Prevalence of cardiovascular disease risk factors and long-term outcomes in the Saudi population: Results from the Prospective Urban Rural Epidemiology study (PURE-Saudi)

Objective We report the prevalence of unhealthy lifestyle behaviors, cardiovascular disease (CVD) risk factors, and long-term outcomes within the Saudi population, stratified by age, sex, and place of residence. Methods The Prospective Urban Rural Epidemiology (PURE) study is a global cohort study including adults of 35–70 years old in 20 countries. PURE-Saudi study participants were recruited from 19 urban and 6 rural communities randomly selected from the Central province (Riyadh and Alkharj) between February 2012 and January 2015. Clinical follow-up of major CVD events and mortality is ongoing. Results The PURE-Saudi study enrolled 2047 participants (mean age, 46.5 ± 9.12 years; 43.1% women; 24.5% rural). Overall, 69.4% had low physical activity, 49.6% obesity, 34.4% unhealthy diet, 32.1% dyslipidemia, 30.3% hypertension, 25.1% diabetes, 12.2% were current smokers, 15.4% self-reported feeling sad, 16.9% had history of stress (several periods), 6.8% had permanent stress, 0.98% had history of stroke, 0.64% had heart failure, and 2.5% had coronary heart disease (CHD). Compared to women, men were more likely to be current smokers (21% vs. 0.45%, p<0.001), have diabetes (28.2% vs. 21.3%, p<0.001), and have history of CHD (3.2% vs. 1.6%, p=0.02); while women were more likely to be obese (58.6% vs. 42.8%, p<0.001), have central obesity (70.7% vs. 32.7%, p<0.001), self-report sadness (22.7%, vs. 9.9% p<0.001), experience stress (several periods), feel permanent stress (9.9% vs. 4.5%, p<0.001), and have low education (46.6% vs. 20.2%, p<0.001). on subjects self-reported responses.

factors in the adult Saudi population, with higher rates in rural than urban areas. National public awareness programs and multi-faceted healthcare policy changes are urgently needed to reduce the future burden of CVD risk and mortality.

Introduction
Cardiovascular disease (CVD) is the leading cause of mortality worldwide, contributing to 31% of all deaths. [1] CVD is also becoming a major health concern in the Gulf Council Countries (GCC) including Saudi Arabia, as it is estimated that the overall deaths from CVD account for over 45% of all deaths. [1,2] The most common CVD risk factors were identified in the INTERHEART and INTERSTROKE studies were hypertension, diabetes, dyslipidemia, obesity, smoking, physical activity, poor diet, and alcohol consumption. [3,4] In the Gulf countries, lifestyle has changed dramatically due to the rapid urbanization with an increasing in the poor diet and the adoption of a sedentary lifestyle.
Consequently, the rates of CVD risk factors and the non-communicable diseases among the Gulf population are also likely to have increased; the prevalence sometimes exceed that of developed countries. [5] In Saudi Arabia, there was very limited national representative data on the prevalence of CVD, high prevalence of key risk factors was observed, [2, and we lack data on CVD incidence as no large long term cohort study has been completed that compared CVD risk factors and cardiovascular outcomes and mortality among Saudi population. Therefore, well-designed national population-based cohort study focusing on CVD and its associated risk factors is needed.
The Prospective Urban Rural Epidemiology (PURE) study is a prospective cohort study that aimed to collect data on social, environmental, and individual CVD risk factors and chronic diseases in high-, middle-, and low-income countries.
[33] Saudi Arabia has been classified as high-income country and joined the global PURE in 2012, and PURE Saudi is the first cohort study that aims to investigate the prevalence of unhealthy lifestyle behavior, CVD risk factors, events and mortality rates among different age groups, men vs women, and urban vs rural.

