Key Points
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The metabolic syndrome is a constellation of risk factors that even in the absence of diabetes precedes development of cardiovascular disease.
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Visceral obesity and ensuing insulin resistance have been proposed as central features of the pathophysiology of metabolic syndrome.
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The definitions of metabolic syndrome have evolved over time and include visceral obesity, dyslipidemia, hypertension, and hyperglycemia.
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The prevalence of metabolic syndrome is approximately 34% among U.S. adults and is growing.
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Initial evaluation of coronary heart disease risk in metabolic syndrome subjects without diabetes involves global risk estimation by Framingham or other algorithms for risk prediction.
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Novel risk factors such as high-sensitivity C-reactive protein as well as subclinical atherosclerosis (from carotid ultrasound, computed tomography, or ankle-brachial index) can refine the estimation of cardiovascular disease risk.
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The treatment of metabolic syndrome centers around lifestyle modification, supplemented with appropriate pharmacologic management, when indicated, for dyslipidemia, hypertension, and hyperglycemia.
The metabolic syndrome is a clustering of risk factors including visceral obesity, dyslipidemia, hypertension, and hyperglycemia, each an important risk factor for development of diabetes and cardiovascular disease (CVD). The constellation of these risk factors was initially described by Reaven as syndrome X and included insulin resistance, hyperglycemia, hypertension, low high-density lipoprotein cholesterol (HDL-C), and high very-low-density lipoprotein triglycerides. Cross-sectional surveys indicate that in the United States, one third of adults and an alarming proportion of youth have the metabolic syndrome.
Although there have been advances in understanding of the pathophysiology, epidemiology, and prognostic implications of the metabolic syndrome and treatment strategies for it, uncertainties persist about whether metabolic syndrome has utility beyond its individual components. Focus on the metabolic syndrome ensures that attention is drawn clearly to the risk of CVD at all levels of the health care system. In particular, the metabolic syndrome criteria with the basic screening tool of waist measurement allow a relatively simple stepwise approach with particular attention to early detection of those at risk so that intervention can start. Although the metabolic syndrome may influence choice of drug therapies, its presence essentially denotes the need to emphasize lifestyle management in clinical practice. In this chapter, we outline the historical perspective, pathophysiology, and evolving definitions of the metabolic syndrome; its significance as a tool for cardiovascular risk assessment; and therapeutic options.
Historical Perspective
As early as 1923, Kylin, a Swedish physician, described the clustering of cardiovascular risk factors, such as hypertension, obesity, and gout. More recently, in 1988, Reaven linked insulin resistance to hyperglycemia and hypertension and called this clustering “syndrome X.” In time, syndrome X took on the name metabolic syndrome and similar synonyms, such as the insulin resistance syndrome and the cardiometabolic syndrome. The American Association of Clinical Endocrinologists in 2001 promoted the recognition of the metabolic syndrome as a diagnostic entity with its own ICD-9 code. This action gave physicians the ability to diagnose and to manage the syndrome as its own entity rather than as component diagnoses. Moreover, in the same year, the Third Adult Treatment Panel of the National Cholesterol Education Program promoted the utility of easily determined criteria for defining the metabolic syndrome, which remain the most widely used criteria in the United States. Similar criteria were proposed shortly thereafter by the International Diabetes Federation, except that they focused on abdominal obesity to be one of the three criteria required for diagnosis of the metabolic syndrome.
Then, in a joint statement, the American Diabetes Association and the European Association for the Study of Diabetes (ADA-EASD) questioned the value of diagnosis of the syndrome. The main concerns that the ADA-EASD joint statement outlined included ambiguous or incomplete criteria for the diagnosis of the metabolic syndrome, uncertain role of insulin resistance as the cause of the syndrome, CVD risk attributable to the metabolic syndrome possibly not being greater than that attributable to individual components of the syndrome, and treatment of the metabolic syndrome not being different from treatment of component features.
In contrast, the position of the American Heart Association and the National Heart, Lung, and Blood Institute is that “… recognition of the syndrome in clinical practice is encouraged for the identification of a multiple-risk-factor condition and to promote lifestyle therapies that will reduce all of the metabolic risk factors simultaneously.”
These differing position statements are essentially matters of perspective. In reviewing previous literature on the metabolic syndrome, Blaha and Elasy found that some papers used the metabolic syndrome as a study exposure (the clinical epidemiologic perspective) and that others used it as an outcome (the pathophysiologic perspective). In their analysis, they found that the ADA-EASD position statement aligns with the pathophysiologic perspective and that the basis for most of the expressed concerns is the imprecise definition of the syndrome and incomplete understanding of its pathophysiology. By contrast, the American Heart Association position statement aligns itself with the clinical epidemiologic perspective and finds the recognition of features of the metabolic syndrome of substantial clinical use in the identification of patients at high risk for atherosclerotic events.
Pathophysiology
Insulin resistance was proposed by Reaven to play the causative role in the pathophysiology of metabolic syndrome. It is certainly closely related to several of the components of the metabolic syndrome, and several metabolic pathways linking insulin resistance to the other factors, such as dyslipidemia and hypertension, have been proposed. Insulin is a hormone that facilitates glucose uptake in adipocytes, hepatocytes, and skeletal muscle ( Fig. 22-1 ). It also regulates hepatic glucose production and lipolysis. Insulin resistance has been defined as a condition of decreased responsiveness of target tissues to normal levels of circulating insulin, resulting in hyperinsulinemia.
