COPD and comorbidities

Marc Decramer and Wim Janssens

Respiratory Division, University of Leuven, Belgium

Address for correspondence:

Professor Marc Decramer

Chief Respiratory Division

University Hospital

University of Leuven

Herestraat 49

3000 Leuven

Belgium

Tel: +32-16-346807

marc.decramer@uzleuven.be

Key Words

COPD, comorbidities, cardiovascular disease, lung cancer, osteoporosis, muscle weakness,

inactivity, systemic inflammation, bronchodilators, inhaled corticosteroids

1

Summary

Epidemiological studies demonstrated that COPD is frequently associated with

comorbidities, the most significant being cardiovascular disease, lung cancer, osteoporosis,

muscle weakness and cachexia. Mechanistically, environmental risk factors such as smoking,

unhealthy diet, exacerbations and physical inactivity or inherent factors such as genetic

background and aging contribute to this association. No convincing evidence has been

provided that treatment of COPD would reduce comorbidities, although some indirect

indications are available. There is also no clear evidence that treatment of comorbidities

improves COPD, although observational studies would suggest such effects for statins, ß-

blockers and angiotensin converting enzyme blockers and receptor antagonists. At present,

we lack large scale prospective studies. Reduction of common risk factors appears the most

powerful approach to reduce comorbidities. It remains doubtful whether reducing “spill

over” of local inflammation from the lungs or reducing systemic inflammation with inhaled

or systemic anti-inflammatory drugs, respectively, would also reduce COPD-related

comorbidities.

Word Count: 148

2

Introduction

COPD is a progressive debilitating disease with high prevalence. It is currently the

fourth most prevalent cause of death and it is responsible for very high expenditures in the

health care system and economic costs. A recent analysis from the Harvard School of Public

Health showed that the global economic costs generated by COPD amount to 2.1 trillion US

dollar and are expected to increase to 4.8 trillion by 20301. A considerable fraction of these

costs is due to the fact that this is a complex disease associated with several significant

comorbidities2.

Patients with COPD suffer among others from cardiovascular and cerebrovascular

disease, lung cancer, muscle weakness and osteoporosis. Other comorbidities include:

hypertension, arrhythmias, metabolic syndrome, diabetes, gastro-esophageal reflux disease,

hematological coagulopathy, anemia, polycythemia, sleep apnea, endocrine disturbances,

renal dysfunction etc…A randomly selected sample of 1,522 patients who were enrolled in a

health maintenance organization in 1997, had on average 3.7 comorbid conditions

compared with 1.8 in controls3. These comorbidities contribute significantly to reduced

health status, increased health care utilization, all cause hospital admission and mortality 4;5.

In fact, COPD patients are more likely to die from comorbidities than from the disease itself.

In a well-designed study critically studying and adjudicating the causes of death in COPD by a

panel of senior physicians, only 40% of the deaths were definitely or probably related to

COPD, whereas 50% were unrelated to COPD, while 9% was unknown6. One third of the

deaths was due to cardiovascular disease.

The present article will briefly review the evidence for a link between COPD and the

major comorbidities of the disease, with focus on the mechanisms of their association with

COPD and finally, discuss the implications of these links to the treatment of COPD. We will

only address the major comorbidities, of which mechanistic links with COPD have recently

been studied.

Search strategy

We searched the Cochrane Library, PubMed, and Embase for papers published in

2008-2012. We used the terms “COPD and comorbidities”, “COPD and cardiovascular

disease”, “COPD and lung cancer”, “COPD and osteoporosis”, and “COPD and muscle

3

weakness”, “COPD and statins”, “COPD and Angiotensin II Converting Enzyme inhibitors”,

“COPD and Angiotensin Receptor Blockers”, “Lung cancer and statins”. We also searched the

reference lists of identified articles for further relevant papers, and we included older widely

cited publications. Because of the restriction of the number of references, only a fraction of

the retrieved references could be used. We selected original references published in major

journals, that demonstrated associations or mechanisms for the first time. We avoided citing

articles that were purely confirmatory.

Because of the extent of this field, it was not possible to comprehensively address all

comorbidities. Instead, we focused on mechanisms of comorbidities, particularly on those

comorbidities on which’s mechanisms significant research was conducted in recent years.

Our choice was supported by the number of articles retrieved by a search in PubMed. For

each of the comorbidities we performed this search by the term “comorbidity and COPD and

mechanisms”. This search yielded 237 articles for “cardiovascular disease”, 125 for “lung

cancer”, 53 for “diabetes”, 52 for “osteoporosis and muscle weakness”, 18 for

“cerebrovascular disease”, and 13 for “anxiety and depression”.

Cardiovascular disease

Cardiovascular disease is not a clearly defined concept. It usually encompasses

ischemic heart disease, congestive heart failure, pulmonary vascular disease, coronary artery

disease, peripheral vascular disease, and stroke and /or transient ischemic attack. It may also

include biomarkers of disease such as lipid abnormalities or inflammatory markers of

disease. The present section will primarily focus on ischemic heart disease, because recent

mechanistic work was focused on this area.

The association of COPD with cardiovascular disease is well established3;7. Progressive

respiratory failure only accounts for about 1/3 of COPD deaths, indicating that a large

number of COPD patients die from other causes8. In a pooled analysis of two large

epidemiological studies, the Atherosclerosis Risk in Communities, ARIC, Study and the

Cardiovascular Health Study, CHS, involving over 20,000 adults, the prevalence of

cardiovascular disease in COPD patients was 20-22% compared to 9% in subjects without

COPD7. In the ARIC study, among people with severe COPD (GOLD stage III and IV), 32% of

4

deaths were due to respiratory causes, whereas 24% were due to lung cancer and 13 % were

cardiac related. This high prevalence of cardiovascular mortality was confirmed by the

adjudicated causes of death found in the TORCH-study6. Among patients with moderate

COPD (GOLD stage II) only 4% of the deaths were respiratory related, 25% were due to lung

cancer and 28% were cardiac related9. In a recent review, Sin et al. confirmed this

relationship between FEV1 and the causes of death (Figure 1)10.Taken together, this shows

that particularly in patients with mild and moderate disease a substantial fraction of

mortality is due to cardiovascular disease and lung cancer.

An analysis of data from the National Health and Nutrition Examination Survey

(NHANES) further corroborated the relationship between reduced pulmonary function and

cardiovascular mortality. This was done by the demonstration of increased cardiovascular

mortality in patients with reduced pulmonary function, even with small decrements, that

strictly still fell within the normal range11. This relationship was also shown in lifetime non-

smokers in a meta-analysis of published studies, indicating that exposure to tobacco smoke

was not the sole reason for this association11.

Several recent studies further confirmed the links between COPD and incidence of

cardiovascular disease. First, a large population based study demonstrated an increased

relative risk of comorbid cardiovascular disease and subsequent MI and stroke in patients

with COPD12. Second, arterial stiffness, measured non-invasively as aortic pulse wave velocity

is a known marker of cardiovascular events and mortality in the general population. COPD

patients have been shown to have increased arterial stiffness13 compared to age-matched

and smoking-matched controls, and this correlated with the degree of airflow obstruction

and CT-quantified emphysema14. Third, two studies showed a relationship between COPD

and either previous cerebrovascular events15 or incidence of acute stroke12.

