. The metabolic syndrome - a
new worldwide definition. Lancet 2005; 336:1059. Copyright 2005 Elsevier. Updated data from:
the International Diabetes Federation, 2006. Available at:
http://www.idf.org/webdata/docs/MetS_def_update2006.pdf.
Prevalence of NCEP ATP III metabolic syndrome
among subjects in the NHANES III survey, by age
Adapted from: Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic
syndrome among US adults: findings from the third National Health and
Nutrition Examination Survey. JAMA 2002; 287:356.
Prevalence of NCEP ATP III metabolic syndrome
among subjects in the NHANES III survey by
race/ethnicity and sex
Adapted from: Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic
syndrome among US adults: findings from the third National Health and
Nutrition Examination Survey. JAMA 2002; 287:356.
Therapeutic goals for management of metabolic syndrome
Goals
Lifestyle risk factors
Abdominal obesity Year 1: reduce body weight 7 to 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 intermittent
moderate intensity exercise 5X/wk, but preferably daily
Atherogenic diet Reduced intake saturate fat, trans fat, cholesterol
Metabolic risk factors
Dyslipidemia
Primary target
elevated LDL-C
High risk*: <100 mg/dL (2.6 mmol/>L); optional <70 mg/dL
Moderate risk: <130 mg/dL (3.4 mmol/L)
Lower risk: <160 mg/dL (4.9 mmol/L)
Secondary target
elevated non-
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 target
reduced 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
Proinflammatory
state
Lifestyle therapies; no specific interventions
DM: diabetes mellitus; IFG: impaired fasting glucose; bp: blood pressure.
* High risk: diabetes, known coronary artery disease.
Data from: Grundy S, Cleeman J, Daniels S, et al. Diagnosis and management of the metabolic
syndrome. An American Heart Association/National Heart, Lung, and Blood Institute scientific
statement. Circulation 2005; 112:2735.
Definitions of metabolic syndrome in children and adolescents
Parameters
Modified ATP
III
IDF (10 to 16
years)
NHANES III
Required
Waist
circumference
90th percentile* 90th percentile
Number of
abnormalities
3 2 All
Triglyceride >95th percentile 150 mg/dL (1.7
mmol/L)
110 mg/dL (1.24
mmol/L)
HDL <5th percentile <40 mg/dL (1.03
mmol/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 glucose
tolerance
100 mg/dL (5.6
mmol/L)
Fasting 110 mg/dL (6.1
mmol/L)
ATP III: Adult Treatment Panel; IDF: International Diabetes Federation; NHANES: National
Health and Nutrition Examination Survey; HDL: high-density lipoprotein; BP: blood pressure.
* Ethnic-specific waist circumference (see Fernandez JR, Redden DT, Pietrobelli A, et al. Waist
circumference percentiles in nationally representative samples of African-American, European-
American, and Mexican-American children and adolescents. J Pediatr 2004; 145:439).

The Metabolic Syndrome (Insulin Resistance Syndrome or Syndrome X)

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14/4/2014 The metabolic syndrome (insulin resistance syndrome or syndrome X)

14/4/2014 The metabolic syndrome (insulin resistance syndrome or syndrome X)

14/4/2014 The metabolic syndrome (insulin resistance syndrome or syndrome X)

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