Individual and Combined Cardiometabolic Morbidities and the Subsequent Risk of Cardiovascular Events in Chinese Adults: The China Cardiometabolic Disease and Cancer Cohort Study

Background The data regarding the association between main cardiometabolic morbidities such as diabetes, hypertension, and dyslipidemia and the subsequent risk of CVD events in Chinese adults are still limited. Therefore, we investigated the associations between individual and combined cardiometabolic morbidities and incident cardiovascular events in Chinese adults. The China Cardiometabolic Disease and Cancer Cohort Study was a prospective, nationwide, and population-based cohort study of 20 Chinese communities from various geographic regions. A comprehensive set of questionnaires, clinical measurements, oral glucose tolerance tests (OGTTs), and laboratory examinations were carried out at baseline (2011-2012) and follow-up visits (2014-2016). 133572 participants aged ≥ 40 years who were free from cardiovascular disease (CVD) at baseline were included in the study.

with diabetes plus hypertension (HR, 2.67; 95%CI, 2.33-3.06), diabetes plus dyslipidemia (1.57; 1.32-1.87), and hypertension plus dyslipidemia (2.12; 1.88-2.39) exhibited signi cantly higher risk for CVD events. Moreover, participants with the combination of diabetes, hypertension and dyslipidemia exhibited the highest risk for CVD events (HR, 3.06; 95%CI, 2.71-3.46). Multivariable-adjusted HRs (95% CIs) for CVD associated with diabetes based on fasting glucose ≥7.0 mmol/L, OGTT-2h glucose ≥11.1 mmol/L, and hemoglobin A1c ≥6.5% were 1.64 (1.51-1.78), 1.57 (1.45-1.69), and 1.54 (1.42-1.66), respectively; associated with hypertension based on systolic blood pressure ≥140 mmHg and diastolic blood pressure Cardiovascular disease (CVD) is the leading cause of death and disease burden in China [1]. It has been estimated that aging, sedentary lifestyle, and population growth will increase the CVD burden by more than a half over the next 20 years, and the projected unfavorable trends in diabetes, hypertension, and dyslipidemia could largely accelerate the CVD epidemic [2]. China has become the epicenter of diabetes and hypertension. According to data from the China National Survey and the China Hypertension Survey, there were approximately 11.2% and 23.2% of Chinese adults living with diabetes and hypertension, respectively [3][4]. Moreover, diabetes and hypertension will accelerate the increasing prevalence of dyslipidemia, and it has been estimated that these cardiometabolic morbidities will lead to an increase of 9.2 million cases of CVD during 2010 to 2030 in China [2]. A detailed description of the relationships of these cardiometabolic morbidities, individually and collectively, with cardiovascular events could provide valuable public health implications for effective prevention and control of CVD. However, the data regarding the association between main cardiometabolic morbidities such as diabetes, hypertension, and dyslipidemia and the subsequent risk of CVD events in Chinese adults are still limited.
To this end, we investigated the associations between individual and combined cardiometabolic morbidities including diabetes, hypertension, and dyslipidemia and incident cardiovascular events in Chinese adults aged 40 years or older in a nationwide prospective cohort study.

Study design and population
The China Cardiometabolic Disease and Cancer Cohort (4C) Study is a population-based, multicenter, prospective cohort study. The study design of the 4C Study has been described in detail previously [5][6]. During 2011 to 2012, 193846 adults aged ≥ 40 years were recruited from 20 different communities from various geographic regions in China to represent the general population. During 2014 to 2016, all participants were invited to attend an in-person visit, and 170240 participants (87.8%) were successfully followed up. According to standardized protocols, a comprehensive set of questionnaires, clinical measurements, oral glucose tolerance tests (OGTTs), and laboratory examinations were carried out at baseline and follow-up visits. In this study, 133572 participants who had complete baseline information on diabetes, hypertension, and dyslipidemia, were free from CVD at baseline, and had complete ascertainment of CVD events during follow-up were included in the main analyses of the associations between these morbidities and incident CVD. To analyze the associations between cardiometabolic disorders and CVD events, we further excluded participants without complete information on glucose tolerance status, glycated hemoglobin A1c (HbA1c), blood pressures, and lipid pro les at baseline, and 129072 participants were included in the analyses. This study was approved by the Medical Ethics Committee of Ruijin Hospital, Shanghai Jiao Tong University. All study participants provided written informed consent.

