Trends in cardiovascular risk factors in diabetic patients in comparison to general population in Iran: findings from National Surveys 2007–2016

To determine levels of change in risk factors for cardiovascular disease among people with and without a previous diagnosis of diabetes from 2007 to 2016 in Iran. Data were obtained from five rounds of the World Health Organization STEPwise approach to Surveillance (STEPS) cross-sectional surveys. Participants were 7665 and 93,733 adults with and without known diabetes, respectively, aged 25–65 years. We used logistic and linear regressions to assess the trends of risk factors. Individuals with known diabetes compared to those without the condition, experienced greater reductions in mean levels of systolic blood pressure (3.0 vs. 0.5 mmHg among women and 3.9 vs. 1.6 mmHg among men), diastolic blood pressure (6.4 vs. 5.11 mmHg in women and 3.3 vs. 1.8 mmHg in men), and non-HDL cholesterol (42.4 vs. 27.2 mg/dL among women and 30.3 vs. 21.0 mg/dL among men) throughout these years. Men with diabetes also showed a greater reduction in the prevalence of daily cigarette smoking compared to their non-diabetic counterparts (7.3% vs. 2.3%). Fasting plasma glucose decreased among subjects with diabetes but increased among those without diabetes. Significant increases were observed in proportions who met goals for blood pressure, triglycerides, non-HDL cholesterol and LDL cholesterol in both groups; however, almost half of diabetic subjects did not achieve risk factor goals in 2016. Secondary prevention in diabetic patients was more effective than primary prevention in the general population; however, the rate of diabetic patients who met the designated goals for each risk factor was still suboptimal.


Trends of risk factors in persons with known diabetes.
Among those with diabetes, there were significant reductions of mean SBP (from 134 to 131 mmHg in women and 134 to 130 mmHg in men), DBP (from 86 to 79 mmHg in women and 84 to 81 mmHg in men), LDL cholesterol (from 132 to 99 mg/dL in women and 121 to 97 mg/dL in men), non-HDL cholesterol (from 168 to 126 mg/dL in women and 155 to 125 mg/dL in men) and triglycerides (from 177 to 127 mg/dL in women and 171 to 146 mg/dL in men) in both sexes. Furthermore, there were significant reductions in FPG among women (from 147 to 139 mg/dL) and HDL cholesterol among men (from 40 to 35 mg/dL) (Figs. 1 and 2). There was not enough evidence supporting a significant trend for BMI and waist circumference. Table 2 shows the trends of meeting goals/optimum levels of risk factors among persons with and without known diabetes. In both sexes, there were significant increases in the proportion of participants with an optimum level of blood pressure (from 47 to 58% in women and 55 to 62% in men), LDL cholesterol (from 21 to 54% in women and 26 to 57% in men), non-HDL cholesterol (from 21 to 58% in women and 26 to 59% in men), and triglycerides (from 36 to 66% in women and 39 to 53% in men). Glycemic control improved in diabetic women (from 49 to 55%) ( Table 2) but not in diabetic men. Nevertheless, the prevalence of subjects who met HDL cholesterol goal significantly reduced in both sexes (from 19 to 17% in women and 44 to 23% in men).

Trends of risk factors among persons without known diabetes.
There were a significant reduction in mean levels of lipid profiles, specially non-HDL cholesterol (from 146 to 119 mg/dL in women and 113 to 97 in men, 2007 vs. 2016) and triglycerides (from 132 to 100 mg/dL in women and 143 to 118 mg/dL in men) and prevalence of smoking (especially in men from 29.1 in 2007 to 21.8% in 2016) in both sexes. Regarding blood pressure, declining trends for mean DBP in both sexes and mean SBP in men were observed (Fig. 1). However, there was a slight, but statistically significant, increase in FPG (from 89 to 91 mg/dL in women and from 90 to 92 mg/dL in men, 2007 vs. 2016) and waist circumference (from 88.0 to 88.8 cm in women and from 88.7 to 91.0 in men). Only men had a significant increase in BMI (from 25.2 to 25.9 kg/m 2 ) (Fig. 1).
