Introduction

Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease with significant extrapulmonary effects and associated comorbidities that may contribute to its severity in individual patients [1]. In 2005 it was the fourth leading cause of death [2] and is associated with cardiovascular disease [3].

Obesity is one of the greatest public health challenges of the twenty-first century, and its prevalence has tripled in many European countries in the past 30 years [4]. In addition, obesity is responsible for 2–8 % of health costs and 10–13 % of deaths. The metabolic syndrome (MetS) is a complex of interrelated medical disorders that increase the risk of developing type-2 diabetes and cardiovascular disease [5]. Approximately 34 % of American adults older 20 years of age and over [6, 7] and 25–30 % of European adults [8] have MetS. The prevalence increases with age and is strongly correlated with high body mass index [6]. The MetS is associated with an increase of cardiovascular disease and mortality [9, 10]. It has a rising prevalence worldwide that relates to increasing obesity and sedentary lifestyles.

In patients with COPD, the frequencies of obesity and MetS are on average 18 and 47 %, respectively [12]. The MetS is more prevalent in younger patients and in earlier stages of COPD, and it is suggested that these patients may constitute a specific COPD phenotype [12].

The aim of the present study was to determine the relationship between the clinical characteristics and the MetS in COPD patients.

Methods

Study design

ECCO is the acronym in Spanish of “EPOC Con COmorbilidad”, that is, “COPD with comorbidity study”. It is an observational, cross-sectional, multicenter study, participated by 26 hospital centers throughout Spain (see “Appendix”). Detailed features of the study have been reported elsewhere [13, 14]. Each researcher included the patients admitted with a COPD exacerbation that were attended consecutively between January 1, 2007, and December 31, 2008. COPD was diagnosed with spirometry in stable condition, preceding admission, according to GOLD guidelines [1]). All participating patients were GOLD II or higher (predicted FEV1 <80 % and postbronchodilator FEV1/FVC <0.7). The primary objective was to determine the prevalence of MetS in COPD patients, and secondary objectives were to establish the clinical and lung function differences between COPD patients with and without MetS.

Evaluation of MetS

The diagnosis of MetS was established using the following criteria: body mass index >30 kg/m2, fasting glucose ≥100 mg/dL or drug treatment for elevated glucose, systolic ≥130 or diastolic ≥85 mmHg blood pressure or antihypertensive drug treatment in a patient with history of hypertension, triglycerides ≥150 mg/dL or drug treatment for elevated triglycerides, high-density lipoprotein cholesterol (HDL-C) <40 mg/dL in men or <50 mg/dL in women, or drug treatment for reduced HDL-C. The presence of any three of the five criteria constitutes a diagnosis of the MetS [5].

Procedures

A comprehensive questionnaire with demographic and relevant clinical data was administered to patients upon admission, and a detailed physical examination was also undertaken. Data registered included age, gender, smoking history, total number of admissions for COPD or other causes and number of acute COPD exacerbations in the previous 12 months. To assess associated comorbidities we used the Charlson index [15] as well as other conditions not included in this index that are prevalent in COPD [16], namely osteoporosis, anemia, hypertension, dyslipidemia, and alcoholism. Baseline dyspnoea prior to admission was assessed with the modified (5-point) Medical Research Council (mMRC) dyspnoea scale. Body mass index was calculated as weight/height squared, and it was expressed in kg/m2. Fasting venous blood was collected and plasma glucose, HDL-C, and triglycerides were measured.

The study was approved by the Clinical Investigation Ethics Committee of the coordinating center, Hospital de la Vega Baja in Orihuela, Alicante, and all patients signed informed, written consent form.

Statistical analysis

Reported prevalence of MetS in American and European adults is within 20–34 % [6–8]. Assuming a 5 % type I error and a 5 % precision, a sample size of 323 patients was calculated.

Quantitative data are presented as mean ± SD. Comparison of variables between the two groups was performed using the ANOVA test.

Qualitative data are presented as absolute frequencies and percentages. Comparison between two groups was performed using χ 2 and Fisher exact tests. Comparison among three or more groups was performed using χ 2 test for trend.

A logistic regression model was constructed using the variables with statistical significance in the univariate analysis. In all analysis p values <0.05 were considered statistically significant.

Statistical analysis was performed using the software G-Stat 2.0 (www.e-biometria.com).

Results

The flow chart of study participants is presented in Fig. 1. Finally we included 375 patients, 333 men and 42 women, with a mean (SD) age of 73.7 (8.9) years. The characteristics of patients are given in Table 1.

