Cardiovascular and Metabolic Risk ORIGINAL ARTICLE

Prognostic Impact of Metabolic Syndrome by Different Definitions in a Population With High of Obesity and The Strong Heart Study

1,2 5 GIOVANNI DE SIMONE, MD JAMES M. GALLOWAY, MD, MPH syndrome also predicts higher cardiovascular 1 6 RICHARD B. DEVEREUX, MD HELAINE E. RESNICK, PHD event rates in diabetic participants, a predic- 2 MARCELLO CHINALI, MD FOR THE STRONG HEART STUDY tion that is greatest using the WHO definition. 3 LYLE G. BEST, MD INVESTIGATORS 4 ELISA T. LEE, PHD Diabetes Care 30:1851–1856, 2007

he metabolic syndrome represents OBJECTIVE — This study analyzed which definition of the metabolic syndrome is more clusters of cardiovascular risk fac- predictive of cardiovascular events in both diabetic and nondiabetic members of a population- tors, assuming that cardiovascular based sample. T risk is amplified more than is expected from the effect of single risk factors (1). RESEARCH DESIGN AND METHODS — A 10-year, longitudinal follow-up of the Many studies support the utility of this Strong Heart Study cohort has been evaluated. The analysis included 3,945 participants (2,384 female) with complete data (1,700 with diabetes and 1,468 with arterial ) for definition (2,3), but others have ques- evaluation of metabolic syndrome. Those with prevalent cardiovascular were excluded tioned the incremental utility of this ap- (n ϭ 287, of whom 127 were female). Prevalence of metabolic syndrome was assessed based on proach (4). the World Health Organization (WHO), the National Education Program Adult An element of potential confusion Treatment Panel (NCEP ATP) III, and International Diabetes Federation (IDF) definitions. The concerning the real prognostic utility of main outcome was 10-year of combined fatal and nonfatal cardiovascular events, defining metabolic syndrome is the avail- including , coronary heart disease, and congestive heart failure. ability of several definitions (5–9), reflect- ing different strategies, either identifying RESULTS — Fatal and nonfatal cardiovascular events occurred in 1,120 participants. After a main characteristic as a necessary fac- adjusting for age, sex, and diabetes, metabolic syndrome by all definitions was significantly tor (5,7,9) associated with other variable associated with higher incidence of cardiovascular events (all P Ͻ 0.0001). In nondiabetic risk factors or accepting varied combina- individuals, incident cardiovascular event rates were about 30–40% higher in those with met- tions of characteristics (6,8). Other differ- abolic syndrome, without a significant difference among definitions (0.03 Ͻ P Ͻ 0.001), and ences may also be important, including remained significant in WHO and NCEP ATP III definitions even after further adjustment for partition values and methods to define obesity, hypertension, and low HDL cholesterol. In the diabetic group, metabolic syndrome risk abnormalities. Ͻ for cardiovascular events was greatest using the WHO definition (P 0.002 vs. other models). At present, few data exist comparing the correlates and prognostic significance CONCLUSIONS — In individuals without diabetes, metabolic syndrome is associated with of the definitions of metabolic syndrome incident , especially with WHO and NCEP ATP III definitions. Metabolic in the same population. Accordingly, we compared the ability of the most used def- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● initions of metabolic syndrome to predict From the 1Division of Cardiology, Weill Medical College of Cornell University, New York, New York; the 2 3 cardiovascular events in the Strong Heart Department of Clinical and Experimental Medicine, Federico II University, Naples, Italy; Missouri Breaks Study (SHS) cohort. Industries Research, Timber Lake, South Dakota; the 4Center for American Indian Health Research, Uni- versity of , Oklahoma City, Oklahoma; the 5Indian Health Service, University of , Tucson, Arizona; and the 6Medstar Research Institute, Washington, DC. RESEARCH DESIGN AND Address correspondence and reprint requests to Giovanni de Simone, MD, Department of Clinical and METHODS — The SHS is a popula- Experimental Medicine, Federico II University Hospital, v.S.Pansini 5, 80131 Naples, Italy. E-mail: [email protected]. tion-based of cardiovascular Received for publication 18 October 2006 and accepted in revised form 30 March 2007. risk factors and disease in 4,549 American Published ahead of print at http://care.diabetesjournals.org on 17 April 2007. DOI: 10.2337/dc06-2152. Indians from three communities in Ari- The views expressed in this paper are those of the authors and do not necessarily reflect those of the Indian zona, seven in Southwestern Oklahoma, Health Service. Abbreviations: HOMA, homeostasis model assessment; IDF, International Diabetes Federation; NCEP and three in South and North Dakota, as ATP, National Cholesterol Education Program Adult Treatment Panel; SHS, Strong Heart Study; WHO, extensively described (10–14). Partici- World Health Organization. pants seen during the baseline exam, in A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion 1989–1992, were representative of the factors for many substances. source population (15). © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby For the present analysis, individuals marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. with prevalent cardiovascular disease