Finally, COPD was shown to be associated with diseases that are known to enhance

the cardiovascular risk profile. In the abovementioned combined analysis of the ARIC and

CHS population-based studies, including more than 20,000 people, the odds ratio for having

hypertension compared to normal subjects was 1.4 in GOLD stage II, and 1.6 in GOLD stage

III and IV7. Most studies did not find associations between COPD and dyslipidemia16, or

metabolic syndrome17;18. Several studies found an enhanced prevalence of diabetes in COPD

5

patients7;9;17;19;20, , but the odds ratio of having diabetes was reduced in older patients19. The

association of COPD with diabetes, however, was not found in a meta-analysis performed by

others21.

The mechanistic links between COPD and cardiovascular disease are complex,

multifactorial and not entirely understood (Figure 2). The observed association between

both diseases is to a large extent explained by the presence of common risk factors. Within

these factors distinction can be made between environmental risk factors, most of them

being largely modifiable (lifestyle), and inherent risk factors that predispose individuals to

disease, but which cannot be altered. Of all combined risk factors, smoking is by far the most

important, but the risk attributable to inactivity and unhealthy diet should not be

underestimated. Genetic predisposition and aging are inherent factors, but still poorly

understood.

In contrast to COPD in which the amount of pack-years smoked is an important risk

determinant19, cardiovascular risk is known to steeply increase with very low levels of smoke

exposure and to flatten out with high exposure levels22. Especially small inhaled particles

(Particulate Matter, PM2.5 and PM0.1 with a respective diameter less than 2.5μm and less

than 0.1μm) are of interest as they have the capability to be inhaled deeply into the lungs

and to be deposited in the respiratory bronchioles and alveoli. Once lodged in the small

airways, these particles may induce pulmonary inflammation and bronchiolitis known to be

the earliest lesions seen in COPD23. The progressive accumulation of macrophages,

neutrophils and B and T- lymphocytes within and around small airways produces a cocktail

of pro-inflammatory mediators (such as TNFα, IL-1, IL-6, IL-8, GM-CSF), proteases (MMP-9,

MMP-12 and elastase), and reactive oxygen species. These mediators translocate to the

systemic circulation where they activate the vascular endothelium, platelets and liver cells.

Eventually, a pro-inflammatory and pro-coagulant state is generated, which results in

endothelial dysfunction, enhances plaque formation and promotes arteriosclerosis10;24.

Moreover, bone marrow progenitor cells are stimulated to release monocytes and

neutrophils which are preferentially attracted to the sites of inflammation particularly the

lung16.

6

Although systemic inflammation accelerates the progression of atherosclerosis,

stable plaques do not usually cause acute coronary syndromes. Vulnerable plaques are

characterized by a larger lipid core with increased content of oxidized LDL, increased

inflammatory cells, smooth muscle proliferation and thinning of the fibrous cap18. In unstable

angina the widespread presence of neutrophilic inflammation in the coronary arteries

regardless of the culprit stenosis, indicates that bursts of inflammation precede the rupture

of a vulnerable plaque21. For COPD in particular, Van Eeden and colleagues hypothesized

that acute episodes of lung inflammation should be considered as the main triggers for such

events25. This hypothesis was confirmed by the observation that in a large UK general

practice database acute respiratory infections had a much stronger association with acute

coronary syndrome than urinary tract infections26. Moreover, an acute exacerbation of COPD

was shown to be associated with a 5 day transiently increased risk for acute myocardial

infarction27. The latter may also be related to the increased fibrinogen levels and the

resultant pro-thrombotic state27. Apart from the indirect effects of small particle inhalation

to vascular inflammation, it is now well accepted that PM0.1 and PM2.5 also translocate

through gaps between alveolar epithelial cells directly into the systemic circulation. Their

immediate effect on platelets and endothelial cells results in oxidative stress, vascular

dysfunction and peripheral thrombosis28.

It is unclear whether systemic inflammation may catalyze or even perpetuate an

ongoing pulmonary inflammatory response. If this would be true, it could mean that other

risk factors of systemic and vascular inflammation, such as visceral obesity, diabetes and

inactivity may increase the risk for COPD onset or progression. To a certain extent,

epidemiological studies support this idea by showing that inactivity, unhealthy diet, obesity

and poor glycemic control are associated with reduced pulmonary function, airway hyper-

reactivity and eventually COPD29;30. Regardless of a cause or consequence relationship, the

high prevalence of these factors in COPD is unequivocally associated with an increased risk

of cardiovascular disease within this patient group.

Finally, it should be stressed that mechanisms other than atherosclerosis and plaque

rupture may cause acute cardiovascular events in COPD31. Acute hypoxemia, chronic anemia

and severe respiratory distress may cause a cardiac event, especially in patients with diffuse

coronary lesions. Arrhythmia’s and sudden death may be triggered by the combination of

7

different pro-arrhythmic drugs such as inhaled or oral bronchodilators and antibiotics.

Pulmonary vascular remodeling with pulmonary hypertension may lead to acute right heart

failure. Hyperinflation and increased falls in intra-thoracic pressure may compromise

ventricular preload and afterload leading to left ventricular dysfunction and acute heart

failure. As most of these factors cluster together on the moment of an acute exacerbation, it

is obvious that these episodes are often associated with major cardiovascular events and

high mortality32.

Lung Cancer

COPD is an independent risk factor for the development of lung cancer, increasing

lung cancer risk two- to six fold, compared with incidence rates of smokers without COPD 33-

37. Reduced FEV1 was shown to increase the risk of incident lung cancer independently of

smoking history36. Moreover, COPD was also associated with lung cancer in never-smokers35.

Hence, the association between COPD and lung cancer was not solely due to smoking.

Airflow obstruction and emphysema were also shown to be independent risk factors for lung

cancer33;36;37. About 50% of the patients with lung cancer have COPD (Figure 3). This is in line

with the studies cited above showing that lung cancer is one of the major causes of death in

patients with COPD7;9;38. This risk appears to be greater in patients with mild to moderate

disease, than in more severe disease7;9;33;37-39 . In addition, the risk is greater for squamous

cell cancer than for adenocarcinoma37 and persists for as many as 20 years after smoking

cessation40. In contrast to the exposure-response curve for cardiovascular risk, lung cancer

risk gradually increases with increased exposure and becomes proportionally more

important at higher total levels of PM2.5 exposure22.

Non-small cell lung carcinoma accounts for 85% of all lung cancer cases in the US and

squamous cell carcinoma41, which is most related to COPD39, still represents the most

common histological subtype, certainly in men. The origin of squamous lung cancer is

complex and subject of intense research. Carcinogenesis in the lung should be seen as a

stepwise progression from premalignant alterations in the epithelium (hyperplasia and

8

dysplasia) over the development of carcinoma in situ to cancer. Squamous cell carcinoma

results from the accumulation of multiple independent genetic and epigenetic abnormalities,

including DNA sequence alterations, copy number changes, promotor hypermethylation and

miRNA silencing. These abnormalities result in the activation of oncogenes and the

inactivation of tumor suppressor genes, which accumulate in normal histological and

premalignant cells where they may persist for years after smoking cessation40;42;43. Lung

cancer is identified by its origin, in particularly the first cell type that suffers from oncogenic

mutation and uncontrolled cell growth. However, tumors, including lung tumors, are not

only clonal expansions of an individual cell but comprise a heterogeneous population of

cells. Cancer stem cells (CSC) possess the capacity of self-renewal and multipotent

differentiation into a heterogeneous offspring. Epithelial to mesenchymal transition (EMT) is

proposed as a mechanism that may attribute stem cell characteristics to well differentiated

epithelial cells44.