In terms of optimal level of risk factors, we showed a significant increase in the proportion of those who had an optimal level of blood pressure (from 74. 6 . 1). Moreover, women without known diabetes showed an increase in FPG while there was a significant reduction among their counterparts. Waist circumference increased among men without known diabetes, while it remained unchanged among those with known diabetes (Fig. 1). Regarding meeting risk factor goals, women with diabetes had significantly more increase in the proportion that met goals of triglycerides compared to non-diabetic  www.nature.com/scientificreports/

Discussion
In this study, we assessed national trends of cardio-metabolic risk factors from 2007 to 2016 in Iran concerning diabetes status. We provided some evidence on the effects of national efforts for primary and secondary prevention of cardio-metabolic disorders in a Middle Eastern country. There were significant improvements in blood pressure levels, non-HDL lipids, and daily smoking in the Iranian population; however, a deterioration in levels of HDL cholesterol was observed among those with and without diabetes. Importantly, we found increasing levels of obesity measurements and FPG in those without diabetes. Our findings suggest that secondary prevention has been more successful than primary prevention in reducing risk factors as they showed that changes in blood pressure, non-HDL cholesterol, FPG, and obesity (only in men) were more favorable in those with diabetes than those without the condition. Despite improvements over the past decade, meeting CVD risk factor goals, particularly among those with diabetes, remained suboptimal as almost half of Iranians with diabetes did not achieve risk factor goals. Our findings regarding improvements in blood pressure and non-HDL lipid levels are in line with those of previous studies on Iranian populations, showing similar decreasing trends [10][11][12] Notably, in this study, we had a higher proportion of participants, with and without diabetes who met goals of blood pressure and non-HDL lipids (53%-92%) compared with previous studies conducted in Iran (36%-87%) [10][11][12] . Our findings are also in line with those of the Global Burden of Disease (GBD) and NCD Risk Factor Collaboration (NCD-RisC), which showed reductions in the burden of high blood pressure and dyslipidemia in the Middle East and Worldwide [13][14][15] . Investigations from other countries have shown similar trends. Declines in mean SBP, DBP, LDL, non-HDL cholesterol and rate of smoking with more significant decreases among individuals with diabetes have been reported in studies from the National Health And Nutrition Examination Survey (NHANES) and the Framingham Heart Study in the US 16,17 and the Health Survey for England 18 . Accordingly, the prevalence of meeting blood pressure and LDL goals has been improved in the US 16,17 . Decreasing trends in high blood pressure were also found in Table 2. Age-adjusted percentages of subjects with and without diagnosed diabetes who reached goals/ optimum levels of blood pressure, fasting plasma glucose and lipid measures. *Known diabetes mellitus. www.nature.com/scientificreports/ studies from France and Japan, while the prevalence of hypercholesterolemia increased 19,20 . The results regarding HDL-cholesterol and triglycerides are different, from decreasing to no change or increasing 21,22 . Regarding the management of diabetes, in line with our findings, a study across 28 low-middle income countries uncovered poor control of diabetes, indicating a significant unmet need for diabetes care in these countries 23 . However, our results show that around 40-50% of our diabetic men and women reached the goal for glucose control, defined as FPG < 130, versus 23% on average in these 28 low-middle income countries, with a definition of FPG < 180 mg/ dl; indicating much better situation of glucose control in Iran. As one of the first countries from the Eastern Mediterranean Regional Office of WHO, Iran has responded to "a call for action" for the prevention and control of diabetes mellitus; and the national program was designed in 1996. The aim of this program is primary, secondary, and tertiary prevention, through community and high-risk screening, and the integration of diabetes care into the primary healthcare network. After the implementation in 2016 of IraPEN, an adaptation of WHO's Package of essential NCD (PEN) interventions for primary health care, this program integrated into the guidelines for prevention and control of major NCDs in the primary health care system. The current study shows that secondary prevention in diabetic patients has been more effective than primary prevention in the general population for controlling CVD risk factors, i.e., risk factors decreased more in diabetic patients than in non-diabetic subjects in the general population. However, the rate of diabetic patients who met the designated goals for each risk factor was still suboptimal.
The favorable changes may be rooted in nutritional habits, physical activity levels, smoking, and anti-hypertension or lipid-lowering drug consumption, all of which are known to be important determinants of blood pressure and serum lipid levels 10,11 . Previous studies showed that Iranian families had reduced the consumption of hydrogenated oil 24,25 and salt 26 , which could explain the favorable blood pressure and lipid trends in Iranians. Further, previous studies showed increasing use of anti-hypertension or lipid-lowering drugs among Iranian 10-12 . Nevertheless, the decreasing trends in blood pressure and lipid levels in our population could hardly be explained by an increase in physical activity, since it was shown that low physical activity is common in Iranian community 27,28 .
Notably, by showing a significant reduction in the prevalence of daily smoking among those without known diabetes, this study suggests that efforts for lowering the prevalence of smoking have been successful in controlling the increasing trends 10 . The decrease in the prevalence of daily smoking in this group might also contribute to the decline in non-HDL lipid and blood pressure given the substantial evidence on the positive correlation of smoking with high blood pressure and dyslipidemia 29,30 .
On the contrary, we showed a rise in levels of obesity measurements in individuals without known diabetes (WC in both genders and BMI in men), which is probably the main reason for the increasing fasting plasma glucose trends in this group 31,32 . Contrary to the results of the previous studies that showed growing trends for HDL cholesterol in Iranian population 10 , this study showed a significant reduction in HDL cholesterol in those with and without diabetes. As shown in previous studies, decreasing levels of HDL cholesterol are mostly due to poor dietary habits and low levels of physical activity 33,34 . Deterioration in obesity measurements and HDL cholesterol levels should raise the alarm for policymakers as it indicates efforts for improvement of dietary habits and physical activity came short in this Iranian population. Based on previous studies in Iran 28,[35][36][37][38] , the most important barriers to healthy nutrition and physical activity were interpersonal/cultural effects, lack of access to healthy foods, food preferences, media advertisements, nutrition transition, lack of time, motivation and prioritizing other activities over sports and high costs of the facilities. Therefore, feasible and effective national intervention programs are needed to curb current obesity epidemics by overcoming the barriers to healthy nutrition and physical activity. Despite the promising findings of several community-wide lifestyle intervention programs in Iran, such as Tehran Lipid and Glucose Study 39 and Isfahan Healthy Heart Program 40 , these programs did not scale up in national levels.
In accordance with the evidence showing a correlation between diabetes and other cardio-metabolic risk factors, we showed risk factor levels were higher in those with diabetes compared to those without it 10,31 . Our findings support that the efforts on controlling blood pressure, dyslipidemia and obesity had more impacts among people with diabetes rather than non-diabetics. First of all, this is because diabetic patients experienced more reduction in mean SBP, DBP and non-HDL lipids. In addition, their obesity and blood glucose measurements remained steady, while people without diabetes showed a significant increase in obesity measurements. Favorable trends in dyslipidemia, obesity and blood glucose control in known diabetics may be due to improvements in care, knowledge and attitude towards diabetes as well as better adherence to lifestyle and pharmaceutical interventions. Previous studies show advancements in the quality of diabetes care, affordability of medications, and screening for undiagnosed diabetes as well as increasing trends in consumption of glucose-lowering (twofold in men and 1.5-fold in women) and lipid-lowering drugs (fourfold in men and 2.5-fold in women) among those with known diabetes 10,41 . Educational interventions in Iran, such as Self-Management Education (PDSME) program, also proved to be effective in improving the knowledge and practice of diabetes 42,43 , which is highly correlated with control of related risk factors 44 .
Nevertheless, in this study, the prevalence of daily smoking remained steady in participants with diabetes, while its prevalence reduced significantly in those without the disease. These findings are in contrast with those of a previous study that showed an increasing trend for smoking in those with diabetes was significantly higher than increases in smoking prevalence in those without diabetes 10 . This discrepancy may indicate favorable and radical changes in the prevalence of smoking. Another explanation may be the differences in the study sample and definition of smoking in this study compared to the previous studies, which were mostly cohort studies with local study samples and various definitions of smoking 10,11 . Further research is needed to provide more robust evidence on trends for smoking prevalence in Iran.
Since, during the last decades, the highest number of STEPS surveys in the Middle East have been conducted in Iran, it was made possible to investigate the secular trend of CVD risk factors using national data for the first Scientific RepoRtS | (2020) 10:11724 | https://doi.org/10.1038/s41598-020-68640-9 www.nature.com/scientificreports/ time in this region 45 . Standardized measurement methods throughout the study period were used and large sample sizes and multiple measurements led to high precision in estimating the prevalence and trends of different risk factors. However, there are some limitations. We only assessed these trends for 10 years. Although the sampling methods were representative of the Iranian population, there were some minor differences that were addressed using post-stratification weighting based on age, sex, region and province categories of population in 2011 as a reference for all years. Finally, the biochemical measurements were only available for three STEPs cycles.
conclusion Non-HDL lipids and blood pressure levels in the Iranian population improved significantly in those with and without diabetes. Moreover, obesity measurements and fasting plasma glucose worsened in diabetic persons. This study showed favorable changes in blood pressure, non-HDL cholesterol, blood glucose, and obesity (only in men) were more prominent in people with diabetes compared to those without known diabetes. This indicating secondary prevention efforts have been more effective than primary prevention in Iran.

Methods
This study is conducted on the data documented from five STEPwise approaches to Surveillance (STEPS) surveys (2007, 2008, 2009, 2011, and 2016). The first STEPS in 2005 was not included due to the inconsistency of some measurement methods. STEPS is a standardized survey designed to help the World Health Organization (WHO) member states collect and disseminate consistent data about non-communicable diseases (NCD) and enable comparisons over time. A brief explanation of the samplings of the surveys is presented as follows.
All methods in the current study were carried out following relevant guidelines and regulations, the Center for Disease Control, Ministry of Health and Medical Education in Iran approved all experimental protocols, and all participants gave informed consent. The sampling method in 2007, 2008 and 2009 was similar. The sampling was conducted at levels of towns, villages and districts of large cities using a randomized cluster sampling scheme. In each province, 1000 individuals were selected in 50 clusters. Each cluster included 20 individuals, 10 women and 10 men, living in neighboring households.
The 2011 survey used a multistage cluster random sampling scheme. At the first stage, distinct counties or a group of adjacent counties were listed as the primary sampling units (PSU). Fifty PSUs were then picked by applying probability proportionate to size (PPS) random sampling. Within each PSU, urban and rural areas were listed as possible secondary sampling units (SSU) from which twelve SSUs were picked by employing the PPS method similar to the previous step. In the third stage, a list of households in each SSU referenced by their 10-digit postal codes was developed, of which twenty postal addresses were selected randomly. At the final stage, one individual was selected from each selected household using Kish tables provided by WHO, and they were interviewed at their houses.
In 2016, a systematic cluster random sampling scheme was designed to select 31,050 individuals in 3105 clusters (10 subjects from each cluster) from urban and rural areas of all provinces. To estimate the minimum sample size at the province level, calculations were based on the province with the lowest population density. The sample size in other provinces was determined according to their population ratio to that province. To control non-response errors and mind the effect of sampling design, 10% was added to the estimated sample size of each province. Also, to minimize costs, in more crowded provinces (those with more than 800 clusters), half of the estimated sample size was considered, but the applied weight in the subsequent analysis was doubled.

Medical history, clinical examination and laboratory measurements. Standard questionnaires
based on the WHO STEPS were used to collect demographic information as well as the past medical history of diabetes, medication use and cigarette smoking. Blood pressure was measured three times at five-minute intervals. The average of second and third readings was considered as the participants' blood pressure.
All biochemical measurements were assessed in venous samples drawn after 12-14 h overnight fasting according to a standard protocol and sent to collaborating centers. In 2007 and 2011, Fasting Plasma Glucose (FPG) was measured with enzymatic colorimetric methods with a glucose oxidase test and serum lipids, including total cholesterol, high-density lipoprotein (HDL) cholesterol and triglycerides were determined by enzymatic methods (Pars Azmun, Karaj, Iran). In 2016, venous samples were transferred to the Central Reference Laboratory in Tehran and all laboratory tests were measured using the auto analyzer (Cobas C311 Hitachi High-Technologies Corporation) approved by Reference Laboratory. Low-density lipoprotein (LDL) cholesterol was calculated by the modified Friedewald equation to be consistent among all STEPS surveys 46 . Definition of terms. Known diabetes was defined as a positive response to either of the two following questions: (1) "Have you ever been told by a doctor or other health worker that you have diabetes?" and (2) "Are you currently taking insulin or oral medication for diabetes prescribed by a doctor or other health worker?". Hypertension goal/optimum level was defined as mean systolic blood pressure (SBP) < 140 mmHg or mean diastolic blood pressure (DBP) < 90 mmHg 47 . Participants who smoked cigarettes daily were considered ' daily smokers' . Glycemic control was defined as a goal of FPG < 130 mg/dL in diabetic subjects and an optimum level Scientific RepoRtS | (2020) 10:11724 | https://doi.org/10.1038/s41598-020-68640-9 www.nature.com/scientificreports/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creat iveco mmons .org/licen ses/by/4.0/.