DIABETES CARE, VOLUME 30, NUMBER 7, JULY 2007 1851 Metabolic syndrome

Table 1—Definition of metabolic syndrome according according to the WHO, NCEP ATP III, and IDF

ATP III (any Factor WHO (main criterion ϩ 2 factors)* combination of 3 factors) IDF (main criterion ϩ 2 factors) BMI (kg/m2) Ͼ30 — — Abdominal obesity (men/women) Waist-to-hip ratio Ͼ0.9/0.85 Waist Ͼ102/88 cm Waist >94/80 cm† Triglycerides (mg/dl) Ն150 Ն150 Ն150 HDL cholesterol (mg/dl) (men/women) Ͻ35/39 Ͻ40/50 Ͻ40/50 Blood pressure (mmHg) Ն140/Ն90 Ն130/Ն85 Ն140/Ͼ90 or Ͼ130/Ͼ85 HOMA‡ >4.3 —— Present — Present Fasting glucose (mg/dl) >110 Ն110 Ն100 Fasting insulin — — — Urinary albumin excretion Ն20 ␮g/min or Ն30 mg/g creatinine — — Sine qua nonfactors are in bold. *According to the WHO, either BMI or abdominal obesity represents one criterion. †Ethnic group waist circumference (as measure of central obesity): Europid men Ն94 and women Ն80 cm; South Asian men Ն90 and women Ն80 cm; Chinese men Ն90 and women Ն80 cm; and Japanese men Ն85 and women Ն90 cm. Ethnic South and Central American populations use South Asian recommendations until more specific data are available. Sub-Saharan African populations use European data until more specific data are available. Eastern Mediterranean and Middle East (Arab) populations use European data until more specific data are available. ‡According to the WHO, HOMA, type 2 diabetes, and fasting glucose are alternatives, fulfilling one criterion.

(n ϭ 287, 127 of whom were female) were Ն126 mg/dl or antidiabetes treatment) for HOMA index was arbitrarily deter- excluded. Prevalent and incident cardio- and impaired fasting glucose (Ն110 mg/ mined in the nondiabetic SHS partici- vascular events (cardiovascular death, dl) were diagnosed by 1997 American Di- pants as the lower boundary of the highest stroke, congestive heart failure, myocar- abetes Association recommendations tertile (4.3). Thus, insulin resistance sta- dial infarction, and coronary heart disease (17). Obesity was classified based on the tus was defined as the presence of type 2 [coronary angiography, combination of 1998 National Institutes of Health guide- diabetes or fasting glucose Ն110 mg/l or typical symptoms with positive treadmill lines (18) (BMI Ն30 kg/m2). Central fat HOMA index Ͼ4.3. Hypertension was tests or abnormal imaging stress test, or distribution was based on waist circum- defined by Joint National Committee VII revascularization procedures]) were con- ference and defined in relation to sex- criteria (blood pressure Ն140/90 mmHg firmed by the SHS mortality and morbid- specific cutoff points used in the different or use of antihypertensive treatment). ity committees, using specified criteria for definitions examined in this study (Table causes of fatal and nonfatal cardiovascular 1). For the International Diabetes Feder- Statistical analysis events (16). ation (IDF) definition, the values pro- Data were analyzed using SPSS (version Diabetic participants were included; posed for Europids have been adopted. A 12.0; SPSS, Chicago, IL). Data are ex- participants with fasting triglyceride lev- random urine sample was used to mea- pressed as means Ϯ SD. All variables de- els Ͼ750 mg/dl were excluded. Thus, sure albumin and creatinine (11). viating from normal distribution were log 3,945 participants (2,384 women) with- Table 1 shows the criteria used to de- transformed before parametric statistics. out prevalent cardiovascular disease and fine metabolic syndrome by three guide- The urinary albumin-to-creatinine ratio is available data (1,700 with diabetes and lines: those by the World Health presented as median (interquartile 1,468 with hypertension) were included Organization (WHO) (5,9), the National range). An indicator variable was in- in the analysis. Cholesterol Education Program Adult cluded for the three field centers: Arizona, Treatment Panel (NCEP ATP) III (6), and South and North Dakota, and Oklahoma. Laboratory tests and definitions of the IDF (9). Insulin-glucose homeostasis Participants were categorized into groups metabolic syndrome for the WHO definition was estimated by according to the presence of metabolic Fasting plasma glucose and lipid profile the homeostasis model assessment syndrome, defined by each definition. were measured by standard methods (HOMA) equation (19). Based on the The 10-year relative risk of combined (12). Diabetes (fasting plasma glucose WHO recommendation, a partition value fatal and nonfatal cardiovascular events