Data collection
According to a standard protocol, data collection was performed in local community clinics by trained study personnel at baseline and the follow-up visit. A questionnaire comprising information on demographic characteristics, lifestyle factors (including alcohol drinking and cigarette smoking) was administered by trained interviewers. Current alcohol drinker was de ned as a person who drank alcohol regularly in the past 6 months. Smoking status were categorized as current, former, and never smoking.
Education attainment was categorized as less than high school and high school or more. Physical activity was assessed by the International Physical Activity Questionnaire [7]. The metabolic equivalent (MET) was calculated to estimate average weekly energy expenditure. Physical activity was categorized as active (≥600 MET-min per week), insu ciently active (>0 to <600 MET-min per week), and inactive (0 MET-min per week) [8].
Height and body weight were measured according to the standard protocol, and body mass index (BMI) was calculated as the weight in kilograms divided by height in meters squared. After at least a 5-minute quiet rest, every participant needed to measure blood pressure in a seated position for three times, and an automated electronic device (OMRON Model HEM-752 FUZZY) was used to measure blood pressure. Before the blood pressure measurement, alcohol, coffee, tea, smoking, and exercise should be avoided at least 30 minutes. At last, the 3 readings were averaged for the analysis.
After an overnight fast of at least 10 hours, all participants underwent an OGTT, and blood samples were collected at 0 and 2 hours. Fasting and 2-hour plasma glucose concentrations was measured locally within 2 hours after blood sample collection using the glucose oxidase or hexokinase method under a stringent quality control program. Finger capillary whole-blood samples were collected by the Hemoglobin Capillary Collection System (Bio-Rad Laboratories) and were stored at 2℃ to 8℃ and shipped to the central laboratory in the Shanghai Institute of Endocrine and Metabolic Diseases, which was certi cated by the National Glycohemoglobin Standardization Program and the College of American Pathologists Laboratory Accreditation Program. HbA1c was measured by high-performance liquid chromatography using the VARIANT II Hemoglobin Testing System (Bio-Rad Laboratories) within 4 weeks after collection. The capillary HbA1c values and the venous values from whole-blood samples, which collected using ethylene diamine tetraacetic acid dipotassium tubes, were highly correlated (r = 0.99) in a validation subsample [9]. Total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides (TG) were measured using an autoanalyzer (ARCHITECT ci16200 analyzer; Abbott Laboratories) at the central laboratory.

Diagnosis of Diabetes, hypertension and dyslipidemia
According to the American Diabetes Association 2010 criteria, diabetes was de ned as fasting plasma glucose level of 126 mg/dL (7.0 mmol/L) or more, or OGTT-2 h plasma glucose level of 11.1 mmol/L or more, or HbA1c level of 6.5% or more, or by a self-reported previous diagnosis by health care professionals [10]. Dyslipidemia was de ned as LDL cholesterol ≥160 mg/dL (4.14 mmol/L), or HDL cholesterol <40 mg/dL (1.04 mmol/L), or triglycerides ≥200 mg/dL (2.26 mmol/L), or total cholesterol ≥240 mg/dL (6.22 mmol/L), or taking lipid-lowering medications [11]. Hypertension was de ned as systolic blood pressure (SBP) ≥140 mmHg, or diastolic blood pressure (DBP) ≥90 mmHg, or by a selfreported previous diagnosis by health care professionals [12].

Ascertainment of Cardiovascular Events
The outcome of this study was the composite of incident fatal or nonfatal CVD events, which included myocardial infarction, stroke, cardiovascular death, and hospitalized or treated heart failure. The ascertainment of cardiovascular events has been described in detail previously [6].

Statistical Analysis
Continuous variables were presented as means with standard deviations (SDs) and categorical variables were presented as numbers with percentages. Person-time for every participant was calculated from the date of enrollment to the date of CVD diagnosis, death, or the end of follow-up. We rst calculated the hazard ratios (HRs) and 95% con dence intervals (CIs) for CVD events using the Cox proportional hazards models in all participants, with multivariable adjustment for age, sex, education attainment (below high school, high school or above), BMI, physical activity (inactive, insu ciently active, active), smoking status (never, former, current), and drinking status (never, former, current). Next, we calculated all these above hazard ratios (HRs) and 95% con dence intervals (CIs) for CVD events among men and women, respectively. We then calculated the multivariable-adjusted HRs and 95% CIs for incident of CVD events for participants with cardiometabolic disorders, which were de ned by measures of glucose, blood pressures, and lipids, in comparison with participants without the relative disorders. We also assessed the associations between cardiometabolic disorders and CVD events by sex strati cations. All statistical analyses were performed by using SAS software, version 9.4 (SAS Institute Inc). A two-sided P value <0.05 was considered statistically signi cant.

Results
Baseline key characteristics of 133572 participants (46125 men and 87447 women) are shown in Table 1. Compared with women, men were older, had higher proportions of high school or further education, and were more likely to be current smokers, current drinkers, and be physically inactive. Generally, compared with women, men had poorer cardiometabolic pro les, with higher proportions of diabetes, hypertension, and dyslipidemia, and had higher levels of BMI, fasting glucose, OGTT-2 h glucose, HbA1c, SBP, DBP and LDL cholesterol and a lower level of HDL cholesterol.    129072 participants with complete cardiometabolic disorders were included in the analysis.
*HRs (95% CIs) indicate risks for incident cardiovascular events for participants with cardiometabolic disorders, compared with participants without the relative disorders; with adjustment for age, sex, education attainment (below high school, high school or above), body mass index, physical activity (inactive, intermediate active, active), smoking status (never, former, current), and drinking status (never, former, current).

