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Relation of the Number of Metabolic Syndrome Risk Factors With All-Cause and Cardiovascular Mortality
Relation of the Number of Metabolic Syndrome Risk Factors With All-Cause and Cardiovascular Mortality John S. Ho, MDa,*, John J. Cannaday, MDa, Carolyn E. Barlow, MSb, Tedd L. Mitchell, MDa, Kenneth H. Cooper, MDa, Shannon J. FitzGerald, PhDa The metabolic syndrome (MS) is a constellation of risk factors associated with diabetes and cardiovascular disease. This syndrome consists of at least 3 parameters assessing central obesity, hypertension, high-density lipoprotein cholesterol, triglycerides, and impaired glucose metabolism. Whether persons with 4 or 5 risk factors are at higher risk than those with 3 risk factors is unclear. Also unclear is whether those without the MS but with 1 or 2 risk factors warrant therapy. We assessed cardiovascular and all-cause mortality as a function of the number of these risk factors. We followed 30,365 men for a median follow-up of 13.6 years. During follow-up, 1,449 participants died, 527 from cardiovascular causes. All of the individual parameters defining the MS were significantly associated with both all-cause and cardiovascular mortality (p <0.001). After adjustment for age and the other MS variables, hypertension was the most potent risk factor whereas central obesity and hypertriglyceridemia remained associated with both all-cause and cardiovascular mortality. A highly significant trend was also noted between both all-cause or cardiovascular mortality and the number of risk factors (p <0.001 for trend). Risk increased incrementally, beginning at 1 risk factor for cardiovascular mortality and at 2 risk factors for all-cause mortality. In conclusion, there is a continuum of risk as the number of metabolic syndrome risk factors increases. These findings add to the growing evidence that central obesity can independently and adversely affect health. © 2008 Elsevier Inc. All rights reserved. (Am J Cardiol 2008;102:689 – 692) At present, whether the number of component risk factors is important in defining the metabolic syndrome (MS) is unclear. Should persons with 1 or 2 of these risk factors be considered as not having the MS? Conversely, are persons with 4 or 5 risk factors at greater risk than those with MS with 3 risk factors? To answer these questions, we assessed cardiovascular and all-cause mortality as a function of the number of MS risk factors. Materials and Methods The study group included all eligible men from 1979 to 2004 who presented to our institution for a preventive medical examination. Participants gave informed consent before participation in the Aerobics Center Longitudinal Study, which was approved annually by The Cooper Institute Institutional Review Board. All study participants underwent questioning by a physician regarding the presence of any of the traditional cardiovascular risk factors. Diabetes was defined as a previously documented fasting blood glucose of ⱖ126 mg/dL or
a
Cooper Clinic, Dallas, Texas; and bThe Cooper Institute, Dallas, Texas. Manuscript received March 21, 2008; revised manuscript received and accepted May 1, 2008. The development of the Aerobics Center Longitudinal Study database was partially supported by Grants AG06945 and HL62508 and by the Communities Foundation of Texas on recommendation of Nancy Ann and Ray L. Hunt. *Corresponding author: Tel: 972-560-2741; fax: 972-560-2681. E-mail address: [email protected] (J.S. Ho). 0002-9149/08/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2008.05.010
