Sex based pharmacological treatment in patients with metabolic syndrome: Findings from the Isfahan healthy heart program

Pharmacological therapy is a critical step in the management of individuals with the metabolic syndrome (MetS) when lifestyle modifications cannot achieve the therapeutic goals. However, it has been well-documented that there is no single best therapy other than weight loss, and that treatment should be targeted at individual components of the MetS. The objective of this study was to investigate the treatment of individual components of the MetS in a population-based sample of individuals with clustering MetS components. In a cross-sectional population-based survey, we studied a randomly collected sample of men and women who had participated in the baseline survey of a community-based program in three Central Iranian counties in 2000 to 2001. Demographic data, medical status, and drug history were obtained by questionnaire. We evaluated the association between clustering of the MetS components and pharmacological treatment of cardiovascular risk factors. The most common pharmacologic agents prescribed for individuals with the MetS were beta-blockers (72.8%), followed by lipid-lowering agents (36%) with no significant gender difference. A high level of compliance with drug treatment was noted. Further research is warranted to understand the compliance behavior of patients with the MetS.


INTRODUCTION
Despite the international campaign against noncommunicable diseases (NCD) over the past 20 years, cardiovascular diseases (CVD) remain the leading cause of death in most of the Western world, with a rapidly *Corresponding author.E-mail: gharipour@crc.mui.ac.ir.
Tel:  Abbreviation: NCD, Non-communicable disease; CVD, cardiovascular disease; MetS, metabolic syndrome; LDL, low density lipoprotein cholesterol; IHHP, Isfahan healthy heart program; BMI, body mass index; WC, Waist circumference.increasing trend in developing countries (Alsaraj et al., 2009).The metabolic syndrome (MetS) is associated with increased risk of developing NCD, notably diabetes and CVD (Grundy et al., 2005).It has been demonstrated that many middle-aged individuals with the MetS are at increased 10-year absolute risk of CVD (Grundy et al., 2005).Individuals with coronary heart disease, stroke or diabetes are in the high-risk category and should be treated (Deedwania and Gupta, 2006).Delavari and colleagues have reported alarming prevalence rates of the MetS and its components, as defined by different sets of criteria.The age-standardized prevalence of the MetS was about 34.7% based on the ATP III criteria, and was higher in women, in urban areas, and in the 55 to 64 year age-group compared with the prevalence in men, in rural areas, and in other age groups, respectively (Delavari et al., 2009).Components of the MetS that need controlling are atherogenic dyslipidemia, hypertension, elevated fasting glucose, prothrombotic factors and proinflammatory states (5).The therapeutic approach involves intervention at a macro level, and control of multiple risk factors using lifestyle modifications (diet control and increased physical activity, pharmacotherapy (obesity control drugs) and targeted approach to individual risk factors (Delavari et al., 2009;Deedwania and Volkova, 2005;Esteghamati et al., 2006;Sarrafzadegan et al., 2009;Misra et al., 2002).Pharmacological therapy is a critical step in the management of individuals with the MetS when lifestyle modifications fail to achieve desirable therapeutic goals (Grundy, 2005).
A recent American Heart Association and National Heart Lung Blood Institute scientific statement highlights the importance of controlling individual risk factors in the MetS.However, it has been demonstrated that other than weight loss, there is no "single best" therapy, and that treatment should target individual components of the MetS (Grundy et al., 2005).The objective of this study was to investigate the prevalence of pharmacological treatment of individual components of the MetS in a population-based sample of individuals with clustering of the Mets components.

