European Journal of Cardiovascular Medicine

Chronic Obstructive Pulmonary Disease (COPD) is characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lung to noxious particles or gases. According to GOLD, Chronic Obstructive Pulmonary Disease (COPD) is defined as ‘a preventable and treatable disease with some significant extra pulmonary effects that may contribute to the severity in individual patients’.⁽¹⁾ Clinically diagnosis of COPD is considered in a patient who has history of exposure to risk factors such as cigarette/bidi smoking, occupational exposure to dust, chemicals or smoke from home cooking (e.g. chullah). They usually present with the characteristic symptoms of persistent progressive dyspnoea, chronic cough and sputum production.

Diagnosis is confirmed by spirometry which is the gold standard investigation and is also used for grading the severity of disease.In addition, as COPD results from inflammation and/or alterations in repair mechanisms, the ‘‘spill-over’’ of inflammatory mediators into the circulation may result in important systemic manifestations of the disease, such as skeletal muscle wasting and cachexia. Systemic inflammation may also initiate or worsen co-morbid diseases, such as ischemic heart disease, heart failure,osteoporosis, normocytic anaemia, lung cancer, depression and diabetes. Thus COPD can no longer be considered a disease only of the lungs, as it is often associated with a wide variety of systemic consequences.

Metabolic syndrome, which is a cluster of obesity, hypertension, insulin resistance and dyslipidemia is increasingly recognized as an important co-morbidity in COPD. It is associated with systemic inflammation and physical inactivity which are also relevant extrapulmonary markers of morbidity and mortality in COPD.⁽²⁾ Patients with COPD and metabolic syndrome have higher risk of mortality than those without metabolic syndrome.⁽³⁾

There appears to be a two-way association between COPD and metabolic syndrome where in one hand the systemic inflammation and physical inactivity in COPD predisposes to metabolic syndrome,while on other hand, systemic inflammation associated with metabolic syndrome may worsen COPD. Hence this study was planned to estimate the prevalence of metabolic syndrome in stable patients of COPD and to assess the association between severity of COPD and metabolic syndrome.

This crosssectional study was conducted in 101 patients from the Medicine and Chest OPD of AIIMS New Delhi.

Duration:2 years

Patients with diagnosis of COPD based on the GOLD guidelines with post broncho-dilator FEV₁/FVC <0.7 of predicted values with a compatible clinical presentation were included in the study (Table 1). Exclusion criteria were having acute exacerbation in the last 6 weeks defined by the  presence of one or more of the following findings: increase in sputum purulence, increase in sputum volume, and worsening of dyspnoea  and patients on hypolipidemic drugs.

Table 1: GOLD criteria for COPD severity

Detailed history and clinical examination were done.

Anthropometric examination:

• Weight in kg,Height in cm,BMI in kg/m²
• Waist circumference in cm, to measure waist circumference, top of right iliac crest was first located. A measuring tape was then placed in a horizontal plane around abdomen just above the iliac crest. Before reading tape measure, it was ensured that the tape was snug but did not compress the skin and was parallel to floor. Measurement was made at the end of a normal expiration
• Hip circumference in cm, measured at the level of the greater trochanters.
• Waist hip ratio.
• Mid-arm circumference (MAC) in cm, was measured midway between acromian and olecranon on the right arm for consistency.
• Skin fold thickness was measured in mm at four sites (biceps, triceps, subscapular, suprailiac) on the right side of the body using a Harpenden skin fold caliper (British Indicators Ltd., London, UK)

Blood Pressure: Using mercury sphygmomanometer to nearest 2 mmHg in sitting position after at least 5 min rest

Fasting blood glucose was estimated through Glucose oxidase method

Body Composition Analysis: Measurement was done using Bio-Impedance method by Tanita Analyzer, TBF-410. This included age, weight, height, BMI, BMR, impedance and total body fat.  

Metabolic Syndrome: Metabolic syndrome was diagnosed by NCEP ATP III criteria with waist circumference of ≥ 90 cm in males and ≥ 80 cm in females(Asian cut off values) (Table 2)

Table 2: NCEP ATP III Criteria for Metabolic Syndrome

Pulmonary Function Test: Lung volumes and capacities were measured in all patients by a dry rolling seal electronic spirometer (Morgan UK S232). The calibration of the equipment and the procedure adopted during the test were in accordance with the requirements of the American Thoracic Society Snowbird Workshop on the standardization of pulmonary function testing.⁽⁴⁾ Measurements included Forced Vital Capacity (FVC),Forced Expiratory Volume in 1 second (FEV₁) Maximum Mid-expiratory flow rate (FEF 25-75) Peak Expiratory Flow rate (PEFR).