Table 2—Metabolic syndrome by different definitions (see Table 1): concordance and differences in blood pressure and urinary albumin-to- creatinine ratio

Systolic blood Diastolic blood pressure (mmHg) pressure (mmHg) Urinary albumin/creatinine ratio Prevalence of No metabolic syndrome Men Women No MetS MetS MetS MetS No MetS MetS WHO 48 53 122 Ϯ 16 133 Ϯ 20 75 Ϯ 979Ϯ 10 6.60 (3.40–12.5) 28.18 (7.62–153.74) ATP III 44 63 121 Ϯ 17 132 Ϯ 20 75 Ϯ 978Ϯ 10 6.96 (3.57–15.73) 16.55 (6.38–82.58) IDF 59 73 120 Ϯ 16 131 Ϯ 19 74 Ϯ 978Ϯ 10 6.90 (3.59–15.94) 13.62 (5.54–62.25) Data are means Ϯ SD, percentages, or median (interquartile range). MetS, metabolic syndrome.

1852 DIABETES CARE, VOLUME 30, NUMBER 7, JULY 2007 de Simone and Associates

Table 3—The 10-year hazard for incident fatal/nonfatal cardiovascular associated with met- Cardiovascular risk in the metabolic abolic syndrome, according to three different definitions, adjusting for age, sex, field center, syndrome and diabetes Over the follow-up time (119 Ϯ 45 months), 1,157 cardiovascular events Diabetes No diabetes P Ϫ2 log likelihood were adjudicated, including 176 , 299 myocardial infarctions, 226 other WHO 2.29 (1.97–2.67) 1.54 (1.32–1.80) Յ0.0001 15,033 clinical manifestations of coronary heart ATP III 2.45 (2.12–2.84) 1.42 (1.22–1.66) Յ0.0001 15,043 disease, 394 cases of congestive heart fail- IDF 2.59 (2.25–2.98) 1.37 (1.17–1.61) Յ0.0001 15,049 ure, and 62 sudden deaths. The incidence Data are HRs (95% CI) for metabolic syndrome. Comparison between likelihood functions has been done for of combined fatal and nonfatal cardiovas- 1 d.f. cular events was 2.38-fold greater in par- ticipants with than in those without was estimated for each definition. Log- lent: 0.56 and 0.59 for men and women metabolic syndrome (95% CI 2.04–2.73) by the WHO definition, 2.12-fold greater cumulative hazard functions were com- between WHO and NCEP ATP III, 0.58 (1.81–2.47) by the ATP III definition, and puted by Cox regression, adjusting for age and 0.77 between NCEP ATP III and IDF, (years), field center, sex, and diabetes. 1.92-fold greater (1.62–2.27) by the IDF and only 0.49 and 0.50 between WHO definition (all P Ͻ 0.0001). Table 3 shows Additional models were also adjusted for and IDF definitions, respectively. the other components of metabolic syn- that metabolic syndrome was always as- Table 2 also shows that, due to differ- sociated with increased rate of cardiovas- drome. Cox regression was also run sep- ing high blood pressure criteria, the Ͻ arately for diabetic and nondiabetic cular events (all P 0.0001), even WHO definition was associated with independent of age, sex, field center, and participants. slightly higher blood pressure levels than To compare the independent prog- presence of diabetes. The regression was NCEP ATP III or IDF. Urinary albu- model including metabolic syndrome by nostic effect of metabolic syndrome by the min-to-creatinine ratio was highest in three definitions, likelihood functions the WHO definition was significantly participants with metabolic syndrome by were compared (20). The difference be- more predictive than the other models, 2 the WHO definition (including this pa- Ͻ tween two Ϫ2 log likelihoods has a ␹ including the other