Insulin resistance arises from both genetic and acquired defects. A major contributor to the development of insulin resistance is an overabundance of circulating free fatty acids, released from an expanded adipose tissue mass. Free fatty acids reduce insulin sensitivity in muscle by inhibiting insulin-mediated glucose uptake. Increased levels of circulating glucose increase pancreatic insulin secretion, resulting in hyperinsulinemia. In the liver, free fatty acids increase the production of glucose, triglycerides, and secretion of very-low-density lipoproteins. The consequence is the reduction in glucose transformation to glycogen and increased lipid accumulation in triglycerides.
Multiple mechanisms have been proposed to explain the link between hypertension and insulin resistance. Hyperinsulinemia is associated with adrenergic overactivity, leading to increased cardiac output and urinary catecholamine excretion. Insulin also has an antinatriuretic effect, causing sodium retention and plasma volume expansion. Increased sympathetic activity also stimulates the renin-angiotensin system (RAS). There is also an effect of insulin resistance on endothelial function. The elevation in free fatty acids and tumor necrosis factor-α (TNF-α) and the decrease in adiponectin adversely affect endothelial function and promote atherogenesis.
More recently, it has been suggested that low-grade inflammation underlies or exacerbates the syndrome. The excess adipose tissue observed in the metabolic syndrome results in overproduction of the inflammatory cytokines TNF-α, interleukin-6, and C-reactive protein (CRP).
Defining Metabolic Syndrome
During the past decade, several different definitions of metabolic syndrome have been proposed and used ( Table 22-1 ). This has led to confusion and lack of comparability between studies. The first attempt to define metabolic syndrome was by a World Health Organization (WHO) diabetes group in 1998, which proposed a working definition that could be modified as more information became available. Most of the criteria in the WHO definition were based on Reaven’s suggestions for syndrome X with the addition of obesity and microalbuminuria. The essential components of metabolic syndrome were considered to be glucose intolerance, impaired glucose tolerance or diabetes, and insulin resistance together with two or more of the following: raised arterial pressure, raised triglycerides, or low levels of HDL-C; central obesity or body mass index (BMI) > 30 kg/m 2 ; and microalbuminuria (see Table 22-1 ). Other possible components of the syndrome, such as hyperuricemia, coagulation disorders, and raised circulating levels of plasminogen activator inhibitor 1 (PAI-1), were mentioned but not added as necessary components of the syndrome. The European Group for the Study of Insulin Resistance then produced a modification of the WHO criteria excluding people with diabetes and requiring hyperinsulinemia to be present.
| WHO (1999) | EGIR (1999) | NCEP ATP III (2001), AHA/NHLBI (2005) | IDF (2005) |
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* Revisions incorporated by the American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) definition (2005). EGIR, European Group for the Study of Insulin Resistance; IDF, International Diabetes Federation; NCEP ATP III, National Cholesterol Education Program Adult Treatment Panel III; WHO, World Health Organization.
In 2001, the U.S. National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) recognized the existence of the metabolic syndrome as a major contributor to cardiovascular risk. A strong emphasis of the definition was on recognition of people at high risk for CVD in addition to the conventional risk factors of low-density lipoprotein cholesterol (LDL-C), smoking, and family history. They produced a set of criteria in which people had to meet three of the five criteria that were similar to those of the WHO group but also showed some significant differences. Specifically, these criteria included increased waist circumference, elevated blood pressure, impaired fasting glucose, increased triglycerides, and low HDL-C. Central adiposity was represented by waist circumference. Also, HDL-C and raised triglycerides could count separately. Blood pressure was also slightly lower for the ATP III definition (130/85 mm Hg or higher) than for the WHO criteria, and NCEP ATP III restricted glucose to the fasting state and included known diabetes. It was generally agreed that the NCEP ATP III definition was simpler for use in clinical practice.
The International Diabetes Federation (IDF) believed there was a strong need for one practical definition that would be useful in any country for the identification of people at high risk for diabetes and CVD. Central obesity, as assessed by waist circumference, was agreed as essential because of the strength of the evidence linking waist circumference with CVD and the other metabolic syndrome components; its inclusion as a required component meant that this could be used as an initial screening, followed by evaluation of the other components only if it is increased. The waist circumference cutoff selected was lower than the NCEP ATP III recommendations (above 94 cm in men and 80 cm in women), and ethnic-specific waist circumference cutoffs have been incorporated into the definition, including lower cutoffs in Asians/South Asians of 90 cm in men and 80 cm in women. These cutpoints are also recommended for those of Central and South American ancestry. The levels of the other variables were as described by ATP III, except that the revised cut point from the American Diabetes Association for impaired fasting glucose (100 mg/dL) was used. The consensus group also recommended additional criteria that should be part of further research into metabolic syndrome, including tomographic assessment of visceral adiposity and liver fat, biomarkers of adipose tissue (adiponectin, leptin), apolipoprotein B, LDL particle size, formal measurement of insulin resistance and an oral glucose tolerance test, endothelial dysfunction, urinary albumin, inflammatory markers (CRP, TNF-α, interleukin-6), and thrombotic markers (PAI-1, fibrinogen).