The underlying pathways by which COPD may predispose to oncogenesis in the lung

are extremely complex (Figure 4). We only mention the major mechanisms, each of them

being reviewed elsewhere. Firstly, genome wide association studies and genetic case-control

studies have highlighted common genetic loci conferring increased risk to lung cancer and

COPD. Chromosomal regions repeatedly being associated to both diseases, locate at 15q25

(containing the nicotinic acetylcholine receptor subunit genes), 5p15 (containing the human

telomerase reverse transciptase genes), 4q31 (containing the Hedgehog-interacting protein

and glycophorin A genes) and 6p21 (containing the HLA-B associated transcript 3).

Importantly, these regions do not only confer increased risk but also encode for proteins

that are involved in the pathogenesis of both diseases45-49.

Secondly, epigenetic modifications, potentially heritable changes without altering

DNA sequence, play a critical role in the determination of gene expression in lung cancer50-52.

Exposure of airway epithelial cells to tobacco smoke induces a myriad of DNA and histone

modifications by methylation-acetylation as wells as alterations in miRNA expression53;54. It is

hypothesized that some of these patterns predispose to COPD and cancer development55;56.

Thirdly, persistent chronic inflammation has been linked to cancer 57. In a prospective

population-based cohort study of 7,000 individuals, subjects with elevated serum CRP levels

were found to have an increased likelihood of lung cancer diagnosis58. A retrospective

9

analysis of 10,474 COPD patients described a reduced risk of lung cancer in patients on

inhaled corticosteroids59. From a mechanistic point of view, different pro-inflammatory

mediators (TNF-α, TGF-β, prostaglandins), reactive oxygen species and intracellular signaling

pathways (NF-kβ, PI3kinase, p38-MAPK, JAK/STAT) that are activated in COPD, compose a

complex microenvironment which promotes EMT and the development of lung cancer60;61.

Factors such as hypoxia, the release of vascular growth factors and proteases are other key

elements for tumor growth and invasion, whereas specific macrophages found within the

tumor may promote tumor suppression and survival56;62.

Overall, the different mechanisms linking COPD with lung cancer are underscored by

their strong epidemiological association. These combined mechanisms do not only imply

increased risk for developing cancer but may also determine prognosis once lung cancer has

occurred. Of course, COPD will impair cancer survival because treatment options are often

reduced by the underlying condition. In early stage lung cancer, however, airway obstruction

or emphysema seems to associate with higher recurrence rates after complete resection63;64,

indicating that NSCLC behaves more aggressively in COPD.

Osteoporosis, muscle weakness and cachexia

A third group of comorbidities includes muscle, fat and bone wasting. These changes

in body composition cluster together and associate with emphysema or “wasting” of the

lung65. Sin et al.66 used the data of NHANES III to show that airflow obstruction was

independently associated with reduced bone mineral density. Prevalence of osteoporosis

increased as the severity of airflow obstruction increased. In severe COPD, 33% of women

had osteoporosis and virtually all had osteopenia. Even in GOLD stage II the prevalence of

osteopenia and osteoporosis was significantly increased, reaching 57 and 21 %, respectively.

The risk was significantly less in men, with a prevalence of osteoporosis in severe airflow

obstruction of 11%, and a prevalence of osteopenia of 60%. Nevertheless, their risk was still

3 times higher than expected. This risk was independent of the classical confounding factors

such as use of oral corticosteroids, inactivity, malnutrition, smoking and hypogonadism. In a

recent systematic review by Graat-Verboom et al., including 13 studies encompassing 775

COPD patients, the prevalence of osteoporosis ranged from 9 to 69% and the prevalence of

10

osteopenia from 27 to 67%67. In general, osteoporosis in COPD was shown to be related to

disease severity, CT-quantified emphysema, arterial stiffness, systemic inflammatory

markers, BMI, Parathyroid hormone levels, use of systemic corticosteroids and physical

activity levels66;68-70, although causality was never demonstrated.

It is known for a long time that COPD is associated with muscle weakness 71;72. A

recent study demonstrated that 32% of COPD patients had quadriceps strength below lower

limits of normal. About 25% of patients in GOLD stage I and II exhibited muscle weakness,

whereas 38% of patients in GOLD stage IV were affected by it73. Skeletal muscle endurance

was significantly more impaired than strength74. This muscle weakness is known to have

several serious consequences, including exercise intolerance71;72 , reduced health related

quality of life, enhanced utilization of health care resources75 and enhanced mortality76. It

has a multitude of causes of which physical inactivity77;78 and systemic inflammation79 are

presumably the most prominent. Physical inactivity is particularly pronounced in patients

with severe disease, but is already present in the milder stages of the disease77;78. Watchki et

al.80 recently demonstrated that physical inactivity is the strongest predictor of mortality in

patients with COPD. Other causes of muscle weakness include: regular treatment with

systemic corticosteroids81, hypoxemia, hypercapnia, undernutrition, electrolyte

disturbances, cardiac failure, hypogonadism82 etc..

Cachexia can be defined as the involuntary loss of more than 5% body weight with

signs of systemic inflammation, anorexia and loss of muscle mass83. Weight loss is the direct

result of a negative energy balance between intake and output. Daily energy expenditure is

composed of resting energy expenditure (REE), energy consumed for physical activity and a

minor fraction (less than 10%) for diet induced thermogenesis. In patients with COPD, REE is

elevated which might be in part due to the increased oxygen cost of breathing 84. However,

several studies in severe COPD have shown that REE does not correlate with TLC or FEV 1 and

that it is independent of body weight, suggesting that other factors are involved85;86. Hypoxia

with increased oxidative stress and the release of HIF-1, and systemic inflammation (TNF-α,

soluble TNF receptor) seem to be key factors in this process87. Hypoxia and systemic

inflammation modulate appetite and anorexia. In COPD, appetite scores were 45% lower in

cachectic than non-cachectic patients and correlated with systemic inflammatory markers88.

The same inflammatory parameters were also associated with the failure to regain weight to

11

oral food supplements89. Furthermore, hypoxia and inflammation also affect ghrelin, leptin

levels, insulin-like growth factor-1, growth hormone and insulin resistance which may switch

the body from an anabolic to a catabolic state90. Finally, hypoxia, inflammation and oxidative

stress, have been associated to muscle atrophy, fiber type shifts from oxidative type I fibers

to glycolytic type II fibers, increased proteolysis and reduced mitochondrial biogenesis, all

phenotypic characteristics observed in limb muscles of patients with COPD91. Similarly, TNFα and HIF-1 are also proven activators of osteoclasts which degrade bone leading to

osteoporosis92, which may explain why different organ systems are affected simultaneously.

