Trajectories of Entering the Metabolic Syndrome
The Framingham Heart Study
Background— We evaluated the progression of the metabolic syndrome (MetS) and its components, the trajectories followed by individuals entering MetS, and the manner in which different trajectories predict cardiovascular disease and mortality.
Methods and Results— Using data from 3078 participants from the Framingham Offspring Study (a cohort study) who attended examinations 4 (1987), 5 (1991), and 6 (1995), we evaluated the progression of MetS and its components. MetS was defined according to the Adult Treatment Panel III criteria. Using logistic regression, we evaluated the predictive ability of the presence of each component of the MetS on the subsequent development of MetS. Additionally, we examined the probability of developing cardiovascular disease or mortality (until 2007) by having specific combinations of 3 that diagnose MetS. The prevalence of MetS almost doubled in 10 years of follow-up. Hyperglycemia and central obesity experienced the highest increase. High blood pressure was most frequently present when a diagnosis of MetS occurred (77.3%), and the presence of central obesity conferred the highest risk of developing MetS (odds ratio, 4.75; 95% confidence interval, 3.78 to 5.98). Participants who entered the MetS having a combination of central obesity, high blood pressure, and hyperglycemia had a 2.36-fold (hazard ratio, 2.36; 95% confidence interval, 1.54 to 3.61) increase of incident cardiovascular events and a 3-fold (hazard ratio, 3.09, 95% confidence interval, 1.93 to 4.94) increased risk of mortality.
Conclusions— Particular trajectories and combinations of factors on entering the MetS confer higher risks of incident cardiovascular disease and mortality in the general population and among those with MetS. Intense efforts are required to identify populations with these particular combinations and to provide them with adequate treatment at early stages of disease.
Received February 2, 2009; accepted September 4, 2009.
Improvements in healthcare and living conditions accompanied by the westernization of the global lifestyle have given rise to pathological conditions such as the metabolic syndrome (MetS).1
Clinical Perspective on p 1950
First labeled by Reaven in 1988 as “syndrome X,”2 different criteria exist to define the MetS.3–6 In general, MetS can be defined as the concomitant occurrence of multiple metabolic irregularities that may include hypertension, dyslipidemia, abdominal obesity, insulin resistance, and microalbuminuria, depending on the selected definition.3–6 Independently of the criteria chosen, the MetS has been widely associated with an increased risk of diabetes mellitus, cardiovascular disease (CVD), and cholesterol gallstones, among other pathological conditions, in several studies.6–9 For example, individuals with the MetS experience a 2-fold and 5-fold increase in the risk of developing CVD and diabetes mellitus, respectively.6,7 Even though it is fundamental to accurately manage MetS to control current global epidemics of CVD and diabetes mellitus,1,7 the pathogenesis of the MetS and the manner in which its components interact and evolve remain uncertain. Moreover, the trajectories followed by individuals entering the MetS definition and the manner in which these trajectories modify the lifetime experience of CVD and mortality are poorly understood and have hardly been explored. These factors may hamper the adequacy of management among individuals with MetS. Further understanding of the development and progression of the MetS and its components is required.
We sought to evaluate in adult populations from the Framingham Offspring Study (FOS) the distribution and progression of the MetS and its components, the trajectories followed by those entering the MetS, and the potential effect of individual trajectories on subsequent CVD and mortality. Additionally, we evaluated whether these trajectories differ by smoking status.
The original Framingham Heart Study cohort started between 1948 and 1951 with 5209 (45% men) residents of Framingham, Mass. The FOS cohort is composed of the offspring and their spouses of the original Framingham Heart Study and was examined beginning in 1971–1975 and approximately every 4 to 8 years since then. This cohort consists of 5124 participants (48% men) aged 5 through 70 years at baseline. Further description of the Framingham Heart Study and the FOS can be found elsewhere.10–12
We selected data from participants attending each of examinations 4 (1987–1991), 5 (1991–1995), and 6 (1995–1998) and who were evaluated for the presence/absence of the 5 components of the MetS at each examination as defined below. Of 4019 participants who attended examination 4, 730 people were excluded because they did not attend all of examinations 4, 5, and 6; 211 were further excluded because they had missing data on at least 1 of the components of the MetS. In total, we analyzed data from 3078 participants of the FOS.
Assessment of MetS
Presence of MetS was evaluated at examinations 4 though 6. To define MetS, we used the Adult Treatment Panel III criteria, which classifies individuals as having the MetS if they have at least 3 of the following 5 components: (1) men with waist circumference (WC) >40 inches (102 cm) or women with WC >35 inches (88 cm); (2) men with high-density lipoprotein (HDL) cholesterol <40 mg/dL or women with HDL cholesterol <50 mg/dL; (3) triglycerides of ≥150 mg/dL; (4) high blood pressure (systolic blood pressure ≥130 mm Hg or diastolic blood pressure ≥85 mm Hg or on antihypertensive treatment); and (5) fasting glucose of ≥100 mg/dL.6 This definition uses a cutoff level of fasting glucose of ≥100 mg/dL, as suggested recently by the American Diabetes Association and the American Heart Association.
Assessment of CVD and Diabetes Mellitus
CVD was defined as the presence of 1 or more definite manifestations of coronary heart disease (angina pectoris, coronary insufficiency, myocardial infarction, and sudden or not sudden death as consequence of coronary disease), congestive heart failure, stroke, transient ischemic attack, and intermittent claudication. A panel of 3 physicians evaluated all events; the agreement of all 3 was required. Diabetes mellitus was defined by having a random glycemia ≥200 mg/dL or being treated with insulin and/or oral antidiabetic agents. More details on the evaluation of outcomes are available elsewhere.13
Progression of the MetS Components
To determine the progression of MetS and its components, we measured the sex-pooled and sex-specific prevalence of MetS and of each individual component at each of examinations 4 to 6. We then grouped the individual components into pairs (there are 10 possible pairs). For each pair, we identified the subgroup of participants who at some point experienced both components of the pair for at least 1 of examinations 4 to 6. Then, of these participants, we determined the frequency with which each component first presented itself at an examination before the other component and the frequency at which the 2 components first presented together (at the same examination).
Components and Triads: Frequency and Prediction of MetS
In participants who did not have MetS at examination 4 but who experienced MetS at examination 5 or 6 (n=776; 376 men and 400 women), we evaluated the sex-pooled and sex-specific incidence of each component of the MetS and of each triad of factors that permitted the diagnosis of MetS. “Triads” were defined as the simultaneous combination of any 3 different components of the MetS that would guarantee a diagnosis of MetS (a participant could have experienced >1 triad; eg, if a participant experienced a MetS diagnosis because of high blood pressure, large WC, high triglycerides, and low HDL, the participant would be considered as experiencing the following 3 triads:  high blood pressure, large WC, and high triglycerides;  high blood pressure, large WC, and low HDL; and  large WC, high triglycerides, and low HDL).
We assessed the age- and sex-adjusted relation between examination 4 prevalences of MetS components with the future (examination 5 or 6) occurrence (yes/no) of MetS. This assessment was performed with the use of sex-pooled stepwise logistic regression, in which age and sex were forced into the model as independent variables and with the examination 4 presence (yes/no) of each of the 5 components as candidates for entry into and remaining in the logistic model as independent variables at a 0.05 level of significance. Incident MetS developed by at least examination 5 and/or 6 was outcome. This was performed twice: once for all participants in the study and once for all participants without MetS at examination 4 (n=2356; 1058 men and 1298 women). Assessments of the significance of the component-by-sex (age and smoking) interaction were performed in separate logistic models (1 model per component); factor-specific age-adjusted logistic regression results (except for age) were inspected for components for which the factor-by-component interaction was significant at the 0.05 level.
Triads and Prediction of CVD and Mortality
We evaluated whether the incidence of the 5 most frequent triads has an impact on each of incident CVD and mortality through 2007. This assessment was performed with the use of stepwise sex-pooled Cox proportional hazards regression (after assumption of proportionality was tested and met), in which age and sex were forced into the model as independent variables and with the incidence (yes/no) of each of the 5 triads as candidates for entry into and remaining in the Cox model as independent variables at a 0.05 level of significance. This was performed twice: once for all participants in the study without MetS at examination 4 regardless of subsequent incidence of MetS and once for all participants without MetS at examination 4 who experienced MetS by examination 6. Analysis on CVD incidence further excluded participants with prevalent CVD at examination 4. Participants not experiencing the outcome by 2007 are censored at the end of 2007 or last known follow-up date, whichever is earlier. Assessments of the significance of the triad-by-sex interaction were performed in separate Cox regression analysis (1 model per triad); sex-specific Cox regression results were inspected for triads for which the sex-by-component interaction was significant at the 0.05 level.
In addition to the different components of the MetS, smoking is perhaps the most important factor that, if present, provides the highest risk on incident CVD. Hence, we repeated the analyses of frequency of components and triads and of prediction of MetS by stratifying for smoking status (nonsmokers versus current and former smokers).
All analyses were conducted with the use of SAS version 9.1 and adjusted or stratified for age and/or sex. Potential factor-by-sex interactions were evaluated. A 2-sided α of 0.05 was used to claim statistical significance.
All authors participated actively in all and each of the following aspects for this article: conception and design or analysis and interpretation of data; drafting of the article or revising it critically for important intellectual content; and final approval of the version to be published. Oscar H. Franco, as guarantor of this article, accepts full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish. The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written. All authors declare having acted independently from the funders of this project. Ethical approval was not required because this was a secondary data analysis.
The mean age of the population was 51.6 years at baseline (examination 4). There were more women (51.6%); 6.4% and 4.2% had a previous diagnosis of CVD and diabetes mellitus, respectively (Table 1). Mean levels of the components of the MetS at baseline were as follows: WC 35.1 inches, systolic blood pressure 126.2 mm Hg, diastolic blood pressure 79.1 mm Hg, HDL cholesterol 49.9 mg/dL, triglycerides 120.4 mg/dL, and fasting glucose 94.6 mg/dL.
Participants with MetS at examination 4 (722) were older than those without it (54.9 versus 50.6 years; P<0.001) and had a higher prevalence of diabetes mellitus (13.3% versus 1.4%; P<0.001) and CVD (11.9% versus 4.8%; P<0.001) but were similar with respect to current/former smoking status (43.5% versus 42.5%) (Table 1).
Prevalence and Progression of MetS
At examination 4, 722 (23.5%) of participants had a diagnosis of MetS (Table 2). Prevalence of the 5 components of MetS at examination 4 (for all participants) was as follows: 25.7% had large WC, 38.7% had low HDL, 23.8% were hypertriglyceridemic, 48.4% were hypertensive, and 18.9% had hyperglycemia (Table 2).
The prevalence of MetS increased from examination 4 to 5 by 10.6% and from examination 4 to 6 by 17.2% (Table 2). Hyperglycemia experienced the highest increase from examination 4 to examination 6 (from 18.9% to 42.8%) followed by central obesity (from 25.7% to 50.7%). High blood pressure and hypertriglyceridemia each experienced an ≈8% increase in prevalence from examination 4 to 6, whereas low levels of HDL decreased slightly from 38.7% at examination 4 to 36.4% at examination 6 (Table 2).
At examination 4, women and men had similar prevalences of large WC and low HDL. Women had lower levels of hypertriglyceridemia (16.8% versus 31.3%), high blood pressure (41.3% versus 56.0%), and hyperglycemia (13.8% versus 24.4%) than did men. Nevertheless, by examination 6, women seemed to overtake men and even surpass them in the case of prevalence of large WC. Although a 10% and 20% difference in prevalence of high blood pressure and hyperglycemia remained between men and women at examination 6, women experienced a larger increase in prevalence of the different components of the MetS from examination 4 to examination 6 than did men. This was the case for all components except for the prevalence of low HDL, which decreased among women (37.5% to 32.0%) but remained stable among men (Table 2).
Sequential Progression of Components of MetS
When low levels of HDL cholesterol were present at any examination, having low levels of HDL cholesterol generally preceded the appearance of any other component (Table 3). For example, of the 963 participants who ended up experiencing the HDL and hyperglycemia component simultaneously during at least 1 of examinations 4 to 6, 494 (51.3%) of the participants had low levels of HDL before presenting with hyperglycemia versus 108 (11.2%) who presented with hyperglycemia first and 361 (37.5%) who presented with both simultaneously at the examination. The next dominant component in terms of sequential appearance was high blood pressure, and the least dominant was hyperglycemia (Table 3). Very similar findings were obtained when the population was stratified by sex, except that high blood pressure became the factor that preceded all the others among women (data not presented).
Frequency of Factors and Triads on Entering the MetS
Of the participants without MetS at examination 4 but with MetS at examination 5 or 6, high blood pressure was the component that appeared most frequently with MetS, followed by WC, hypertriglyceridemia, hyperglycemia, and low HDL (77.3%, 68.8%, 65.5%, 60.8%, 59.1%, respectively) (Table 4). The order of levels of incident factors changed when the population was stratified by sex. In women, central obesity had the highest incidence level followed by high blood pressure, hypertriglyceridemia, low HDL, and hyperglycemia. The sequential order in men was as follows: high blood pressure, hyperglycemia, hypertriglyceridemia, low HDL, and large WC (Table 4).
For participants without MetS at examination 4, the 5 triads (combination of any 3 components that guarantees diagnosis with MetS by examination 5 or 6) with the largest incidences were as follows, in order of descending frequency: (1) WC+high blood pressure+hyperglycemia; (2) HDL+high blood pressure+hypertriglyceridemia; (3) WC+hypertension+hypertriglyceridemia; (4) high blood pressure+hyperglycemia+hypertriglyceridemia; and (5) HDL+WC+high blood pressure (Table 4). When stratified by sex, the triad of large WC+high blood pressure+hyperglycemia still occurred most frequently (Table 4), and 3 of the 5 most frequent triads for men and women combined were also in the set of 5 most frequent triads for each of men and women separately.
Value of Examination 4 MetS Components Prevalence in Predicting MetS
To evaluate the predictive ability of the presence of individual components at examination 4 on occurrence of MetS by examinations 5 or 6, we conducted stepwise logistic regression analysis adjusting for age and sex, with the presence (yes/no) of the 5 individual components at examination 4 as candidates for entry into the model at the 0.05 significance level (Table 5). All participants were included in this analysis.
All MetS components significantly predicted MetS by examination 5 or 6 in the presence of the other components, with the presence of large WC conferring the highest effect (odds ratio, 4.76; 95% confidence interval [CI], 3.79 to 5.98) (Table 5). There was significant interaction with sex only for high blood pressure (P=0.0465); the interaction is not due to a difference in direction of blood pressure effect across sexes but rather a difference in magnitude of effect.
Similar results were obtained for those free from MetS at examination 4 (data not shown).
Predictive Value of Entering Combinations (Triads) on Incident CVD and Mortality
The prevalence of the top 5 most frequent triads for entering the MetS at examinations 5 or 6 (from Table 4) was assessed for ability to predict the incidence of each of CVD and all-cause mortality after baseline (defined as the examination of incident MetS or examination 4 if no incident MetS) until 2007 (average follow-up period: 14 years). In total, there were 244 CVD events for a rate of 11.0% (244/2217); this is equivalent to 0.00769 CVD events per person-year of follow-up. Split by sex, we observed for men a 14.3% CVD rate (139/974) and 0.01021 per person-year of follow-up, whereas for women the rate was 8.4% (105/1243) and 0.00579 per person-year of follow-up. The mortality rate for the overall population was 8.3% (195/2356), with a rate of 0.00532 deaths per person-year of follow-up. This rate was higher for men with 120/1058 (11.3%) and 0.00739 per person-year of follow-up than for women with 75/1298 (5.8%) and 0.00368 per person-year of follow-up.
Age- and sex-adjusted stepwise Cox proportional hazards regression, with the prevalence of each of the 5 triads as candidates for entry at the 0.05 level of significance, was used for this analysis. Participants with prevalent MetS were excluded from these analyses; for the analysis on incident CVD, participants with prevalent CVD at examination 4 were also excluded.
Only 2 of the top 5 triads examined had a significant impact on incident CVD (Table 6), with the triad of large WC+high blood pressure+hyperglycemia conferring the highest risk of developing CVD (hazard ratio, 2.36; 95% CI, 1.54 to 3.61). The other significant triad was that of HDL+high blood pressure+hypertriglyceridemia. In addition, only these 2 triads had a significant effect on predicting mortality. A combination of large WC+high blood pressure+hyperglycemia bestowed a >3-fold increased risk of future mortality (hazard ratio, 3.09; 95% CI, 1.93 to 4.94), whereas the combination of HDL+high blood pressure+hypertriglyceridemia represented an almost 3-fold increased risk of mortality (hazard ratio, 2.73; 95% CI, 1.63 to 4.58). None of the other top 5 triads (or any other below the top 5; data not shown) had a significant effect on mortality (Table 6).
After the analyses were repeated for only individuals with MetS by examination 5 or 6, only the large WC+high blood pressure+hyperglycemia triad had a significant effect on future CVD (hazard ratio, 1.64; 95% CI, 1.05 to 2.57), but no triads had a significant effect on incident mortality.
We repeated the analyses of the frequency of factors and triads on entering the MetS by smoking status. Among nonsmokers, high blood pressure remained the most present factor when classified as having MetS, followed by large WC (data not shown). In contrast, the most prevalent factor for smokers was hypertriglyceridemia, followed by high blood pressure. The order of the triads did not differ substantially by smoking status, and the top 5 triads remained relatively the same (data not shown).
We identified different trajectories by which individuals enter the MetS and determined that the specific trajectory followed has a significant impact on subsequent risk of developing CVD and on mortality. Participants who entered the MetS having a combination of central obesity, high blood pressure, and hyperglycemia had a 2.36-fold increase in incident CVD events and a 3-fold increased risk of mortality in the general population.
Those with prevalent MetS having this combination of factors represented a 1.64- and 1.58-fold higher risk of future CVD events and mortality, respectively.
Among our participants, MetS was a highly prevalent condition that increased dramatically in a relatively short period of time. From 23.5% at baseline, the prevalence of MetS almost doubled after 10 years of follow-up (40.6%). Except for low levels of HDL, which remained stable over the period examined, all other components experienced a substantial increase during the observation period. High levels of fasting glucose more than doubled in prevalence as well as large WC; the latter, in the case of women, almost tripled. Although at baseline women had less prevalence of all components of MetS than men, after 10 years of follow-up they surpassed men on levels of central obesity and almost caught up with all other factors. This could be due in part to the age of our population and the effect that menopause may have exerted among our participants during the observation. A delayed increase in high blood pressure levels among women also explains the higher increase in prevalence of MetS compared with among men. High blood pressure among women tended to lead all other factors, whereas for men the factor that preceded all others was low levels of HDL, reflecting perhaps different hepatic lipase activity and lifestyles between sexes, an earlier decrease in physical activity levels during middle age among men, or perhaps an inherent effect of using different cutoff points for men and women when defining low levels of HDL. Central obesity is another factor that seemed to affect women more significantly than men. Levels of large WC in women not only tripled during follow-up but were also the factor most often present when MetS occurred, whereas for men large WC was the factor that was least present, and high blood pressure had the leading role. This may reflect a faster accumulation of visceral fat among middle-aged women that seems to start at a later age compared with men. When we compared the prevalence and presentation sequence of the MetS factors by smoking status, high blood pressure remained as the most prevalent factor, only surpassed among smokers by hypertriglyceridemia.
Irrespective of sex and smoking status, the combination of large WC+high blood pressure+hyperglycemia was the most prevalent triad, followed by the combination of low HDL+high blood pressure+hypertriglyceridemia. High blood pressure was not only the most frequent factor in the analyses of frequencies irrespective of sex but played a central role in the trajectories followed to enter the MetS. Along with high blood pressure, 2 distinctive phenotypes played a significant role: (1) a combination of central obesity and dysregulation of glucose metabolism and (2) a phenotype characterized by dyslipidemia. These 2 idiosyncratic phenotypes in combination with high blood pressure were also the only ones to provide a significantly higher risk of future CVD and mortality in any of the potential triads. No other combination of factors, other than these 2, had a significant effect compared with the others. In the case of the combination of high blood pressure+large WC+hyperglycemia, this effect was also evident for populations with MetS, highlighting not only its importance for the prevention of MetS, CVD, and mortality but also the meaningful role that it might play in adequate clinical management of those with established MetS. These results also occurred irrespective of the presence or absence of diabetes; when we repeated the analyses after excluding those with diabetes, we found similar results (data not presented).
The levels of prevalence of the MetS and its components identified in our study fall well within the ranges of those found and reported in previous publications.14–20 Nevertheless, to our knowledge, our study is the first to not only evaluate the levels of prevalence but also to elucidate the progression of the syndrome and its factors, to identify and characterize the different trajectories that populations follow to enter the MetS, and to evaluate the effect that those trajectories exert on future CVD events and mortality. Although 23% of our population were excluded because they did not attend all examinations or had missing data on the components of MetS, this study represents a well-characterized historic cohort with a long follow-up period that allows us to not only elucidate the progression and trajectories that populations follow while entering MetS but also the effect that these trajectories have on future prognosis. Participants included in the FOS were mainly white; therefore, our results may not apply to other ethnic groups, and any generalization should be considered with care. A relevant limitation of our study is that we could not evaluate the effect of the different MetS components completely independent of other risk factors of CVD and mortality, such as alcohol consumption and socioeconomic status, because data for these factors were incomplete, unreliable, or unavailable for a large proportion of or for all of our population. It is possible that part of the observed differences in future CVD and mortality between the different triads could be explained by the differences in alcohol intake and socioeconomic status. However, the extent of the alcohol intake and socioeconomic effect cannot be calculated with the available data.
MetS is a highly prevalent condition that is increasing dramatically and affects a large proportion of the middle-aged population. Not all individuals with MetS enter the syndrome with an identical combination of factors. Certain trajectories and combinations of components confer higher risks of incident CVD and mortality. Among these, 2 confer a significantly higher risk compared with the others. Both have high blood pressure as a central factor, 1 additionally has central obesity and hyperglycemia, and the other is characterized by dyslipidemia. Intense efforts are required to identify populations with these particular combinations and to provide them with adequate treatment at early stages of disease.
We thank the participants of the Framingham Heart Study for their continuous support.
Sources of Funding
This study was funded by Unilever plc. The funding organization did not participate in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, and approval of the manuscript.
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Metabolic syndrome (MetS), the concomitant occurrence of multiple metabolic irregularities, has been associated with a significant risk of future diabetes mellitus, cardiovascular disease, and mortality. Nevertheless, the manner in which the syndrome evolves and the manner in which the future trajectories of disease develop remained uncertain. Using data from 3708 participants of the Framingham Offspring Study, we evaluated in adults the distribution and progression of the MetS and its components, the trajectories followed by those entering the MetS, and the potential effect of individual trajectories on the subsequent development of cardiovascular disease and mortality. MetS was defined according to the Adult Treatment Panel III criteria. After 10 years of follow-up, the prevalence of MetS almost doubled. Hyperglycemia and central obesity experienced the highest increase. High blood pressure was most frequently present when a diagnosis of MetS occurred (77.3%), and presence of central obesity conferred the highest risk of developing MetS (odds ratio, 4.75; 95% confidence interval, 3.78 to 5.98). Participants who entered the MetS having a combination of central obesity, high blood pressure, and hyperglycemia had a 236% increase in incident cardiovascular events and a 309% increased risk of mortality. MetS is highly prevalent and is increasing dramatically; however, not all individuals who are diagnosed with MetS enter the diagnosis with the identical combination of factors, and we identified 2 particular combinations of components that confer higher risks of incident cardiovascular disease and mortality. Intense efforts are required to identify populations with these particular combinations and to provide them with adequate treatment at early stages of disease.
Guest Editor for this article was Robert H. Eckel, MD.