Severity of dyspnoea:  Severity of dyspnoea was  assessed by Six minute walk test (6MWT) ,Modified Medical Research Council Dyspnoea grading & Visual Analog Scale.

Six Minute Walk Test (6MWT): was performed in accordance with the American Thoracic Society Guidelines.⁴

Modified Medical Research Council Dyspnoea scale: Self perceived dyspnoea in relation to physical activity were assessed by using the MMRC dyspnoea scale.(Table 3)             

Table 3: Modified Medical Research Council Dyspnoea Scale(MMRC)

2D Echocardiography:Transthoracic 2D Echocardiography was performed for determination for Pulmonary artery systolic pressure(PASP)

PASP=4(Tricuspid Regurgitation Velocity)² +Right Atrial Pressure

BODE INDEX: BODE index consists of Body mass index (B) measured by calculating the ratio of body weight in kg and square of height in meters, airflow obstruction(O) measured by FEV₁, functional dyspnoea (D) calculated by MMRC dyspnoea scale and exercising capacity(E) measured by 6 min walk test.

LIPID PROFILE

Measurement of serum lipids: Total cholesterol, TG and HDL cholesterol by immunocolorimetric assay (RANDOX LAB,U.K) LDL cholesterol measured indirectly using Freidwald equation, LDL-C = Total cholesterol – [Triglycerides/5 + HDL-C].

SERUM INSULIN: Serum samples were sent immediately in ice packs, centrifuged and stored at -80˚C. Serum Insulin was measured by immunoradiometric assay using Insulin (e) IRMA KIT (Immunotech, Prague Czech Republic).

Visceral Fat Accumulation: Visceral fat accumulation was done by single section CT scan at the level  of umbilicus(L2,L3 level) using sensation 40 scanner (Siemens).⁽⁵⁾ Measurement was done by drawing region of interest (ROI) by a single radiologist. The attenuation value of fat was taken in range of -50 to -350 HU. Volume of the section was taken and was converted into cross sectional area by dividing with section thickness.

STATISTICAL ANALYSIS

Data was checked for skewness and log transformation was made in appropriate cases. Categorical variables were compared by Chi-square/Fischer exact test. Two group and multiple group comparisons for normal data was done by Student’s t test and One Way ANOVA respectively with Bonferroni correction. Group comparisons for ordinal, non normal and skewed data was performed by Mann Whitney U and Kruskal-Wallis test. Correlation analysis done by Pearson’s correlation/Spearman’s rank order test. Independent variable analysis was performed by multivariate logistic regression method. Data analysis was done by SPSS version 22.

A total of 164 patients with clinical suspicion of COPD, were screened for eligibility.  Among those, 63 patients were excluded from the study since 58 patients were having acute exacerbation and 5 patients were on hypolipidemic drugs. Study was conducted in 101 patients. Amongst the study population, 75% were males and 25% were females.

Sixty five(65%) of patients were smokers with median smoking of 15 pack years and 37% of them were current smokers. The mean age of study population was 60.8±8.8years. The mean age for females and males were 57.2±6.1 and 62.1+9.2years respectively. The mean BMI and waist circumference of the patients were  21.7+4.1 kg/m² and 84.5±13.4 cm respectively.

Baseline Characteristics:

Patients were divided into four groups, according to the results of the spirometry(figure 1): stage I-mild COPD {n=6, (6%); three males and three females}; stage II - moderate COPD {n=45, (44%); thirty four males and eleven females}; stage III - severe COPD {n=36, (36%); twenty five males and eleven females} and stage IV - very severe COPD {n=14, (14%); thirteen males and one female} There was no difference in gender proportion between various stages of COPD (p:0.253).