Comorbidity and aging

Aging is associated with an increased incidence of non-communicable diseases

including cardiovascular disease, type II diabetes, osteoporosis, cancer, and COPD93. The

cellular equivalent to physiological aging is senescence94 . Replicative senescence refers to

telomere shortening which, at a critical length, induces stress signals which lead to cell cycle

arrest. However, external stressors such as oxidative stress may also induce premature

senescence. One implication of senescence is that cells, notably progenitor cells, have

decreased regenerative properties and accumulate DNA damage. Equally important is the

pro-inflammatory phenotype of senescent cells releasing a cocktail of cytokines (including IL-

1, IL-8, IL-6) that propagate inflammatory processes and may induce senescence in adjacent

cells95. In COPD, telomeres of circulating white blood cells and lung epithelial cells are

shorter than that of age-matched controls96. Shortened telomeres in animals predispose to

emphysema97 and in humans deficient telomerase activity or polymorphisms in the

corresponding gene predispose to COPD and lung cancer47;98;99. It suggests that premature

senescence in COPD renders progenitor cells unable to repair damaged tissue, that it

contributes to the persistent ‘inflammaging’ in lungs or circulation, and that it may

predispose to cancer95;100. One promising target in this regard may be SIRT-1101. Sirtuins are

type III histone deacetylases (HDAC) that mediate gene silencing. SIRT-1 is subjected to

posttranslational modifications by cigarette smoke and oxidative stress. Its down-regulation,

which is well documented in COPD102, results in the activation of pro-inflammatory and

oncogenic pathways, impaired DNA repair and reduced mitochondrial biogenesis, all

characteristics of cellular senescence. Upregulation of SIRT-1 by caloric restriction in case of

12

obesity, physical activity and eventually drugs (resveratrol, SRT1720,…) are therefore

appealing strategies in the treatment of COPD103, among others.

Implications for treatment of COPD

Treatment of comorbidities

Comorbidities should be detected in the medical follow-up scheme for COPD

patients. At present, no clear guidelines on how and when to screen for comorbidities, are

available. To the best of our knowledge, no specific randomized controlled studies are

available on the treatment of comorbidities in patients prospectively identified as having

COPD. Nevertheless, common sense dictates that comorbidities should be treated in COPD

patients with the treatment regimens that were shown to be effective. Detection and

treatment of cardiovascular disease is of prime importance. It is now clearly shown that

cardio-selective ß-blockers such as atenolol and bisoprolol, that play a pivotal role in the

treatment of these diseases are safe in patients with COPD. Many physicians were reluctant

to administer these medicines to COPD patients because of fear of inducing

bronchoconstriction or blocking the effect of ß-agonists. In a Cochrane d-base analysis they

did not adversely affect FEV1, respiratory symptoms or the response of FEV1 to ß2-

agonists104. Three recent studies advanced new arguments in support of the use of ß-

blockers. The first study demonstrated that ß-blockers may reduce the risk for mortality and

exacerbations in patients with COPD105. Along the same lines, a recent systematic review and

meta-analysis of nine retrospective cohort studies found a reduction of COPD-related

mortality of 31%106. Finally, another study clearly demonstrated the safety of ß-blockers

during COPD exacerbations107, while avoiding immortal time bias of which several other

studies suffered108. Taken together, at present there is no reason to withhold ß-blockers in

patients with COPD, who need ß-blockers because of other medical conditions. On the

contrary, these medicines appear beneficial in these patients (see below).

Lung cancer obviously should be treated appropriately, taking into account that

resectibility may be limited in patients with COPD109. Screening programmes are likely to be

more beneficial in the high risk groups and hence, specific cancer treatments or

13

chemopreventive strategies need to be developed for COPD110. Early prevention and

treatment of osteoporosis is very important in COPD patients92. An algorithm was developed

by Lehouck et al. based on major and minor criteria92. Briefly, patients with osteopenia or

osteoporosis not requiring treatment with systemic corticosteroids nor exhibiting major

fragility fracture (spine/hip) should receive 800 IU of Vitamin D and 1g of calcium daily.

Patients with severe osteoporosis or osteopenia with documented fragility fracture or

receiving systemic corticosteroids chronically should also receive antiresorptive therapy

(bisphosphonates). Effects of inhaled corticosteroids on bone loss and fracture risk have not

been shown convincingly111,112.

Finally, treatment of muscle weakness is important in patients with COPD as well.

Respiratory rehabilitation is the best way to improve muscle strength and was shown to

improve exercise tolerance and health-related quality of life113. Improvements in health-

related quality of life are generally larger than what is usually obtained with

pharmacotherapy.

How to treat mechanistic links?

Smoking cessation is of prime importance to reduce disease progression,

comorbidities and mortality38. Two other pivotal modifiable etiologic factors appear to be

systemic inflammation and physical inactivity. At present there is no compelling evidence

that reducing systemic inflammation or increasing physical activity level, affects

comorbidities of the disease. Reducing systemic inflammation could be achieved by inhaled

corticosteroids that would potentially reduce spill-over of inflammation from the lungs or

with systemic anti-inflammatory agents. At present, neither of these two treatment

approaches appears to be effective. First, at least two studies showed that fluticasone either

or not combined with salmeterol reduced local inflammation in the airways, but failed to

reduce systemic markers of inflammation like CRP or IL-6114;115. Second, four pivotal studies

demonstrated that the new phosphodiesterase-4 inhibitor roflumilast administered orally,

although it succeeded in producing a slight improvement in FEV1 (39-48 mL vs. placebo) and

reducing exacerbation rate by 17%, did not affect systemic levels of CRP116;117.

14

It appears likely that increasing physical activity level in COPD patients would result in

a number of beneficial effects on comorbidities, since physical inactivity is a risk factor for

most of the comorbidities. However, at present no studies are available on the effect of

activity action plans on comorbidities in COPD patients. In addition, it proved difficult to

improve activity levels in COPD patients even with well supervised rehabilitation

programmes, which only resulted in small and variable improvements in daily activity

levels118.

Does treatment of COPD improve comorbidities?

At present the effects of COPD treatments on comorbidities have not been addressed

in a prospective randomized study. Even more so, patients with significant comorbidities

have regularly been excluded from treatment trials. This needs to be addressed in future

trials. Nevertheless, some evidence from large trials is available indicating that treatment

with bronchodilators may reduce comorbidities. First, both the UPLIFT and TORCH trial

provided evidence for at least a trend towards reduced “all cause” mortality rate with

tiotropium119 and the fixed combination of fluticasone and salmeterol120, respectively.

Although, the effect was in general small and the trend was strictly not significant in the

TORCH study and variably significant in the UPLIFT study (significant on-treatment and at the

end of treatment including vital status information of patients who dropped out prematurely

from the trial, but not after 30 days washout), this at least suggests that mortality also from

other causes than COPD may be affected. Indeed, the trend was not confined to lower

respiratory mortality, but also included cardiovascular mortality. The SUMMIT study

prospectively investigates the effects on mortality of treatment with the fixed combination

of a new long-acting ß2-agonist Vilanterol and a new long-acting inhaled corticosteroid

Fluticasone fuorate and its single components, in 16,000 patients with moderate COPD and a

history of cardiovascular disease or at increased risk for it121.

Second, a significant reduction in the incidence of myocardial infarction as a serious

adverse event was observed119. This was confirmed in a pooled analysis of 30 tiotropium

15

trials122. In this analysis including 19,545 patients, adverse events, serious adverse events,

and fatal adverse events were all significantly reduced with tiotropium. In addition, “all

cause” mortality was reduced by 12%, cardiovascular mortality was reduced by 23%, and a

composite cardiovascular endpoint (major cardiovascular events) was reduced by 17%, all of

which reached statistical significance. All of these are promising signals, but need

confirmation in specifically designed large prospective trials, having comorbidity as a primary

endpoint.

Does treatment of comorbidities improve COPD?

This is the last and probably most intriguing question. Again we currently lack

specifically designed prospective studies, but a number of observational studies have

provided indications that some treatments regularly used for comorbidities such as statins,

may also affect the course of COPD123-125. In the study with the longest follow-up, Van Gestel

et al.125 followed 3,371 patients who underwent vascular surgery, of whom 810 had COPD.