treatment with antidiabetic medications. Hypertension was either self-reported or defined as a previously documented systolic blood pressure ⱖ140 mm Hg or a diastolic blood pressure ⱖ90 mm Hg (or both). Hyperlipidemia was either self-reported or defined as a previously documented total cholesterol level of ⱖ200 mg/dL. Moreover, all participants were questioned regarding current tobacco or cigarette use. Participants also underwent objective assessments for each of the MS components. Each of these MS components was defined per the updated and most recent MS definition put forth by the American Heart Association (AHA) and National Heart, Lung, and Blood Institute (NHLBI) in 2005.1 Per these guidelines, the metabolic syndrome is present when at least 3 of various metabolic abnormalities exist in an individual. These defining parameters include a) fasting plasma glucose ⱖ100 mg/dL; b) high-density lipoprotein (HDL) cholesterol ⬍40 mg/dL in men or ⬍50 mg/dL in women; c) triglycerides ⱖ150 mg/dL; d) waist circumference ⬎102 cm in men or ⬎88 cm in women; and e) systolic blood pressure ⱖ130 mm Hg or diastolic blood pressure ⱖ85 mm Hg or self-report of hypertension. This most recent MS definition mirrors the guidelines provided by the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III),2 with the exception that the cut-off point for impaired fasting glucose was lowered from 110 mg/dl to 100 mg/dl. Follow-up of the study participants continued either until their death or until December 31, 2004. Deaths were identified from the National Center for Health Statistics’ National Death Index. Cardiovascular mortality was defined as www.AJConline.org
690
The American Journal of Cardiology (www.AJConline.org)
Table 1 Baseline characteristics based on vital status in men, Aerobics Center Longitudinal Study, 1979 to 2004 Variable
Alive (n ⫽ 28916)
Dead – All Causes (n ⫽ 1449)
Dead – CVD (n ⫽ 527)
Age (yrs) Hypertension Diabetes mellitus Hyperlipidemia Current tobacco use Triglyceride (mg/dL) Total cholesterol (mg/dL) Non-HDL cholesterol (mg/dL) HDL cholesterol (mg/dL) Glucose (mg/dL) Systolic Blood Pressure (mmHg) Diastolic Blood Pressure (mmHg) Waist girth (cm) High triglycerides Low HDL High glucose
44 ⫾ 10 31.8% 4.9% 59.5% 16.7% 113 (79,168) 207.9 ⫾ 4.2 162.2 ⫾ 44.6 45.9 ⫾ 12.3 100.3 ⫾ 16.9 121.4 ⫾ 13.3 81.5 ⫾ 9.6 94.2 ⫾ 11.1 31.4% 32.9% 44.1%
52 ⫾ 11* 47.1%* 7.0%* 67.7%* 26.9%* 129 (88,190)* 218.8 ⫾ 43.2* 174.7 ⫾ 44.8* 44.0 ⫾ 12.5* 108.0 ⫾ 32.3* 126.1 ⫾ 15.6* 83.5 ⫾ 10.4* 96.9 ⫾ 11.5* 39.6%* 40.9%* 56.6%*
55 ⫾ 10* 57.5%* 14.6%* 75.1%* 26.8%* 140 (97,205)* 226.9 ⫾ 43.3* 184.2 ⫾ 43.3* 42.7 ⫾ 12.1* 111.3 ⫾ 34.9* 129.7 ⫾ 16.7* 85.2 ⫾ 10.8* 98.9 ⫾ 12.2* 45.2%* 44.2%* 59.4*
* p ⬍0.001 when compared to those alive.
Table 2 Hazard ratios* (95% CI) for all-cause and cardiovascular mortality according to presence of metabolic factors, Aerobics Center Longitudinal Study, 1979 to 2004 Variable High abdominal obesity High triglycerides Low HDL Hypertension Impaired fasting glucose
All-Cause Mortality
Cardiovascular Mortality
1.32 (1.17, 1.50) 1.13 (1.01, 1.28) 1.10 (0.99, 1.30) 1.42 (1.27, 1.58) 1.10 (0.99, 1.23)
1.52 (1.25, 1.84) 1.31 (1.08, 1.58) 1.18 (0.98, 1.43) 1.84 (1.52, 2.23) 1.07 (0.89, 1.28)
* Adjusted for age plus all other variables in the model.
Codes 390 to 449.9 of the International Classification of Diseases, Ninth Revision. We compared descriptive characteristics of participants by vital status. The age-adjusted incidence rates of all-cause and cardiovascular mortality were reported according to the number of MS components present (0-5). We used Cox’s proportional hazard regression to determine the age-adjusted hazard ratio for all-cause and cardiovascular mortality according to the presence of specific metabolic risk factors as defined by the updated NCEP-ATP III guidelines put forth by the AHA and NHLBI1. 95% confidence intervals (CI) around all hazard ratios were calculated. We also determined the hazard ratios for all-cause and cardiovascular mortality by the number of MS components present. These models were adjusted for age, non-HDL cholesterol, hypertension, health status, and current smoking. We conducted all data analyses using SAS 9.1 statistical software (SAS Institute, Inc., Cary, North Carolina). Results The study population consisted of 30,365 men who presented to our clinic from 1979 to 2004 and gave consent for inclusion in the Aerobics Center Longitudinal Study. These patients were followed to December 31, 2004, for a median
Figure 1. Mortality rates/10,000 person-years by number of metabolic components present. The striped bars represent all-cause mortality and the white bars represent cardiovascular mortality.
