OBJECTIVE—To examine the long-term association of metabolic syndrome with mortality among those at high risk for cardiovascular disease (CVD).

RESEARCH DESIGN AND METHODS—A total of 10,950 Multiple Risk Factor Intervention Trial (MRFIT) survivors were followed for mortality an additional median 18.4 years (1980–1999). Proportional hazards models examined multivariate-adjusted risks associated with Adult Treatment Panel III–defined metabolic syndrome conditions, with BMI substituted for waist circumference.

RESULTS—At MRFIT annual visit 6, 4,588 (41.9%) men, mean age (±SD) 53.0 ± 5.9 years, had metabolic syndrome and 6,362 did not. Comparing men with metabolic syndrome to men without, adjusted hazard ratios (HRs) were 1.21 (95% CI 1.13–1.29), 1.49 (1.35–1.64), and 1.51 (1.34–1.70) for 18-year total, CVD, and coronary heart disease mortality, respectively. Among men with metabolic syndrome, elevated glucose (1.54 [1.34–1.78]) and low HDL cholesterol (1.45 [1.17–1.54]) were most predictive of CVD mortality, followed by elevated BMI (1.34 [1.17–1.54]), elevated blood pressure (1.25 [0.98–1.58]), and elevated triglycerides (1.06 [0.86–1.30]). In contrast, for men without metabolic syndrome, the HR for low HDL cholesterol was 1.02 (0.86–1.22). Among metabolic syndrome men with no nonfatal CVD event, smokers with elevated LDL cholesterol showed higher CVD mortality (1.79 [1.22–2.63]) compared with nonsmokers without elevated LDL cholesterol; this additional risk was even greater for metabolic syndrome men with a nonfatal CVD event (2.11 [1.32–3.38]).

CONCLUSIONS—Metabolic syndrome is associated with an increased risk of mortality. Among those with metabolic syndrome, risk is further increased by having more metabolic syndrome conditions, by cigarette smoking, and by elevated LDL cholesterol. Primary prevention of each metabolic syndrome condition should be emphasized, and presence of each condition should be treated in accordance with current guidelines.

Metabolic syndrome is a clustering of major cardiovascular disease (CVD) risk factors. The Adult Treatment Panel III (ATP-III) (1) of the National Cholesterol Education Program defines metabolic syndrome as the occurrence of three or more of the following conditions: low HDL cholesterol, elevated triglycerides, elevated blood pressure, elevated fasting glucose or impaired glucose tolerance, and central adiposity; alternate definitions exist (2–4). Metabolic syndrome prevalence is on average 20–25% among U.S. adults but varies widely by age, race/ethnicity, adiposity, and definition used (5–13). Similar or lower prevalences have been seen in Canadian and European (6,14–20) and Asian (6,21–25) cohorts. Rising obesity and diabetes in the U.S. (26) and elsewhere (27,28) will likely increase the prevalence of metabolic syndrome (29,30).

The metabolic syndrome mortality risk among those with CVD, or elevated CVD risk (e.g., LDL cholesterol), has only been briefly studied. Metabolic syndrome prevalences up to 84% have been found in cohorts with elevated CVD risk or prior CVD (31–37). Research examining cardiovascular outcomes following metabolic syndrome (34,38–43) generally had limited follow-up. We examined the associations of metabolic syndrome and its underlying conditions with 18-year total, CVD, and coronary heart disease (CHD) mortality in men at above-average risk of CHD who were randomized into the Multiple Risk Factor Intervention Trial (MRFIT). The long follow-up and large cohort allowed examination of the association of metabolic syndrome with mortality for specific subgroups and of having additional risk factors such as smoking and elevated LDL cholesterol.

MRFIT procedures

Previous reports detail MRFIT (44–48), a primary prevention trial of a CHD mortality intervention among men aged 35–57 years at increased risk but without clinical CHD. At screen 1 (1973–1976), 361,662 men at 22 clinical centers in 18 U.S. cities were scored for CHD risk (based on serum cholesterol, diastolic blood pressure [DBP], and cigarette smoking). Men in the top 10–15% of the risk distribution, but with no history of heart attack, treatment for diabetes, DBP ≥115 mmHg, or serum cholesterol ≥350 mg/dl, were invited to screen 2. Screen 2 excluded men with extreme obesity, clinical evidence of CVD or other serious disease, untreated symptomatic diabetes, diets incompatible with the MRFIT intervention (including excessive alcohol intake), treatment with certain medications (e.g., hypoglycemic or lipid-lowering agents), DBP ≥120 mmHg, or refusal to consider quitting smoking. At screen 3, 12,866 men were randomized to special intervention (SI group; n = 6,428, dietary counseling to lower cholesterol, smoking cessation counseling, and antihypertension medication) or usual care (UC group; n = 6,438, referred to their usual physicians). All participants were asked to return to their clinical center annually for at least 6 years (follow-up >90% at each) for comprehensive evaluation, risk factor assessment, and medical history update including medications.

This study’s cohort included 11,490 participants who attended annual visit 6 (1980–1982). Of the 1,376 participants who did not, 430 were during-trial decedents. Analyses excluded men missing data for three or more metabolic syndrome conditions (n = 133) or for adjusting variables (n = 407, primarily alcohol use and lipid fractions), leaving 10,950 men. Baseline for this study is annual visit 6.

Definition of metabolic syndrome

Metabolic syndrome at annual visit 6 was defined from ATP-III (1) by three or more conditions including BMI ≥30 kg/m2 (waist circumference was not measured), triglycerides ≥150 mg/dl, HDL cholesterol <40 mg/dl, systolic blood pressure (SBP) ≥130 mmHg (or DBP ≥85 mmHg or using antihypertensives), and fasting glucose ≥110 mg/dl (or using insulin or hypoglycemic agents). We counted men on lipid-lowering drugs (n = 26) as meeting the triglycerides and HDL cholesterol criteria, even if their measures while on medication were <150 and ≥40 mg/dl, respectively.

Data collection

Race/ethnicity, education, and parental histories of CVD (heart attack, hypertension, stroke, or other CHD) and diabetes were self-reported at screening. At annual visit 6, disrobed height and weight were recorded, and 12-h fasting blood samples were centrally analyzed for serum glucose, cholesterol, triglycerides, HDL cholesterol, and LDL cholesterol (49,50). Blood pressure was the average of two measurements according to a standard protocol by certified observers (51). Antihypertensive use was from trial prescription and/or self-report. Participants self-reported cigarette use (usual number smoked per day), alcohol use (number of drinks consumed per week), and physical activity (equal to or more than others their age).

During-trial nonfatal CVD was defined by any of the following: coronary bypass surgery, stroke, clinical myocardial infarction, or silent myocardial infarction on resting electrocardiogram at or before annual visit 6 (49,52). Annual visit 6 resting electrocardiogram abnormalities were recorded from any of the following: Q wave findings, ST-segment elevations and depressions, negative T waves, high R waves, conduction defects, frequent ventricular premature beats, complete atrioventricular and bundle-branch block, supraventricular tachycardia, and left axis deviation. Morbidity data were not collected posttrial.

Mortality end point definition

Total, CVD, and CHD mortality were primary end points. For decedents through 31 December 1990, vital status was determined by clinical center staff (through 28 February 1982) or by matching identifying information with National Death Index or Social Security Administration records (53–57). Two nosologists coded cause-specific mortality based on death certificates using ICD-9; a third nosologist adjudicated disagreements. For 1991–1999, dates and causes of death were obtained using National Death Index Plus (58–61). CVD mortality was ICD-9 350–459 and ICD-10 I00-I99 and CHD mortality was ICD-9 410–414 and 429.2 and ICD-10 I20-I25.