MATERIALS AND METHODS
The Isfahan healthy heart program (IHHP) was conducted in three Central Iranian counties; Isfahan and Najaf-Abad were intervention areas and Arak served as a reference area.Located at 375 km north-west of Isfahan, Arak was selected as the reference area owing to similarity of its socioeconomic, demographic and health profile to that of intervention areas, as well as good cooperation (Sarraf-Zadegan et al., 2003).Started in 2000, IHHP consisted of three phases; baseline survey and situational analysis were conducted in phase I, interventions in phase II (late 2001 to 2005), and post-intervention survey for outcome evaluation in phase III (2007) (Sarrafzadegan et al., 2006(Sarrafzadegan et al., , 2009)).
IHHP aimed to reduce modifiable CVD risk factors in the general population through 10 distinct interventional projects, targeting diet, physical activity and smoking.Details and methods of the study have been described elsewhere (Sarrafzadegan et al., 2006(Sarrafzadegan et al., , 2009)).Briefly, IHHP featured a multistage sampling design.The clusters were selected from the community based on demographic and socioeconomic characteristics.Sample units aged 19 years were selected randomly and stratified according to age and sex.Sociodemographic data and information on health behaviors, including nutritional habits, physical activity and smoking, as well as medical status, drug history, and laboratory data were collected.Written informed consent was obtained from all participants before they entered the study.The Research and Ethical Committee of Cardiovascular Research Center approved IHHP.This sub-study reports the findings of the baseline survey of IHHP in 2000 in Isfahan.

Exclusion criteria
Pregnant women and those with known thyroid abnormality and/or mental disease were excluded.

Anthropometric measurements
Weight and height were measured with calibrated instruments using standard protocols.Body mass index (BMI) was calculated as weight (kg) divided by the square of height (m 2 ).Waist circumference (WC) and hip circumference were measured and recorded in centimetres using standard WHO methods (Tavassoli et al., 2010).

Laboratory measurements
Fasting (>12 h) venous blood samples were collected from all participants.Standard laboratory kits (Pars Azmoun Co., Tehran, Iran) and methods were used to measure serum lipid profiles and fasting blood glucose (FBG).All blood samples were frozen at -20°C to be assayed within 72 h at the central laboratory of Isfahan Cardiovascular Research Center (ICRC) which is subject to external national, and international quality control.An Elan autoanalyzer (made in Germany) was used in the baseline survey and was validated against the Department of Epidemiology, K.U.Leuven, Belgium.A Hitachi auto-analyzer (made in Japan) was used in the 2007 survey and was validated against lab quality external assessment services, Helsinki, Finland.Both quality controls showed good correlations.

Participants
In the first phase of IHHP some parameters, such as insulin resistance were not collected so we used the updated ATP-III definition for the MetS.Participants were considered as having the MetS when they met three or more of the following criteria: WC 102 cm (40 in) in men and 88 cm (35 in) in women; HDL <1.03 mmol/L (40 mg/dl) in men and <1.30 mol/L (50 mg/dl) in women or receiving specific treatment for this lipid abnormality; triglycerides 1.7 mmol/L (150 mg/dl) or specific treatment for this lipid abnormality; systolic blood pressure 130 mmHg or diastolic blood pressure 85 mmHg, or treatment of previously diagnosed hypertension; and fasting glucose 5.6 mmol/L (100 mg/dl) (15).

Pharmacological treatment
The pattern of medication use was defined according to the type of drugs used to control and/or treat the MetS components.Medications used for hypertension, dyslipidemia and insulin resistance were recorded in detail.Medications were later classified according to pharmacological category.Anti-hypertensive drugs were calcium channel blockers, beta-blockers, angiotensinconverting enzyme (ACE) inhibitors, and thiazides.Drugs used for diabetes were thiazolidinediones, biguanides and insulin.Dyslipidemic drugs were statins, fibrates, nicotinic acid, and statin plus fibrate.Aspirin use was also recorded.

Statistical analyses
Results are reported as the mean ± standard deviation (SD).The difference between quantitative variables was assessed using the independent t-test.Chi-square test was used to evaluate the difference between qualitative variables in individuals with the MetS and those without according to sex.P values of 0.05 or less were Hypertriglyceridemia was the most prevalent risk factor among individuals with the MetS (89.8%).Systolic blood pressure was elevated in 65.2% of men and 48.4% of women with the MetS, compared to 13.9% of women and 6.7% of men without MetS.The prevalence of abdominal obesity and low HDL-C was 86.4 and 75.8%, respectively.
Table 3 shows the number of patients receiving different categories of drugs for control of various MetS components, according to sex.Beta-blockers accounted for the most commonly used single medications (54%), with no significant difference between men (58.1%) and women (52.8%).
The least frequently used drugs were thiazides.Glucose-lowering agents were the most commonly prescribed drugs for individuals with the Mets (men: 90.5%, women: 90.7%, total: 90.7%).Statins were the least frequently used medications in both men (3.4%) and women (1.7%).Aspirin was used by 7%, and the use of herbal medicine was uncommon.
Hypertension and diabetes were more frequently managed with beta-blockers (54%) and glibenclamide (90.6%), respectively.No significant difference was observed between men and women regarding the types of medications used.