follow-up of 13.6 years. The average baseline age was 44.4 ⫾ 10 years. There was a low baseline prevalence of diabetes (5%) and of current tobacco use (17.2%). Hypertension was present in 32.5% of the study participants, whereas hyperlipidemia was seen in 40% to 50% of the study group. Table 1 compares the baseline characteristics and laboratory values of the study participants who survived to those who died during follow-up. Age and the traditional cardiovascular risk factors of hypertension, hyperlipidemia, diabetes, and current tobacco use were found to be significantly associated with all-cause mortality. The laboratory abnormalities defining the presence of the MS were also significantly associated with all-cause mortality. Fasting glucose, triglyceride levels, systolic blood pressure, diastolic blood pressure, and abdominal girth were all higher in those who
Preventive Cardiology/Metabolic Syndrome Risk Factors and Mortality Table 3 Hazard ratios* (95% CI) for all-cause and cardiovascular mortality according to number of metabolic syndrome components present, Aerobics Center Longitudinal Study, 1979 to 2004 Number of Metabolic Syndrome Components Present 0 1 2 3 4 5
All-Cause Mortality
Cardiovascular Mortality
1.00 1.20 (0.98, 1.46) 1.58 (1.30, 1.92) 1.70 (1.38, 2.09) 1.83 (1.82, 3.35) 2.60 (1.99, 3.41)
1.00 1.83 (1.21, 2.77) 2.43 (1.63, 3.63) 2.82 (1.87, 4.25) 2.81 (1.81, 4.34) 5.52 (3.48, 8.75)
* Adjusted for age, non-HDL cholesterol, health status, and smoking status. Table 4 Hazard ratios* (95% CI) for all-cause and cardiovascular mortality in nonhypertensives according to number of metabolic syndrome components present, Aerobics Center Longitudinal Study, 1979 to 2004 Number of Metabolic Syndrome Components Present 0 1 2 3 4
All-Cause Mortality
Cardiovascular Mortality
1.00 1.15 (0.94, 1.40) 1.37 (1.11, 1.69) 1.47 (1.14, 1.89) 1.86 (1.31, 2.65)
1.00 1.27 (0.85, 1.88) 1.65 (1.09, 2.48) 1.88 (1.19, 2.96) 2.91 (1.67, 5.07)
* Adjusted for age, non-HDL cholesterol, health status, and smoking status.
died than in those who survived. Conversely, HDL cholesterol was lower in those who died than in those who survived. Similar results were found when a similar analysis for cardiovascular mortality was performed. Table 2 describes the adjusted hazard ratios of the individual MS risk factors for all-cause and cardiovascular mortality. Hypertension, hypertriglyceridemia, and central obesity were associated with both all-cause and cardiovascular mortality. A low HDL level and an impaired fasting glucose were not significantly associated with either allcause or cardiovascular mortality after adjustment for age and the other MS risk factors. Figure 1 plots all-cause and cardiovascular mortality rates as a function of the number of MS risk factors. A highly significant relation was noted. As more MS risk factors were present, the mortality rate increased. A similar relation was seen with cardiovascular mortality rates. Table 3 lists the adjusted hazard ratios (HRs) for both all-cause and cardiovascular mortality as a function of the number of individual MS risk factors. MS risk factors were a stronger predictor for cardiovascular mortality (HR 1.83 to 5.52) than for all-cause mortality (HR 1.20 to 2.60). In addition, risk for both all-cause and cardiovascular mortality increased as the number of MS risk factors increased. To rule out an overriding role of hypertension, a subgroup analysis was also performed on those without hypertension (Table 4). This analysis revealed a similar relation between the number of risk factors and increasing mortality from either all-cause or cardiovascular causes. We did, however, note a significant weakening of this relation when hypertension was excluded.
691
Discussion Our study is among the largest to date to formally evaluate the relation of MS risk factors with all-cause and cardiovascular mortality. Previous studies3–7 have mostly focused upon the metabolic syndrome as an “all-or-none” condition, not distinguishing those with 3 risk factors from those with either 4 or 5 risk factors. Moreover, those with 1 to 2 risk factors were categorized as not having the metabolic syndrome. The results of our study suggest that this method of distinguishing those with from those without MS can potentially underestimate mortality risk. An increasing gradient of risk appears to increase as the number of MS risk factors increase. This relation exists for both all-cause and cardiovascular mortality, independent of the other traditional cardiovascular risk factors. This increased risk begins with the presence of just 1 MS risk factor for cardiovascular mortality and with 2 risk factors for all-cause mortality. Moreover, the increased risk does not plateau after the presence of 3 MS risk factors. Our findings are in line with multiple studies3–7 noting an increased risk for all-cause or cardiovascular mortality when the MS is present. Wilson et al3 and Isomaa et al4 noted an increased cardiovascular mortality rate when the MS was present. Subsequently, Hunt et al,5 Katzmarzyk et al,6 and Lakka et al7 noted an increased risk for both all-cause and cardiovascular mortality with the MS. However, none of these studies formally evaluated the relation of the number of MS risk factors with mortality risk. Recently, several studies have evaluated the mortality risk of 1 to 2 MS risk factors. In a study by Malik et al,8 1 to 2 metabolic syndrome risk factors were predictive of coronary heart disease and cardiovascular mortality but not for all-cause mortality. In a study by Hu et al,9 more than 2 metabolic syndrome risk factors were predictive of both cardiovascular and all-cause mortality. In an early study by Ford10 and in another recent study by Kadota et al,11 a positive but statistically insignificant trend was noted between the number of MS risk factors and all-cause mortality. Our study confirms that mortality risk increases with either 1 or 2 MS risk factors. Moreover, there appears to be no “plateau” effect because the presence of 4 or 5 risk factors confers an increased mortality risk when compared with those with 3 risk factors. In the present study, hypertension was found to be the most potent predictor of both all-cause and cardiovascular mortality, even after adjustment for the other MS risk factors. This finding was not unexpected because hypertension is a well known and traditional cardiovascular risk factor. Our study is also in accord with the results of Isomaa et al,4 Hunt et al,5 and Malik et al8, who noted increased cardiovascular mortality with hypertension. Somewhat surprisingly, neither low HDL nor impaired fasting glucose exhibited a significant association with either all-cause or cardiovascular mortality in this study after adjustment for the other risk factors. In contrast to these findings, impaired fasting glucose was associated with allcause mortality in studies by Malik et al8 and Ford.10 In studies by Malik et al8 and Schillaci et al,12 low HDL was associated with coronary heart disease. We surmise that the
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present study was underpowered to detect a mortality effect with these parameters because relatively little clinical variation was seen with either the HDL or fasting blood glucose levels. In contrast, central obesity and hypertriglyceridemia proved particularly significant in this study. Like hypertension, a well-validated traditional risk factor, both of these MS components increased all-cause and cardiovascular mortality in this study, even after adjustment for the other risk factors. Previous work examining this issue has been mixed. In a study by Schillaci et al,12 central obesity was not significantly associated with an increase in cardiovascular event rate. In the study by Hunt et al,5 central obesity was associated with increased cardiovascular mortality, although this finding was not adjusted for the presence of the other MS risk factors. Our findings lend credence to the growing body of evidence that central obesity can independently and adversely affect health. Although intriguing, this study has limitations. The study was observational in nature, and our analysis may not have taken into account all confounding variables. Moreover, we utilized mortality data from the National Center for Health Statistics, and the effects of misclassification and underreporting could not be estimated. Acknowledgment: We thank the Cooper Clinic physicians, nurses, and technicians for collecting the baseline data and The Cooper Institute for maintaining the database. 1. Grundy S, Cleeman J, Daniels S, Donato K, Eckel R, Franklin B, Gordon D, Krauss R, Savage P, Smith S, Spertus J, Costa F. Diagnosis and management of the metabolic syndrome. An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005;112:2735–2752.