Statistical methods

Participant characteristics, including prevalences of each metabolic syndrome condition, were summarized by annual visit 6 metabolic syndrome presence or absence. Mortality from annual visit 6 through 1999 was compared between metabolic syndrome groups using age-adjusted death rates.

Multivariate-adjusted proportional hazards models (62), stratified by clinical center, tested risk associated with metabolic syndrome and with an increasing number of metabolic syndrome conditions. Adjusting variables were SI/UC groups, age, African American or not, years of education, parental histories of CVD and diabetes, during-trial nonfatal CVD event, cigarette smoking status at screening, and annual visit 6 smoking status, cigarettes per day, alcoholic drinks per week, physical activity, fasting total cholesterol, LDL cholesterol, and resting electrocardiogram abnormalities.

Because cholesterol treatment guidelines are written for LDL cholesterol (1), and goals depend on additional risk factors such as smoking, we examined metabolic syndrome mortality risk for prespecified subgroups: age, African American or not, nonfatal CVD event, smoking status, and LDL and total cholesterol levels. We examined the mortality risk independently associated with each metabolic syndrome condition, adjusting for the other conditions. Lastly, we examined the mortality risk associated with having other risk factors in addition to metabolic syndrome, including nonfatal CVD event, smoking, and elevated LDL cholesterol. P values given throughout are two tailed; no adjustments for multiple comparisons were made.

Cohort characteristics

Risk factors were reduced at the end of MRFIT active intervention: average blood pressure after 6 years went from 136/91 mmHg at screening to 124/80 mm/Hg among SI men and from 135/91 to 127/84 mm/Hg among UC men, and average cholesterol went from 240 to 228 mg/dl and from 240 to 233 among SI and UC men, respectively. Neither total nor cause-specific mortality differed between SI and UC subjects (45).

Of 10,950 men, 4,588 (41.9%) had metabolic syndrome at annual visit 6, while 6,362 (58.1%) did not (Table 1). Metabolic syndrome men were more likely to have a parent with diabetes; were less likely to be African American; had on average fewer years of education and higher glucose, triglycerides, SBP, DBP, total cholesterol, and BMI and lower HDL cholesterol; and rated themselves as less physically active than their peers. Metabolic syndrome men were also less likely to be smokers or drinkers of alcohol and had lower average drinks per week, cigarettes per day, and LDL cholesterol.

Among those with metabolic syndrome, 57.9% had three conditions, 32.3% had four, and 9.9% had all five. Elevated blood pressure, elevated triglycerides, and low HDL cholesterol were most common (many MRFIT participants had elevated blood pressure and/or cholesterol at trial’s onset) followed by elevated BMI and elevated glucose, similar for those without metabolic syndrome. Among those with metabolic syndrome, the most common combination of the three or more conditions was elevated blood pressure, elevated triglyceridess, and low HDL cholesterol, with 29.6%. Those three plus elevated glucose accounted for 13.3%, those three plus elevated BMI accounted for 13.1%, and all five accounted for 9.9%. Each other combination accounted for <7%.

Mortality associated with metabolic syndrome

Median mortality follow-up was 18.4 years, with 3,623 deaths, including 1,745 CVD and 1,218 CHD deaths. Age-adjusted total, CVD, and CHD death rates per 10,000 person-years were higher among those with metabolic syndrome than those without (all log-rank test P < 0.0001) (Table 1).

Proportional hazards models showed highly significant differences between men with and without metabolic syndrome (Table 2). Multivariate-adjusted hazard ratios (HRs) were 1.21 (95% CI 1.13–1.29), 1.49 (1.35–1.64), and 1.51 (1.34–1.70) for total, CVD, and CHD mortality, respectively. After further adjustment for annual visit 6 levels of glucose, HDL cholesterol, triglycerides, SBP, and BMI, HRs decreased to 1.11 (1.02–1.20), 1.23 (1.09–1.38), and 1.20 (1.04–1.39). Adjustment instead for trial-averaged values decreased HRs further to 1.02 (0.94–1.11), 1.11 (0.99–1.25), and 1.11 (0.96–1.28). Results were similar when the 2005 International Diabetes Federation definition of metabolic syndrome (4) was used: 1.21 (1.12–1.31) for total, 1.48 (1.33–1.66) for CVD, and 1.48 (1.30–1.69) for CHD mortality.

An increasing number of metabolic syndrome conditions was associated with higher mortality, up to CHD mortality more than three times higher for five conditions compared with none (Table 2). Significant linear trends with number of conditions were observed for total, CVD, and CHD mortality (HR 1.11, 1.23, and 1.24, respectively, all P < 0.0001). When triglycerides and HDL cholesterol conditions did not incorporate lipid-lowering drug use, 26 men were no longer considered as having metabolic syndrome. Multivariate-adjusted metabolic syndrome HRs were then nearly identical: 1.21 (95% CI 1.13–1.30) for total, 1.49 (1.35–1.65) for CVD, and 1.51 (1.34–1.70) for CHD mortality.

CVD mortality associated with metabolic syndrome for subgroups

The association of metabolic syndrome with CVD mortality did not vary significantly across subgroups for SI/UC group, age, African American or not, nonfatal CVD, smoking, LDL cholesterol, and total cholesterol (Table 3). Among those with metabolic syndrome, there was little evidence of increased risk at higher LDL or total cholesterol levels (Table 3); similar results were found for those without metabolic syndrome. In contrast, among those with metabolic syndrome, smokers had substantially higher risk of CVD mortality than never smokers (HR 2.05 [95% CI 1.61–2.62]), while former smokers showed only marginally higher risk than never smokers (1.18 [0.96–1.45]); similar results were seen among those without metabolic syndrome. Having nonfatal CVD was associated with similarly higher risk for both those with metabolic syndrome (1.63 [1.42–1.87]) and those without metabolic syndrome (1.60 [1.38–1.87]).

CVD mortality associated with each metabolic syndrome condition

Among men with metabolic syndrome, elevated glucose and low HDL cholesterol were most predictive of CVD mortality (Table 4), while elevated blood pressure and elevated BMI were less so. (Many MRFIT participants had elevated blood pressure at trial’s onset, and extremely obese men were excluded.) After adjusting for other risk factors and the other conditions, among men with metabolic syndrome, the HR for CVD mortality comparing those with elevated glucose with those without was 1.54 (95% CI 1.34–1.78), those with low HDL cholesterol to those without was 1.45 (1.18–1.77), those with elevated BMI to those without was 1.34 (1.17–1.54), those with elevated blood pressure to those without was 1.25 (0.98–1.58), and those with elevated triglycerides to those without was 1.06 (0.86–1.30). Results were similar among men without metabolic syndrome except for low HDL cholesterol (1.02 [0.80–1.22]). Dividing the blood pressure condition into very high risk (SBP ≥140 or DBP ≥90, regardless of antihypertensive drug use) and high risk (130 ≤ SBP < 140 or 85 ≤ DBP < 90 or antihypertensive drug use) yielded higher HRs for very high risk than high risk (Table 4).