Figure 1: Distribution of patients according to severity of COPD

Table 4: Spirometry, dysnoea and exercise capacity of patients

FVC- Forced vital capacity, FEV₁- Forced expiratory flow at 1 minute, FEV₁(% Predicted)- FEV₁ % of predicted, VAS-Visual analog scale, BODE-Body mass index, airflow obstruction, dysnoea and exercise capacity,6MWD-Six minute walk distance(meters),PASP-Pulmonary Artery Systolic Pressure

Table 5: Baseline characteristics according to severity of COPD

Prevalence of metabolic syndrome

The prevalence of metabolic syndrome in Stage I,II,III & IV were 33.3%, 42.2%, 36.1% and 35.7% respectively. Overall prevalence was 38.6%. The prevalence of metabolic syndrome in various stages of COPD is shown in figure 2.

Figure 2: Prevalence of metabolic syndrome

Comparison of metabolic profile with severity of COPD

The occurrence of deranged blood pressure and metabolic abnormalities with varying severity of COPD was analyzed.Deranged metabolic profiles were compared between combined GOLD I/II and GOLD III/IV (table 6).No statistical significant difference was found among groups in the occurrence of metabolic syndrome (p:0.684).Deranged blood pressure(systolic ≥ 130 or diastolic ≥ 85 mmHg or known hypertensive) was found in 53.4% subjects. It was also the commonest abnormality found defining the presence of metabolic syndrome. However no significant difference was seen in the occurrence of deranged blood pressure among different groups of COPD (p:0.701).

Among metabolic abnormalities no significant statistical difference was seen among different groups of COPD except fasting blood glucose. The fasting blood glucose level (≥ 100 mg/dL or known diabetic) was found to be abnormal among 37.6% subjects.14 subjects were known diabetic. The prevalence of deranged fasting blood glucose decreased from 66.6% in stage I to 21.4% in stage IV. There was significant difference in the presence of abnormal blood glucose level between stage I/II and stage III/IV of COPD (p:0.041).

Serum fasting insulin was also performed as an ancillary investigation for metabolic syndrome.No significant difference was seen between groups (p:0.11, figure 3). Serum fasting insulin level correlated well with the presence of metabolic syndrome (r =0.324, p:0.004). Insulin levels also strongly correlated with BMI (r = 0.501, p:<0.001), waist circumference (r =0.467, p:<0.001) and total body fat (r =0.497, p:<0.001). Serum insulin level also correlated with fasting blood glucose levels after excluding known diabetics on treatment (r =0.231, p:0.043).

Visceral fat accumulation by single section non contrast CT scan at the level of umbilicus was performed in 27 subjects. The median visceral fat accumulation was found to be 108 (IQR:57. 8-191.9) cm². Out of 27 subjects, 9 had visceral fat in excess of 130 cm². All these subjects had metabolic syndrome.

Visceral fat accumulation also strongly correlated with BMI(r=0.746,p<0.001), waist circumference(r=0.69,p 0.01) and total body fat(r=0.51,p 0.025).

Table 6: Relation of deranged metabolic profile with severity of COPD

FBG: Fasting blood glucose, HDL: High density lipoprotein, LDL: Low density  lipoprotein,
TG: Triglycerides, TC: Total cholesterol,WC:Waist circumference

Figure 3: Relation of fasting serum Insulin with severity of COPD

In order to assess the independent predictors of metabolic syndrome in COPD, the subjects were divided into two groups; one with metabolic syndrome (n=39) and the other without metabolic syndrome (n=62). On multivariate logistic regression analysis only total body fat was found to be independent predictor for the development of metabolic syndrome in COPD {p:0.016, AOR:1.21 (1.03-1.42)}

(Table 7): Multivariate logistic regression analysis for predictors
of metabolic syndrome in COPD (Table 7)

MS:Metabolic syndrome,AOR: Adjusted odds ratio ,BMI:Body mass index,MMRC:Modified medical research council,VAS:Visual analog scale,6MWD:Six minute walk distance

We conducted this cross sectional study to know the prevalence of metabolic syndrome associated with COPD. Recently an increasing body of epidemiological evidence has shown that various co-morbidities like osteoporosis, cardiovascular disease, diabetes mellitus, dyslipidemia etc are more common in COPD than non COPD participants.One hypothesis is that systemic inflammation which occurs in COPD is responsible for these co morbid conditions. Although these co morbid conditions are reported frequently, data regarding its prevalence had varied in different studies and various regions. There are only few data available regarding prevalence of metabolic syndrome in COPD.