Study design and participants
the study design, methods (including sampling, information gathered, and follow-up strategy), and participant characteristics of the PURE study have been published previously. [33][34][35][36] Briefly, adults aged between 35 years and 70 years from 367 urban and 302 rural communities in 20 countries were included. Households were eligible if one or more of the households' members was aged between 35 and 70 years and the household members intended to stay at that address for a further four years.
Risk factors and medical history were documented, and a physical examination was performed on subjects who provided written informed consent. Details of sampling, information gathered, and follow-up strategy have been previously reported in several publications. [34,35] Procedures Data regarding the demographic factors, socioeconomic status, medical history, health behaviors (e.g., smoking, physical activity, diet, alcohol intake), and subjects' household members were collected by using standardized questionnaires. In addition, we collected information regarding psychosocial factors and other CVD risk factors such as hypertension, diabetes and obesity as described in the INTERHEART study. [3] Anthropometric measures included weight, height, body mass index, waist circumferences and blood pressure. Physical activity was measured using the International Physical Activity Questionnaire (IPAQ) and was categorized according to the metabolic equivalent of task (MET) per min per week into low (3000 MET min per week) activity. Subjects were considered to have diabetes if a physician had previously diagnosed them with diabetes and/or if they had a fasting plasma glucose level of ≥126 mg/dl (7.0 mmol/l) or were being treated with glucoselowering medication. Subjects with history of hypertension, current use of antihypertensive medication and/or a blood pressure ≥ 140/90 mm Hg were considered to have hypertension. All subjects were asked whether they had a medical diagnosis of hypertension (awareness) and whether they were receiving antihypertensive medication (treatment). Hypertension control was defined as the proportion of subjects with an average systolic and diastolic blood pressure of < 140/90 mm Hg. A total cholesterol level > 5.2 mmol/l (201 mg/dl) was considered to be an elevated level. Major CVD (myocardial infarction or angina, stroke or heart failure) were the main clinical outcomes included in the analyses based on subjects self-reported responses.

PURE Saudi
Recruitment of Saudi individuals for the PURE study was carried out between February 2012 and January 2015. Nineteen urban and six rural communities were enrolled from the city of Riyadh and Alkharj (Central province). Urban communities involved were defined according to the governmental geographic distribution of the districts, while rural communities were defined as those regions located at least 50 km away from the center of Riyadh. Due to cultural acceptance, the study team met the participants in the primary health care centers (PHCC) in each community. The database of each PHCC was screened and the eligible subjects were invited to participate in the study by calling and/or sending them a short text message service to their mobile phones. A target number of at least 50 subjects were required to be enrolled per each PHCC. All subjects were encouraged to invite their eligible family members who were living within the same household. All blood samples were shipped to the laboratory in the King Khalid University Hospital at King Saud University, Riyadh. Subsequently, the blood results were returned to the treating physicians at the PHCC for further assessment and management.
During the follow-up period, the study team conducted a reminder call at 18 months after the baseline recruitment by telephone to remind the subjects about their upcoming follow-up at 3, 6, and 9 years.

Statistical analysis
Data are summarized as means and standard deviations for continuous variables and as numbers and percentages for categorical variables. Age was categorized into three groups: 35-49 years, 50-59 years and 60-70 years. Education was categorized as high (i.e., trade school, college or university); medium (i.e., secondary school or high school), low (i.e., primary education or no education) or unknown. Proportions and means were compared using Chi-square test and t tests, respectively, using 2-sided testing. A P value of less than 0.05 was considered statistically significant.

Overall cohort
The PURE-Saudi study enrolled 2047 participants, with mean age of 46.5±9.12 years (Table 1). There were 1165 men (56.9%) and 882 women (43.1%). Around one third of the total cohort had low educational level. The median body mass index (BMI) of the participants was 29.9, where majority of them were either overweight (35.3%) or obese (49.6%). Among obese patients, 30% had BMI between 30-35, and 19.5% had BMI > 35. The prevalence of abdominal obesity defined as waist circumference >102 cm (men) or >88 cm (women) was 49%. This prevalence is increased to 74.3% when the measured waist circumference >90 cm (men) or >85 cm (women). The prevalence of hypertension was 30.3%, out of which only 61.1% were aware of it, 58.9% were treated and 30.7% participants achieved blood pressure control. Approximately 34.4% of the total cohort reported eating unhealthy diet, 69.4% of participants reported low physical activity, 12.2% were current smokers, and 10.6% were former smokers. The prevalence of diabetes was 25.1%, out of which 2.7% were on insulin therapy, 60.7% received oral hypoglycemic agents (OHA), 6.6% received both (insulin and OHA), and 30% received no treatment. About one third (32.1%) had high total cholesterol level, however, only 0.9% were on statin therapy. Moreover, the prevalence of self-reported of being sad or blue was 15.4%, while 16.9% had reported history of several feeling of stress and 6.8% had permanent feeling of stress. History of stroke was found in 0.98%, heart failure in 0.64%, and coronary heart disease in 2.5%. In addition, the median INTERHEART risk score was 11.

Young vs Middle vs Old age
Compared to the younger and middle age groups (35-49 years and 50-59 years), older participants (60-70 years)  respectively. Moreover, the median level of glucose and triglycerides were significantly increased with advanced age (Additional Table 1).

Follow-up
There were 6 patients diagnosed with cancer and total of 22 deaths (at rate of 0.07 and 0.26 per 100 person years of follow-up respectively). The overall rates of major cardiovascular events showed similar pattern to that for mortality, where 24 had a myocardial infarction, 6 had a stroke, 4 had heart failure, and 34 had at least one major cardiovascular events with rates of 0.29, 0.07, 0.05, and 0.41 per 100 person years of follow-up respectively.