CVD mortality associated with additional risk factors

Among men with metabolic syndrome, we examined mortality risk associated with having additional risk factors: nonfatal CVD, cigarette smoking, and LDL cholesterol ≥130 mg/dl. For those without nonfatal CVD, CVD mortality was substantially higher with both smoking and elevated LDL cholesterol (HR 1.79 [95% CI 1.22–2.63]) relative to men with neither. For those with nonfatal CVD, CVD mortality was even more elevated with both (2.11 [1.32–3.38]) compared with neither. Among all men, considering seven conditions (five metabolic syndrome conditions, smoking, and elevated LDL cholesterol), CVD mortality risk increased with more conditions: relative to men with none, HRs were 1.53 (0.56–4.21) for one condition, 1.92 (0.71–5.16) for two, 2.19 (0.82–5.89) for three, 2.62 (0.98–7.05) for four, 3.43 (1.27–9.24) for five, 4.71 (1.73–12.80) for six, and 5.68 (1.97–16.41) for all seven.

Metabolic syndrome in the MRFIT survivors was associated with higher 18-year total, CVD, and CHD mortality even after adjusting for SI/UC group, age, African American or not, education, physical activity, and other CVD risk factors. The association increased with number of metabolic syndrome conditions present, up to total mortality twice as high and CVD and CHD mortality almost three times as high among those with all five conditions compared with those with none. Elevated glucose and low HDL cholesterol were most predictive of CVD mortality among those with metabolic syndrome. In contrast, low HDL cholesterol was not predictive among men without metabolic syndrome. Lastly, mortality among men with metabolic syndrome was higher for smokers with elevated LDL cholesterol, regardless of nonfatal CVD status.

Our work is unique for its large sample size and long mortality follow-up but limited by lack of posttrial morbidity, restriction to men, and exclusion of during-trial decedents. The MRFIT age range and exclusion criteria, such as for severe disease (e.g., cancer) or factors thought likely to interfere with the intervention (e.g., extreme obesity, excessive alcohol consumption), also limit the generalizability. Men randomized to MRFIT were at above-average risk for CHD (47). Other follow-up studies among high-risk groups have been of shorter duration but have also shown high prevalence of and poor prognosis following metabolic syndrome (32,34,39,40). Other studies in general populations have found lower prevalence of metabolic syndrome but similarly unfavorable prognosis of metabolic syndrome (38,41–43).

Our metabolic syndrome definition was based on ATP-III (1) but included use of certain medications, as done elsewhere (8,14–16,20,22,24,32,35,39,40). MRFIT did not collect waist circumference; we used BMI instead, as done elsewhere (12,14,15). Use of BMI may have resulted in lower estimated effects than waist circumference would have shown because BMI includes total fat mass. Waist circumference reflects visceral fat mass, more directly related to insulin resistance (63–69).

Metabolic syndrome has had multiple and changing definitions, indicating the uncertainty about a unifying pathogenesis. This is despite Reaven’s (70) assertion that the “basic abnormality leading to all of these changes is resistance to insulin-mediated disposal,” supported by the significant association of ATP-III–defined metabolic syndrome with measured insulin resistance among healthy adults (71) with high specificity (72). Nevertheless, in a recent extensive review (73), the imprecision of the metabolic syndrome definition led the authors to doubt the value of using the syndrome as a marker for CVD risk and to emphasize the importance of treatment of all CVD risk factors. This view is supported by our results showing an increased risk with additional metabolic syndrome conditions, from one condition to the full complement of five, along with a further increase in risk with smoking and elevated LDL cholesterol. In a population study in the U.K., analysis of different ways of combining the conditions of metabolic syndrome showed that this clustering had no greater predictive value beyond the consideration of all of the individual risk factors (74). This held true in the MRFIT cohort as well when adjusting for trial-averaged risk factors but not for single ascertainment of risk factors. As the utility of metabolic syndrome continues to be debated, Grundy et al. (75) describe metabolic syndrome as a combination of metabolic risk factors and underlying risk factors, which give rise to the metabolic risk factors, and recognize that metabolic syndrome is not a discrete entity known to be caused by a single factor; they emphasize again its strong association with obesity.

The justification for invoking the syndrome (Mitka [76], quoting Scott Grundy, chair of ATP-III) was to garner attention and action by primary care physicians who had apparently paid scant regard to the admonition for weight reduction promulgated in ATP-II (77). However, there is real danger that such concentration on a cluster of three of five conditions (unjustified by the additive predictiveness of all five) will distract from the need to address all risk factors including those not part of the five, namely LDL cholesterol and smoking.

Table 1—

Participant characteristics according to metabolic syndrome presence at this study’s baseline (annual visit 6)

With metabolic syndromeWithout metabolic syndromeP value for group difference
n (%) 4,588 (41.9) 6,362 (58.1)  
Characteristics at screening    
    African American (%) 5.9 8.2 <0.0001 
    Education (years) 13.8 ± 2.9 14.0 ± 2.9 <0.0001 
    Parental history of CVD (%) 77.0 75.5 0.06 
    Parental history of diabetes (%) 21.6 17.1 <0.0001 
    SI group (%) 50.0 51.0 0.21 
Metabolic syndrome markers at annual visit 6    
    Fasting glucose (mg/dl) 115.3 ± 37.4 97.7 ± 15.3 <0.0001 
    Fasting triglycerides (mg/dl) 270.8 ± 207.0 139.6 ± 72.9 <0.0001 
    Fasting HDL cholesterol (mg/dl) 35.2 ± 8.0 46.5 ± 11.8 <0.0001 
    SBP (mmHg) 125.7 ± 14.2 122.6 ± 14.4 <0.0001 
    DBP (mmHg) 83.4 ± 8.5 80.9 ± 8.6 <0.0001 
    BMI (kg/m2) 29.5 ± 3.9 26.3 ± 3.0 <0.0001 
Metabolic syndrome conditions at annual visit 6    
    Elevated glucose or drug use* (%) 44.3 7.7 <0.0001 
    Elevated triglycerides or drug use† (%) 88.9 30.0 <0.0001 
    Low HDL cholesterol or drug use† (%) 82.5 27.0 <0.0001 
    Elevated blood pressure or drug use‡ (%) 91.3 61.6 <0.0001 
    Elevated BMI (%) 45.2 8.9 <0.0001 
Characteristics at annual visit 6    
    Age (years) 53.0 ± 5.9 53.0 ± 5.9 0.66 
    Smoker (%) 34.3 41.2 <0.0001 
    Cigarettes per day among smokers 28.2 ± 15.1 29.0 ± 15.1 0.07 
    Alcohol drinker (%) 82.5 86.1 <0.0001 
    Drinks per week among drinkers 10.8 ± 11.4 12.4 ± 12.9 <0.0001 
    Physical activity more than peers (%) 70.6 79.5 <0.0001 
    Fasting total cholesterol (mg/dl) 232.4 ± 38.6 229.0 ± 36.3 <0.0001 
    Fasting LDL cholesterol (mg/dl) 145.6 ± 35.5 154.7 ± 33.4 <0.0001 
    Fasting LDL cholesterol ≥130 mg/dl (%) 68.0 77.8 <0.0001 
    During-trial nonfatal CVD (%) 23.3 18.8 <0.0001 
    Resting electrocardiogram abnormality (%) 33.3 33.9 0.49 
Mortality    
    Total number of deaths (rate)§ 1,660 (228.5) 1,963 (189.6) <0.0001 
    Number of CVD deaths (rate)§ 899 (123.7) 846 (81.6) <0.0001 
    Number of CHD deaths (rate)§ 633 (86.9) 585 (55.9) <0.0001 
With metabolic syndromeWithout metabolic syndromeP value for group difference
n (%) 4,588 (41.9) 6,362 (58.1)  
Characteristics at screening    
    African American (%) 5.9 8.2 <0.0001 
    Education (years) 13.8 ± 2.9 14.0 ± 2.9 <0.0001 
    Parental history of CVD (%) 77.0 75.5 0.06 
    Parental history of diabetes (%) 21.6 17.1 <0.0001 
    SI group (%) 50.0 51.0 0.21 
Metabolic syndrome markers at annual visit 6    
    Fasting glucose (mg/dl) 115.3 ± 37.4 97.7 ± 15.3 <0.0001 
    Fasting triglycerides (mg/dl) 270.8 ± 207.0 139.6 ± 72.9 <0.0001 
    Fasting HDL cholesterol (mg/dl) 35.2 ± 8.0 46.5 ± 11.8 <0.0001 
    SBP (mmHg) 125.7 ± 14.2 122.6 ± 14.4 <0.0001 
    DBP (mmHg) 83.4 ± 8.5 80.9 ± 8.6 <0.0001 
    BMI (kg/m2) 29.5 ± 3.9 26.3 ± 3.0 <0.0001 
Metabolic syndrome conditions at annual visit 6    
    Elevated glucose or drug use* (%) 44.3 7.7 <0.0001 
    Elevated triglycerides or drug use† (%) 88.9 30.0 <0.0001 
    Low HDL cholesterol or drug use† (%) 82.5 27.0 <0.0001 
    Elevated blood pressure or drug use‡ (%) 91.3 61.6 <0.0001 
    Elevated BMI (%) 45.2 8.9 <0.0001 
Characteristics at annual visit 6    
    Age (years) 53.0 ± 5.9 53.0 ± 5.9 0.66 
    Smoker (%) 34.3 41.2 <0.0001 
    Cigarettes per day among smokers 28.2 ± 15.1 29.0 ± 15.1 0.07 
    Alcohol drinker (%) 82.5 86.1 <0.0001 
    Drinks per week among drinkers 10.8 ± 11.4 12.4 ± 12.9 <0.0001 
    Physical activity more than peers (%) 70.6 79.5 <0.0001 
    Fasting total cholesterol (mg/dl) 232.4 ± 38.6 229.0 ± 36.3 <0.0001 
    Fasting LDL cholesterol (mg/dl) 145.6 ± 35.5 154.7 ± 33.4 <0.0001 
    Fasting LDL cholesterol ≥130 mg/dl (%) 68.0 77.8 <0.0001 
    During-trial nonfatal CVD (%) 23.3 18.8 <0.0001 
    Resting electrocardiogram abnormality (%) 33.3 33.9 0.49 
Mortality    
    Total number of deaths (rate)§ 1,660 (228.5) 1,963 (189.6) <0.0001 
    Number of CVD deaths (rate)§ 899 (123.7) 846 (81.6) <0.0001 
    Number of CHD deaths (rate)§ 633 (86.9) 585 (55.9) <0.0001 