Most recently, the NCEP ATP III definition has undergone a revision in the American Heart Association/National Heart, Lung, and Blood Institute scientific statement on the diagnosis and management of the metabolic syndrome (see Table 22-1 ). Many of these revisions bring ATP III in line with the IDF recommendations. Given the recent American Diabetes Association revision of the lower cut point of impaired fasting glucose to 100 mg/dL, this lower cut point has now been adopted in the revised definition. In addition, the criteria for elevated blood pressure, elevated triglycerides, and low HDL-C now also include medication for these conditions. The statement also comments on possible ethnic differences and that lower waist values may be adopted in certain ethnic groups, such as those recommended by the IDF.
Prevalence and Epidemiology
The most recent data from the National Health and Nutrition Examination Survey (NHANES) 2003-2006 show a prevalence of metabolic syndrome of 34% among U.S. adults by the NCEP ATP III guidelines criteria. This estimate is identical to that with use of data from NHANES 1999-2002, which showed a prevalence (age adjusted) of metabolic syndrome of 34.4% among men and 34.5% among women by NCEP definition, with higher estimates of 40.7% and 37.1%, respectively, by the IDF definition ( Fig. 22-2 ). Earlier data among U.S. adults show a substantially lower prevalence of approximately 25% in U.S. adults examined in 1988-1994, with increases in prevalence from 1988-1994 to 1999-2000 noted to be most dramatic among women (increase of 23.5% during this period) and attributable mainly to increases in high blood pressure, waist circumference, and hypertriglyceridemia.
Wide variations in prevalence of metabolic syndrome are observed across ethnic groups within the United States and worldwide but depend on the definition used. Despite attempts in recent years to reach an agreement on the definition of the metabolic syndrome, comparison of prevalences published for different populations is difficult because studies often differ with respect to the study design, the sample selection, the year that a study was conducted, the precise definition of the metabolic syndrome used, and the age and sex distribution of the population itself. Despite these obstacles, Cameron and associates reported on the prevalence of the NCEP ATP III definition of the metabolic syndrome among various populations around the world ( Fig. 22-3 ). Looking at those studies that include a population sample aged 20 to 25 years and older, the prevalence varies from 8% (India) to 24% (United States) in men and from 7% (France) to 46% (India) in women.
In a large United Kingdom study, South Asians had the highest prevalence of metabolic syndrome (29% in men and 32% in women by the NCEP definition) and European women the lowest (14%). In a large study involving 11 European cohorts, prevalence with use of a modified WHO definition was slightly higher in men (15.7%) than in women (14.2%). Also, in Greek adults, age-adjusted prevalences of metabolic syndrome were 24.5% by the NCEP ATP III definition versus 43.4% by the IDF definition. Lower prevalence rates were recently noted by the ATP III definition among 2100 Italian adults: 18% in women and 15% in men.
Ethnic-specific data among U.S. adults have shown metabolic syndrome to be most prevalent among Mexican Americans; among African Americans, in particular men, prevalence was lower than in whites ( Fig. 22-4 ). From the Mexico City Diabetes Study, prevalence estimates from 1997-1999 show 39.9% of men and 59.9% of women to have the metabolic syndrome, representing little change from 1990-1992 among men (38.9%) but a decrease in women from that period (65.4%). Increases in prevalence were attributed to those with elevated waist circumference, elevated fasting glucose value, and low levels of HDL-C. These data, however, contrast with a nationwide study in Mexico involving 2158 men and women aged 20 to 69 years, in which the age-adjusted prevalence of metabolic syndrome was noted to be 13.6% by WHO criteria and 26.6% by the NCEP ATP III definition (and 9.2% and 21.4%, respectively, among those without diabetes).
Among Asian populations, lower prevalences of metabolic syndrome are generally noted. For example, among Hong Kong Chinese, prevalence was 9.6% by the NCEP definition and 13.4% by the WHO definition, but in another study of Hong Kong Chinese, prevalences were greater: 16.7% by the NCEP definition but 21.2% with incorporation of lower waist circumference criteria recommended for Asians by the WHO ( > 80 cm for men and > 90 cm for women). In 1230 Korean adults aged 30 to 79 years, the prevalence by WHO criteria was 21.8% in men and 19.4% in women; however, this increased to 34.2% of men and 38.7% of women with use of the modified NCEP definition. Japanese and Mongolian adults had prevalences of only 6% and 12%, respectively, by ATP III criteria; however, these estimates did not factor in lower IDF-recommended waist circumference cut points for Asians.
Among U.S. adolescents aged 12 to 19 years from the NHANES 2001-2006 survey, a prevalence of metabolic syndrome of 8.6% overall (10.8% in males and 6.1% in females) has been recently reported, a clear increase from an overall prevalence of 6.4% in 1999-2000 and 4.2% in 1988-1992. In a school-based cross-sectional study of 1513 black, white, and Hispanic teens, the overall prevalence of NCEP-defined metabolic syndrome was 4.2%, and that of WHO-defined metabolic syndrome was 8.4%; among obese teens, this increased to 19.5% and 38.9%, respectively. Moreover, nonwhite teens were more likely to have metabolic syndrome defined by WHO criteria. A recent review on the prevalence of metabolic syndrome in children and adolescents found ranges from 1.2% to 22.6%, with rates of up to 60% observed in the overweight and obese, in 36 studies from general population and community-based sampling.