Short-term mortality (30 days) was reduced by 52% and long-term mortality by 33%. Short-

term mortality was only reduced with normal doses of statins, whereas long-term mortality

was reduced with both normal and low doses (Figure 6). Although this signal is promising, it

is clear that this is a retrospective cohort studies and hence, that it suffers from the

methodological problems associated with such studies. Two recent systematic reviews of

observational studies confirmed these effects of statins, including effects on COPD

exacerbations, all-cause mortality, COPD-related mortality, incidence of respiratory-related

urgent care, intubations for COPD exacerbations and attenuated decline in pulmonary

function126;127. A large scale prospective study is desperately needed.

The mechanism of action of statins is promising in any event. Statins reduce

cholesterol levels by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A, HMG-CoA,

reductase128. This is the basis of their established role in atherosclerotic disease 129. They also

reduce the stability of lipid raft formation with subsequent effects on immune activation and

regulation, and prevent the prenylation of signaling molecules with subsequent

16

downregulation of gene expression. Both these effects result in reduced cytokine,

chemokine, and adhesion molecule expression, with downstream effects. Clinically, these

result in reductions of CRP levels and hence, in systemic inflammation, the potential cause of

systemic effects in COPD. These anti-inflammatory effects may also be beneficial to the

action of statins in cardiovascular disease. Whether they are a significant mode of action in

COPD patients is not clear at present.

Statins may also have effects on the development of lung cancer in COPD patients. In

a retrospective cohort study involving 3,371 patients undergoing vascular surgery between

1990 and 2006, including 1,310 with COPD, an association was present between COPD and

risk for lung cancer and extrapulmonary cancer. A trend for reduced lung cancer mortality

was observed with statins, while extrapulmonary cancer was also significantly reduced130.

The STATCOPE-trial presently investigates the effects of simvastatin on exacerbation rate in

patients with moderate to severe COPD (NCT011061671).

Similarly, in studies by Mancini et al.123 and Mortensen124 et al. the effects of

angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARB) on

mortality in COPD patients were studied. Mancini et al. found a 38% risk reduction for death

in the group with concomitant heart disease with ARB only, while Mortensen et al. found a

38% risk reduction with ACEinhibitors/ARB in all patients. In both studies risk reduction was

considerably larger (56 and 60%, respectively), when these medications were combined with

statins.

Finally, also ß-blockers may be of benefit in patients with COPD, not only because of

their effect in cardiovascular comorbidities, but also because of an effect on the course of

COPD itself. Two retrospective cohort studies108;113 found reductions in “all cause” mortality

and a reduction in the risk for a COPD exacerbation and hospital admission, suggesting that

these drugs may affect the natural history of this disease. Randomized controlled studies,

however, are required before initiation of ß-blocker therapy to achieve mortality benefit in

COPD, can be widely recommended.

Conflict of interest statement

17

MD has received speaker fees from AstraZeneca, GlaxoSmithKline, Boehringer-Pfizer, and

Novartis, consulting fees from AstraZeneca, Boehringer-Pfizer, Dompé, GlaxoSmithKline,

Novartis, Nycomed and Vectura, and grant support from AstraZeneca, Boehringer-Pfizer,

GlaxoSmithKline and Chiesi. He has no stock holdings in pharmaceutical companies and

never received grant support from the Tobacco Industry. WJ has received consulting fees

from AstraZeneca, Boehringer-Pfizer, and Novartis.

Word count body of text: 5,218

18

Figure 1.

Relationship between lung function and % deaths due to cardiovascular disease ( ), lung cancer ( ), and respiratory failure ( ) in four large cohorts of COPD patients based on different mean FEV1 values (1-4)10. Reproduced with permission.

19

Lung cancer

Cardiovascular disease

Respiratory failure

80%

60%

40%

20%

20% 40% 60% 80%

mean FEV1%pred

% of total mortality

(1) (2) (3) (4)

Figure 2.

Diagram linking COPD with cardiovascular disease. Aging and genetics should be considered as inherent processes that affect all of the other mechanisms, whereas smoking, inactivity, poor diet and exacerbations are modifiable environmental factors.

20

smoking

Systemic oxidative stress inflammation

Lung oxidative stress inflammation

poor dietinactivity

Arterial hypertensionObesityDiabetesHypercholesterolemia

Endothelial dysfunction + Vascular

inflammation

Arteriosclerosis

Airway remodelling +Emphysema

COPD

exacerbations

aging genetics

Plaque rupture

AMI/Stroke

Figure 3.

Relationship between lifetime risk of chronic obstructive pulmonary disease (COPD; Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2+) and lung cancer in chronic smokers (n = 100). Assuming ∼20 (20%) out of 100 of smokers get COPD (GOLD 2+; ) and ∼10 (10%) out of 100 of smokers get lung cancer , and given that 50% of the patients with lung cancer have COPD, then five out of 20 with COPD develop lung cancer, while five out of 80 with normal lung function get lung cancer37. Hence 25% of the patients with COPD would develop lung cancer, while only 6% of the smokers with normal lung function would develop lung cancer, accounting for a 4-fold increase in incidence rate. Reproduced with permission.

21

Smokers with “normal” lung function

Lung cancer

COPD

Figure 4.

Diagram linking COPD with lung cancer. EMT= Epithelial to Mesenchymal Transition, CSC= Cancer Stem Cells. Smoking is the main risk factor for lung cancer but also for COPD which on the background of aging and genetics, contributes to tumor genesis.

22

Small airways diseaseAlveolar destruction

CSC EMT

Tumor growthMetastasis

Bronchial epithelial cellgenetics

aging

Lung cancer

Tumor cells

Epi/Genomic alterations

COPD

Bronchial epithelial cell

Epigenetic modifications Lung inflammation

Oxidative stress

smoking

Figure 5.

Diagram linking COPD with altered body composition. Aging and genetics should be considered as inherent processes that affect all of the other mechanisms, whereas smoking, inactivity, anorexia and exacerbations are modifiable environmental factors.

23

aging genetics

exacerbations

Airway remodellingEmphysema

Osteoporosisinactivity

anorexia

dyspnea - hypoxiaCOPD

Muscle weakness

Cachexia

Lung oxidative stress inflammation

Systemic oxidative stress inflammation

smoking

Figure 6.

Upper Panel: Effects of statin treatment on survival in patients with and without COPD.Lower Panel: Effects of statin dose on short-term (left) and long-term (right) mortality in patients with and without COPD125. Reproduced with permission.

24

Reference List

(1) Bloom D, Cafiero E, Abrahams-gessel S et al. The global economic burden of noncommunicable diseases. Geneva: World Economic Forum. www.weforum.org/EconomicsOfNCD. 2011.

(2) Decramer M, Rennard S, Troosters T et al. COPD as a lung disease with systemic consequences--clinical impact, mechanisms, and potential for early intervention. COPD 2008; 5:235-256.

(3) Mapel DW, Hurley JS, Frost FJ et al. Health care utilization in chronic obstructive pulmonary disease. A case-control study in a health maintenance organization. Arch Intern Med 2000; 160:2653-2658.

(4) Divo M, Cote C, de Torres JP et al. Comorbidities and risk of mortality in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012; 186:155-161.

(5) Patel AR, Hurst JR. Extrapulmonary comorbidities in chronic obstructive pulmonary disease: state of the art. Expert Rev Respir Med 2011; 5:647-662.

(6) McGarvey LP, John M, Anderson JA et al. Ascertainment of cause-specific mortality in COPD: operations of the TORCH Clinical Endpoint Committee. Thorax 2007; 62:411-415.