Data are means ± SD, unless otherwise indicated. Numbers of deaths (death rates) are over a median of 18.4 years. P values shown are from general linear model F tests, logistic model χ2 tests, or log-rank tests, as appropriate. Drug use includes

*

insulin/hypoglycemic agents,

†

lipid-lowering agents, or

‡

antihypertensive agents.

§

Rates are age-adjusted death rates per 10,000 person-years.

View Large
Table 2—

Relative mortality for those with metabolic syndrome compared with those without and for those with the specified number of metabolic syndrome conditions compared with those with no conditions (annual visit 6)

Smoking and age adjusted
Multivariate adjusted
HR (95% CI)P valueHR (95% CI)*P value
Total mortality     
    Metabolic syndrome (yes versus no) 1.26 (1.18–1.35) <0.0001 1.21 (1.13–1.29) <0.0001 
    One condition versus none 1.10 (0.95–1.28) 0.22 1.06 (0.92–1.24) 0.42 
    Two conditions versus none 1.14 (0.98–1.32) 0.09 1.09 (0.94–1.27) 0.25 
    Three conditions versus none 1.22 (1.05–1.42) 0.008 1.16 (1.00–1.34) 0.06 
    Four conditions versus none 1.50 (1.29–1.76) <0.0001 1.41 (1.20–1.66) <0.0001 
    Five conditions versus none 2.19 (1.82–2.64) <0.0001 1.96 (1.62–2.38) <0.0001 
    Linear trend with number of conditions 1.13 (1.10–1.16) <0.0001 1.11 (1.08–1.14) <0.0001 
CVD mortality     
    Metabolic syndrome (yes versus no) 1.58 (1.43–1.73) <0.0001 1.49 (1.35–1.64) <0.0001 
    One condition versus none 1.14 (0.90–1.46) 0.28 1.09 (0.86–1.39) 0.48 
    Two conditions versus none 1.40 (1.10–1.77) 0.005 1.29 (1.02–1.63) 0.04 
    Three conditions versus none 1.66 (1.32–2.10) <0.0001 1.51 (1.19–1.92) 0.0006 
    Four conditions versus none 2.15 (1.69–2.75) <0.0001 1.98 (1.55–2.53) <0.0001 
    Five conditions versus none 3.34 (2.53–4.40) <0.0001 2.98 (2.24–3.95) <0.0001 
    Linear trend with number of conditions 1.25 (1.21–1.30) <0.0001 1.23 (1.18–1.28) <0.0001 
CHD mortality     
    Metabolic syndrome (yes versus no) 1.60 (1.43–1.80) <0.0001 1.51 (1.34–1.70) <0.0001 
    One condition versus none 1.18 (0.88–1.58) 0.31 1.12 (0.84–1.51) 0.44 
    Two conditions versus none 1.45 (1.09–1.93) 0.01 1.32 (0.99–1.76) 0.06 
    Three conditions versus none 1.76 (1.32–2.34) 0.0001 1.59 (1.19–2.11) 0.002 
    Four conditions versus none 2.20 (1.64–2.96) <0.0001 2.01 (1.49–2.72) <0.0001 
    Five conditions versus none 3.56 (2.56–4.96) <0.0001 3.18 (2.26–4.47) <0.0001 
    Linear trend with number of conditions 1.26 (1.21–1.32) <0.0001 1.24 (1.18–1.30) <0.0001 
Smoking and age adjusted
Multivariate adjusted
HR (95% CI)P valueHR (95% CI)*P value
Total mortality     
    Metabolic syndrome (yes versus no) 1.26 (1.18–1.35) <0.0001 1.21 (1.13–1.29) <0.0001 
    One condition versus none 1.10 (0.95–1.28) 0.22 1.06 (0.92–1.24) 0.42 
    Two conditions versus none 1.14 (0.98–1.32) 0.09 1.09 (0.94–1.27) 0.25 
    Three conditions versus none 1.22 (1.05–1.42) 0.008 1.16 (1.00–1.34) 0.06 
    Four conditions versus none 1.50 (1.29–1.76) <0.0001 1.41 (1.20–1.66) <0.0001 
    Five conditions versus none 2.19 (1.82–2.64) <0.0001 1.96 (1.62–2.38) <0.0001 
    Linear trend with number of conditions 1.13 (1.10–1.16) <0.0001 1.11 (1.08–1.14) <0.0001 
CVD mortality     
    Metabolic syndrome (yes versus no) 1.58 (1.43–1.73) <0.0001 1.49 (1.35–1.64) <0.0001 
    One condition versus none 1.14 (0.90–1.46) 0.28 1.09 (0.86–1.39) 0.48 
    Two conditions versus none 1.40 (1.10–1.77) 0.005 1.29 (1.02–1.63) 0.04 
    Three conditions versus none 1.66 (1.32–2.10) <0.0001 1.51 (1.19–1.92) 0.0006 
    Four conditions versus none 2.15 (1.69–2.75) <0.0001 1.98 (1.55–2.53) <0.0001 
    Five conditions versus none 3.34 (2.53–4.40) <0.0001 2.98 (2.24–3.95) <0.0001 
    Linear trend with number of conditions 1.25 (1.21–1.30) <0.0001 1.23 (1.18–1.28) <0.0001 
CHD mortality     
    Metabolic syndrome (yes versus no) 1.60 (1.43–1.80) <0.0001 1.51 (1.34–1.70) <0.0001 
    One condition versus none 1.18 (0.88–1.58) 0.31 1.12 (0.84–1.51) 0.44 
    Two conditions versus none 1.45 (1.09–1.93) 0.01 1.32 (0.99–1.76) 0.06 
    Three conditions versus none 1.76 (1.32–2.34) 0.0001 1.59 (1.19–2.11) 0.002 
    Four conditions versus none 2.20 (1.64–2.96) <0.0001 2.01 (1.49–2.72) <0.0001 
    Five conditions versus none 3.56 (2.56–4.96) <0.0001 3.18 (2.26–4.47) <0.0001 
    Linear trend with number of conditions 1.26 (1.21–1.32) <0.0001 1.24 (1.18–1.30) <0.0001 
*