Cardiovascular Risk in Persons with the Metabolic Syndrome
Prediction of Diabetes
Recent analysis of data from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) study and the British Regional Heart Study (BRHS) found a strong association of metabolic syndrome with the incidence of type 2 diabetes. Metabolic syndrome predicted an increased risk of diabetes in PROSPER participants (HR = 4.41; 95% CI, 3.33-5.84), and an even stronger association was observed in BRHS participants (HR = 7.47; 4.90-11.46). Similarly, data from the San Antonio Heart Study (n = 2559) showed that the metabolic syndrome predicted diabetes beyond glucose intolerance alone.
Prediction of Cardiovascular Events and Mortality
The risk of CVD has been well studied and documented in persons with diabetes; in fact, diabetes is considered to be a coronary heart disease (CHD) risk equivalent according to the NCEP ATP III guidelines. The East-West study showed that in the absence of prior myocardial infarction, persons with diabetes have a risk of future cardiovascular mortality similar to that of persons with a prior myocardial infarction without diabetes. The presence of both diabetes and prior myocardial infarction is associated with an even higher risk of cardiovascular mortality. In our study involving up to 12 years of follow-up of 6255 adults from NHANES 1988-1994 we demonstrated total mortality to be similar among persons with diabetes but without preexisting CVD and those with CVD without diabetes ( Fig. 22-5 ).
The combination of diabetes and metabolic syndrome is associated with a much higher prevalence of CHD, and even those with metabolic syndrome in the absence of diabetes have a higher prevalence of CHD than do those with diabetes who do not have the metabolic syndrome. Conversely, among those with preexisting atherosclerotic vascular disease, metabolic syndrome is highly prevalent. Among a cross-sectional survey of 1117 patients with CHD, cerebrovascular disease, peripheral vascular disease, or abdominal aortic aneurysm, an overall prevalence of metabolic syndrome was noted to be 46%; it was 58% in those with peripheral vascular disease, 41% in those with CHD, 43% in those with CVD, and 47% in those with abdominal aortic aneurysm. Moreover, age did not have an impact on these prevalences.
We recently demonstrated in the U.S. population of men and women a twofold greater risk of mortality from CHD and CVD in persons with metabolic syndrome; even those with metabolic syndrome but without diabetes and those with only one or two metabolic syndrome risk factors were at an increased risk of death from CHD and CVD. Increased risks associated with metabolic syndrome held similarly for men and women. Moreover, those with diabetes had a risk of future mortality similar to that of those with preexisting CVD. Those with both diabetes and preexisting CVD had the highest risk. These observations are consistent with other reports documenting the prognostic importance of the metabolic syndrome; among 6447 men in the West of Scotland study, it predicted both incident diabetes (HR, 3.50; 95% CI, 2.51-4.90) and CHD events (HR = 1.30; 95% CI, 1.00-1.67) ; and among 1209 Finnish men observed for 11.4 years, it predicted increased CVD mortality (2.6- to 4.2-fold increased risk, depending on definition used) and total mortality (1.9- to 3.3-fold increased risk, depending on definition used).
More recently, Jeppesen and colleagues presented analysis of data from a large Danish population-based study of 2493 men and women and used both insulin resistance and metabolic syndrome as predictors of incident CVD. They reported that both insulin resistance and metabolic syndrome were independent predictors; the relative risk for CVD was 1.49 (95% CI = 1.07-2.07) for insulin resistance as quantified by homeostasis model assessment (HOMA-IR) and 1.56 for NCEP-defined metabolic syndrome (95% CI = 1.12-2.17).
Other U.S. population-based studies have also demonstrated a relation of metabolic syndrome to cardiovascular event risk. In the Framingham Offspring Study, Rutter and coworkers showed an age-, sex-, and CRP-adjusted hazard ratio for metabolic syndrome of 1.8 (95% CI = 1.4-2.5) for prediction of incident CVD events during 7 years. Moreover, among 12,089 black and white middle-aged individuals in the Atherosclerosis Risk in Communities (ARIC) study, in which metabolic syndrome was found prevalent in 23% of those without diabetes or prevalent CVD at baseline, during an average 11 years of follow-up, those with versus without metabolic syndrome were 1.5 to 2 times more likely to develop CHD in risk factor–adjusted analyses. However, metabolic syndrome did not improve risk prediction beyond that achieved by the Framingham risk score.