definitions (both P distribution, which, for this comparison, rameter among criteria for definition), but 0.002). ␣ Յ also higher in the NCEP ATP III and IDF Alternative Cox regression models has 1 d.f. (20). Two-tailed 0.01 iden- Ͻ tified significant differences among the definitions (all P 0.0001), than in par- adjusted for obesity, low HDL choles- three models. ticipants without metabolic syndrome. terol, and hypertension, in addition to the The criteria for adiposity proposed by covariates used in the previous model. Al- RESULTS — Table 2 shows that the the WHO identified 83% of participants though reduced, the hazard ratios (HRs) IDF definition yielded the highest preva- with central fat distribution in the absence of metabolic syndrome remained statisti- lence of metabolic syndrome in both men of metabolic syndrome (compared with cally significant for the definitions by the and women. The WHO definition re- 96% in those with metabolic syndrome). NCEP ATP III (HR 1.28 [95% CI 1.04– 1.56], P Ͻ 0.02) and the WHO (1.35 sulted in a similar proportion of metabolic The difference between groups without Ͻ syndrome in men and women, whereas (66% with central fat) vs. with metabolic [1.11–1.64], P 0.002) but not by IDF (1.12 [0.92–1.36], P Ͼ 0.2). NCEP ATP III and IDF showed a substan- syndrome (100% with central fat) was tially higher prevalence in women, with more accentuated in the IDF and maximal Cardiovascular risk in diabetic and the greatest sex difference by the NCEP with the NCEP ATP III definition (50 vs. Ͻ nondiabetic subjects ATP III definition (both P 0.0001). The 91%, respectively). In all definitions, one- coefficient of concordance (k) among the In both diabetic and nondiabetic partici- half or more of individuals free of the syn- pants, the prognostic effect of metabolic different definitions in the recognition of drome exhibited central fat distribution. metabolic syndrome status was not excel- syndrome was confirmed for all three def- initions (Table 4). The HR for incident composite fatal and nonfatal events was Table 4—The 10-year hazard for incident fatal/nonfatal cardiovascular events in separate ϳ30–40% higher in nondiabetic partici- nondiabetic and diabetic subgroups of the SHS, in relation to presence of metabolic syndrome, pants with metabolic syndrome, by all according to 3 different definitions, adjusting for age, sex, and field center definitions, without significant differ- ences among them (Fig. 1). In contrast, in Increase in diabetic participants, the HR for the met- cardiovascular risk 95% CI P Ϫ2 log likelihood abolic syndrome was not statistically sig- nificant using the IDF definition (26% Nondiabetic increased risk), was higher with the NCEP WHO 1.28 1.03–1.59 Յ0.03 5,309 ATP III definition (43% increased risk), ATP III 1.40 1.13–1.73 Յ0.002 5,305 and was highest with the WHO definition IDF 1.44 1.17–1.78 Յ0.001 5,302 (near-doubled risk), a difference that was Diabetic statistically significantly (P Ͻ 0.001). WHO 1.94 1.51–2.47 Յ0.0001 8,381 ATP III 1.43 1.13–1.81 Յ0.003 8,404 CONCLUSIONS — This study dem- IDF 1.26 0.99–1.62 Յ0.07 8,410 onstrates that in the SHS cohort, meta- Comparison between likelihood functions has been done for 1 d.f. bolic syndrome by all three examined