Fig. 1
figure 1

Flow chart CONSORT of patients considered in the study. AECOPD acute exacerbation of COPD, MetS metabolic syndrome

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Table 1 Demographic and clinical characteristics of COPD participants with and without MetS
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Prevalence of MetS and its components

One hundred and sixty-one (42.9 %) patients had MetS. The prevalence of MetS in COPD patients was more frequent in women (59.5 %) than in men (40.8 %), p = 0.02, but with no differences in age or smoking history, either by current status or in pack-years. Hyperglycemia and high blood pressure were the most frequent components of MetS (Fig. 2). Women met more components of MetS [2.74 (0.96) vs. 2.25 (1.10); p = 0.006] and had more frequent hyperglycemia (92.9 vs. 78.1 %; p = 0.02) than men. In COPD patients with MetS, there was no difference in the number of components by gender.

Fig. 2
figure 2

Metabolic syndrome and its components by gender. HBP high blood pressure, HG hyperglycemia, HTG hypertrygliceridemia, LHC low HDL-cholesterol, MetS metabolic syndrome

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MetS and lung function

Patients with MetS had less airflow obstruction, either expressed by FEV1 and FEV1/FVC ratio compared with patients without MetS (p < 0.01). They presented less severe GOLD stages, but had more elevated grade of dyspnoea measured with mMRC scale and used more inhaled steroids (Table 1). Further, they had neither more exacerbations in the previous year nor more admissions for COPD, although they were hospitalized more frequently for any cause. Interestingly, there was an inverse association of MetS with greater GOLD COPD severity, the frequencies of MetS being 51.2, 41.8, and 25.5 % in patients with GOLD stages II, III, and IV, respectively (χ 2 for trend p = 0,003). A lower proportion of patients in GOLD stage IV had high blood pressure (Table 2). Patients in more severe GOLD stages significantly used more inhaled steroids (18.9, 22.4, 36.2 % in stages II, III, and IV, respectively, χ 2 for trend p = 0.03) but not more systemic steroids (7.9, 12.4, 12.8 % in stages II, III, and IV, respectively, χ 2 for trend p = 0.22).

Table 2 MetS and its components by GOLD COPD spirometric classification
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In addition, patients treated with inhaled corticosteroids had lower FEV1 than others [40.9 (13.5) vs. 44.1 % (12.0); p = 0.03].

MetS and comorbidities

Patients with MetS had more comorbidities (Table 1). They had a higher Charlson score compared with patients without MetS [2.88 (1.61) vs. 2.45 (1.83), p = 0.02). Diabetes, coronary artery disease, heart failure, and osteoporosis were also more frequently present in COPD patients with MetS (p < 0.05).

Factors associated with the presence of MetS

In a multivariate logistic analysis, the presence of MetS was independently associated with FEV1, inhaled steroids, osteoporosis, diabetes, and heart failure (Table 3).

Table 3 Crude and adjusted factors associated with MetS in COPD patients
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MetS and mortality

Fifteen (4.0 %) patients died during admission. In-hospital mortality was higher in patients with MetS (5.7 vs. 1.9 %; p = 0.07), but this difference was not statistically significant.

Discussion

The main findings of our study were that more than 40 % of COPD patients had MetS, and although MetS was associated with less impaired lung function and actually it had an inverse association with GOLD COPD severity, these patients had more hospital admissions and burden: they had more osteoporosis and heart failure. In addition, COPD patients with MetS had a less obstructive pattern.

The prevalence of MetS in our study is higher than in previous studies in the general population, but it is similar to others in European elderly populations. Hildrum et al. [8], report a prevalence of MetS of 45 % in men and of 60 % in women aged 70–79 years. The presence of MetS in COPD patients depends both on the study inclusion criteria and the criteria used to diagnose MetS. In Germany, using the International Diabetes Foundation criteria, the prevalence was estimated at 47.5 % [11]; by contrast, in Greece, using the criteria of Adult Treatment Panel III criteria and excluding patients with diabetes, known history of cardiovascular disease and other comorbidities, it was found to be 21 % [12]. Other studies conducted in China and Japan report that 22.6 and 23 % of COPD patients have MetS, respectively [17, 18]. Other studies with smaller populations report prevalences of 28 and 47 % [19, 20]. To label MetS we have used the unified criteria that do not require waist circumference as an obligatory component [5]. To our knowledge, there are no existing reports that have used these criteria. This could explain why the prevalence we find is higher than the one in other studies.