In 2175 elderly subjects in the Cardiovascular Health Study, metabolic syndrome defined by the ATP III but not by the WHO criteria was associated with a significant 38% increased risk (HR, 1.38; 95% CI = 1.06-1.79) of coronary or cerebrovascular events. In the San Antonio Heart Study, among 2815 subjects aged 24 to 64 years, the NCEP metabolic syndrome definition predicted all-cause mortality (multivariable hazard ratio = 1.47; 95% CI = 1.13-1.92), but the WHO metabolic syndrome definition did not; among those without diabetes or prior CVD, the NCEP metabolic syndrome definition predicted only cardiovascular mortality (HR, 2.01; 95% CI = 1.13-3.57); there was evidence also for stronger relations of metabolic syndrome with cardiovascular mortality in women compared with men. Among a large, primarily healthy cohort of 19,223 men who received a clinical examination and fitness examination, adjusted relative risks for all-cause and cardiovascular mortality were 1.29 (1.05-1.57) and 1.89 (1.36-2.60), respectively, among those with versus without metabolic syndrome. Additional adjustment for cardiorespiratory fitness, however, resulted in associations being no longer significant. Also, among 10,950 men in the Multiple Risk Factor Intervention Trial (MRFIT), modified NCEP-defined metabolic syndrome was associated with increased hazard ratios during a median of 18.4 years of follow-up for total mortality (1.21 [1.13-1.29]), CVD mortality (1.49 [1.35-1.64]), and CHD mortality (1.52 [1.34-1.70]), with elevated blood glucose and low HDL-C being the factors most predictive of CVD mortality among those men with metabolic syndrome.
In a meta-analysis of risks for all-cause mortality, CVD, and diabetes, Ford noted that among studies that used the exact NCEP definition of the metabolic syndrome, relative risks (and 95% confidence intervals) associated with the metabolic syndrome were 1.27 (0.90-1.78) for all-cause mortality, 1.65 (1.38-1.99) for CVD, and 2.99 (1.96-4.57) for diabetes. For the WHO definition, corresponding estimates were 1.37 (1.09-1.74), 1.93 (1.39-2.67), and 2.60 (1.55-4.38). The authors concluded population attributable fractions of the metabolic syndrome to be 6% to 7% for all-cause mortality, 12% to 17% for CVD, and 30% to 52% for diabetes.
The association between metabolic syndrome and CVD events may be attenuated in certain population subgroups. A study by Sattar and coworkers fueled the controversy over the importance of metabolic syndrome for determination of vascular risk. A nonsignificant relationship was observed between metabolic syndrome and incident CVD in an elderly cohort from the PROSPER study (HR, 1.07; 95% CI = 0.86-1.32), and a weak association was observed in a similar cohort from the BRHS study (HR, 1.27; 1.04-1.56). In another study looking at the predictive value of metabolic syndrome in the elderly, Mozaffarian and colleagues used data from the Cardiovascular Health Study and examined data from 4258 U.S. adults. Although those with metabolic syndrome had a 22% higher mortality risk (RR, 1.22; 95% CI, 1.11-1.34), in looking at the population attributable risk fraction [PAR %], higher proportions of death were attributable to elevated fasting glucose and hypertension (PAR, 22.2%) than to metabolic syndrome (PAR, 6.3%). This study reinforces the concept that there is limited short-term risk assessment value in using metabolic syndrome. In general, the metabolic syndrome may help identify younger cohorts who face a high long-term cardiovascular risk.
Finally, a large meta-analysis of the risk of incident cardiovascular events and death associated with metabolic syndrome analyzed data from 37 studies and 172,573 individuals. Metabolic syndrome in this analysis had a much stronger association with cardiovascular events and death, with a relative risk of 1.78 (95% CI = 1.58-2.00) ( Fig. 22-6 ). This relationship was stronger in women and remained significant after adjustment for traditional cardiovascular risk factors.
Prediction of Stroke
Metabolic syndrome is also related to the risk of stroke. Among 14,284 subjects with CHD, 26% of whom had the metabolic syndrome, those with metabolic syndrome but without diabetes had a 1.49-fold greater odds for ischemic stroke or transient ischemic attacks (95% CI, 1.20-1.84), whereas those with diabetes had a 2.29-fold increased odds (95% CI, 1.88-2.78); risks were higher in women than in men. Case-control studies have also recently reported on the association of metabolic syndrome with stroke. In a Japanese study, among 197 stroke survivors and 356 matched controls, metabolic syndrome was associated with a significant 3.1-fold greater odds of stroke. In another case-control study in Greece involving 163 stroke survivors aged 70 years and older and 166 controls, in risk factor–adjusted analyses, metabolic syndrome was associated with a 2.6-fold greater odds of stroke.
Metabolic Syndrome Risks Among Subjects with Known Cardiovascular Disease
Among subjects with established CVD, the metabolic syndrome is also associated with future CVD event risk. Among subjects with acute coronary syndromes within the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial, 38% of patients met the criteria for metabolic syndrome; those with metabolic syndrome had a hazard ratio of 1.49 (95% CI, 1.24-1.79) for the primary endpoint of death, nonfatal myocardial infarction, cardiac arrest, or recurrent unstable myocardial ischemia. Within the GISSI-Prevenzione trial, among 11,232 patients with a prior myocardial infarction, those with metabolic syndrome had a 29% greater risk of death and 23% greater risk of major cardiovascular events; these risks were amplified in diabetic patients (68% and 47%, respectively). Finally, of interest are data from the Scandinavian Simvastatin Survival Study (4S) showing, among 3933 nondiabetic subjects with known CHD, those with the metabolic syndrome to have at least as great (if not greater) reduction in the risk of total mortality (RR, 0.54), coronary mortality (RR, 0.39), or major coronary artery disease events (RR, 0.59) as those without the metabolic syndrome (0.72, 0.62, and 0.71, respectively).
