Waist-to-Height Ratio, Waist Circumference, Body Mass Index and Risk of Cardiometabolic Multimorbidity: A National Longitudinal Cohort Study

Background: Cardiometabolic multimorbidity is an increasing public health burden. This study aimed to evaluate the association of waist-to-height ratio (WHtR), waist circumference (WC) and body mass index (BMI) with risk of cardiometabolic multimorbidity. Methods: We used data from the China Health and Retirement Longitudinal Study (CHARLS). 10521 participants aged 45 and over were recruited, including 8807 individuals with 0 cardiometabolic disease at baseline (stage (cid:0) ) and 1714 individuals with 1 cardiometabolic disease at baseline (stage (cid:0) ). Logistic regression was conducted to estimate the odds ratios (ORs) and condence intervals (CIs). Net reclassication index (NRI) and integrated discrimination improvement (IDI) were used to evaluate the incremental predictive value beyond conventional factors. Results: In stage (cid:0) , increased risk of cardiometabolic multimorbidity was observed among participants with WHtR ≥ 0.5 (OR: 1.76, 95% CI: 1.05–2.97), WC ≥ 85 (men) + WC ≥ 75 (women) (OR: 1.77, 95% CI: 1.05–2.97) or BMI ≥ 24 (OR: 1.48, 95% CI: 0.98–2.24). Furthermore, both NRI and IDI of WHtR and WC were higher than those of BMI. In stage (cid:0) , the adjusted ORs (95% CIs) of WHtR ≥ 0.5, WC ≥ 85 (men) + WC ≥ 75 (women), and BMI ≥ 24 were 2.04 (1.24–3.35), 2.07 (1.28–3.34), and 1.47 (1.06–2.04), respectively. In addition, WC exhibited the highest NRI and IDI. Conclusions: WHtR, WC and BMI are independent predictors of cardiometabolic multimorbidity in middle-aged and elderly Chinese population. WHtR and WC show better abilities in predicting cardiometabolic multimorbidity than BMI.


Introduction
Cardiometabolic diseases, including stroke, diabetes, and heart disease, are the leading cause of deaths worldwide [1,2]. With the rapid population aging, cardiometabolic multimorbidity, de ned as the cooccurrence of 2 or more cardiometabolic diseases, has become a prominent public health concern.
Remarkably, the health damages attributed to cardiometabolic multimorbidity are far more signi cant than a single cardiometabolic disease. It is reported that, when compared with elderly people without cardiometabolic diseases, individuals with any of cardiometabolic diseases or with any two of cardiometabolic diseases were estimated to have reduced life expectancies of 7 years and 12 years, respectively [3]. Furthermore, individuals with one cardiometabolic disease or with cardiometabolic multimorbidity also had 1.41 and 1.89 times the odds of higher mental stress than those without cardiometabolic disease, respectively [4]. However, as a major and persistent problem [5,6], cardiometabolic multimorbidity has been quite inadequately studied, and early prevention measures need to be taken urgently.
Obesity has been acknowledged as an important risk factor for cardiometabolic diseases. Large amounts of evidence also showed that body mass index (BMI), a common measure of obesity, could predict single cardiometabolic diseases. In contrast, only a few studies reported the prospective association of BMI with cardiometabolic multimorbidity in Europe and America [7,8]. However, the evidence for this association remains to be further validated in Asian populations. Recently, waist circumference (WC) and waist-toheight ratio (WHtR) have been proposed to be important anthropometric indicators of abdominal obesity [9,10], and many studies demonstrated that these two indicators were superior to BMI in predicting single cardiometabolic diseases [9][10][11][12][13][14][15]. Nevertheless, the relationship between WHtR, WC and cardiometabolic multimorbidity has yet to be assessed.
In this study, we investigated the longitudinal relationship between BMI, WHtR, WC, and cardiometabolic multimorbidity in the middle-aged and elderly Chinese population. Our aims are two-fold: (1) to assess the association of BMI, WHtR and WC with cardiometabolic multimorbidity; (2) to compare the predictive ability of BMI, WHtR, and WC in risk of cardiometabolic multimorbidity.

Study Design
We used data from the China Health and Retirement Longitudinal Study (CHARLS) [16]. CHARLS is a nationally representative longitudinal survey, which collects data from individuals aged 45 and above in China. A wide range of information concerning the economic standing, physical and psychological health, demographics and social networks has been collected. Anthropometric indicators and cardiometabolic diseases have also been assessed in CHARLS. The rst national baseline survey of CHARLS was conducted in 2011-2012, which included 10,257 households and 17,708 individuals from 150 counties/districts and 450 villages/resident communities [17]. Participants were then followed up every 2 years. Details of the study design of CHARLS can be found in previous literature [18]. This study was approved by Biomedical Ethics Review Committee of Peking University. All participants signed informed consents.