2. 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 2001;285:2486 –2497. 3. Wilson P, Kannel W, Silbershatz H, D’Agostino R. Clustering of metabolic factors and coronary heart disease. Arch Intern Med 1999; 159:1104 –1109. 4. Isomaa B, Almgren P, Tuomi T, Forsen B, Lahti K, Nissen M, Taskinen M, Groop L. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 2001;24:683– 689. 5. Hunt K, Resendez R, Williams K, Haffner S, Stern M. National Cholesterol Education Program versus World Health Organization metabolic syndrome in relation to all-cause and cardiovascular mortality in the San Antonio Heart Study. Circulation 2004;110:1251– 1257. 6. Katzmarzyk P, Church T, Blair S. Cardiorespiratory fitness attenuates the effects of the metabolic syndrome on all-cause and cardiovascular disease mortality in men. Arch Intern Med 2004;164:1092–1097. 7. Lakka H, Laaksonen D, Lakka T, Niskanen L, Kumpusalo E, Tuomilehto J, Salonen J. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 2002;288:2709 – 2716. 8. Malik S, Wong N, Franklin S, Kamath T, L’Italien G, Pio J, Williams G. Impact of the metabolic syndrome on mortality from coronary heart disease, cardiovascular disease, and all causes in United States adults. Circulation 2004;110:1245–1250. 9. Hu G, Qiao Q, Tuomilehto J, Balkau B, Borch-Johnsen K, Pyorala K, for 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 2004;164:1066 – 1076. 10. Ford E. The metabolic syndrome and mortality from cardiovascular disease and all-causes: findings from the National Health and Nutrition Examination Survey II mortality study. Atherosclerosis 2004;173: 309 –314. 11. Kadota A, Hozawa A, Okamura T, Kadowak T, Nakmaura K, Murakami Y, Hayakawa T, Kita Y, Okayama A, Nakamura Y, et al., for the NIPPON DATA Research Group. Relationship between metabolic risk factor clustering and cardiovascular mortality stratified by high blood glucose and obesity. Diabetes Care 2007;30:1533–1538. 12. Schillaci G, Pirro M, Vaudo G, Gemilli F, Marchesi S, Porcellati C, Mannarino E. Prognostic value of the metabolic syndrome in essential hypertension. J Am Coll Cardiol 2004;43:1817–1822.
a
Cooper Clinic, Dallas, Texas; and bThe Cooper Institute, Dallas, Texas. Manuscript received March 21, 2008; revised manuscript received and accepted May 1, 2008. The development of the Aerobics Center Longitudinal Study database was partially supported by Grants AG06945 and HL62508 and by the Communities Foundation of Texas on recommendation of Nancy Ann and Ray L. Hunt. *Corresponding author: Tel: 972-560-2741; fax: 972-560-2681. E-mail address: [email protected] (J.S. Ho). 0002-9149/08/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2008.05.010
treatment with antidiabetic medications. Hypertension was either self-reported or defined as a previously documented systolic blood pressure ⱖ140 mm Hg or a diastolic blood pressure ⱖ90 mm Hg (or both). Hyperlipidemia was either self-reported or defined as a previously documented total cholesterol level of ⱖ200 mg/dL. Moreover, all participants were questioned regarding current tobacco or cigarette use. Participants also underwent objective assessments for each of the MS components. Each of these MS components was defined per the updated and most recent MS definition put forth by the American Heart Association (AHA) and National Heart, Lung, and Blood Institute (NHLBI) in 2005.1 Per these guidelines, the metabolic syndrome is present when at least 3 of various metabolic abnormalities exist in an individual. These defining parameters include a) fasting plasma glucose ⱖ100 mg/dL; b) high-density lipoprotein (HDL) cholesterol ⬍40 mg/dL in men or ⬍50 mg/dL in women; c) triglycerides ⱖ150 mg/dL; d) waist circumference ⬎102 cm in men or ⬎88 cm in women; and e) systolic blood pressure ⱖ130 mm Hg or diastolic blood pressure ⱖ85 mm Hg or self-report of hypertension. This most recent MS definition mirrors the guidelines provided by the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III),2 with the exception that the cut-off point for impaired fasting glucose was lowered from 110 mg/dl to 100 mg/dl. Follow-up of the study participants continued either until their death or until December 31, 2004. Deaths were identified from the National Center for Health Statistics’ National Death Index. Cardiovascular mortality was defined as www.AJConline.org
690
The American Journal of Cardiology (www.AJConline.org)
Table 1 Baseline characteristics based on vital status in men, Aerobics Center Longitudinal Study, 1979 to 2004 Variable
Alive (n ⫽ 28916)
Dead – All Causes (n ⫽ 1449)
Dead – CVD (n ⫽ 527)
Age (yrs) Hypertension Diabetes mellitus Hyperlipidemia Current tobacco use Triglyceride (mg/dL) Total cholesterol (mg/dL) Non-HDL cholesterol (mg/dL) HDL cholesterol (mg/dL) Glucose (mg/dL) Systolic Blood Pressure (mmHg) Diastolic Blood Pressure (mmHg) Waist girth (cm) High triglycerides Low HDL High glucose
44 ⫾ 10 31.8% 4.9% 59.5% 16.7% 113 (79,168) 207.9 ⫾ 4.2 162.2 ⫾ 44.6 45.9 ⫾ 12.3 100.3 ⫾ 16.9 121.4 ⫾ 13.3 81.5 ⫾ 9.6 94.2 ⫾ 11.1 31.4% 32.9% 44.1%
52 ⫾ 11* 47.1%* 7.0%* 67.7%* 26.9%* 129 (88,190)* 218.8 ⫾ 43.2* 174.7 ⫾ 44.8* 44.0 ⫾ 12.5* 108.0 ⫾ 32.3* 126.1 ⫾ 15.6* 83.5 ⫾ 10.4* 96.9 ⫾ 11.5* 39.6%* 40.9%* 56.6%*
55 ⫾ 10* 57.5%* 14.6%* 75.1%* 26.8%* 140 (97,205)* 226.9 ⫾ 43.3* 184.2 ⫾ 43.3* 42.7 ⫾ 12.1* 111.3 ⫾ 34.9* 129.7 ⫾ 16.7* 85.2 ⫾ 10.8* 98.9 ⫾ 12.2* 45.2%* 44.2%* 59.4*
* p ⬍0.001 when compared to those alive.