(7) Mannino DM, Thorn D, Swensen A et al. Prevalence and outcomes of diabetes, hypertension and cardiovascular disease in COPD. Eur Respir J 2008; 32:962-969.

(8) Zielinski J, MacNee W, Wedzicha J et al. Causes of death in patients with COPD and chronic respiratory failure. Monaldi Arch Chest Dis 1997; 52:43-47.

(9) Mannino DM, Doherty DE, Sonia BA. Global Initiative on Obstructive Lung Disease (GOLD) classification of lung disease and mortality: findings from the Atherosclerosis Risk in Communities (ARIC) study. Respir Med 2006; 100:115-122.

(10) Sin DD, Anthonisen NR, Soriano JB et al. Mortality in COPD: Role of comorbidities. Eur Respir J 2006; 28:1245-1257.

(11) Sin DD, Wu L, Man SF. The relationship between reduced lung function and cardiovascular mortality: a population-based study and a systematic review of the literature. Chest 2005; 127:1952-1959.

(12) Feary JR, Rodrigues LC, Smith CJ et al. Prevalence of major comorbidities in subjects with COPD and incidence of myocardial infarction and stroke: a comprehensive analysis using data from primary care. Thorax 2010; 65:956-962.

(13) Mills NL, Miller JJ, Anand A et al. Increased arterial stiffness in patients with chronic obstructive pulmonary disease: a mechanism for increased cardiovascular risk. Thorax 2008; 63:306-311.

(14) McAllister DA, Maclay JD, Mills NL et al. Arterial stiffness is independently associated with emphysema severity in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007; 176:1208-1214.

25

(15) Barr RG, Celli BR, Mannino DM et al. Comorbidities, patient knowledge, and disease management in a national sample of patients with COPD. Am J Med 2009; 122:348-355.

(16) Terashima T, Klut ME, English D et al. Cigarette smoking causes sequestration of polymorphonuclear leukocytes released from the bone marrow in lung microvessels. Am J Respir Cell Mol Biol 1999; 20:171-177.

(17) Cazzola M, Bettoncelli G, Sessa E et al. Prevalence of comorbidities in patients with chronic obstructive pulmonary disease. Respiration 2010; 80:112-119.

(18) Kullo IJ, Edwards WD, Schwartz RS. Vulnerable plaque: pathobiology and clinical implications. Ann Intern Med 1998; 129:1050-1060.

(19) Buist AS. International variation in the prevalence of COPD (the BOLD Study): a population-based prevalence study. 2007.

(20) Sode BF. Myocardial infarction and other co-morbidities in patients with chronic obstructive pulmonary disease: a Danish nationwide study of 7.4 million individuals. 2011.

(21) Buffon A, Biasucci LM, Liuzzo G et al. Widespread coronary inflammation in unstable angina. N Engl J Med 2002; 347:5-12.

(22) Pope CA, III, Burnett RT, Turner MC et al. Lung cancer and cardiovascular disease mortality associated with ambient air pollution and cigarette smoke: shape of the exposure-response relationships. Environ Health Perspect 2011; 119:1616-1621.

(23) Hogg JC, Chu F, Utokaparch S et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med 2004; 350:2645-2653.

(24) Suwa T, Hogg JC, Quinlan KB et al. Particulate air pollution induces progression of atherosclerosis. J Am Coll Cardiol 2002; 39:935-942.

(25) Van Eeden S, Leipsic J, Paul Man SF et al. The Relationship between Lung Inflammation and Cardiovascular Disease. Am J Respir Crit Care Med 2012; 186:11-16.

(26) Smeeth L, Thomas SL, Hall AJ et al. Risk of myocardial infarction and stroke after acute infection or vaccination. N Engl J Med 2004; 351:2611-2618.

(27) Donaldson GC, Hurst JR, Smith CJ et al. Increased risk of myocardial infarction and stroke following exacerbation of COPD. Chest 2010; 137:1091-1097.

(28) Nemmar A, Hoylaerts MF, Hoet PH et al. Possible mechanisms of the cardiovascular effects of inhaled particles: systemic translocation and prothrombotic effects. Toxicol Lett 2004; 149:243-253.

(29) Garcia-Aymerich J, Lange P, Benet M et al. Regular physical activity modifies smoking-related lung function decline and reduces risk of chronic obstructive pulmonary disease: a population-based cohort study. Am J Respir Crit Care Med 2007; 175:458-463.

(30) Leone N, Courbon D, Thomas F et al. Lung function impairment and metabolic syndrome: the critical role of abdominal obesity. Am J Respir Crit Care Med 2009; 179:509-516.

26

(31) Falk JA, Kadiev S, Criner GJ et al. Cardiac disease in chronic obstructive pulmonary disease. Proc Am Thorac Soc 2008; 5:543-548.

(32) Fabbri LM, Beghe B, Agusti A. Cardiovascular mechanisms of death in severe COPD exacerbation: time to think and act beyond guidelines. Thorax 2011; 66:745-747.

(33) de Torres JP, Bastarrika G, Wisnivesky JP et al. Assessing the relationship between lung cancer risk and emphysema detected on low-dose CT of the chest. Chest 2007; 132:1932-1938.

(34) Mannino DM, Aguayo SM, Petty TL et al. Low lung function and incident lung cancer in the United States: data From the First National Health and Nutrition Examination Survey follow-up. Arch Intern Med 2003; 163:1475-1480.

(35) Turner MC, Chen Y, Krewski D et al. Chronic obstructive pulmonary disease is associated with lung cancer mortality in a prospective study of never smokers. Am J Respir Crit Care Med 2007; 176:285-290.

(36) Wilson DO, Weissfeld JL, Balkan A et al. Association of radiographic emphysema and airflow obstruction with lung cancer. Am J Respir Crit Care Med 2008; 178:738-744.

(37) Young RP, Hopkins RJ, Christmas T et al. COPD prevalence is increased in lung cancer, independent of age, sex and smoking history. Eur Respir J 2009; 34:380-386.

(38) Anthonisen NR, Skeans MA, Wise RA et al. The effects of a smoking cessation intervention on 14.5-year mortality: a randomized clinical trial. Ann Intern Med 2005; 142:233-239.

(39) de Torres JP, Marin JM, Casanova C et al. Lung cancer in patients with chronic obstructive pulmonary disease-- incidence and predicting factors. Am J Respir Crit Care Med 2011; 184:913-919.

(40) Spira A, Beane J, Shah V et al. Effects of cigarette smoke on the human airway epithelial cell transcriptome. Proc Natl Acad Sci U S A 2004; 101:10143-10148.

(41) Molina JR, Yang P, Cassivi SD et al. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc 2008; 83:584-594.

(42) Sato M, Shames DS, Gazdar AF et al. A translational view of the molecular pathogenesis of lung cancer. J Thorac Oncol 2007; 2:327-343.

(43) Spira A, Beane JE, Shah V et al. Airway epithelial gene expression in the diagnostic evaluation of smokers with suspect lung cancer. Nat Med 2007; 13:361-366.

(44) Sato M, Shames DS, Hasegawa Y. Emerging evidence of Epithelial-to-Mesenchymal Transition in lung carcinogenesis. Respirology 2012.

(45) Pillai SG, Ge D, Zhu G et al. A genome-wide association study in chronic obstructive pulmonary disease (COPD): identification of two major susceptibility loci. PLoS Genet 2009; 5:e1000421.