Discussion
In this Chinese nationwide prospective cohort study of 133572 middle-aged and elderly adults, we provided comprehensive data on relationships of individual and combined cardiometabolic morbidities including diabetes, hypertension, and dyslipidemia with the subsequent risk of CVD events. In this study, compared with participants without diabetes, hypertension, and dyslipidemia, participants with diabetes or hypertension only exhibited signi cantly higher risk of CVD events, while participants with dyslipidemia only showed no excess risk of CVD. When analyzed collectively, these morbidities showed an additively increased risk of CVD events, with the combination of diabetes, hypertension, and dyslipidemia conferred the highest risk for CVD events. Our ndings were independent from controversial risk factors, and were generally consistent by sex.
Cardiovascular complications are the leading cause of disability and mortality in patients with type 2 diabetes [13][14], and diabetes increases the risk of CVD events for more than 2-fold independent of conventional risk factors [15][16]. Recently, ndings from the Da Qing IGT and Diabetes Study revealed that during 23 years of follow-up, CVD was the predominant cause of deaths among Chinese adults with newly diagnosed diabetes, responsible for 47.5% of deaths in men and 49.7% in women [17]. As for hypertension, a prospective observational global study of 1 million people from 61 populations with an average follow up of 12 years provided robust data that clinic SBP or DBP was independently, directly, positively and continuously associated with the risk of cardiovascular mortality, stroke, and coronary heart disease events [18]. The Asia Paci c cohort study (APCSC) including 13 Chinese populations also con rmed that elevated blood pressures signi cantly increased the risk for ischemic heart disease and stroke events [19]. And interestingly, these above associations were stronger in Asian populations than in New Zealand and Australia populations: in Australian and New Zealand populations, with every respectively; while the corresponding risks were 53% and 31% in Asian populations [19]. Our ndings were in line with previous studies by supporting the strong and independent impacts of diabetes and hypertension on incident CVD events, and extended previous ndings by highlighting the comprehensive management of diabetes and hypertension could be more effective for the prevention and control of CVD events.
In the primary prevention of CVD, treatment measures and intervention goals for blood lipids should be determined according to the degree of CVD risk, and it is necessary to take personalized comprehensive treatment decisions to minimize the overall risk of CVD patients [20]. Emerging evidence suggested that TC and LDL-C are positively correlated with the CVD risk, and lowering LDL-C level has been regarded as the primary intervention target of lipid regulation therapy [21]. The Feno brate Intervention and Event Lowering in Diabetes study [22] and Helsinki Heart Study [23] showed that a reduction in TG was associated with a lower risk of atherosclerotic CVD. Because no research intervention has targeted only HDL, it is di cult to determine whether increasing HDL levels alone is clinically bene cial from clinical trials [24][25]. However, the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial documented that increasing HDL and lowering TG signi cantly reduced the rate of coronary events in individuals with ASCVD and low HDL-C [25][26]. In this study, compared with adults without diabetes, hypertension, and dyslipidemia, adults with only dyslipidemia exhibited no signi cant excess risk for CVD events. However, participants with TC ≥ 6.22 mmol/L, LDL-C ≥ 4.14 mmol/L or TG ≥ 2.26 mmol/L did confer higher CVD risks than those with normal blood lipids. Meanwhile, we found dyslipidemia in combination with diabetes or hypertension exhibited signi cantly higher risks for CVD events. Our observations might be explained, at least partly, by the potential reason that adults with dyslipidemia were more prone to be accompanied with obesity, diabetes and hypertension, and the complex interplay between dyslipidemia and multiple risk factors largely determined the overall risk of CVD events [27].

Strengths And Limitations
To the best of our knowledge, this is the rst study to comprehensively investigate the associations between individual and combined cardiometabolic morbidities and incident CVD events in Chinese adults. Our ndings emphasized the importance of a comprehensive management of cardiometabolic morbidities to promote the e ciency of prevention and control of CVD events. The strengths of this study included the prospective study design, the large nationwide sample size, and the comprehensive cardiometabolic measurements. However, this study also has several limitations. First, the follow-up duration was relatively short, which might limit the statistical power for CVD events. Second, although we have carefully adjusted for a series of confounders in the analyses, the residual and unmeasured confounders and possible reverse causation could not be fully ruled out and the bias is likely to be present. Third, our analyses were restricted to middle-aged and elderly Chinese adults, therefore the generalization of our ndings to other ethnic groups should be cautious.

Conclusions
This prospective nationwide population-based study of Chinese adults provided quantitative data that main cardiometabolic morbidities including diabetes, hypertension, and dyslipidemia, individually and collectively, associated with increased risks of CVD events. Our ndings underlined the importance of taking into account of diabetes, hypertension, and dyslipidemia together in the primary prevention and control of CVD to reduce the disease burden. Declarations