Adjusting variables: SI/UC group, age, race/ethnicity (African American or not), education, parental histories of heart disease and diabetes, participant during-trial nonfatal CVD event, smoking status (cigarette smoker, yes versus no) at screening, and annual visit 6 measures of smoking status, cigarettes per day, alcoholic drinks per week, physical activity, fasting total cholesterol, LDL cholesterol, and resting electrocardiogram abnormality.

View Large
Table 3—

Cardiovascular mortality associated with metabolic syndrome (annual visit 6) for various subgroups of men

With metabolic syndrome: comparison of subgroups
Without metabolic syndrome: comparison of subgroups
Within subgroups: comparison of metabolic syndrome (with versus without)
P§
n*Rate†HR (95% CI)‡n*Rate†HR (95% CI)‡HR (95% CI)‡
Age at annual visit 6         
    <50 years 1,486 76.3 0.53 (0.45–0.62) 2,090 50.0 0.50 (0.43–0.60) 1.54 (1.25–1.89) 0.68 
    ≥50 years 3102 142.7 1.00 4272 90.5 1.00 1.47 (1.31–1.64)  
Race/ethnicity         
    African American 272 97.2 0.73 (0.53–1.01) 519 87.5 0.98 (0.76–1.26) 1.13 (0.76–1.67) 0.15 
    Other 4,316 125.0 1.00 5,843 81.2 1.00 1.52 (1.37–1.68)  
Randomized MRFIT group         
    SI group 2,292 122.5 1.07 (0.94–1.23) 3,256 78.8 1.03 (0.89–1.18) 1.52 (1.33–1.75) 0.63 
    UC group 2,296 125.1 1.00 3,106 84.7 1.00 1.45 (1.27–1.67)  
During-trial nonfatal CVD         
    Yes 1,070 194.7 1.63 (1.42–1.87) 1,195 128.6 1.60 (1.38–1.87) 1.50 (1.27–1.78) 0.89 
    No 3,518 103.7 1.00 5,167 70.9 1.00 1.48 (1.32–1.67)  
Annual visit 6 smoking status         
    Current 1,574 171.2 2.05 (1.61–2.62) 2,624 109.2 2.11 (1.62–2.75) 1.50 (1.30–1.73) 0.93 
    Former 2,255 106.8 1.18 (0.96–1.45) 2,843 68.3 1.25 (0.99–1.57) 1.47 (1.26–1.70)  
    Never 759 90.3 1.00 895 55.6 1.00 1.54 (1.17–2.03)  
Annual visit 6 LDL cholesterol         
    ≥160 mg/dl 1,575 122.0 0.98 (0.81–1.18) 2,758 85.7 1.16 (0.92–1.44) 1.40 (1.20–1.63) 0.43 
    130–159 mg/dl 1,545 130.8 1.10 (0.93–1.30) 2,192 83.6 1.24 (1.02–1.52) 1.46 (1.24–1.71)  
    <130 mg/dl 1,468 117.9 1.00 1,412 70.3 1.00 1.65 (1.35–2.02)  
Annual visit 6 total cholesterol         
    ≥240 mg/dl 1,866 117.8 0.98 (0.77–1.23) 2,360 85.8 1.12 (0.88–1.44) 1.40 (1.20–1.64) 0.52 
    200–239 mg/dl 1,889 132.0 1.11 (0.91–1.35) 2,677 82.9 1.16 (0.95–1.42) 1.54 (1.34–1.79)  
    <200 mg/dl 833 118.7 1.00 1,325 71.6 1.00 1.62 (1.29–2.03)  
With metabolic syndrome: comparison of subgroups
Without metabolic syndrome: comparison of subgroups
Within subgroups: comparison of metabolic syndrome (with versus without)
P§
n*Rate†HR (95% CI)‡n*Rate†HR (95% CI)‡HR (95% CI)‡
Age at annual visit 6         
    <50 years 1,486 76.3 0.53 (0.45–0.62) 2,090 50.0 0.50 (0.43–0.60) 1.54 (1.25–1.89) 0.68 
    ≥50 years 3102 142.7 1.00 4272 90.5 1.00 1.47 (1.31–1.64)  
Race/ethnicity         
    African American 272 97.2 0.73 (0.53–1.01) 519 87.5 0.98 (0.76–1.26) 1.13 (0.76–1.67) 0.15 
    Other 4,316 125.0 1.00 5,843 81.2 1.00 1.52 (1.37–1.68)  
Randomized MRFIT group         
    SI group 2,292 122.5 1.07 (0.94–1.23) 3,256 78.8 1.03 (0.89–1.18) 1.52 (1.33–1.75) 0.63 
    UC group 2,296 125.1 1.00 3,106 84.7 1.00 1.45 (1.27–1.67)  
During-trial nonfatal CVD         
    Yes 1,070 194.7 1.63 (1.42–1.87) 1,195 128.6 1.60 (1.38–1.87) 1.50 (1.27–1.78) 0.89 
    No 3,518 103.7 1.00 5,167 70.9 1.00 1.48 (1.32–1.67)  
Annual visit 6 smoking status         
    Current 1,574 171.2 2.05 (1.61–2.62) 2,624 109.2 2.11 (1.62–2.75) 1.50 (1.30–1.73) 0.93 
    Former 2,255 106.8 1.18 (0.96–1.45) 2,843 68.3 1.25 (0.99–1.57) 1.47 (1.26–1.70)  
    Never 759 90.3 1.00 895 55.6 1.00 1.54 (1.17–2.03)  
Annual visit 6 LDL cholesterol         
    ≥160 mg/dl 1,575 122.0 0.98 (0.81–1.18) 2,758 85.7 1.16 (0.92–1.44) 1.40 (1.20–1.63) 0.43 
    130–159 mg/dl 1,545 130.8 1.10 (0.93–1.30) 2,192 83.6 1.24 (1.02–1.52) 1.46 (1.24–1.71)  
    <130 mg/dl 1,468 117.9 1.00 1,412 70.3 1.00 1.65 (1.35–2.02)  
Annual visit 6 total cholesterol         
    ≥240 mg/dl 1,866 117.8 0.98 (0.77–1.23) 2,360 85.8 1.12 (0.88–1.44) 1.40 (1.20–1.64) 0.52 
    200–239 mg/dl 1,889 132.0 1.11 (0.91–1.35) 2,677 82.9 1.16 (0.95–1.42) 1.54 (1.34–1.79)  
    <200 mg/dl 833 118.7 1.00 1,325 71.6 1.00 1.62 (1.29–2.03)  
*

Number of men.