Global Risk Assessment of Metabolic Syndrome
To best target treatment strategies, adequate assessment of risk for CVD is needed in persons with metabolic syndrome. Initial evaluation of risk can be determined by Framingham risk scores, given the significant heterogeneity in estimated risk of persons with metabolic syndrome. In a study applying Framingham global risk algorithms to the U.S. population with metabolic syndrome, 38.5% were classified as low risk (<6% 10-year risk of CHD), 8.5% were classified as moderate risk (6% to 10% 10-year risk of CHD), 15.8% were classified as moderately high risk (10% to 20% 10-year risk of CHD), and 37.3% were classified as high risk (>20% 10-year risk of CHD, or preexisting CVD or diabetes).
Older persons or those who are smokers or have increased total cholesterol or increased LDL-C levels, even if only minimal elevations of defined metabolic syndrome risk factors are present, may be at intermediate or higher risk of CHD. However, an important limitation of Framingham risk or other global risk algorithms is that they often do not include critical metabolic syndrome risk factors such as fasting glucose concentration or elevated triglycerides, which, although possibly not providing additive predictive value in a general population, could be critically important in stratifying risk in those with metabolic syndrome. Therefore, in situations in which a calculated global risk score results in a borderline figure (e.g., 18% to 19% 10-year risk), the presence of significant metabolic risk factors not included in the global risk algorithm may warrant the individual to be stratified to a higher risk stratum (e.g., >20% or CHD risk equivalent status in this case). The scientific statement on the clinical management of the metabolic syndrome released by the American Heart Association and National Heart, Lung, and Blood Institute noted, however, that the Framingham algorithms do capture most of the risk for CVD in persons with the metabolic syndrome and that adding obesity, triglyceride levels, and fasting glucose concentration does not appear to increase the power of prediction.
For those with diabetes, the United Kingdom Prospective Diabetes Study (UKPDS) in 2001 developed a risk engine based on data from 4540 male and female patients with diabetes to predict the risk of new CHD events. Unlike previously published equations, this model is diabetes specific and incorporates glycemia, systolic blood pressure, and lipid levels in addition to age, sex, ethnic group, smoking status, and time since diagnosis of diabetes. Recent reports have examined the performance of this risk engine in relation to the Joint British Societies (JBS) risk calculator and the earlier version of the Framingham risk equations that incorporated diabetes status. Among 700 patients with type 2 diabetes, the UKPDS risk calculator identified a higher mean 10-year CHD risk (21.5%) than the JBS risk calculator did (18.3%).
The more recent report compared the ability of the UKPDS risk engine and the Framingham risk equation to predict events that actually occurred among 428 subjects with newly diagnosed type 2 diabetes observed for a median of 4.2 years. The Framingham risk equations significantly underestimated the overall number of cardiovascular events by 33% and coronary events by 32%, compared with a lower and nonsignificant underestimation of coronary artery disease events of 13% by the UKPDS risk engine, although both similarly performed in terms of discrimination and calibration for a 15% 10-year CHD risk threshold. Another risk calculator was derived from the Prospective Cardiovascular Münster (PROCAM) study. In another study, adjustment of the PROCAM estimated global risk to include BMI or waist circumference corresponded very well with observed cardiovascular event rates.
Utility of Novel Biomarkers for Additional Risk Assessment in the Metabolic Syndrome
Once global risk assessment is done, additional information about the CHD risk for a given individual can be made with information obtained from novel biomarkers. For example, there has been interest in whether the addition of such risk factors as high-sensitivity CRP (hsCRP), fibrinogen, and small dense LDL will further add to prediction of risk in persons with metabolic syndrome. It has been shown that hsCRP levels add predictive value for CVD risk among individuals with metabolic syndrome. In the Nurses’ Health Study, among persons with metabolic syndrome, age-adjusted incidence rates of future CVD events of 3.4 and 5.0 per 1000 person-years were demonstrated for those with hsCRP levels of 3 mg/L or more and levels of less than 3 mg/L, respectively, with additive effects of higher hsCRP levels also observed for those with four or five metabolic syndrome risk factors. Framingham investigators recently reported hsCRP levels to provide additive value over metabolic syndrome in predicting CVD events. In addition, the authors have reported that in the NHANES 1999-2000 sample, those with increased hsCRP levels and metabolic syndrome had a similar odds of CVD as those with diabetes and low hsCRP levels, and those with diabetes and high hsCRP levels had the highest odds of CVD.
Importantly, the JUPITER trial has shown that screening for hsCRP can identify within the primary prevention setting a subset of patients (those with elevated hsCRP levels) most likely to benefit from preventive therapy with a statin. Both patients with and without metabolic syndrome, all of whom had hsCRP levels >2 mg/L, benefited from treatment. Disputing the relative importance of hsCRP, a recent comprehensive meta-analysis from the Emerging Risk Factors Collaboration examined data from 54 studies and 160,309 participants and found that statistical adjustment for conventional cardiovascular risk factors resulted in attenuation of the linear relationship between hsCRP concentration and CHD, stroke, and other vascular mortality. The role of other novel risk markers, such as fibrinogen, interleukin (IL-1, IL-6), and adiponectin levels, in providing additive risk stratification in persons with metabolic syndrome needs to be examined and documented before any recommendations can be made.