(46) Truong T, Hung RJ, Amos CI et al. Replication of lung cancer susceptibility loci at chromosomes 15q25, 5p15, and 6p21: a pooled analysis from the International Lung Cancer Consortium. J Natl Cancer Inst 2010; 102:959-971.

27

(47) Wauters E, Smeets D, Coolen J et al. The TERT-CLPTM1L locus for lung cancer predisposes to bronchial obstruction and emphysema. Eur Respir J 2011; 38:924-931.

(48) Young RP, Whittington CF, Hopkins RJ et al. Chromosome 4q31 locus in COPD is also associated with lung cancer. Eur Respir J 2010; 36:1375-1382.

(49) Young RP, Hopkins RJ, Whittington CF et al. Individual and cumulative effects of GWAS susceptibility loci in lung cancer: associations after sub-phenotyping for COPD. PLoS One 2011; 6:e16476.

(50) Brock MV, Hooker CM, Ota-Machida E et al. DNA methylation markers and early recurrence in stage I lung cancer. N Engl J Med 2008; 358:1118-1128.

(51) Hu Z, Chen J, Tian T et al. Genetic variants of miRNA sequences and non-small cell lung cancer survival. J Clin Invest 2008; 118:2600-2608.

(52) Rauch TA, Zhong X, Wu X et al. High-resolution mapping of DNA hypermethylation and hypomethylation in lung cancer. Proc Natl Acad Sci U S A 2008; 105:252-257.

(53) Schembri F, Sridhar S, Perdomo C et al. MicroRNAs as modulators of smoking-induced gene expression changes in human airway epithelium. Proc Natl Acad Sci U S A 2009; 106:2319-2324.

(54) Liu F, Killian JK, Yang M et al. Epigenomic alterations and gene expression profiles in respiratory epithelia exposed to cigarette smoke condensate. Oncogene 2010; 29:3650-3664.

(55) Guzman L, Depix MS, Salinas AM et al. Analysis of aberrant methylation on promoter sequences of tumor suppressor genes and total DNA in sputum samples: a promising tool for early detection of COPD and lung cancer in smokers. Diagn Pathol 2012; 7:87.

(56) Rooney C, Sethi T. The epithelial cell and lung cancer: the link between chronic obstructive pulmonary disease and lung cancer. Respiration 2011; 81:89-104.

(57) Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet 2001; 357:539-545.

(58) Siemes C, Visser LE, Coebergh JW et al. C-reactive protein levels, variation in the C-reactive protein gene, and cancer risk: the Rotterdam Study. J Clin Oncol 2006; 24:5216-5222.

(59) Parimon T, Chien JW, Bryson CL et al. Inhaled corticosteroids and risk of lung cancer among patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007; 175:712-719.

(60) Walser T, Cui X, Yanagawa J et al. Smoking and lung cancer: the role of inflammation. Proc Am Thorac Soc 2008; 5:811-815.

(61) Adcock IM, Caramori G, Barnes PJ. Chronic obstructive pulmonary disease and lung cancer: new molecular insights. Respiration 2011; 81:265-284.

(62) Welsh TJ, Green RH, Richardson D et al. Macrophage and mast-cell invasion of tumor cell islets confers a marked survival advantage in non-small-cell lung cancer. J Clin Oncol 2005; 23:8959-8967.

28

(63) Sekine Y, Yamada Y, Chiyo M et al. Association of chronic obstructive pulmonary disease and tumor recurrence in patients with stage IA lung cancer after complete resection. Ann Thorac Surg 2007; 84:946-950.

(64) Ueda K, Jinbo M, Li TS et al. Computed tomography-diagnosed emphysema, not airway obstruction, is associated with the prognostic outcome of early-stage lung cancer. Clin Cancer Res 2006; 12:6730-6736.

(65) Ohara T, Hirai T, Muro S et al. Relationship between pulmonary emphysema and osteoporosis assessed by CT in patients with COPD. Chest 2008; 134:1244-1249.

(66) Sin DD, Man JP, Man SF. The risk of osteoporosis in Caucasian men and women with obstructive airways disease. Am J Med 2003; 114:10-14.

(67) Graat-Verboom L, Wouters EF, Smeenk FW et al. Current status of research on osteoporosis in COPD: a systematic review. Eur Respir J 2009; 34:209-218.

(68) Ferguson GT, Calverley PM, Anderson JA et al. Prevalence and progression of osteoporosis in patients with COPD: results from the TOwards a Revolution in COPD Health study. Chest 2009; 136:1456-1465.

(69) Graat-Verboom L, van den Borne BE, Smeenk FW et al. Osteoporosis in COPD outpatients based on bone mineral density and vertebral fractures. J Bone Miner Res 2011; 26:561-568.

(70) Sabit R, Bolton CE, Edwards PH et al. Arterial stiffness and osteoporosis in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007; 175:1259-1265.

(71) Gosselink R, Troosters T, Decramer M. Peripheral muscle weakness contributes to exercise limitation in COPD. Am J Respir Crit Care Med 1996; 153:976-980.

(72) Hamilton AL, Killian KJ, Summers E et al. Muscle strength, symptom intensity, and exercise capacity in patients with cardiorespiratory disorders. Am J Respir Crit Care Med 1995; 152:2021-2031.

(73) Seymour JM, Spruit MA, Hopkinson NS et al. The prevalence of quadriceps weakness in COPD and the relationship with disease severity. Eur Respir J 2010; 36:81-88.

(74) Nici L, Donner C, Wouters E et al. American Thoracic Society/European Respiratory Society statement on pulmonary rehabilitation. Am J Respir Crit Care Med 2006; 173:1390-1413.

(75) Decramer M, Gosselink R, Troosters T et al. Muscle weakness is related to utilization of health care resources in COPD patients. Eur Respir J 1997; 10:417-423.

(76) Marquis K, Debigare R, Lacasse Y et al. Midthigh muscle cross-sectional area is a better predictor of mortality than body mass index in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2002; 166:809-813.

(77) Pitta F, Troosters T, Spruit MA et al. Characteristics of physical activities in daily life in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2005; 171:972-977.

(78) Watz H, Waschki B, Meyer T et al. Physical activity in patients with COPD. Eur Respir J 2009; 33:262-272.

29

(79) Spruit MA, Gosselink R, Troosters T et al. Muscle force during an acute exacerbation in hospitalised patients with COPD and its relationship with CXCL8 and IGF-I. Thorax 2003; 58:752-756.

(80) Waschki B, Kirsten A, Holz O et al. Physical activity is the strongest predictor of all-cause mortality in patients with COPD: a prospective cohort study. Chest 2011; 140:331-342.

(81) Decramer M, Lacquet LM, Fagard R et al. Corticosteroids contribute to muscle weakness in chronic airflow obstruction. Am J Respir Crit Care Med 1994; 150:11-16.

(82) Van Vliet M., Spruit MA, Verleden G et al. Hypogonadism, quadriceps weakness, and exercise intolerance in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2005; 172:1105-1111.

(83) Muscaritoli M, Anker SD, Argiles J et al. Consensus definition of sarcopenia, cachexia and pre-cachexia: joint document elaborated by Special Interest Groups (SIG) "cachexia-anorexia in chronic wasting diseases" and "nutrition in geriatrics". Clin Nutr 2010; 29:154-159.

(84) Donahoe M, Rogers RM, Wilson DO et al. Oxygen consumption of the respiratory muscles in normal and in malnourished patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 1989; 140:385-391.