Discussion
The PURE-Saudi is the first cohort study in Saudi Arabia that assessed the current prevalence of CVD risk factors, in addition to the long-term clinical outcomes. Being part of the internationally standardized and validated surveys of the global PURE study allows for a valid interpretation and direct comparison of the results in the context of other enrolled countries with variable economic scales and health care systems. Our study showed two major findings. First, the high prevalence of CVD risk factors among the Saudi population: two-thirds had low physical activity, about half had obesity, one third consumed unhealthy diet, about one third had dyslipidemia, about one third had hypertension, and about one quarter had diabetes. Second, the relative proportion of the individual CVD risk factors varies according to age, sex, and residence place.
The PURE-Saudi study confirms that the prevalence of un-healthy life styles and CAD risk factors remains high in the Saudi population despite over a decade of several previous population crosssectional surveys (Additional Table 4 48] Forgetting to take medical therapies and medication side effects were important barriers to medication adherence. [48] Analysis data from a large household survey of 10,735 participants to identify barriers to healthcare in Saudi Arabia found that neither distance to nor type of healthcare clinic were barriers to management of chronic diseases, and highlighted the importance to individual's healthcare seeking practices rather than system based as potential barriers. Possibly that some Saudi population have specific healthcare-seeking practices and they mostly seek healthcare when they are sick and that contradict the concept of an old Arab proverb 'Prevention is better than treatment'. [49] Lack of primary care physicians knowledge and awareness of hypertension guidelines was also found where one-fourth of 322 primary care physicians had deficient knowledge regarding the correct definition of hypertension. [50] Regarding the healthcare systems barriers, inappropriate coordination between medical sectors has been reported as about one third of Saudi hypertensive patients did not have hypertension file at the primary health care centers and they received medical care at different health care sectors that led to missing their regular appointments. [47].
One of the main findings of PURE Saudi is that women are more obese compared to men. Possible explanation of higher obesity prevalence in women in this cohort may be due to some sociocultural factors and governmental bylaws such as -only until recently-the requirement of women to have a car driver for transportation purposes and barriers to practice physical activities in public places that could lead to increasing prevalence of sedentary lifestyle and obesity in Saudi women. Therefore, increasing accessibility of women to exercise facilities and providing safe walking areas are likely to help to reduce the obesity prevalence. Recently, women gymnasia in Saudi Arabia became more accessible and women were allowed to drive by themselves, which could potentially help in improving access to a healthier lifestyle. On the other hand, the lower rate of diabetes in women than men in our study may attributed to the well-recognized greater willingness of women than men to seek medical advice. [51] In addition, women are also more willing than men to adhere to diabetes daily management such as restricted diet, blood glucose monitoring, and medication adherence. [52] Another important issue to be highlighted is the common belief that risk of developing CVD is higher in individuals who live in urban areas compared to those in rural areas. [53]. Findings from the global PURE cohort from high-income countries reported that similar INTERHEART risk score among population in rural areas in comparison to urban population.
[35] However, the PURE Saudi study showed that population living in rural areas had higher CVD risk factors particularly in the prevalence of diabetes, hypertension and obesity compared to the urban population. Possible reasons might be related to 'urbanization of rural life', a term that described by some researchers, [54] where agriculture became mechanized, and cars are used for rural transport, road infrastructure improved, and more consumption of processed carbohydrates and commercially prepared and processed food through national and transnational companies, all of these would contribute to the increase in rural obesity. [55][56][57] In addition, the limited time and space for cooking healthy meals and possibly perceptions of large weight as a sign of affluence could also exacerbate these effects. [57,58] Our findings might also reflect less access to and /or low availability of a health care prevention and management facilities in the rural areas. The reason behind these disparities may be due to inconsistent insurance policies, poor healthcare infrastructure and privatization, and accessibility to healthcare facilitates which largely focus on the urban population, leaving the rural population at disadvantage. [59] The higher prevalence of diabetes in rural rather than urban areas provide support for the link between diabetes and lifestyle risk factors (lifestyle changes are less prominent in rural areas). In addition, the lower educational level among rural population as demonstrated in this study may also partly explain the differences in risk factor levels, resembling what was found in the Vasterbotten Intervention Program study in Sweden. [60] For instance, rural population with only primary education level had consistently higher prevalence of hypertension than urban population with higher educational levels. [60] The data form global PURE that assessed socioeconomic status and risk of CVD in 20 low, middle, and high-income countries, education, rather than wealth, was the socioeconomic indicator most consistently associated with outcomes where the major CVD events and all cause morality were more common among people with low levels of education in all types of country studied. However, variances in outcomes between educational levels were not explained by variances in risk factors, which decreased as educational level increased in high-income countries, but increased as educational level increased in low-income countries.(61) Furthermore, results from MONICA study suggested that lower education level among rural population could enhance CVD risk, but causality is difficult to prove. [62] In the present study, individuals living in urban areas were more prevalent in the consumption of unhealthy diet, sadness and stress. Recent global systematic evaluation of dietary consumption patterns across 195 countries found that improvement of diet prevents one in every five deaths globally and suboptimal diet was responsible for more deaths than other risk factors including smoking, highlighting the urgent need to improve people diet. [63] Urbanization is also associated with factors that could potentially influence the mental health and possibly the development of CVD, such as increased life stressors, overcrowding, higher level of violence, and less social support. [64] However, beside stress caused by transition from rural area to urban area, other cultural factors interplay with urban dynamics might contribute to the development psychological-related problems.
Therefore, understanding how cultural dynamics interact with adaptation to urban life may help in appropriate management of mental disorders in cities. [65] Awareness of the negative impact of urbanization on mental health is needed across the Saudi society.
Healthcare is one of the main focus areas of the Saudi Vision 2030 where the Saudi government has initiated radical changes in the structure and function of its health-care system through its National Transformation Program (NTP) to achieve quality care and effective service delivery. In addition, the government has already recognized the importance of the primary prevention of CVD diseases and has announced recently four major projects, which aim to improve people lifestyle. [66][67][68][69][70][71] Furthermore, the World Heart Federation (WHF) has undertaken an initiative to develop a series of Roadmaps to reduce premature deaths from CVD by at least 25% by 2025. These Roadmaps can be used as guidance for countries toward developing or updating their national NCD programs for the prevention and control of NCD. [72] There are few limitations of our study. First, the sampling framework of the PURE-Saudi Study was not nationally representative; hence caution is needed in generalizing our findings to the whole Saudi population. Second, follow-up rates of CVD events and mortality were low, this might be due to short duration of follow-up and the sample size that was relatively small compared to the large population of Saudi Arabia. There are currently ongoing efforts to expand PURE Saudi to a larger population across all areas in the country in order to have meaningful event rates in the follow up. Lastly, we can not exclude the role of genetic predisposition to such high prevalence of CVD risk factors, which could be related to the high consanguinity in the Saudi population. We have reported recently a high prevalence of familial hypercholesterolemia in Saudi Arabia and the rest of the Arabian Gulf countries. [73] In conclusion, the PURE-Saudi is the first population cohort study in Saudi Arabia. It demonstrated the continued high prevalence of CVD risk factors in the adult Saudi population despite over a decade of several population surveys, and some of these factors were even more prevalent in the rural than the urban population. National awareness programs and multi-faceted health care policy changes are urgently needed to reduce the future burden of CVD risk and mortality.

Contributions
KFA and SY developed the study design. KFA, HA and MQA facilitated data gathering. KFA, MAB, THA and SR performed the data analysis and drafted the manuscript. All authors contributed to the interpretation of results and the revision of the manuscript as well as approved the final manuscript.

Ethics approval and consent to participate
King Saud University Ethics Committee granted ethical approval. Participation in the study was voluntary and all eligible subjects who provided written informed consent were enrolled.

Consent for publication
Not applicable.

Competing interests
The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript. The authors declare that they have no competing interests.   13.00 (9.00,18.00) 10.00 (6.00,14.00) < 0.0 † Low educational level was defined as no education, primary education only, or unknown educational level.
‡ Participants who were not current or former smokers are those who had never smoked (data not shown).
§ Diet quality was determined on the basis of the Alternative Healthy Eating Index, which ranges from 6 to 70, with higher scores indicating more healthful eating. An unhealthful diet was considered to be a score of less than 31. ¶ Low physical activity was defined as 600 or fewer metabolic equivalents per minute per week. ◊ Participants were considered to have hypertension if they had a blood pressure greater than 140/90 mm Hg or if they reported a history of hypertension.** Participants were considered to have diabetes if they reported having diabetes or if they had a fasting glucose level higher than 7.0 mmol per liter (126 mg per deciliter). Ⱶ Participants were considered to have dyslipidemia if they reported having dyslipidemia or if they had a total cholesterol level higher than 5.2 mmol/l (201 mg/dl); data on lipid profile level were available for 1775 participants. † † The body-mass index (BMI) is the weight in kilograms divided by the square of the height in meters. ‡ ‡ The INTERHEART Risk Score is a validated score for quantifying risk-factor burden without the use of laboratory testing. Scores range from 0 to 48, with higher scores indicating greater risk-factor burden.