Metabolic Syndrome Components and Long-Term Incidence of Cardiovascular Disease in Eastern Mediterranean Region: A 13-Year Population-Based Cohort Study

Background

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the world and the leading cause of death in the East Mediterranean Region (EMR) that accounts for 27.4% of total deaths in this region. Iran, with 46% of total deaths attributable to CVD, is among the high-risk countries in EMR. ¹ Overweight, obesity, diabetes, dyslipidemia, hypertension, and a cluster of clinical symptoms of so-called metabolic syndrome (MetS) are the main contributors to CVD-related morbidity and mortality.

The report by the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) defines MetS as a cluster of metabolic risk factors including central obesity, elevated triglycerides, hypertension, low levels of high-density lipoprotein (HDL), and elevated fasting plasma glucose (FPG). ^2,3 MetS is common throughout the world, with an estimated prevalence of 10%–40% in different countries and even higher estimates as much as 85% in specific populations. ^{4 –6} The prevalence of MetS in the United States has increased from 28% in the 1988–1994 survey to 34% in the 1999–2004 survey. ⁷ The interest in MetS increased after the definition of NCEP ATP III as it had an acceptable performance, compared with well-known measures such as body mass index (BMI), in assessment of amount and distribution of body fat and prediction of future conditions such as diabetes (T2D) and CVD. ⁸ MetS prevalence is age dependent and the reported prevalence in different age groups of the Iranian adult population ranges from 33.7% to 34.6% with higher rates in women. ^{9 –11}

There is increasing evidence that MetS is a precursor to several conditions, mainly atherosclerotic CVD (ASCVD) and T2D, and increases both incidence and mortality. ³ The risk of CVD in individuals with MetS is twice that in general populations. ^2,9 Several studies have shown that the mortality rate in ASCVD patients was higher in MetS individuals who are likely related to multiple metabolic risk factors of MetS, where meeting more of the five criteria increases the risk. ^3,12 However, the components of MetS are inter-related and contribute synergistically to augmented risk of CVD and T2D. ¹³ Further, the role of each MetS component in later complications is not fixed and the amount of contribution depends on various factors such as ethnicity, race, sex, and the number of concomitant components. ^3,8,13 The effect of such combinations, sometimes called trajectories, on subsequent CVD and mortality has been evaluated in The Framingham Offspring Study. ¹⁴ It considered the most prevalent triads of MetS components and assessed which combinations have associations with future CVD. The current research aimed at assessing the relationship between MetS and CVD and at evaluating the effect and predictive value of triads of MetS components on subsequent CVD in participants of an ongoing prospective study in Iran.

Materials and Methods

Results

The sample included 1387 adults, 51.3% of whom were female, with age of 47.4 ± 9.2 years (48.2 ± 9.6 for males and 46.6 ± 8.7 for females) in 2001. The prevalence of MetS and T2D was 34.4% (19.5% of which were diabetic) and 9.7%, respectively. Other descriptive statistics of participants at baseline are shown in Table 1. We assessed the association between MetS and future CVD by using logistic regression in Table 2. The adjusted results indicated that the odds of developing CVD in MetS cases, irrespective of its composing components, was 1.76; 95% CI = 1.22–2.55 times that in MetS-free cases.

The prevalence of MetS components in each examination is shown in Table 3. Among single components, the prevalence of hypertension (BP) and hyperglycemia (FPG) increased over time whereas the prevalence of the other components decreased. In MetS-free participants at baseline who developed MetS in the study course (n = 366), HDL (6.3%), TG (83.6%), BP (81.4%), WC (71.0%), and FPG (41.6%) were the most frequent MetS components. The five most frequent triple combinations of MetS components in all individuals diagnosed with MetS in the study were HDL + WC + TG (480 cases), HDL + WC + BP (470 cases), HDL + BP + TG (469 cases), WC + BP + TG (463 cases), and HDL + FPG + TG (233 cases). Table 4 shows the adjusted results of Cox regression on these combinations. HDL + BP + WC was the only triple combination that showed a significant association with CVD incidence with HR = 1.66; 95% CI = 1.04–2.67.

Discussion

This study was conducted to evaluate the association between CVD and MetS and to examine the ability of triple MetS components in prediction of future CVD events in individuals with MetS. Besides the contribution of MetS to increased risk of CVD, we observed that combinations of MetS components have implications for risk modification and prognosis. Our findings showed that, among the most frequent triple combinations of MetS components, diagnosis of MetS based on HDL + WC + BP leads to the highest risk of CVD incidence with HR = 1.66.

Despite controversies on the definition of MetS, it has value in identifying individuals at higher risk of diabetes and CVD who may be considered at low risk by single criteria or fall below the threshold needed for initiation of drug therapy. ^8,18,19 The results of a cohort study on the 30–75-year-old population showed that MetS is a more powerful tool in predicting coronary heart disease, CVD, and total mortality than its every single component. ⁸ In a large sample prospective cohort, the presence of one to two MetS components was associated with increased risk of mortality from CHD and CVD and MetS was a stronger predictor of CHD, CVD, and total mortality than its single components, where HR of CVD mortality was 1.10 for individuals with one or two components and 1.47 for MetS individuals. ²⁰ A systematic review and meta-analysis of 87 studies concluded that the risk of cardiovascular outcomes in MetS individuals is twice that in the MetS-free population. ²¹

A large number of studies have argued for physiological and pathophysiological mechanisms for each MetS component in subsequent CVD incidence. ^22,23 Among the other components, hypertension and hyperglycemia have been shown to have specific importance in acute ischemic noncardioembolic stroke, myocardial infarction, and cardiovascular death. ^24,25

In The Framingham Offspring Study, WC and BP along with hyperglycemia were the most predictive of CVD risk among triple components of MetS with estimated HR of 2.36; 95% CI = 1.54–3.61. HDL, BP, and TG were the second triple with HR of 1.94; 95% CI = 1.19–3.16. As expected, hypertension is likely the most important feature in MetS to be controlled to prevent subsequent CVD incidence. It seems that aging, less activity, and increase in overweight prevalence will increase MetS prevalence and both short- and long-term risk of CVD worldwide. ⁷

Lipid profiles are core components of MetS that contribute to cardiovascular incidence and mortality. Low HDL cholesterol levels are associated with increased risk of cardiovascular events, independently from low-density lipoprotein (LDL) cholesterol. ^26,27 Results of a large prospective study in the CVD-free Japanese population suggested an inverse association between HDL cholesterol and coronary heart disease. ²⁷

A large number of studies have concluded that cardiovascular events increase with serum TG levels. ^{27 –29} Both low HDL cholesterol and high TG levels are in direct association with small dense LDL cholesterol, the most atherogenic portion of LDL cholesterol. ⁷ However, whether raising HDL cholesterol by intervention could reduce cardiovascular risk remains disputable. ^30,31

WC was found to be one of the three factors most strongly associated with CVD risk. The mechanism is unclear and was not sought in this study. It is possible, however, that WC is associated with CVD risk through disturbed adipose tissue function. The imbalances in various adipokines released by excess accumulated visceral fat could result in metabolic disorders and subsequent conditions. ⁷ The role of leptin and adiponectin, an adipose tissue-specific hormone, in cardiovascular events is conflicting. ³² Regardless of weight and BMI, leptin has direct association with MetS and is positively associated with hypertension and obesity indices, with stronger association with abdominal adiposity mainly measured by WC. ^{33 –39} Also, adiponectin has reverse association with metabolic disorders and obesity anthropometrics such as WC and its concentration is low in obese subjects. ^6,40

WC has better performance in risk prediction than other indices of general obesity such as BMI. After some age, especially in old age, BMI becomes constant as a result of muscle volume loss. However, abdominal fat mass measured by WC continues to increase. ⁷ The increase in WC is not reflected properly by BMI and therefore, the predictive ability of BMI is decreased. Even though weight management is the cornerstone in CVD risk reduction, WC should be monitored as another key component. ⁴¹

Conclusion

MetS prevalence is increasing and individuals enter MetS with different trajectories, some of which are more likely to result in CVD. Proper and punctual preventive measures could help in controlling MetS prevalence and subsequent risk of diabetes and cardiovascular events. It would be useful to identify the most predictive factors to initiate such interventions, rather than waiting for all MetS components or symptoms of CVD in this population.