Study Population
All participants recruited in the national baseline survey were included if they met the following criteria: (1) aged at least 45 years; (2) no history of cardiometabolic multimorbidity at baseline; (3) collected anthropometric indicators successfully; (4) successfully followed up. Finally, we included 8807 individuals without any cardiometabolic disease at baseline and 1714 individuals with one of cardiometabolic diseases at baseline (Figure 1).

WHtR, WC and BMI Measurements
BMI was calculated as weight (kg) divided by the square of height (m). WHtR was de ned as WC (cm) divided by height (cm). Height and weight were measured by vertical height measuring instrument and weighing scale with bare feet and light clothes. When measuring WC, the measured personnel used a soft ruler to circle the waist horizontally at the level of the navel.

Cardiometabolic multimorbidity and outcomes
Cardiometabolic multimorbidity is de ned as having two or more of the following three diseases: diabetes, stroke, and heart problems [3]. The diagnosis of cardiometabolic diseases was determined by participants' self-reported information. This study evaluated the development of cardiometabolic multimorbidity from two situations: 1) From 0 cardiometabolic disease at baseline to cardiometabolic multimorbidity (stage ); 2) From 1 cardiometabolic disease at baseline to cardiometabolic multimorbidity (Stage ). For the rst situation, subjects who did not suffer from any of the three diseases in 2011 were included. Subsequently, people who eventually developed two or more cardiometabolic diseases during follow-up were deemed as individuals with cardiometabolic multimorbidity. For the second situation, participants having only one of the three diseases in 2011 were included, and then developing one or more new-onset cardiometabolic diseases during follow-up was de ned as cardiometabolic multimorbidity.

Covariates
Covariates included sociodemographic characteristics, lifestyle factors and current disease status [19].
Sociodemographic characteristics included age (years), gender (male/female), education level (less than lower secondary education/upper secondary & vocational training/tertiary education), and residence (rural/urban). Lifestyle factors included smoking status (ever smoking/never smoking) and drinking status (ever drinking/never drinking). Current diseases (yes/no) included hypertension, cancer, lung disease, psychological problems, arthritis, dyslipidemia, liver disease, kidney disease, stomach/digestive system diseases, and asthma.

Statistical Analysis
Categorical variables were presented by frequency (percentage) and compared by the Chi-square test.
Continuous data were described as median (inter-quartile range) and compared by the Wilcoxon rank sum test [20,21].
For subsequent analyses, we converted the continuous variables into binary variables, using the cut-off values of 24kg/m 2 for BMI [20], 0.5 for WHtR [13], and 75 cm (women) and 85cm (men) for WC [22], respectively. Binary logistic regression model was used to access the associations of BMI, WHtR and WC with cardiometabolic multimorbidity, and the odds ratios (ORs) and 95% con dence intervals (CIs) were estimated. Net reclassi cation index (NRI) and integrated discrimination improvement (IDI) were calculated to compare the predictive utilities of BMI, WHtR and WC for cardiometabolic multimorbidity beyond other conventional factors [17,23].
All analyses were performed using SAS 9.4 (SAS Institute, Cary, NC, USA). A two-sided P-value less than 0.05 was deemed statistically signi cant.

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Stage : From 0 cardiometabolic disease to cardiometabolic multimorbidity A total of 8807 participants without any cardiometabolic disease at baseline were included in this stage.