†

Rates are age-adjusted CVD death rates per 10,000 person-years.

‡

Adjusting variables (not including the corresponding subgroup variable for each subgroup analysis): SI/UC group, age, race/ethnicity (African American or not), education, parental histories of heart disease and diabetes, participant during-trial nonfatal CVD event, smoking status (cigarette smoker, yes versus no) at screening, and annual visit 6 measures of smoking status, cigarettes per day, alcoholic drinks per week, physical activity, fasting total cholesterol, LDL cholesterol, and resting electrocardiogram abnormality.

§

P values correspond to likelihood ratio tests for interactions of metabolic syndrome with each subgroup.

View Large
Table 4—

Importance of each metabolic syndrome condition in predicting cardiovascular mortality, separately for the 4,588 men with and 6,362 men without metabolic syndrome (annual visit 6)

With metabolic syndrome (n = 4,625)
Without metabolic syndrome (n = 6,411)
P‖
n*HR (95% CI)†n*HR (95% CI)†
Conditions as originally defined      
    Elevated glucose or drug use‡ 2,028 1.54 (1.34–1.78) 489 1.43 (1.12–1.78) 0.52 
    Low HDL cholesterol or drug use§ 3,787 1.45 (1.18–1.77) 1,720 1.02 (0.86–1.22) 0.006 
    Elevated triglycerides or drug use§ 4,079 1.06 (0.86–1.30) 1,906 1.02 (0.87–1.19) 0.79 
    Elevated blood pressure or drug use 4,188 1.25 (0.98–1.58) 3,913 1.37 (1.16–1.62) 0.53 
    Elevated BMI 2,067 1.34 (1.17–1.54) 563 1.20 (0.94–1.55) 0.58 
With blood pressure divided      
    SBP ≥140 or DBP ≥90 mmHg 1,255 1.32 (1.02–1.72) 1,317 1.46 (1.19–1.79) 0.53 
    130 ≤ SBP < 140 or 85 ≤ DBP < 90 or antihypertensive drug use 2,933 1.21 (0.95–1.55) 2,596 1.30 (1.09–1.56) 0.67 
With metabolic syndrome (n = 4,625)
Without metabolic syndrome (n = 6,411)
P‖
n*HR (95% CI)†n*HR (95% CI)†
Conditions as originally defined      
    Elevated glucose or drug use‡ 2,028 1.54 (1.34–1.78) 489 1.43 (1.12–1.78) 0.52 
    Low HDL cholesterol or drug use§ 3,787 1.45 (1.18–1.77) 1,720 1.02 (0.86–1.22) 0.006 
    Elevated triglycerides or drug use§ 4,079 1.06 (0.86–1.30) 1,906 1.02 (0.87–1.19) 0.79 
    Elevated blood pressure or drug use 4,188 1.25 (0.98–1.58) 3,913 1.37 (1.16–1.62) 0.53 
    Elevated BMI 2,067 1.34 (1.17–1.54) 563 1.20 (0.94–1.55) 0.58 
With blood pressure divided      
    SBP ≥140 or DBP ≥90 mmHg 1,255 1.32 (1.02–1.72) 1,317 1.46 (1.19–1.79) 0.53 
    130 ≤ SBP < 140 or 85 ≤ DBP < 90 or antihypertensive drug use 2,933 1.21 (0.95–1.55) 2,596 1.30 (1.09–1.56) 0.67 

HRs are for presence versus absence of that condition, and P values are for metabolic syndrome by condition interaction tests.

*

Number of men with that condition.

†

Adjusting variables: SI/UC group, age, race/ethnicity (African American or not), education, parental histories of heart disease and diabetes, participant during-trial nonfatal CVD event, smoking status (cigarette smoker, yes versus no) at screening, and annual visit 6 measures of smoking status, cigarettes per day, alcoholic drinks per week, physical activity, LDL cholesterol, resting electrocardiogram abnormality, and each of the other metabolic syndrome conditions. Drug use includes

‡

insulin/hypoglycemic agents,

§

lipid-lowering agents, or

antihypertensive agents.

‖

P values correspond to z tests for interactions of metabolic syndrome with each condition.

View Large

The Multiple Risk Factor Intervention Trial was conducted under contract with the National Heart, Lung, and Blood Institute (NHLBI), Bethesda, MD. This work was supported by NHLBI Grants no. R01-HL-43232 and no. R01-HL-68140.

These results were presented in part at the American Heart Association Scientific Sessions 2003.

1.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults: Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III).
JAMA
 
285
:
2486
–2497,
2001
2.
Alberti KG, Zimmet PZ: Definition, diagnosis, and classification of diabetes mellitus and its complications. I. Diagnosis and classification of diabetes mellitus provisional report of a WHO consultation.
Diabet Med
 
15
:
539
–553,
1998
3.
Balkau B, Charles MS: Comment of the provisional report from the WHO consultation: European Group for the Study of Insulin Resistance (EGIR).
Diabet Med
 
16
:
442
–443,
1999
4.
Zimmet P, Alberti G, Shaw J: A new IDF worldwide definition of the metabolic syndrome: the rationale and the results.
Diabetes Voice
 
50
:
31
–33,
2005
5.
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
 
287
:
356
–359,
2002
6.
Eckel RH, Grundy SM, Zimmet PZ: The metabolic syndrome.
Lancet
 
365
:
1415
–1428,
2005
7.
Janssen I, Katzmarzyk PT, Ross R: Body mass index, waist circumfrence, and health risk: evidence in support of current National Institutes of Health guidelines.
Arch Intern Med
 
162
:
2074
–2079,
2002
8.
Resnick HE, Jones K, Ruotolo G, Jain AK, Henderson J, Lu W, Howard BV: Insulin resistance, the metabolic syndrome, and risk of incident cardiovascular disease in nondiabetic American Indians.
Diabetes Care
 
26
:
861
–867,
2003
9.
Ridker PM, Buring JE, Cook NR, Rifai N: C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events.
Circulation
 
107
:
391
–397,
2003
10.
Park Y-W, Zhu S, Palaniappan L, Heshka S, Carnethon MR, Heymsfield SB: The metabolic syndrome: prevalence and associated risk factor findings in the US population from the Third National Health and Nutrition Examination Survey, 1988–1994.
Arch Intern Med
 
163
:
427
–436,
2003
11.
Alexander CM, Landsman PB, Teutsch SM, Haffner SM: NCEP-defined metabolic syndrome, diabetes, and prevalence of coronary heart disease among NHANES III participants age 50 years and older.
Diabetes
 
52
:
1210
–1214,
2003
12.
Meigs JB, Wilson PWF, Nathan DM, D’Agostino RB Sr, Williams K, Haffner SM: Prevalence and characteristics of the metabolic syndrome in the San Antonio Heart and Framingham Offspring studies.
Diabetes
 
52
:
2160
–2167,
2003
13.
Jacobson TA, Case CC, Roberts S, Buckley A, Murtaugh KM, Sung JC, Gause D, Varas C, Ballantyne CM: Characteristics of US adults with the metabolic syndrome and therapeutic implications.
Diabetes Obes Metab
 
6
:
353
–362,
2004
14.
Laaksonen DE, Lakka H-M, Niskanen LK, Kaplan GA, Salonen JT, Lakka TA: Metabolic syndrome and development of diabetes mellitus: application and validation of recently suggested definitions of the metabolic syndrome in a prospective cohort study.
Am J Epidemiol
 