Screening for Subclinical Atherosclerosis
Evaluation of subclinical atherosclerosis may have important implications for persons with metabolic syndrome, given the uncertainty of risk assessment on the basis of global risk assessment alone. Given recent recommendations to target atherosclerosis screening for those with intermediate global risk of CHD whereby those found to have clinically significant atherosclerosis could have their risk level stratified upward (e.g., reclassification of an intermediate-risk individual as high risk), such screening may have implications for refining risk assessment in many persons with metabolic syndrome. Although such screening in persons with diabetes could also offer improved risk stratification, as diabetes is considered a CHD risk equivalent and aggressive treatment guidelines already exist for those with diabetes, such evaluation is not normally recommended for those with diabetes.
Ingelsson and colleagues evaluated the incidence of CVD associated with metabolic syndrome and diabetes according to the presence or absence of subclinical disease, which was categorized on the basis of any abnormalities on carotid ultrasound or ankle-brachial blood pressure, left ventricular hypertrophy on echocardiography or electrocardiography, or abnormal urinary albumin, with data from the Framingham Offspring Study. The authors found that participants who had metabolic syndrome and exhibited subclinical disease had a risk of CVD that was 2.5-fold higher (HR, 2.67; 95% CI, 1.62-4.41) than that of those without metabolic syndrome or subclinical disease. The association of metabolic syndrome and CVD was attenuated in those without subclinical disease (HR, 1.59; 95% CI, 0.87-2.90).
Carotid Ultrasound
Intima-media thickness (IMT) of carotid arteries, as assessed noninvasively by carotid ultrasonography, is also a useful measure of preclinical atherosclerosis. Carotid IMT has been found to predict future risk of myocardial infarction and stroke, and a change in carotid IMT has been validated as a vascular marker for the progression of atherosclerosis. Specifically, studies in patients with the metabolic syndrome have demonstrated that carotid IMT abnormalities exist in patients with this syndrome and predict risk of CHD. Among 313 postmenopausal women, metabolic syndrome conferred an approximate threefold adjusted odds of subclinical carotid atherosclerosis, as measured by carotid IMT. In these women, the metabolic syndrome but not BMI was associated with increased carotid IMT. Obesity had no independent effect, suggesting that metabolic abnormalities mediate the risk of subclinical atherosclerosis. Prospective data also show increased carotid IMT in those with metabolic syndrome. Bonera and associates reported that 51% of people with metabolic syndrome aged 40 to 79 years developed carotid plaque in 5-year follow-up.
An increasing number of metabolic syndrome risk factors have also been shown to predict the progression of carotid IMT in elderly women during a 12-year period. In this prospective study, the more metabolic syndrome risk factors that developed during the 12-year period, the greater was the increase in mean carotid IMT. Incident metabolic syndrome was a stronger predictor of subclinical atherosclerosis than were individual components of the syndrome. Metabolic syndrome was associated with progression of carotid IMT even after the Framingham risk score was accounted for. Finally, a cross-sectional analysis of 14,502 patients in the ARIC study demonstrated that the metabolic syndrome is associated with increased average carotid IMT. In addition, in a separate investigation of 14,502 black and white subjects in the ARIC study comparing those with versus those without metabolic syndrome, both prevalence of CHD (7.4% versus 3.6%) and average carotid IMT were significantly greater in those with versus those without metabolic syndrome. Finally, even among nondiabetic young subjects from the Bogalusa Heart Study (n = 507), composite carotid IMT increased significantly with the number of metabolic syndrome components present, and metabolic syndrome predicted composite carotid IMT 75th percentile or higher by receiver operator characteristics curves.
Whereas the evidence relating metabolic syndrome to carotid IMT is strong, there remains debate as to whether carotid IMT can be used as a surrogate for assessment of the effects of therapy. Although some prevention trials with lipid-lowering medications that used carotid IMT as a surrogate endpoint have shown that retardation in the progression of carotid IMT is accompanied by a reduction of clinical cardiovascular endpoints, others have not shown this.
Coronary Artery Calcification
The presence and extent of coronary artery calcification (CAC) strongly correlate with the overall magnitude of coronary atherosclerosis plaque burden and with the development of subsequent coronary events. The authors have previously demonstrated the presence of metabolic syndrome to be independently associated with an increased likelihood of CAC (compared with those without metabolic syndrome) and those with diabetes to have the highest likelihood of CAC. Moreover, the prevalence of calcium among women with metabolic syndrome was as high as in those with diabetes. Metabolic syndrome without diabetes was independently associated with an increased likelihood of CAC. Similarly, the National Heart, Lung, and Blood Institute Family Heart Study has demonstrated metabolic syndrome to be independently associated with an increased likelihood of CAC and abdominal aortic calcification in both men and women after adjustment for other risk factors.
The Dallas Heart Study assessed the association between metabolic syndrome, diabetes mellitus, and subclinical atherosclerosis defined as CAC or abdominal aortic plaque detected by magnetic resonance imaging. Among 2735 participants, the prevalence of CAC was increased from those with neither metabolic syndrome nor diabetes (16.6%) to metabolic syndrome only (24%), to diabetes only (30.2%), to those with both metabolic syndrome and diabetes (44.7%). After adjustment, metabolic syndrome and diabetes were each independently associated with CAC. Analysis of abdominal aortic plaque showed similar results, with highest prevalence of subclinical atherosclerosis in those with both diabetes and metabolic syndrome.
