Metabolic syndrome in hospitalized patients with chronic obstructive pulmonary disease

Introduction. The metabolic syndrome (MS) affects 21–53% of patients with chronic obstructive pulmonary disease (COPD) with a higher prevalence in the early stages of COPD, with results being highly variable between studies. MS may also affect natural course of COPD—number of exacerbations, quality of life and lung function. Aim. To examine the prevalence of MS and its correlation with comorbidities and COPD characteristics in patients with COPD admitted for exacerbation. Material and methods. 152 patients with COPD admitted for exacerbation were studied for presence of MS. All of them were also assessed for vitamin D status and diabetes mellitus type 2 (DM). Data were gathered for smoking status and exacerbations during the last year. All patients completed CAT (COPD assessment test) and mMRC (Modified Medical Research Council Dyspnea scale) questionnaires and underwent spirometry. Duration of current hospital stay was recorded. Results. 25% of patients have MS. 23.1% of the male and 29.5% of the female patients have MS (p > 0.05). The prevalence of MS in this study is significantly lower when compared to a national representative study (44.6% in subjects over 45 years). 69.1% of all patients and 97.4% from MS patients have arterial hypertension. The presence of MS is associated with significantly worse cough and sleep (1st and 7th CAT questions; p = 0.002 and p = 0.001 respectively) and higher total CAT score (p = 0.017). Average BMI is 27.31. None of the patients have MS and BMI <25. There is a correlation between the presence of MS and DM (p = 0.008) and with the number of exacerbations in the last year (p = 0.015). There is no correlation between the presence of MS and the pulmonary function. Conclusion. This study among hospitalized COPD patients finds comparable but relatively low prevalence of MS (25%) compared to previously published data (21–53%) and lower prevalence compared to general population (44.6%). MS may impact quality of life and the number of exacerbations of COPD. Having in mind that MS is more common in the early stages and decreases with COPD progression, the COPD patients admitted for exacerbation may be considered as having advanced COPD.


INTRODUCTION
Chronic Obstructive Pulmonary Disease (COPD) is a preventable and treatable disease with significant extrapulmonary effects that may contribute to the severity in individual patients. By 2030, COPD will be the fourth cause of mortality worldwide. The extrapulmonary comorbidities influence the prognosis of the patients with COPD (Global Initiative for Chronic Obstructive Lung Disease , 2014).
Metabolic syndrome (MS) is common in patients with COPD. According to the available studies the prevalence of MS in COPD patients varies between 21-53% (Mekov & Slavova, 2013). The prevalence of MS in COPD patients is increased when compared to a control group (Funakoshi et al., 2010;Lam et al., 2010;Marquis et al., 2002;Park et al., 2012).
Many studies examine prevalence of MS in COPD patients (Funakoshi et al., 2010;Lam et al., 2010;Park et al., 2012;Kupeli et al., 2010;Akpinar et al., 2012;Marquis et al., 2005;Minas et al., 2011;Ozgen Alpaydin et al., 2013;Poulain et al., 2008;Watz et al., 2009) with results being highly variable between studies. The prevalence of MS in an unselected Bulgarian population aged 20-80 years is 30.8%. The prevalence of MS for participants over 45 years (the most common age group for the COPD patients) is higher, 44.6% (Borissova et al., 2007). An epidemiological study conducted in Bulgaria in 3,598 COPD patients showed that metabolic syndrome is found in 13.8% of the patients (Pavlov et al., 2010). A more recent study indicates that the prevalence of metabolic syndrome is 41.8% in 141 patients with COPD compared to 39% in the control group of 103 subjects (Stratev et al., 2012). The prevalence of MS in COPD patients, hospitalized for exacerbation is hard to predict because MS tends to be more prevalent in early stages of COPD while patients experiencing severe exacerbation often have advanced disease. On the other side, MS may impact natural course of COPD and predispose to exacerbation which will lead to increased prevalence of MS in this group.
There is not enough data to determine whether the results from these studies are applicable to specific subgroups of patients, such as COPD patients admitted for exacerbation. COPD is increasingly divided in subgroups or phenotypes based on specific features and association with prognosis or response to therapy, the most notable being the feature of frequent exacerbations (Vestbo, 2014). The presence of MS may also have distinctive characteristics for this subgroup ('severe' exacerbator phenotype). The aim of this study is to find out the prevalence of MS in patients with COPD admitted for exacerbation and the correlations of presence of MS with comorbidities and COPD characteristics.