156
:
1070
–1077,
2002
15.
Lakka H-M, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E, Tuomilehto J, Salonen JT: The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men.
JAMA
 
288
:
2709
–2716,
2002
16.
Bonora E, Kiechl S, Willeit J, Oberhollenzer F, Egger G, Bonadonna RC, Muggeo M: Carotid atherosclerosis and coronary heart disease in the metabolic syndrome.
Diabetes Care
 
26
:
1251
–1257,
2003
17.
Anand SS, Yi Q, Gerstein H, Lonn E, Jacobs R, Vuksan V, Teo K, Davis B, Montague P, Yusuf S, the Study of Health Assessment and Risk in Ethnic Groups (SHARE) and Study of Health Assessment and Risk Evaluation in Aboriginal Peoples (SHARE-AP) Investigators: Relationship of metabolic syndrome and fibrinolytic dysfunction to cardiovascular disease.
Circulation
 
108
:
420
–425,
2003
18.
Athyros VG, Mikhailidis DP, Papageorgiou AA, Didangelos TP, Ganotakis ES, Symeonidis AN, Daskalopoulou SS, Kakafika AI, Elisaf M, the METS-GREECE Collaborative Group: Prevalence of atherosclerotic vascular disease among subjects with the metabolic syndrome with or without diabetes mellitus: the METS-GREECE Multicentre Study.
Curr Med Res Opin
 
20
:
1691
–1701,
2004
19.
Lawlor DA, Ebrahim S, Davey Smith G: The metabolic syndrome and coronary heart disease in older women: findings from the British Women’s Heart and Health Study.
Diabet Med
 
21
:
906
–913,
2004
20.
Hu G, Qiao Q, Tuomilehto J, Balkau B, Borch-Johnsen K, Pyorala K, the DECODE Study Group: Prevalence of the metabolic syndrome and its relation to all-cause and cardiovascular mortality in nondiabetic European men and women.
Arch Intern Med
 
164
:
1066
–1076,
2004
21.
Gupta R, Deedwania PC, Gupta A, Rastogi S, Panwar RB, Kothari K: Prevalence of metabolic syndrome in an Indian urban population.
Int J Cardiol
 
97
:
257
–261,
2004
22.
Thomas GN, Ho SY, Janus ED, Lam KS, Hedley AJ, Lam TH, the Hong Kong Cardiovascular Risk Factor Prevalence Study Steering Committee: The US National Cholesterol Education Programme Adult Treatment Panel III (NCEP ATP III): prevalence of the metabolic syndrome in a Chinese population.
Diabetes Res Clin Pract
 
67
:
251
–257,
2005
23.
Yoon YS, Oh SW, Baik HW, Park HS, Kim WY: Alcohol consumption and the metabolic syndrome in Korean adults: the 1998 Korean National Health and Nutrition Examination Survey.
Am J Clin Nutr
 
80
:
217
–224,
2004
24.
Kim MH, Kim MK, Choi BY, Shin YJ: Prevalence of the metabolic syndrome and its association with cardiovascular diseases in Korea.
J Korean Med Sci
 
19
:
195
–201,
2004
25.
Flegal KM, Carroll MD, Ogden CL, Johnson CL: Prevalence and trends in obesity among US adults, 1999–2000.
JAMA
 
288
:
1723
–1727,
2002
26.
Mokdad AH, Bowman BA, Ford ES, Vinicor F, Marks JS, Koplan JP: The continuing epidemics of obesity and diabetes in the United States.
JAMA
 
286
:
1195
–1200,
2001
27.
Zimmet P, Alberti KGMM, Shaw J: Global and societal implications of the diabetes epidemic.
Nature
 
414
:
782
–787,
2001
28.
Lahti-Koski M, Jousilahti, Pietinen P: Secular trends in body mass index by birth cohort in eastern Finland from 1972 to 1997.
Int J Obes
 
25
:
727
–734,
2001
29.
Haffner S, Taegtmeyer H: Epidemic obesity and the metabolic syndrome.
Circulation
 
108
:
1541
–1545,
2003
30.
Kereiakes DJ, Willerson JT: Metabolic syndrome epidemic.
Circulation
 
108
:
1552
–1553,
2003
31.
Rantala AO, Kauma H, Lilja M, Savolainen MJ, Reunanen, Kesäniemi YA: Prevalence of the metabolic syndrome in drug-treated hypertensive patients and control subjects.
J Intern Med
 
245
:
163
–174,
1999
32.
Isomaa B, Almgren P, Tuomi T, Forsen B, Lahti K, Nissen M, Taskinen M-R, Groop L: Cardiovascular morbidity and mortality associated with the metabolic syndrome.
Diabetes Care
 
24
:
683
–689,
2001
33.
Tonstad S, Hjermann I: A high risk score for coronary heart disease is associated with the metabolic syndrome in 40-year-old men and women.
J Cardiovasc Risk
 
10
:
129
–135,
2003
34.
Bruno G, Merletti F, Biggeri A, Bargero G, Ferrero S, Runzo C, Prina Cerai S, Pagano G, Cavallo-Perin P, the Casale Monferrato Study: Metabolic syndrome as a predictor of all-cause and cardiovascular mortality in type 2 diabetes: the Casale Monferrato Study.
Diabetes Care
 
27
:
2689
–2694,
2004
35.
Marchesini G, Forlani G, Cerrelli F, Manini R, Natale S, Baraldi L, Ermini G, Savorani G, Zocchi D, Melchionda N: WHO and ATPIII proposals for the definition of the metabolic syndrome in patients with type 2 diabetes.
Diabet Med
 
21
:
383
–387,
2004
36.
Solymoss BC, Bourassa MG, Lesperance J, Levesque S, Marcil M, Varga S, Campeau L: Incidence and clinical characteristics of the metabolic syndrome in patients with coronary artery disease.
Coron Artery Dis
 
14
:
207
–212,
2003
37.
Marroquin OC, Kip KE, Kelley DE, Johnson BD, Shaw LJ, Bairey Merz CN, Sharaf BL, Pepine CJ, Sopko G, Reis SE, the Women’s Ischemia Syndrome Evaluation Investigators: Metabolic syndrome modifies the cardiovascular risk associated with angiographic coronary artery disease in women.
Circulation
 
109
:
714
–721,
2004
38.
Ford ES: Risks for all-cause mortality, cardiovascular disease, and diabetes associated with the metabolic syndrome: a summary of the evidence.
Diabetes Care
 
28
:
1769
–1778,
2005
39.
Sattar N, Gaw A, Scherbakova O, Ford I, O’Reilly D StJ Haffner SM, Isles C, Macfarlane PW, Packard CH, Cobbe SM, Shepherd J: Metabolic syndrome with and without C-reactive protein as a predictor of coronary heart disease and diabetes in the West of Scotland Coronary Prevention Study.
Circulation
 
108
:
414
–419,
2003
40.
Reilly MP, Wolfe ML, Rhodes T, Girman C, Mehta N, Rader DJ: Measures of insulin resistance add incremental value to the clinical diagnosis of metabolic syndrome in association with coronary atherosclerosis.
Circulation
 
110
:
803
–809,
2004
41.
Rutter MK, Meigs JB, Sullivan LM, D’Agostino RB Sr, Wilson PW: C-reactive protein, the metabolic syndrome, and prediction of cardiovascular events in the Framingham Offspring Study.
Circulation
 
110
:
380
–385,
2004
42.
Malik S, Wong ND, Franklin SS, Kamath TV, L’Italien GJ, Pio JR, Rhys Williams G: Impact of the metabolic syndrome on mortality from coronary heart disease, cardiovascular disease, and all causes in United States adults.
Circulation
 