In addition to having independent effects of other traditional risk factors, metabolic syndrome has a synergistic effect. A cross-sectional study examining the combined effect of high LDL-C and metabolic syndrome on CAC found that CAC in asymptomatic men with moderate or high LDL-C was magnified in persons with metabolic syndrome. LDL-C was more strongly associated with subclinical atherosclerosis when subjects had metabolic syndrome.
Not only metabolic syndrome but high-normal fasting blood glucose concentration has been shown to have increased levels of subclinical atherosclerosis. In one study, high-normal fasting blood glucose concentration was found to be associated with increased CAC in asymptomatic nondiabetic men. The authors found that high-normal fasting blood glucose concentration was associated with CAC independent of metabolic syndrome. In another study, these authors found an association of metabolic syndrome with CAC in asymptomatic men independent of the Framingham risk score. Metabolic syndrome was present in 24% of the study participants. The prevalence of CAC increased with increasing number of metabolic syndrome risk factors. The presence of metabolic syndrome increased the risk of any CAC by almost twofold.
Computed Tomographic Angiography
Recent advances in contrast-enhanced computed tomographic angiography allow the direct visualization of calcified and noncalcified plaque. There are now some data showing that assessment of plaque by this method strongly correlates with cardiovascular events. Using data from the ROMICAT study, Butler and colleagues recently showed that those with metabolic syndrome have a higher prevalence of coronary plaque than do those without metabolic syndrome. The presence of any, calcified, and noncalcified plaque was higher in patients with than without metabolic syndrome (91%, 74%, and 77% versus 46%, 45%, and 40% of coronary segments with plaque, respectively). Metabolic syndrome was independently associated with both the presence and extent of overall plaque after adjustment for the Framingham risk score (odds ratio, 6.7). However, given the current radiation dose from computed tomographic angiography, routine use in asymptomatic patients should be avoided.
Ankle-Brachial Index and Peripheral Arterial Disease
A low ankle-brachial index has been previously shown to strongly predict morbidity and mortality in persons without known CVD. There are limited data on the association of ankle-brachial index with metabolic syndrome. The study population of this cross-sectional survey consisted of 502 patients recently diagnosed with CHD, 236 with stroke, 218 with peripheral arterial disease, and 89 with abdominal aortic aneurysm. The prevalence of the metabolic syndrome in the study population was 45%. In patients with peripheral arterial disease, this was 57%; in CHD patients, 40%; in stroke patients, 43%; and in patients with abdominal aortic aneurysm, 45%. Patients with the metabolic syndrome more often had a decreased ankle-brachial index (14% versus 10%; P = 0.06).
Myocardial Perfusion and Imaging of Inflammation
In addition to direct (multidetector computed tomographic angiography) and indirect (CAC) assessment of coronary plaque, coronary perfusion has also been shown to vary with metabolic syndrome. Some initial observations in this regard include the finding that among persons with metabolic abnormalities (metabolic syndrome or diabetes), there is an increased likelihood of myocardial ischemia, as assessed by nuclear single-photon emission computed tomography (SPECT), at intermediate levels of CAC (e.g., 100 to 399), similar to that of those without such abnormalities who have higher levels of CAC (e.g., > 400). Also, the number of metabolic syndrome abnormalities increases the amount of ischemic area on stress SPECT.
In addition to perfusion imaging, we can now assess degree of inflammation in different vascular beds. Fluorodeoxyglucose (FDG) positron emission tomography can measure inflammation within the aorta and carotid arteries. Interscan plaque FDG variability during 2 weeks was very low, with high intraclass correlation (0.79-0.92) and intraobserver agreement high across most territories, suggesting its usefulness as a noninvasive plaque imaging technique for use in drug intervention studies. A study showed that FDG uptake was significantly associated with waist circumference, HDL-C, HOMA insulin resistance, hsCRP, and a number of metabolic syndrome components ( P < 0.05 to P < 0.001).
Other Subclinical Disease Measures
Others have also examined the relation of metabolic syndrome to other measures of subclinical atherosclerosis. In a random sample of 1153 French adults aged 35 to 65 years, the presence of metabolic syndrome was independently associated with the number of carotid and femoral plaques, carotid IMT, and pulse wave velocity, with odds ratios ranging from 1.8 to 2.15 by use of the NCEP definition and 1.48 to 1.97 with the WHO definition. A recently published investigation from the ARIC study demonstrated a stepwise gradient in echocardiographic left ventricular mass by increasing number of metabolic syndrome disorders (none, any, two, or all three risk factors) in both men and women. Moreover, among overweight hypertensive patients, those with versus without metabolic syndrome had significantly greater left ventricular mass even after control for age, gender, and blood pressure. Finally, in a study of 607 adults with normal left ventricular function assessed by echocardiography, whereas left ventricular ejection fraction was similar among normals, those with one or two metabolic syndrome criteria (pre–metabolic syndrome), and those with metabolic syndrome, there were progressive increases in left ventricular mass and decreases in tissue Doppler imaging of diastolic function. Others, however, have demonstrated that there is greater impairment of global left ventricular function in patients with versus without metabolic syndrome based on an index of myocardial performance.
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