MATERIAL AND METHODS
A total of 152 COPD patients hospitalized for exacerbation were studied for the presence of MS, DM, and vitamin D deficiency and insufficiency using well-established criteria for: • Presence of MS: at least 3 of the following: 1. Elevated waist circumference >102 cm in males, >88 cm in females; 2. Triglycerides >1.7 mmol/L (or on therapy); 3. HDL <1.0 mmol/L in males, <1.3 mmol/L in females (or on therapy); 4. Elevated blood pressure: systolic ≥130 and/or diastolic ≥85 mm Hg (or on therapy); 5. Fasting glucose >5.5 mmol/L (or on therapy) (Alberti et al., 2009).
The diagnosis of COPD was made according to GOLD (Global Initiative for Chronic Obstructive Lung Disease) criteria (DM1). Data were gathered for age, sex, smoking status and number of pack-years, number of bone fractures, therapy for arterial hypertension, therapy for DM, COPD therapy and number of exacerbations in the last year. The patients completed CAT and mMRC questionnaires and underwent pre-and post bronchodilatatory spirometry. Blood pressure was obtained according to the American Heart Association Guidelines (Pickering et al., 2005). A patient was considered as having arterial hypertension if taking antihypertensives.
The inclusion criteria were post bronchodilator spirometry obstruction defined as FEV1/FVC<0.70. All participants in this study signed informed consent.
The exclusion criteria were failure to comply with study procedures (no completed questionnaires, no medical and demographic information, no spirometry, no lab tests) or FEV1/FVC ratio >0.70 after administration of bronchodilator.

Smoking status
Every participant was classified according to smoking status (Schoenborn & Adams, 2010): Never smoker-never smoked a cigarette or who smoked fewer than 100 cigarettes in their entire lifetime.
Former smoker-smoked at least 100 cigarettes in their entire life but were not currently smoking.
Current smoker-had smoked at least 100 cigarettes in their entire life and were still smoking.
Numbers of pack-years were calculated using the formula: Number of pack-years = years of smoking × number of daily smoked cigarettes/20.

Anthropometric indices
Body weight and height were measured and the body mass index (BMI) was calculated by dividing weight by height squared (kg/m 2 ). According to BMI all patients were classified as underweight (<18.5), normal (18.5-24.99), overweight (25-29.99) and obese (>30). Waist circumference was measured at the approximate midpoint between the lower margin of the last palpable rib and the top of the iliac crest according to the WHO STEPS protocol (WHO, 2008). Hip circumference was measured around the widest portion of the buttocks (WHO, 2008). Body adiposity index (BAI) was calculated as: Hip circumference (in cm)/ (Height (in m) X √ Height) − 18.

COPD exacerbations and duration of hospital stay
Data were gathered for number of severe exacerbations (hospitalizations) and moderate exacerbations (antibiotic or/and systemic steroid treatment without hospitalization due to worsening of pulmonary symptoms) (Global Initiative for Chronic Obstructive Lung Disease , 2014) in the previous year. The duration of the current hospital stay was recorded.

Quality of life
Quality of life was assessed with the mMRC scale and CAT questionnaire. Patients were instructed that there were no right or wrong answers. All patients' questions were answered. Patients were classified according to GOLD as having less symptoms (CAT < 10) and breathlessness (mMRC grade 0-1) and more symptoms (CAT ≥ 10) and breathlessness (mMRC grade ≥ 2). Because all patients were hospitalized due to exacerbation there were only group C (high risk, less symptoms) and group D (high risk, more symptoms) patients according to GOLD (Global Initiative for Chronic Obstructive Lung Disease , 2014).

Pulmonary function testing
The spirometry was performed using Minispir ® New spirometer (MIR-Medical International Research, Rome, Italy). Patients were instructed to withdraw using short-acting β2-agonists at least 6 h, long-acting β2-agonist at least 12 h, long acting muscarinic antagonist 24 h and short acting muscarinic antagonist 12 h before the spirometry (Miller et al., 2005). Post bronchodilator spirometry testing was performed 15-30 min after inhalation of 400mcg Salbutamol according to ERS/ATS recommendations (Miller et al., 2005).

Blood samples and analyses
A venous blood sample was collected from each subject after a 12-h fasting. Blood samples were taken as late as possible before discharging (usually on 6th or 7th day

Sample characteristics
A total of 152 COPD patients admitted for exacerbation were recruited from University Specialized Hospital for Active Treatment of Pulmonary Diseases 'Saint Sofia,' Sofia, Bulgaria. Mean age of patients in this study was 65 ± 10 years. 71.1% (108/152) were males, 28.9% (44/152) were females; mean post-bronchodilator FEV 1 was 55.3 ± 19.5%. 15.8% from the patients were never smokers, 57.9%-former smokers and 26.3%-current smokers. 127 patients (83.6%) were receiving inhalatory corticosteroids.  waist circumference (33/38). Arterial hypertension has greatest sensitivity for predicting presence of MS, but is not specific. Elevated waist circumference has greatest accuracy, defined as sum of true results (true positives and true negatives) divided by total number of cases. Number of fulfilled criteria in all patients is given in Table 3.