DISCUSSION
We found a high rate of pharmacological treatment in Iranian subjects with the MetS.The prevalence of the MetS in Iranian populations has already been reported (Grundy et al., 2005).While the MetS has been more commonly reported in the elderly (Sarrafzadegan, 2008), we documented the MetS in men and women of relatively lower mean age (men: 38.796±14.57years, women: 38.99±15.29 years).Of the participants, 86.4,89.8 and 75.8% had abdominal obesity, hypertriglyceridemia and low HDL-C levels, respectively.Except for WC, we found significant differences in the prevalence of MetS components in men and women.In this study, increased WC in women with the MetS was more prevalent than in men.Some earlier studies have reported similar findings (Pacholczyk et al., 2008;Bjornsson, 2008).Epidemiologic data suggest low HDL and high triglyceride (TG) levels as major CVD risk factors associated with the MetS (Grundy et al., 2004).Among the risk factors evaluated in this study, hypertriglyceridemia was the most prevalent in men with MetS, whereas low HDL was the most common risk factor in non-MetS subjects.
However, the most frequent risk factor reported in other studies has been hyper-triglyceridemia, with systolic and/or diastolic hypertension being less common (Israili et al., 2007).Apparently, risk factors such as hypertension and diabetes, which produce more evident complications are more frequently monitored and managed.It may be assumed that the high prevalence of the MetS is due to the high prevalence of hypertriglyceridemia which is more silent in nature and is therefore less frequently monitored and managed.Pharmacological management is suggested next to lifestyle change in management of the MetS.Medication must address the multipronged pathological processes of the MetS and each component should be identified and properly treated.Current therapies for the MetS consist of strategies for management of obesity, insulin resistance, dyslipidemia, and hypertension (Israili et al., 2007).
The pharmacological agents most often suggested are those which decrease insulin resistance (e.g.metformin and thiazolidinediones).Among the medications used in MetS therapy are also fibrates and statins for atherogenic dyslipidemia, and antihypertensives, such as betablockers, ACE inhibitors and angiotensin receptor  (Bianchi et al., 2007).In this study, betablockers were the most frequently prescribed medications for individuals with the MetS, and lipid-lowering agents were prescribed less frequently than antihypertensives (72.8 vs. 36%, respectively).This is in line with another Iranian study demonstrating that beta-blockers were the most commonly prescribed antihypertensives (Khosravi et al., 2006).
Although data on the use of aspirin for primary CVD prevention are being reviewed, 7% of individuals with the MetS in Iran take aspirin on a regular basis.The low rate of aspirin use in our study population may be due to low mean age and low prevalence of CVD risk factors.Owing to its availability and low price, aspirin is the most frequently used antiplatelet drug in Iran.We studied mainly healthy subjects with the MetS, in whom antiplatelet use might not have been indicated, especially given their mean age (men: 38.796±14.57years, women: 38.99 ± 15.29 years).On the other hand, most patients receiving long-term aspirin therapy remain at substantial risk of thrombotic events due to insufficient inhibition of platelets; estimates suggest that between 5.5 and 60% of patients using aspirin may exhibit "aspirin resistance (Gasparyan et al., 2008).Beta-blockers, the statin-fibrate combination and glibenclamide were prescribed more frequently for individuals with the MetS in our study population, reflecting the latest guidelines (Bianchi et al., 2007).

Conclusion
Complications of the MetS were not addressed effectively by management strategies in our study, possibly explaining the increased CVD risk in individuals with the MetS despite pharmacologic treatment.At the same time, our findings suggest that hypertension (systolic and/or diastolic) can be more readily managed in individuals with the MetS.

Table 1 .
Baseline characteristics of population studied by sex.

Table 2 .
Prevalence of cardiovascular risk factors (15) in individuals with or without metabolic syndrome (IHHP).
*indicates: p-value<0.001from comparison between sex and risk factors.

Table 3 .
Pharmacological management the components of the metabolic syndrome by sex (IHHP).