110
:
1245
–1250,
2004
43.
Ford ES: The metabolic syndrome and mortality from cardiovascular disease and all-causes: findings from the National Health and Nutrition Examination Survey II Mortality Study.
Atherosclerosis
 
173
:
309
–314,
2004
44.
Multiple Risk Factor Intervention Trial Research Group: Statistical design considerations in the NHLI Multiple Risk Factor Intervention Trial.
J Chronic Dis
 
30
:
261
–275,
1977
45.
Multiple Risk Factor Intervention Trial Research Group: Multiple risk factor intervention trial: risk factor changes and mortality results.
JAMA
 
248
:
1465
–1477,
1982
46.
Multiple Risk Factor Intervention Trial Research Group: Mortality after 16 years for participants randomized to the Multiple Risk Factor Intervention Trial.
Circulation
 
94
:
946
–951,
1996
47.
Neaton JD, Grimm RH Jr, Cutler JA: Recruitment of participants for the Multiple Risk Factor Intervention Trial (MRFIT).
Control Clin Trials
 
8 (Suppl. 4)
:
41S
–53S,
1987
48.
Benfari RC: The Multiple Risk Factor Intervention Trial (MRFIT): III. The model for intervention.
Prev Med
 
10
:
426
–442,
1981
49.
Widdowson GM, Kuehneman M, DuChene AG, Hulley SB, Cooper GR: Quality control of biochemical data in the Multiple Risk Factor Intervention Trial: central l.
Control Clin Trials
 
7 (Suppl. 3)
:
17S
–33S,
1986
50.
Cohen JD, Grimm RH Jr, McFate Smith W: Multiple Risk Factor Intervention Trial (MRFIT): VI. Intervention on blood pressure.
Prev Med
 
10
:
501
–518,
1981
51.
Prineas RJ, Crow R, Blackburn H:
The Minnesota Code Manual of Electrocardiographic Findings
. Littleton, MA, John Wright PSG,
1982
52.
Multiple Risk Factor Intervention Trial Research Group: Coronary heart disease death, nonfatal acute myocardial infarction, and other clinical outcomes in the Multiple Risk Factor Intervention Trial.
Am J Cardiol
 
58
:
1
–13,
1986
53.
Wentworth D, Neaton JD, Rasmussen W: An evaluation of the Social Security Administration Master Beneficiary Record Index File and the National Death Index in the ascertainment of vital status.
Am J Public Health
 
73
:
1270
–1274,
1982
54.
Boyle CA, Decoufle P: National sources of vital status information: extent of coverage and possible selectivity in reporting.
Am J Epidemiol
 
131
:
160
–168,
1990
55.
Calle EE, Terrell DD: Utility of the National Death Index for ascertainment of mortality among Cancer Prevention Study II participants.
Am J Epidemiol
 
137
:
235
–241,
1993
56.
Horm J:
Assignment of Probabilistic Scores to National Death Index Record Matches
. Hyattsville, MD, National Center for Health Statistics,
1996
57.
Lash TL, Silliman RA: A comparison of the National Death Index and Social Security Administration databases to ascertain vital status.
Epidemiology
 
12
:
259
–261,
2001
58.
International Classification of Diseases, 9th Revision, North American Clinical Modification
. Vol. 
I
. Ann Arbor, MI, Edwards Brothers,
1981
59.
World Health Organization:
International Classification of Diseases, 10th Revision
. Geneva, World Health Org.,
1992
60.
Sathiakumar N, Delzell E, Abdalla O: Using the National Death Index to obtain underlying cause of death codes.
J Occup Environ Med
 
40
:
808
–813,
1998
61.
Doody MM, Hayes HM, Bilgrad R: Comparability of National Death Index Plus and standard procedures for determining causes of death in epidemiologic studies.
Ann Epidemiol
 
11
:
46
–50,
2001
62.
Cox DR: Regression models and life tables with discussion.
J R Stat Soc
 
34
:
187
–220,
1972
63.
Kissebah AH, Vydelingum N, Murray R, Evans DJ, Hartz AJ, Kalkhoff RK, Adams PW: Relation of body fat distribution to metabolic complications of obesity.
J Clin Endocrinol Metab
 
54
:
254
–260,
1982
64.
Frayn KN: Adipose tissue as a buffer for daily lipid flux.
Diabetologia
 
45
:
1201
–1210,
2002
65.
Fujioka S, Matsuzawa Y, Tokunaga K, Kawamoto T, Kobatake T, Keno Y, Kotani K, Yoshida S, Tarui S: Improvement of glucose and lipid metabolism associated with selective reduction of intra-abdominal visceral fat in premenopausal women with visceral fat obesity.
Int J Obes
 
15
:
853
–859,
1991
66.
Yanagisawa K: [The effects of body fat distribution on glucose tolerance in overweight subjects: glucose intolerance and insulin resistance induced by intra-abdominal fat accumulation.]
Nippon Naibunpi Gakkai Zasshi
 
67
:
1240
–1251,
1991
[article in Japanese]
67.
Bosello O, Zamboni M: Visceral obesity and metabolic syndrome.
Obes Rev
 
1
:
47
–56,
2000
68.
Kobayashi H, Nakamura T, Miyaoka K, Nishida M, Funahashi T, Yamashita S, Matsuzawa Y: Visceral fat accumulation contributes to insulin resistance, small-sized low-density lipoprotein, and progression of coronary artery disease in middle-aged nonobese Japanese men.
Jpn Circ J
 
65
:
193
–199,
2001
69.
Nagaretani H, Nakamura T, Funahashi T, Kotani K, Miyanaga M, Tokunaga K, Takahashi M, Nishizawa H, Kishida K, Kuriyama H, Hotta K, Yamshita S, Matsuzawa Y: Visceral fat is a major contributor for multiple risk factor clustering in Japanese men with impaired glucose tolerance.
Diabetes Care
 
24
:
2127
–2133,
2001
70.
Reaven GM: The insulin resistance syndrome.
Curr Atheroscler Rep
 
5
:
364
–371,
2003
71.
Cheal KL, Abbasi F, Lamendola C, McLaughlin T, Reaven GM, Ford ES: Relationship to insulin resistance of the adult treatment panel III diagnostic criteria for identification of the metabolic syndrome.
Diabetes
 
53
:
1195
–1200,
2004
72.
Ascaso JF, Pardo S, Real JT, Lorente RI, Priego A, Carmena R: Diagnosing insulin resistance by simple quantitative methods in subjects with normal glucose metabolism.
Diabetes Care
 
26
:
3320
–3325,
2003
73.
Kahn R, Buse J, Ferrannini E, Stern M: The metabolic syndrome: time for a critical appraisal: joint statement from the American Diabetes Association and the European Association for the Study of Diabetes.
Diabetes Care
 
28
:
2289
–2304,
2005
74.
Yarnell JW, Patterson CC, Bainton D, Sweetnam PM: Is metabolic syndrome a discrete entity in the general population? Evidence from the Caerphilly and Speedwell population studies.
Heart
 
79
:
248
–252,
1998
75.
Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, Gordon DJ, Krauss RM, Savage PJ, Smith SC, Spertus JA, Costa F: Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement.
Circulation
 
112
:
2735
–2752,
2005
76.
Mitka M: Metabolic syndrome recasts old cardiac, diabetes risk factors as a “new” entity.
JAMA
 
291
:
2062
–2063,
2004
77.
National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults: Summary of the second report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II).
JAMA
 
269
:
3015
–3023,
1993

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

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