Lifestyle factors
Our study did not find significant differences in prevalence of MS according to smoking status and number of pack-years. Treatment with inhalatory corticosteroids (ICS) is not risk factor for MS. Fasting glucose level are not influenced by ICS (all p > 0.05) (

Exacerbations and duration of hospital stay
Our study found a significant difference between the number of total exacerbations according to the presence of MS (Table 4, p = 0.015). The number of severe exacerbation, moderate exacerbation and duration of hospital stay did not reach significance.
Triglycerides and blood glucose levels in our study did not correlate with number of exacerbations. Linear

Quality of life
The presence of MS is associated with significantly worse cough and sleep (1st and 7th CAT questions; p = 0.002 and p = 0.001 respectively) and higher total CAT score (p = 0.017) ( Table 5). However prevalence of MS is not significantly different between patients with less symptoms (CAT 0-9) and breathlessness (mMRC 0 or 1) compared to patients with more symptoms (CAT ≥ 10) and breathlessness (mMRC ≥ 2) ( Table 1)

Pulmonary function test (PFT)
Our study did not find differences in FVC, FEV1, FEV1/FVC, FEV6, FEV1/FEV6, PEF, FEF2575 and FEV3 according to the presence of MS. It should be noted that there is tendency for FVC and FEV1/FVC ratio. However, because of this there is significant difference in FEV3/FVC ratio (Table 6).  There is no difference in prevalence of MS in patients with FEV1 <50%, when compared to patients with FEV1 >50% or regarding GOLD stage (Table 1).

DISCUSSION
This study found comparable but relatively low prevalence of MS compared to previous studies (Table 7) (Fig. 1). The prevalence of MS in our study is significantly lower when compared to the general Bulgarian population (44.6% in subjects over 45 years) (Borissova et al., 2007). The odds ratio for COPD patients admitted for exacerbation of having MS is 0.41 compared to general population (95% CI [0.28-0.61], p < 0.0005).
Two Bulgarian studies examined the prevalence of MS in COPD patients. An epidemiological study conducted in Bulgaria in COPD patients reported a prevalence of 13.8%. These results differ significantly from the literature data probably because of the different criteria for metabolic syndrome (presence of DM, BMI >30 and blood pressure >140/90 mmHg) which makes data comparing irrelevant (Pavlov et al., 2010). A more recent study indicates that the prevalence of metabolic syndrome is 41.8% in patients with COPD . However, this study was not conducted using a random sample (exclusion criteria was presence of DM, people were aged 49-79 years for patients with COPD and  Watz et al., 2009 200 Patients with COPD and chronic bronchitis GOLD I-50%; GOLD II-53%; GOLD III-37%; GOLD IV-44%; Chronic bronchitis-53% 35-65 years for controls) (Stratev et al., 2012). Nonetheless it uses similar criteria for MS and when comparing the results our study finds lower prevalence of MS.
The prevalence results could be explained with differences between the populations in different studies (physical activity, diet, lifestyle etc.). For example, Bulgaria is low-income country, which may impact diet preferences and treatment choices. Furthermore, patients in this study had been hospitalized due to exacerbation, which represents the most severe group of COPD patients. Having in mind that MS is more common in the early stages and decreases with COPD progression (Watz et al., 2009), COPD patients hospitalized for exacerbation may be considered as having advanced COPD.
According to the NHANES III study, smokers are more likely to develop MS than nonsmokers in general population, and the risk increases with the number of pack-years even after adjusting for covariates (Park et al., 2003). Our study did not find significant differences in prevalence of MS according to smoking status and number of pack-years. These results could be explained with smoke being the biggest factor in developing COPD and effect of developing MS could be reduced. Moreover nicotine may be an appetite suppressant and lower the weight thus decreasing prevalence of metabolic syndrome (Chiolero et al., 2008). Third, hospitalized COPD patients are patients with predominantly advanced disease and prone to cachexia and wasting. Also, lifestyle changes (quiting smoking) in the presence of the two diseases should be considered which may change the prevalence of MS.
Treatment with inhalatory corticosteroids (ICS) is not risk factor for MS similar to findings for DM (O'Byrne et al., 2012) and fasting glucose level are not influenced by ICS.
COPD is a disease that affects mainly the lungs, but is characterized by systemic inflammation and a number of extrapulmonary manifestations. Only 1/3 of patients with COPD die due to respiratory failure. Main cause of death is lung cancer and cardiovascular complications (Calverley et al., 2007).
The vast majority of patients with COPD have a vitamin D deficiency (Romme et al., 2013). Aside from its role in the metabolism of calcium and phosphorus, vitamin D is involved in the pathogenesis of multiple diseases, including MS, mainly because it affects the secretion and the function of insulin (Ju, Jeong & Kim, 2014). However, in our study vitamin D levels do not significantly differ in relation to presence of MS. Presence of MS is also not related to vitamin D status.
There are no studies that examine the relationship between osteoporosis and MS in patients with COPD. However, both diseases share common risk factors such as smoking, lack of physical activity, and treatment with corticosteroids. Some of the components of the metabolic syndrome (arterial hypertension, elevated triglycerides, reduced HDL cholesterol) are risk factors for low bone density. Systemic inflammation in MS plays a role in the pathogenesis of osteoporosis (McFarlane, 2006). On the other hand, studies examining the relationship between MS and osteoporosis showed inconsistent results, probably due to the protective effect of obesity (Zhou et al., 2013). However, the number of fractures in our study does not significantly differ regarding the presence of MS. The presence of at least one fracture also does not differ significantly in relation to presence of MS.
Most patients with DM have MS, but the opposite is not necessarily true (Ginsberg & Stalenhoef, 2003). The presence of MS in this study is associated with presence of DM, higher BMI and BAI.
Hyperglycemia is associated with elevated glucose concentrations in tissues and bronchial aspirates where it may stimulate infection by enhancing bacterial growth and by promoting bacterial interaction with the airway epithelium (Brennan et al., 2007). Hyperglycemia also impairs both innate and adaptive immunity, suppressing the host response to infection.
The presence of MS in patients with COPD increases the frequency of exacerbations (2.4 vs. 0.7) and their duration-(7.5 vs. 5.0 days) according to Kupeli et al. (2010), and 8 versus 5.5 days, according to Abdelghaffar et al. (2012). Our study found a significant difference between the number of total exacerbations according to the presence of MS. However, the number of severe exacerbation, moderate exacerbation and duration of hospital stay did not differ significantly. Triglycerides and blood glucose levels in our study did not correlate with number of exacerbations as reported by other authors (Kupeli et al., 2010).
The presence of MS is associated with significantly worse cough and sleep and higher total CAT score. This confirms the data about reduced quality of life in patients with MS (Ford & Li, 2008). However, the prevalence of MS is not significantly different between patients with less symptoms (CAT 0-9) and breathlessness (mMRC 0 or 1) compared to patients with more symptoms (CAT ≥10) and breathlessness (mMRC ≥2). These mixed results may be explained with COPD having higher negative impact on quality of life than MS (physical limitation due to shortness of breath) as suggested for DM (Arne, Janson & Janson, 2009), and ameliorating the effect in patients having both diseases.
COPD is characterized by airflow obstruction, which is not fully reversible. MS is associated with a reduction of lung volumes (Fimognari et al., 2007;Leone et al., 2009;Lin et al., 2006;Nakajima et al., 2008;Yeh et al., 2011). It should be noted that some studies found no association between lung function and the presence of MS (Yamamoto et al., 2014). MS in our study is not associated with worsen pulmonary function. There is also no difference in prevalence of MS in patients with FEV1 <50%, when compared to patients with FEV1 >50% or regarding GOLD stage.

CONCLUSIONS
This study finds a 25% prevalence of MS in COPD patients admitted for exacerbation, which is significantly lower than the general population. MS is more prevalent in females, but the gender difference is not statistically significant. In this study, most of the patients are former smokers, and the prevalence of MS does not differ regarding smoking status and treatment with ICS.
The presence of MS is associated with the presence of DM, higher BMI and BAI, more exacerbations during the previous year and lower quality of life. MS is not associated with increased hospital stay and lower pulmonary function.
This study finds comparable but relatively low prevalence of MS compared to previously published data (21-53%). As MS is more common in the early stages and decreases with COPD progression, the COPD patients admitted for exacerbation may be considered as having advanced COPD.

ADDITIONAL INFORMATION AND DECLARATIONS Funding
This manuscript is part of a PhD project, which is partially funded by Medical University-Sofia, Sofia, Bulgaria (grant number 15-D/2014, project number 22-D/2014). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Grant Disclosures
The following grant information was disclosed by the authors: Medical University-Sofia: 15-D/2014.