(85) Nguyen LT, Bedu M, Caillaud D et al. Increased resting energy expenditure is related to plasma TNF-alpha concentration in stable COPD patients. Clin Nutr 1999; 18:269-274.

(86) Cohen RI, Marzouk K, Berkoski P et al. Body composition and resting energy expenditure in clinically stable, non-weight-losing patients with severe emphysema. Chest 2003; 124:1365-1372.

(87) Raguso CA, Luthy C. Nutritional status in chronic obstructive pulmonary disease: role of hypoxia. Nutrition 2011; 27:138-143.

(88) Koehler F, Doehner W, Hoernig S et al. Anorexia in chronic obstructive pulmonary disease--association to cachexia and hormonal derangement. Int J Cardiol 2007; 119:83-89.

(89) Creutzberg EC, Schols AM, Weling-Scheepers CA et al. Characterization of nonresponse to high caloric oral nutritional therapy in depleted patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000; 161:745-752.

(90) Chaiban JT, Bitar FF, Azar ST. Effect of chronic hypoxia on leptin, insulin, adiponectin, and ghrelin. Metabolism 2008; 57:1019-1022.

(91) Wust RC, Degens H. Factors contributing to muscle wasting and dysfunction in COPD patients. Int J Chron Obstruct Pulmon Dis 2007; 2:289-300.

(92) Lehouck A, Boonen S, Decramer M et al. COPD, bone metabolism, and osteoporosis. Chest 2011; 139:648-657.

(93) Barnett K, Mercer SW, Norbury M et al. Epidemiology of multimorbidity and implications for health care, research, and medical education: a cross-sectional study. Lancet 2012; 380:37-43.

(94) Kirkwood TB. Understanding the odd science of aging. Cell 2005; 120:437-447.

30

(95) Faner R, Rojas M, MacNee W et al. Abnormal lung aging in chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2012; 186:306-313.

(96) Morla M, Busquets X, Pons J et al. Telomere shortening in smokers with and without COPD. Eur Respir J 2006; 27:525-528.

(97) Alder JK, Guo N, Kembou F et al. Telomere length is a determinant of emphysema susceptibility. Am J Respir Crit Care Med 2011; 184:904-912.

(98) Amsellem V, Gary-Bobo G, Marcos E et al. Telomere dysfunction causes sustained inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2011; 184:1358-1366.

(99) Mocellin S, Verdi D, Pooley KA et al. Telomerase reverse transcriptase locus polymorphisms and cancer risk: a field synopsis and meta-analysis. J Natl Cancer Inst 2012; 104:840-854.

(100) Ito K, Barnes PJ. COPD as a disease of accelerated lung aging. Chest 2009; 135:173-180.

(101) Baur JA, Ungvari Z, Minor RK et al. Are sirtuins viable targets for improving healthspan and lifespan? Nat Rev Drug Discov 2012; 11:443-461.

(102) Rajendrasozhan S, Yang SR, Kinnula VL et al. SIRT1, an antiinflammatory and antiaging protein, is decreased in lungs of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2008; 177:861-870.

(103) Yao H, Chung S, Hwang JW et al. SIRT1 protects against emphysema via FOXO3-mediated reduction of premature senescence in mice. J Clin Invest 2012; 122:2032-2045.

(104) Salpeter S, Ormiston T, Salpeter E. Cardioselective beta-blockers for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2005;CD003566.

(105) Rutten FH, Zuithoff NP, Hak E et al. Beta-blockers may reduce mortality and risk of exacerbations in patients with chronic obstructive pulmonary disease. Arch Intern Med 2010; 170:880-887.

(106) Etminan M, Jafari S, Carleton B et al. Beta-blocker use and COPD mortality: a systematic review and meta-analysis. BMC Pulm Med 2012; 12:48.

(107) Stefan MS, Rothberg MB, Priya A et al. Association between beta-blocker therapy and outcomes in patients hospitalised with acute exacerbations of chronic obstructive lung disease with underlying ischaemic heart disease, heart failure or hypertension. Thorax 2012; 67:977-984.

(108) Short PM. Effect of beta blockers in treatment of chronic obstructive pulmonary disease: a retrospective cohort study. 2011.

(109) Brunelli A, Charloux A, Bolliger CT et al. ERS/ESTS clinical guidelines on fitness for radical therapy in lung cancer patients (surgery and chemo-radiotherapy). Eur Respir J 2009; 34:17-41.

(110) Aberle DR, Adams AM, Berg CD et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011; 365:395-409.

31

(111) Jones A, Fay JK, Burr M et al. Inhaled corticosteroid effects on bone metabolism in asthma and mild chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2002;CD003537.

(112) Drummond MB, Dasenbrook EC, Pitz MW et al. Inhaled corticosteroids in patients with stable chronic obstructive pulmonary disease: a systematic review and meta-analysis. JAMA 2008; 300:2407-2416.

(113) Troosters T, Casaburi R, Gosselink R et al. Pulmonary rehabilitation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2005; 172:19-38.

(114) Sin DD, Man SF, Marciniuk DD et al. The effects of fluticasone with or without salmeterol on systemic biomarkers of inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2008; 177:1207-1214.

(115) Lapperre TS, Snoeck-Stroband JB, Gosman MM et al. Effect of fluticasone with and without salmeterol on pulmonary outcomes in chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med 2009; 151:517-527.

(116) Calverley PM, Rabe KF, Goehring UM et al. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet 2009; 374:685-694.

(117) Fabbri LM, Calverley PM, Izquierdo-Alonso JL et al. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials. Lancet 2009; 374:695-703.

(118) Cindy Ng LW, Mackney J, Jenkins S et al. Does exercise training change physical activity in people with COPD? A systematic review and meta-analysis. Chron Respir Dis 2012; 9:17-26.

(119) Celli B, Decramer M, Kesten S et al. Mortality in the 4-year trial of tiotropium (UPLIFT) in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2009; 180:948-955.

(120) Calverley PM, Anderson JA, Celli B et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007; 356:775-789.

(121) Vestbo J, Anderson J, Brook RD et al. The study to understand mortality and morbidity in COPD (SUMMIT) study protocol. Eur Respir J 2012.

(122) Celli B, Decramer M, Leimer I et al. Cardiovascular safety of tiotropium in patients with COPD. Chest 2010; 137:20-30.

(123) Mancini GB, Etminan M, Zhang B et al. Reduction of morbidity and mortality by statins, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers in patients with chronic obstructive pulmonary disease. J Am Coll Cardiol 2006; 47:2554-2560.

(124) Mortensen EM, Copeland LA, Pugh MJ et al. Impact of statins and ACE inhibitors on mortality after COPD exacerbations. Respir Res 2009; 10:45.

(125) van Gestel YR, Hoeks SE, Sin DD et al. Effect of statin therapy on mortality in patients with peripheral arterial disease and comparison of those with versus without associated chronic obstructive pulmonary disease. Am J Cardiol 2008; 102:192-196.

32

(126) Dobler CC, Wong KK, Marks GB. Associations between statins and COPD: a systematic review. BMC Pulm Med 2009; 9:32.

(127) Janda S, Park K, FitzGerald JM et al. Statins in COPD: a systematic review. Chest 2009; 136:734-743.

(128) Hothersall E, McSharry C, Thomson NC. Potential therapeutic role for statins in respiratory disease. Thorax 2006; 61:729-734.

(129) Ridker PM, Danielson E, Fonseca FA et al. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet 2009; 373:1175-1182.

(130) van Gestel YR, