Research Article: Age- and sex- specific all-cause mortality risk greatest in metabolic syndrome combinations with elevated blood pressure from 7 U.S. cohorts

Date Published: June 13, 2019

Publisher: Public Library of Science

Author(s): Winnie W. Yu, Arshdeep K. Randhawa, Steven N. Blair, Xuemei Sui, Jennifer L. Kuk, Kiyoshi Sanada.


The association between metabolic syndrome (MetS) and all-cause mortality is well established but it is unclear if there are differences in mortality risk among the 32 possible MetS combinations. Hence, the purpose of this study is to evaluate the associations between different MetS combinations and its individual components with all-cause mortality, and to examine differences in the association by age and sex.

A merged sample of 82,717 adults from 7 U.S. cohorts was used.

In our sample, MetS was present in 32% of men, 34% of women, 28% of younger adults (18–65 years) and 62% of older adults (>65 years) with 14,989 deaths over 14.6 ± 7.4 years of follow-up. Risk of all-cause mortality was higher in younger individuals with a greater number of MetS factors present, but in older adults having all 5 MetS factors was the only combination significantly associated with mortality. Regardless of age or sex, elevated blood pressure was the MetS factor most consistently present in MetS combinations that were significantly and most strongly associated with mortality. In fact, elevated blood pressure in the absence of other risk factors was significantly associated with mortality in men (HR, 95% CI = 1.56, 1.33–1.84), women (HR = 1.62, 1.44–1.81) and younger adults (HR = 1.61, 1.45–1.79). Conversely, waist circumference, glucose and triglycerides in isolation were not associated with mortality (p>0.05).

In a large U.S. population, different combinations of MetS components vary substantially in their associations with all-cause mortality. Men, women and younger individuals with MetS combinations including elevated blood pressure had stronger associations with greater mortality risk, with minimal associations between MetS and mortality risk in older adults. Thus, we suggest that future algorithms may wish to consider differential weighting of these common metabolic risk factors, particularly in younger populations.

Partial Text

Metabolic syndrome (MetS) is the clustering of three or more metabolic risk factors as defined by the revised National Cholesterol Education Program (NCEP) criteria [1]. It is well established that individuals with MetS are at an increased risk for CVD [2–4] and all-cause mortality [5,6]. There is heterogeneity in how MetS is defined [7,8] as well as potential sex and age differences in the way metabolic factor combinations are related with mortality risk [9]. To our knowledge, studies that previously identified MetS combinations and their associations with mortality risks had short follow-up time [10] and low incident all-cause mortality associated with each MetS cluster [11]. Thus, few studies have a large enough sample size to categorize participants into each of the 32 MetS combinations and examine the specific mortality risk associated with each combination separately [9]. Hence, the objective of this study is to determine whether different MetS combinations vary in their associations with all-cause mortality and to determine whether there are differences by age and sex.

The proportion of participants with MetS was 32.3% in men and 34.0% in women. In younger adults, 27.8% had MetS whereas 62.1% of older adults had MetS. Table 1 shows the characteristics of participants stratified by sex, age and MetS status. MetS combinations are categorized by the number of MetS risk factors present. Participant characteristics stratified by each of the 32 MetS combinations is shown in Appendix 1. Clustering of all five risk factors was the most prevalent MetS combination present in 13.2% of men and 17.2% of women with MetS. In men, elevated BP was the most common MetS component (49.4%) whereas elevated waist circumference (45.6%) was the most prevalent in women. The least prevalent component was elevated waist circumference (26.2%) in men and elevated triglycerides (26.9%) in women. In both younger and older adults with MetS, displaying all five metabolic factors was the most prevalent MetS combination (13.7%, 17.8%, respectively). Elevated BP remained the most prevalent MetS component in both younger (41.8%) and older adults (78.8%) whereas elevated triglyceride in younger adults (28.6%) and older adults (42.9%) was the least prevalent metabolic components.

This study demonstrates the heterogeneity of the MetS definition and the variations in MetS combinations in relation to all-cause mortality risk in the U.S. adult population. Results from the analyses provide evidence that the 32 combinations of MetS vary in their associations with mortality by age with only modest differences by sex. In particular, we observe that MetS combinations with elevated BP are more predictive of mortality risk than the other MetS factors in both men and women, and younger populations, with the association between MetS and mortality risk being substantively weaker in older populations.

In a large-scale U.S. sample, the present study provides evidence that MetS is a heterogeneous syndrome wherein the expressions of different metabolic risk factor combinations show substantial variations in its associations with all-cause mortality by age and modestly by sex. Regardless of sex, individuals with elevated BP in isolation or in a combination with other metabolic factors also had greater mortality risk. Thus, we suggest that the metabolic factors within the MetS definition may warrant age- and risk factor-specific weightings to better account for the differences in predictive value of the metabolic risk factors in different age groups.