Table 2 Hazard ratios* (95% CI) for all-cause and cardiovascular mortality according to presence of metabolic factors, Aerobics Center Longitudinal Study, 1979 to 2004 Variable High abdominal obesity High triglycerides Low HDL Hypertension Impaired fasting glucose
All-Cause Mortality
Cardiovascular Mortality
1.32 (1.17, 1.50) 1.13 (1.01, 1.28) 1.10 (0.99, 1.30) 1.42 (1.27, 1.58) 1.10 (0.99, 1.23)
1.52 (1.25, 1.84) 1.31 (1.08, 1.58) 1.18 (0.98, 1.43) 1.84 (1.52, 2.23) 1.07 (0.89, 1.28)
* Adjusted for age plus all other variables in the model.
Codes 390 to 449.9 of the International Classification of Diseases, Ninth Revision. We compared descriptive characteristics of participants by vital status. The age-adjusted incidence rates of all-cause and cardiovascular mortality were reported according to the number of MS components present (0-5). We used Cox’s proportional hazard regression to determine the age-adjusted hazard ratio for all-cause and cardiovascular mortality according to the presence of specific metabolic risk factors as defined by the updated NCEP-ATP III guidelines put forth by the AHA and NHLBI1. 95% confidence intervals (CI) around all hazard ratios were calculated. We also determined the hazard ratios for all-cause and cardiovascular mortality by the number of MS components present. These models were adjusted for age, non-HDL cholesterol, hypertension, health status, and current smoking. We conducted all data analyses using SAS 9.1 statistical software (SAS Institute, Inc., Cary, North Carolina). Results The study population consisted of 30,365 men who presented to our clinic from 1979 to 2004 and gave consent for inclusion in the Aerobics Center Longitudinal Study. These patients were followed to December 31, 2004, for a median
Figure 1. Mortality rates/10,000 person-years by number of metabolic components present. The striped bars represent all-cause mortality and the white bars represent cardiovascular mortality.
follow-up of 13.6 years. The average baseline age was 44.4 ⫾ 10 years. There was a low baseline prevalence of diabetes (5%) and of current tobacco use (17.2%). Hypertension was present in 32.5% of the study participants, whereas hyperlipidemia was seen in 40% to 50% of the study group. Table 1 compares the baseline characteristics and laboratory values of the study participants who survived to those who died during follow-up. Age and the traditional cardiovascular risk factors of hypertension, hyperlipidemia, diabetes, and current tobacco use were found to be significantly associated with all-cause mortality. The laboratory abnormalities defining the presence of the MS were also significantly associated with all-cause mortality. Fasting glucose, triglyceride levels, systolic blood pressure, diastolic blood pressure, and abdominal girth were all higher in those who
Preventive Cardiology/Metabolic Syndrome Risk Factors and Mortality Table 3 Hazard ratios* (95% CI) for all-cause and cardiovascular mortality according to number of metabolic syndrome components present, Aerobics Center Longitudinal Study, 1979 to 2004 Number of Metabolic Syndrome Components Present 0 1 2 3 4 5
All-Cause Mortality
Cardiovascular Mortality
1.00 1.20 (0.98, 1.46) 1.58 (1.30, 1.92) 1.70 (1.38, 2.09) 1.83 (1.82, 3.35) 2.60 (1.99, 3.41)
1.00 1.83 (1.21, 2.77) 2.43 (1.63, 3.63) 2.82 (1.87, 4.25) 2.81 (1.81, 4.34) 5.52 (3.48, 8.75)
* Adjusted for age, non-HDL cholesterol, health status, and smoking status. Table 4 Hazard ratios* (95% CI) for all-cause and cardiovascular mortality in nonhypertensives according to number of metabolic syndrome components present, Aerobics Center Longitudinal Study, 1979 to 2004 Number of Metabolic Syndrome Components Present 0 1 2 3 4
All-Cause Mortality
Cardiovascular Mortality
1.00 1.15 (0.94, 1.40) 1.37 (1.11, 1.69) 1.47 (1.14, 1.89) 1.86 (1.31, 2.65)
1.00 1.27 (0.85, 1.88) 1.65 (1.09, 2.48) 1.88 (1.19, 2.96) 2.91 (1.67, 5.07)
* Adjusted for age, non-HDL cholesterol, health status, and smoking status.