Metabolic syndrome (MetS) tends to be less frequent in patients with very severe COPD. This initially surprising finding is in line with other reports. The frequencies of the MetS in patients with GOLD stages II, III, and IV are 53, 37, and 44 %, respectively, in the study of Watz et al. [11]. In the study of Marquis et al. [12] the overall frequency of MetS in patients with COPD is 21 %, and the frequency decreases to about 10 % at GOLD stages III and IV. The weight loss that frequently occurs in patients who are in the more severe stages of COPD may be the cause of these observations. As in heart failure, we think that the obesity paradox is present in COPD patients, that is, the greater FEV1 values were found in COPD with MetS.

In contrast with the general population findings, hyperglycemia is the component of MetS more frequently observed in COPD patients. This finding can be explained because all our patients were in moderate or higher GOLD stages of COPD, and the use of steroids is high in these patients. In the study of Watz et al. [11], the use of both inhaled and systemic steroids is higher in patients in GOLD stages III and IV without increase of presence of MetS. Also elevated blood pressure was a frequent component in our patients (70 %) as it was reported in other studies [11].

An interesting observation was that patients with MetS had less impaired predicted FEV1 and more dyspnoea compared with those without MetS. This is consistent with the findings of recent studies in overweight and obese patients with COPD [21]. We think that the presence of comorbidities, particularly heart failure, could partly explain this observation. Further, osteoporosis can modify respiratory mechanics and contribute to more breathlessness. More and more severe comorbidities also could explain why COPD patients with MetS have more hospitalizations by any cause without an increase neither of admissions for COPD nor of exacerbations in the previous year. This observation is consistent with recent reports on subtypes of COPD [22]. But contrary to this finding, a prospective study with 106 patients observes that the presence of MetS is associated with an increase of acute exacerbations of COPD [23].

In a multivariate analysis, greater FEV1 and comorbidities were independently associated with MetS. As stated previously, weight loss associated with severity of COPD could explain the association between MetS and greater spirometric values. Osteoporosis and heart failure are conditions that limit the capacity for physical activity and lead to sedentary life styles. These factors predispose to weight gain and, therefore, contribute to having MetS. In addition, physical inactivity increases the levels of inflammatory biomarkers as CRP and interleukin-6, which are high in obese individuals [24, 25].

Recent studies in older patients observe that the association of MetS with bone mineral density is reversed after adjusting for BMI such that MetS is associated with lower bone mineral density [26]. This could explain the association of MetS and osteoporosis that we observed, and that is not in line with previous reports that demonstrate a close relationship between low BMI and osteoporosis in COPD.

To our knowledge this is the first study of MetS in COPD patients with any mortality data. We have observed that mortality during admission was 5.7 % in patients with MetS and 1.9 % in patients without MetS. The difference is clinically relevant but not statistically significant. Our study was not powered to find this difference, but it might be interesting if new short- and long-term studies evaluate mortality in COPD patients with MetS.

Our study has some limitations. First, it is a cross-sectional analysis of patients admitted to Internal Medicine departments. In Spain 37–53 % of COPD patients are admitted to these departments [27, 28]. They are older and have more comorbidities than those admitted to Pulmonology departments [27]. However, the observed prevalence of MetS is similar to those reported in studies conducted in Pulmonology or Rehabilitation departments [11, 20]. Second, about 90 % our patients are men. The small number of women included is similar to that of other studies performed in Spain, where women were exposed to active smoking only after the 1960s. Third, patients recruited had an acute exacerbation. It is possible that patients with MetS have more or less frequent acute exacerbations, and this element could produce some bias in the data. Fourth, we have used the body mass index to diagnose obesity instead of waist circumference. Our patients were recruited during admission for an acute exacerbation of COPD and the variables were collected when the patients were in a clinically stable situation. However, it is known that waist circumferences vary by posture, site of measure, respiratory phase, and time since last meal [29]. To avoid this variability and to increase the accuracy of measure we decided to use the body mass index although it could influence the observed prevalence of abdominal obesity and MetS.

Finally, we suggest that perhaps COPD, MetS, heart failure, and osteoporosis constitute a cluster of diseases that define a disease in some association with physical inactivity and systemic inflammation [30–34].

In summary, our study concludes that MetS is frequent in COPD patients and not only associated with greater FEV1 and milder GOLD COPD severity, but also with more elevated degree of dyspnea and more comorbidities.