DIABETES CARE, VOLUME 30, NUMBER 7, JULY 2007 1853 Metabolic syndrome

,Figure 1—Adjusted cumulative hazard in participants with (—) or without (ۙ) metabolic syndrome, in nondiabetic or diabetic participants according to diagnostic criteria issued by the WHO (top panel), ATP III (middle panel), or IDF (bottom panel). definitions is independently associated recognition of the metabolic syndrome of diabetes. Compared with nondiabetic with a significantly greater rate of incident impressively enhanced the prediction of populations, detecting the full presenta- composite fatal and nonfatal cardiovascu- cardiovascular events, consistent with tion of metabolic syndrome might be less lar events and is a marker of preclinical National Health and Nutrition Examina- important for decision making when dia- cardiovascular disease, represented by tion Survey III results (21), where the age- betes coexists with even one additional the increased urinary albumin-to- adjusted prevalence of coronary heart risk factor. creatinine ratio. The independent associ- disease in the diabetic population without This study identifies similarities ation of metabolic syndrome with metabolic syndrome (8%) was similar to among the three definitions of metabolic cardiovascular events was seen in popu- that in subjects without diabetes or met- syndrome but also reveals differences. In lation strata with or without diabetes. abolic syndrome (9%), while increasing the whole population, combining partic- In participants without diabetes, in- to 14% in nondiabetic subjects with met- ipants with or without diabetes, the creased cardiovascular risk is indepen- abolic syndrome and to 19% in those with model using the WHO definition was a dently associated with metabolic both conditions. However, independent better predictor than models using NCEP syndrome, suggesting that this diagnosis of the presence of full-fledged metabolic ATP III or IDF definitions, with IDF ex- can help identify high-risk individuals. syndrome, attention to all cardiovascular hibiting the lowest fit. When forcing sin- Similarly, among diabetic individuals, risk factors is paramount in the presence gle cardiovascular risk factors into the

1854 DIABETES CARE, VOLUME 30, NUMBER 7, JULY 2007 de Simone and Associates proportional hazard model, only the present analysis also included diabetic 4. Kahn R, Buse J, Ferrannini E, Stern M: WHO and ATP III definitions maintained participants, the follow-up was substan- The metabolic syndrome: time for a criti- an independent prognostic impact, tially longer, and all clinical manifesta- cal appraisal: joint statement from the whereas the IDF definition did not, pos- tions of cardiovascular disease, including American Diabetes Association and the sibly due to lower specificity associated cerebrovascular events and congestive European Association for the Study of Di- abetes. Diabetes Care 28:2289–2304, with the generally lower partition values heart failure, were considered as end 2005 for single factors. points. In particular, incident congestive 5. World Health Organization: Definition, In nondiabetic participants, the risks heart failure (394 adjudicated events) Diagnosis, and Classification of Diabetes and predicted by the three definitions were could be very important, because heart its Complications: Report of a WHO Consul- not statistically different. In contrast, a failure is a relevant end point for obesity tation. Part 1: Diagnosis and Classification of substantial difference was evident among (28–30). Overall, our findings suggest Diabetes Mellitus. Geneva, World Health diabetic participants, with the WHO def- that the metabolic syndrome may take Organization, 1999 (Tech. Rep. Ser., no.) inition significantly superior to those of several years to manifest its effects on clin- 6. Third Report of the National Cholesterol both the NCEP ATP III and IDF (the HR of ical events (as Fig. 1 also suggests). Education Program (NCEP) Expert Panel which was not statistically significant). In conclusion, the NCEP ATP III and on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults Although the NCEP ATP III definition WHO (but not IDF) definitions of meta- (Adult Treatment Panel III) final report. was not intended for diabetic individuals, bolic syndrome predict cardiovascular Circulation 106:3143–3421, 2002 it should be noted that it performed well disease independently of single compo- 7. Balkau B, Charles MA, Drivsholm T, in participants with or without diabetes, nents of the syndrome; their value may be Borch-Johnsen K, Wareham N, Yudkin though slightly less well than WHO in similar in individuals without diabetes, JS, Morris R, Zavaroni I, van Dam R, Fe- those with diabetes. but in diabetes the WHO definition seems skins E, Gabriel R, Diet M, Nilsson P, To evaluate correctly the implications to be more useful. Results of these analy- Hedblad B: Frequency of the WHO met- of these findings, both the characteristics ses, obtained in a population with high abolic syndrome in European cohorts, of the SHS population and the differences of obesity and diabetes, are and an alternative definition of an insulin among the different definitions of meta- likely applicable to other populations of resistance syndrome. Diabetes Metab 28: bolic syndrome have to be taken into ac- different ethnicities in which there is an 364–376, 2002 8. Einhorn D, Reaven GM, Cobin RH, Ford count. The American Indian population epidemic rise of prevalences of over- E, Ganda OP, Handelsman Y, Hellman R, of the SHS is characterized by higher weight and obesity (31), triggering diabe- Jellinger PS, Kendall D, Krauss RM, prevalence of obesity than the overall tes and other metabolic abnormalities Neufeld ND, Petak SM, Rodbard HW, Sei- population in the U.S. and Europe (12), (32). 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