The Prevalence of Cardiovascular Risk Factors in Patients with and Without Metabolic Syndrome in Diabetes Mellitus: A Study Based on Rafsanjan Cohort Study

Cardiovascular disease (CVD) is the leading causes of death and disability in diabetes. This study aimed to determine the prevalence of cardiovascular risk factors in people with and without metabolic syndrome (MtS) in diabetes mellitus (DM). Methods This cross-sectional study was part of Rafsanjan Cohort Study (RCS).as part of the comprehensive PERSIAN (Prospective Epidemiological Research Studies in IrAN) on adults with and without MtS in DM. CVD risk factors, including gender, age, blood pressure, dyslipidemia, smoking, alcohol consumption, fasting blood sugar, creatinine, blood urea, waist circumference, body mass index, family history, physical inactivity, fruit and vegetable consumption were collected in the PERSIAN Cohort Questionnaire. The data were analyzed by SPSS software version 22. creatinine, blood urea nitrogen (BUN), alkaline phosphatase (ALP), waist circumference, body mass index (BMI= weight (kg)/height2 (m)), height and weight, family history of cardiovascular disease, physical inactivity, and insucient consumption of fruits and vegetables. Diabetes the Panel; lipoprotein; High Density Lipoprotein; blood urea nitrogen; ALP, alkaline phosphatase; BMI, body mass index.


Introduction
The International Diabetes Federation (IDF) estimates that diabetes accounts for 8.8% of the world's population and is projected to increase to 642 million by 2040. The prevalence of diabetes mellitus (DM) is constantly increasing over time (1). In Iran, the prevalence of DM in adults aged 25 to 70 years is reported to be 11.9%. It is estimated that by 2030, about 9.2 million Iranians are likely to have DM.
Cardiovascular disease (CVD) is one of the leading causes of death and disability in people with DM (2).
The risk of CVD is constantly increasing by increasing fasting plasma glucose levels, even before reaching a su cient level to diagnose DM (3). DM reduces life expectancy by up to 10 years and more than 50% of patients die of a cardiovascular event (4). People with DM are more likely to be affected by CVD than non-diabetic people (2,5).
Diabetic patients had a 10% higher risk of CVD, a 53% higher risk of MI, a 58% higher risk of stroke, and a 12% higher risk of heart failure than the non-diabetic population. Thus, DM is a major risk factor for CVD and its consequences (6). The literature review shows that in New York, patients with DM are almost three times more likely to develop heart disease than their non-diabetic counterparts (7). This ratio has been studied in some areas in Iran. For instance, the risk of CVD in DM patients in a study in Yazd was about 2-4 times (8). and in another study in Ahvaz was 2-8 times that of the general population (9).
The risk of CVD in DM follows a slope, and the severity of this slope depends on a combination of multiple risk factors (10). Most of these additional risks of CVD in DM are associated with an increased prevalence of known risk factors, such as hypertension, dyslipidemia, and obesity (11). Over the last decade, studies have shown that treating known risk factors for patients with DM is extremely important in reducing the risks of CVD (12). Poor control of most cardiovascular risk factors has been observed in the diabetic population. However, the additional risks of CVD in DM patients cannot be attributed solely to the higher prevalence of known risk factors (13). Therefore, other risk factors may be important in people with DM (14). A set of interrelated risk factors characterize metabolic syndrome (MtS), including hypertension, hyperglycemia, abdominal obesity, and dyslipidemia (15). The disease is associated with an increased risk of cardio-vascular events, DM, and deaths (16).
NCEP-ATPIII (the National Cholesterol Education Program-Adult Treatment Panel) Criteria, IDF, and WHO (World Health Organization) de nitions reported that the prevalence of MtS in DM were 45.8%, 57.7%, and 28%, respectively in India (17). According to a study conducted in Nepal, the total age adjusted prevalence rates of MtS according to Harmonized, NCEP ATP III, WHO and IDF de nitions were 80.3%, 73.9%, 69.9%, and 66.8%, respectively. The lowest agreement was observed between WHO and IDF de nitions and the highest overall agreement was between Harmonized and NCEP ATP III de nitions (18).
The extent of these risk factors has been widely examined in studies; since nding the correlation between DM risk factors and CVD can be effective in preventing the incidence of morbidity and mortality in patients (19). Endocrinologists and cardiologists suggest that more efforts should be made to improve the risk factors for heart disease in diabetic patients due to their higher risk of heart attack and the higher mortality rate (20). Therefore, this study aimed to determine the prevalence of cardiovascular risk factors in people with and without MtS in DM in Rafsanjan adult cohort study.

Materials And Methods
This cross-sectional study was performed based on Rafsanjan Cohort Study (RCS) (21) as part of the comprehensive PERSIAN (Prospective Epidemiological Research Studies in IrAN) (22). The cohort study included 10,000 people aged 35-70 years who were randomly invited to the study from urban and rural areas covered by the health centers of this city. The inclusion criteria of cohort study were 1-Iranian citizenship 2-having an age range of 35-70 years, 3-living at least 9 months a year in the studied area in Rafsanjan city. The exclusion criteria included lack of understanding the Persian language and the existence of severe physical and mental disorders. PERSIAN Cohort standard questionnaires consisting of 482 questions in 3 major sections of general, medical, and nutrition were asked from the participants by a trained interviewer. The validity and reliability of all questionnaires were con rmed. The face to face interview was conducted by trained interviewers and the participants' answers were collected electronically and con dentially after obtaining their consent (21).
In this study, all the DM patients in the cohort population were included based on the past medical history and their self-expression. The presence of MtS in each individual was assessed and they divided to two groups with and without MtS. The diagnostic criteria for this syndrome were de ned in such a way that the patient met at least three of the ve MtS criteria at the same time as described by American Heart Association. (23), including: (a) central obesity determined by waist circumference equal to or greater than 88 cm (35 inches) in women and equal to or greater than 102 cm (40 inches) in men; (b) fasting serum triglyceride level equal to or greater than 150 mg/dL or on drug therapy for hypertriglyceridemia (e.g., brates, nicotinic acid); (c) High Density Lipoprotein (HDL) level less than 50 mg/dL in women and less than 40 mg/dL in men or on drug therapy for low high-density lipoprotein level ( brates, nicotinic acid); (d) elevated diastolic blood pressure equal to or greater than 85 or elevated systolic blood pressure equal to or greater than 130 or on drug therapy for hypertension; (e) elevated fasting glucose level equal to or greater than 100 mg/dL or on drug therapy for hyperglycemia/diabetes.
Demographic and clinical characteristics of individuals were extracted from the cohort center database, including gender, age, education level, residence, race, hypertension, dyslipidemia, smoking, alcohol consumption, systolic and diastolic blood pressure, heart rate, fasting blood sugar, triglycerides, LDL (lowdensity lipoprotein), HDL (High Density Lipoprotein), creatinine, blood urea nitrogen (BUN), alkaline phosphatase (ALP), waist circumference, body mass index (BMI= weight (kg)/height2 (m)), height and weight, family history of cardiovascular disease, physical inactivity, and insu cient consumption of fruits and vegetables.
In this study, the ratio of triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) was less than 2, 2 to 3.8, and more than 3.8, indicating favorable, moderate risk, and high risk of insulin resistance, respectively (24). The participants were classi ed in three different groups in terms of physical activity based on the Scoring the International Physical Activity Questionnaire (IPAQ) recommendations for scoring protocol. The groups included low active (<600 MET-minutes/week); moderate active (≥600 MET-minutes/week) and high active (≥3000 MET-minutes/week) (25), considering the MET-min/wk of the sum of walking, moderate-intensity physical activities, and vigorous-intensity physical activities. In terms of fruit and vegetable consumption, the subjects were divided into two groups according to the WHO recommendation, including high consumption (more than 400 grams of fruits and vegetables per day) and low consumption (less than 400 grams of fruits and vegetables per day) (26). BMI categories were de ned as follows: normal, BMI 20 to 24.9; overweight, BMI 25 to 29.9; obese I, BMI 30 to 34.9; obese II, BMI 35 to 39.9; morbid obesity, BMI ≥40(27).

Statistical analysis:
All the data were entered in SPSS software version 22 and for descriptive analysis of data, mean and standard deviation or frequency and percentage were used. In order to investigate the relationships due to abnormality, Mann-Whitney U test and Chi-square test (for classi cation variables) were used. Multiple logistic regression model was used to determine the factors associated with MtS. The signi cance level (P value) was considered less than 0.05.