The prevalence of metabolic syndrome in COPD varies from region to region. It also depends upon the criteria used for the definition of metabolic syndrome. In a study conducted by Watz H et al in Pulmonary Research Institute at Hospital Grosshansdorf, Schleswig-Holstein, Germany in 2006 with 170 patients of COPD, the frequencies of the metabolic syndrome in patients with Chronic Bronchitis, GOLD Stages 1,2,3 and 4 were 53%, 50%, 37% and 44% respectively (avg 47.5%)⁽⁶⁾

In another study conducted in China by Lam H et al involving 7358 adults, ≥ 50 yrs, COPD was found among 6.7% subjects. Metabolic syndrome was found in 20% subjects using IDF criteria. Here they also found that the risk of metabolic syndrome was higher in those with airflow obstruction than those without {OR: 1.47 (1.12-1.92)}. Of the five components of metabolic syndrome only central obesity was significantly associated with airflow obstruction (OR 1.43; 1.09-1.88) after adjusting for body mass index.⁽⁷⁾

In contrast to the Chinese study, a case control study performed by Kocabas A et al in Turkey did not find any relationship between age, severity of airflow obstruction, smoking status, level of physical activity and presence of metabolic syndrome in patients with COPD.⁽⁸⁾

Furthermore, in a large population based study conducted in Italy by Cazzola M et al in 15018 subjects of COPD, the prevalence of metabolic syndrome was only 0.6% which was not different from general population.⁽⁹⁾

In a case control study in Korea by Park BH et al in 133 COPD subjects, the prevalence of metabolic syndrome was found to be 36.8% using NCEP ATP III criteria. The prevalence of metabolic syndrome was higher among COPD subjects than age & gender matched general population.⁽¹⁰⁾

In a study conducted by Marquis K et al.⁽¹¹⁾ in Canada,the prevalence of metabolic syndrome was found to be 47%.Another study conducted in Canada by Poulain M et al. found the prevalence to be 28%.⁽¹²⁾

So, based on these limited studies it is currently not clear whether COPD has a role in the development of metabolic syndrome or whether other confounding factors are involved in its causation.

In our study the prevalence of metabolic syndrome is 38.6%. In 101 subjects of COPD, metabolic syndrome was found in 39 subjects. The prevalence was significantly higher in females as compared to males (69.2% vs. 28%). The exacerbation frequency was significantly higher in advanced stage as compared to early stage of COPD. This observation warrants the more frequent use of influenza and pneumococcal vaccination among Indian patients.

The prevalence of metabolic syndrome were similar in all stages of COPD (Stage I:33%, StageII:42.2%, Stage III:36.11%, Stage IV:35.7%). The prevalence of deranged fasting glucose was significantly higher in early stages of COPD as compared to advanced stage. This may be attributed to higher body fat and greater proportion of current smokers in early stages in COPD.

Further none of the components of metabolic syndrome was found to be associated with severity of COPD.

The commonest metabolic abnormality found in our study was deranged HDL (50% of subjects). Dyslipidemia was found in 60.4% subjects.Deranged HDL (35%) and triglyceride levels (37%) were also the commonest metabolic abnormalities found in the study conducted by Watz et al.

The prevalence of deranged fasting blood glucose levels in our study is 38.6% which is similar to the study conducted by Watz et al. in Germany(38.2%).Fasting serum insulin level, which indicate insulin resistance correlated positively with presence of metabolic syndrome,BMI,waist circumference, total body fat and fasting blood glucose levels. This shows that central obesity is an important factor in causation of insulin resistance and diabetes mellitus in COPD patients as also seen in general population.

Visceral fat was also found to correlate well with other markers of central obesity: waist circumference, body fat and BMI.

We performed multivariate logistic regression analyses which revealed total body fat as independent predictor of metabolic syndrome in COPD. This also showed that metabolic syndrome in COPD is not associated with its severity.

Our findings show that metabolic syndrome and dyslipidemia are important co-morbidities in patients of COPD. However, the prevalence of metabolic syndrome in COPD is not related to its severity, exercise capacity, severity of dyspnoea, duration of disease or exacerbation frequency.

BMI and total body fat are important predictors of metabolic syndrome in COPD patients similar to general population. We suggest that patients with COPD should routinely have their metabolic profile evaluated irrespective of the stage of disease. Smoking is also found to be associated with deranged fasting blood glucose and serum HDL. We also suggest better implementation of smoking cessation programme in order to prevent these metabolic abnormalities apart from its known effect in improving lung function in COPD patients.

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