died than in those who survived. Conversely, HDL cholesterol was lower in those who died than in those who survived. Similar results were found when a similar analysis for cardiovascular mortality was performed. Table 2 describes the adjusted hazard ratios of the individual MS risk factors for all-cause and cardiovascular mortality. Hypertension, hypertriglyceridemia, and central obesity were associated with both all-cause and cardiovascular mortality. A low HDL level and an impaired fasting glucose were not significantly associated with either allcause or cardiovascular mortality after adjustment for age and the other MS risk factors. Figure 1 plots all-cause and cardiovascular mortality rates as a function of the number of MS risk factors. A highly significant relation was noted. As more MS risk factors were present, the mortality rate increased. A similar relation was seen with cardiovascular mortality rates. Table 3 lists the adjusted hazard ratios (HRs) for both all-cause and cardiovascular mortality as a function of the number of individual MS risk factors. MS risk factors were a stronger predictor for cardiovascular mortality (HR 1.83 to 5.52) than for all-cause mortality (HR 1.20 to 2.60). In addition, risk for both all-cause and cardiovascular mortality increased as the number of MS risk factors increased. To rule out an overriding role of hypertension, a subgroup analysis was also performed on those without hypertension (Table 4). This analysis revealed a similar relation between the number of risk factors and increasing mortality from either all-cause or cardiovascular causes. We did, however, note a significant weakening of this relation when hypertension was excluded.
691
Discussion Our study is among the largest to date to formally evaluate the relation of MS risk factors with all-cause and cardiovascular mortality. Previous studies3–7 have mostly focused upon the metabolic syndrome as an “all-or-none” condition, not distinguishing those with 3 risk factors from those with either 4 or 5 risk factors. Moreover, those with 1 to 2 risk factors were categorized as not having the metabolic syndrome. The results of our study suggest that this method of distinguishing those with from those without MS can potentially underestimate mortality risk. An increasing gradient of risk appears to increase as the number of MS risk factors increase. This relation exists for both all-cause and cardiovascular mortality, independent of the other traditional cardiovascular risk factors. This increased risk begins with the presence of just 1 MS risk factor for cardiovascular mortality and with 2 risk factors for all-cause mortality. Moreover, the increased risk does not plateau after the presence of 3 MS risk factors. Our findings are in line with multiple studies3–7 noting an increased risk for all-cause or cardiovascular mortality when the MS is present. Wilson et al3 and Isomaa et al4 noted an increased cardiovascular mortality rate when the MS was present. Subsequently, Hunt et al,5 Katzmarzyk et al,6 and Lakka et al7 noted an increased risk for both all-cause and cardiovascular mortality with the MS. However, none of these studies formally evaluated the relation of the number of MS risk factors with mortality risk. Recently, several studies have evaluated the mortality risk of 1 to 2 MS risk factors. In a study by Malik et al,8 1 to 2 metabolic syndrome risk factors were predictive of coronary heart disease and cardiovascular mortality but not for all-cause mortality. In a study by Hu et al,9 more than 2 metabolic syndrome risk factors were predictive of both cardiovascular and all-cause mortality. In an early study by Ford10 and in another recent study by Kadota et al,11 a positive but statistically insignificant trend was noted between the number of MS risk factors and all-cause mortality. Our study confirms that mortality risk increases with either 1 or 2 MS risk factors. Moreover, there appears to be no “plateau” effect because the presence of 4 or 5 risk factors confers an increased mortality risk when compared with those with 3 risk factors. In the present study, hypertension was found to be the most potent predictor of both all-cause and cardiovascular mortality, even after adjustment for the other MS risk factors. This finding was not unexpected because hypertension is a well known and traditional cardiovascular risk factor. Our study is also in accord with the results of Isomaa et al,4 Hunt et al,5 and Malik et al8, who noted increased cardiovascular mortality with hypertension. Somewhat surprisingly, neither low HDL nor impaired fasting glucose exhibited a significant association with either all-cause or cardiovascular mortality in this study after adjustment for the other risk factors. In contrast to these findings, impaired fasting glucose was associated with allcause mortality in studies by Malik et al8 and Ford.10 In studies by Malik et al8 and Schillaci et al,12 low HDL was associated with coronary heart disease. We surmise that the