Results
Out of 1933 patients with DM in this study, 1213 (62.8%) were female and 720 (37.2%) were male. The mean age of the participants was 55.92 ± 8.17 years. The prevalence of MtS in this study was estimated to be 80% with a 95% con dence interval 81.8% -78.1%, so that 1546 patients had at least three of the 5 diagnostic factors of MtS. The prevalence of MtS was signi cantly higher in women (66.9%) compared to men (33.1%) (P-value<0.001). Moreover, the mean age of the subjects in the MtS group was signi cantly higher than the group without MtS (56.31±7.98 years compared to 54.37±8.74 years, P-value <0.001). The frequency distribution comparison of demographic and clinical characteristics of the patients in the two groups with and without MtS is given in Table 1 and Figure 1. As can be seen, education level, marital status, smoking, alcohol consumption, history of hypertension, history of ischemic heart disease, family history of stroke, and consumption of fruits and vegetables were signi cantly different between the two groups (P-value <0.05). All the participants were low active and most of the subjects (84.7%) were in the group of low consumption of fruits and vegetables.  Given the abnormal distribution of anthropometric indices and biochemical and laboratory indices, the Mann-Whitney non-parametric test was used for comparing the two groups, which is shown in Table 2.
The median of BMI, systolic blood pressure, diastolic blood pressure, heart rate, triglyceride, ALP, and TG to HDL ratio were signi cantly higher in the MtS group and HDL was signi cantly lower than the group without MtS. In order to investigate the relationship between demographic characteristics, disease history, anthropometric indices, and biochemical factors with MtS, univariate logistic regression was performed for all the studied variables. Then, signi cant variables at the level of 0.1 were entered into the multiple logistic regression model using Backward LR method. According to the results of logistic regression model (Table 3), smoking, alcohol consumption, TG to HDL ratio, abdominal obesity, and hypertension were identi ed as factors associated with MtS in this study. So the risk of MtS was increased by smoking 5.60% (95% con dence interval: 3.67-8.55), alcohol consumption 4.1% (95% con dence interval: 2.32-7.23), TG to HDL ratio 1.42% (95% con dence interval: 1.30-1.55), abdominal obesity 13.73% (95% con dence interval: 9.77-19.29), and hypertension 13.54% (95% con dence interval: 9.55-19.19), respectively. Considering that hypertension and abdominal obesity are the 5 causes of MtS, it is associated with a high risk of developing MtS.

Discussion
Cardiovascular diseases are the leading cause of death and disability in diabetic patients (28). high blood pressure, hyperlipidemia, MtS, and smoking are important risk factors for cardiovascular disease (29), and the association of these factors with cardiovascular disease is completely identi ed (30,31). The results of the present study revealed that in patients with DM smoking, alcohol consumption, triglyceride to HDL ratio, abdominal obesity, and hypertension were identi ed as the factors associated with MtS.
MtS is a set of multiple risk factors for atherosclerotic cardiovascular disease and DM (32). MtS is strongly associated with DM. In this type of diabetes, there is insulin resistance with secondary hyperinsulinemia and it is often associated with high blood pressure, dyslipidemia, atherosclerosis, and most importantly obesity, especially central obesity. Etiology of MtS consists of separate components of the MtS (such as hypertension, DM, dyslipidemia) causing complex conditions (33). The prevalence of MtS in this study was estimated to be 80%. Its prevalence according to IDF criteria in people with Type 2 Diabetes Mellitus in the study by Moreira et al. was reported to be 74.3% *. It was also 69.5% in the study by AlSaraj et al. (34). Different prevalence of MtS in populations, in addition to methodological differences, could be due to various nutritional, epidemiological, and demographic transitions (35), as well as ethnic (36), social, and environmental (37) disparities.
In this study, the prevalence of hypertension in the group without MtS was 15.8% and in the MtS group was 64%. However, the prevalence of hypertension with diabetes varied in different ethnic, racial, and social groups (33). In previous studies, the prevalence of hypertension in patients with diabetes, covering more than 30,000 people in different areas, 70% of diabetic patients have been reported to have hypertension (38). This rate is more consistent with the blood pressure statistics in diabetic patients with MtS in this study.
In the current study, smoking, alcohol consumption, and TG to HDL ratio were also identi ed as factors associated with MtS in patients with DM. These results were con rmed by Lindsay (44), which is higher than the results of the present study. Central obesity is a major risk factor for MtS and diabetes (45), also increases the risk of dyslipidemia and coronary artery disease (46).
Lack of access to complete information in the les and the defects in the les were among the most important limitations of this study, which were controlled as much as possible by removing incomplete les and replacement.

Conclusion
The high prevalence of MtS in patients with DM in Rafsanjan adult cohort study indicates the importance of this issue. Therefore, high risk patients can be identi ed using MtS screening in primary health centers, and they can bene t from timely multifactorial interventions. Reducing smoking and alcohol consumption, and controlling hypertension, hyperlipidemia, and overweight are some of the suggested solutions in this regard.

Consent for publication
Not applicable Availability of data and materials The datasets generated and/or analyzed during the current study are not publicly available due to PERSIAN cohort policy on availability of health care registers, but are available from the corresponding author on reasonable request.

Figure 1
Prevalence (95% con dence interval) of risk factors in the two groups with and without MtS