Discussion
The present study investigated the prospective association of BMI, WHtR and WC with cardiometabolic multimorbidity in a nationally representative cohort. Our results showed that BMI, WHtR and WC were all independently associated with increased risk of cardiometabolic multimorbidity among the middle-aged and elderly Chinese population. Moreover, compared with BMI, WHtR and WC exhibited better predictive utilities in future cardiometabolic multimorbidity.
Cardiometabolic multimorbidity, as a growing problem, poses a major challenge to health care systems throughout the world. Previous studies have suggested that cardiometabolic multimorbidity is much more harmful than a single cardiometabolic disease. For example, compared to the absence of any of the three cardiometabolic diseases, the hazard ratio (HR) for all-cause mortality was about twice in any one of these diseases, 4 times in any two of these diseases, and 7 times in the presence of all three diseases [3]. In view of the serious harm of cardiometabolic multimorbidity, early predictive indicators need to be discovered urgently. However, quite limited studies have investigated the associations of easyto access anthropometric indicators, such as BMI, WHtR and WC, with risk of cardiometabolic multimorbidity. To the best of our knowledge, there are only two studies exploring the link between BMI and cardiometabolic multimorbidity [7,8]. The study by Kivimäki et al. involving 16 longitudinal research databases and 120,813 subjects suggested that the risk of cardiometabolic multimorbidity increased as BMI increased [8]. This comprehensive analysis indicated that compared with healthy-weight individuals, overweight and obesity individuals (BMI ≥ 24) had twice the risk of developing cardiometabolic multimorbidity. The OR values between this study and ours are similar, indicating the predictive power of BMI. However, the Asian population has not been included in this study, and our study can be a supplement in this regard. Another study recruiting 8270 subjects showed that the hazard ratio for overweight/obesity was 1.19 times (95% CI: 1.00-1.43) higher for developing cardiometabolic multimorbidity from 1 baseline cardiometabolic disease than individuals with healthy weight.
WC, as an abdominal obesity measurement indicator, has been supported as an obesity-related health risk indicator for both Western and Asian populations [24][25][26]. Previous studies have suggested that WC has greater predictive power for risk of cardiometabolic diseases than BMI [9,27]. Furthermore, a large amount of evidence has also supported that WHtR was more effective than BMI in predicting coronary heart disease, stroke and diabetes [9, 12-14, 21, 28, 29]. Remarkably, our study also found that WHtR and WC were independent predictors of cardiometabolic multimorbidity. Moreover, WHtR and WC were demonstrated to possess higher predictive abilities on risk of cardiometabolic multimorbidity than BMI in the current study. This phenomenon may be explained by the following reasons. First of all, BMI can only be used to measure the total body fat and cannot represent the body fat distribution [30]. The susceptibility of cardiometabolic diseases may depend on the difference of regional body fat distribution and the ability of subcutaneous adipose tissue [31]. Moreover, WC re ects body fat ratio more accurately than BMI, and it may play an important role in the early development of metabolic syndrome [32,33]. A recent systematic review demonstrated that compared with BMI, WC increased the ability to discriminate adverse cardiometabolic risk outcomes by 3% [29]. In addition, WHtR has been suggested to be less affected by race, age and gender and be relatively more stable [9,11,34]. People with the same BMI might have different risks of cardiometabolic diseases [31]. Even among people with normal BMI, those with high WHtR are more likely to suffer from cardiometabolic diseases. Notably, about 35% of men and 14% of women with high WHtR would be missed if screened by BMI only, which could bring serious consequences for cardiometabolic disease prevention [35]. Considering that WHtR and WC have better predictive power in cardiometabolic multimorbidity than BMI, screening by WHtR and WC might be applicable in future practice.
The exact mechanisms underlying the association between BMI, WHtR, WC, and cardiometabolic multimorbidity remain to be illuminated, but insulin resistance and ectopic fat deposition may be the main contributors. Adipose tissue produces a large amount of bioactive mediators, which leads to insulin resistance. Insulin resistance may cause cardiometabolic diseases in the following ways. First, in a state of insulin resistance, in ammation occurs in the body, which eventually leads to atherosclerosis [36]. Second, insulin resistance affects the production of apolipoprotein A1 (apoA-) or the liver secretion of high-density lipoprotein (HDL), which could be a trigger for metabolic syndrome [37]. Third, insulin resistance would obstruct normal heart function through inhibiting metabolic pathways and over-stimulating growth factors [38]. In addition, ectopic fat deposition triggers a pathological metabolic response, increasing the risk of metabolic diseases [31]. Excess free fatty acids are produced outside the fat storage tissue, and transferred to ectopic sites, including the viscera, heart, and vasculature, ultimately leading to cardiometabolic diseases [39].
There are several merits in this study. Our study is the rst to investigate the association of WHtR and WC with risk of cardiometabolic multimorbidity. Moreover, WHtR and WC were shown to be advantageous in predicting cardiometabolic multimorbidity than BMI. In addition, the two-stage strategy to assess cardiometabolic multimorbidity could provide mutual validation and increase the reliability of the associations. Limitations should be noted as well. First, our research was based on the four-year followup data, preventing the assessments of a long-term association. Second, the cardiometabolic diseases included in this study were self-reported. However, self-reported cardiometabolic diseases have been proved to be highly reliable in large-scale epidemiological studies [40].

Conclusions
In the middle-aged and elderly Chinese population, WHtR, WC and BMI were found to be independent predictors of cardiometabolic multimorbidity. In addition, WHtR and WC exhibited better predictive power in future cardiometabolic multimorbidity than BMI. Our ndings highlight the signi cance of screening and interventions of high-risk individuals through easy-to-access and cost-effective tools, such as WHtR and WC, for the prevention of cardiometabolic multimorbidity.

Declarations
Ethics approval and consent to participate CHARLS was approved by Biomedical Ethics Review Committee of Peking University, and all participants signed informed consents.

Consent for publication
Not applicable.

Availability of data and materials
The data used and analyzed in this study are publicly available from the China Health and Retirement Longitudinal Study (http://charls.pku.edu.cn/zh-CN). Flowchart of participant selection