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present study was underpowered to detect a mortality effect with these parameters because relatively little clinical variation was seen with either the HDL or fasting blood glucose levels. In contrast, central obesity and hypertriglyceridemia proved particularly significant in this study. Like hypertension, a well-validated traditional risk factor, both of these MS components increased all-cause and cardiovascular mortality in this study, even after adjustment for the other risk factors. Previous work examining this issue has been mixed. In a study by Schillaci et al,12 central obesity was not significantly associated with an increase in cardiovascular event rate. In the study by Hunt et al,5 central obesity was associated with increased cardiovascular mortality, although this finding was not adjusted for the presence of the other MS risk factors. Our findings lend credence to the growing body of evidence that central obesity can independently and adversely affect health. Although intriguing, this study has limitations. The study was observational in nature, and our analysis may not have taken into account all confounding variables. Moreover, we utilized mortality data from the National Center for Health Statistics, and the effects of misclassification and underreporting could not be estimated. Acknowledgment: We thank the Cooper Clinic physicians, nurses, and technicians for collecting the baseline data and The Cooper Institute for maintaining the database. 1. Grundy S, Cleeman J, Daniels S, Donato K, Eckel R, Franklin B, Gordon D, Krauss R, Savage P, Smith S, Spertus J, Costa F. Diagnosis and management of the metabolic syndrome. An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005;112:2735–2752.
2. 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 2001;285:2486 –2497. 3. Wilson P, Kannel W, Silbershatz H, D’Agostino R. Clustering of metabolic factors and coronary heart disease. Arch Intern Med 1999; 159:1104 –1109. 4. Isomaa B, Almgren P, Tuomi T, Forsen B, Lahti K, Nissen M, Taskinen M, Groop L. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 2001;24:683– 689. 5. Hunt K, Resendez R, Williams K, Haffner S, Stern M. National Cholesterol Education Program versus World Health Organization metabolic syndrome in relation to all-cause and cardiovascular mortality in the San Antonio Heart Study. Circulation 2004;110:1251– 1257. 6. Katzmarzyk P, Church T, Blair S. Cardiorespiratory fitness attenuates the effects of the metabolic syndrome on all-cause and cardiovascular disease mortality in men. Arch Intern Med 2004;164:1092–1097. 7. Lakka H, Laaksonen D, Lakka T, Niskanen L, Kumpusalo E, Tuomilehto J, Salonen J. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 2002;288:2709 – 2716. 8. Malik S, Wong N, Franklin S, Kamath T, L’Italien G, Pio J, Williams G. Impact of the metabolic syndrome on mortality from coronary heart disease, cardiovascular disease, and all causes in United States adults. Circulation 2004;110:1245–1250. 9. Hu G, Qiao Q, Tuomilehto J, Balkau B, Borch-Johnsen K, Pyorala K, for 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 2004;164:1066 – 1076. 10. Ford E. The metabolic syndrome and mortality from cardiovascular disease and all-causes: findings from the National Health and Nutrition Examination Survey II mortality study. Atherosclerosis 2004;173: 309 –314. 11. Kadota A, Hozawa A, Okamura T, Kadowak T, Nakmaura K, Murakami Y, Hayakawa T, Kita Y, Okayama A, Nakamura Y, et al., for the NIPPON DATA Research Group. Relationship between metabolic risk factor clustering and cardiovascular mortality stratified by high blood glucose and obesity. Diabetes Care 2007;30:1533–1538. 12. Schillaci G, Pirro M, Vaudo G, Gemilli F, Marchesi S, Porcellati C, Mannarino E. Prognostic value of the metabolic syndrome in essential hypertension. J Am Coll Cardiol 2004;43:1817–1822.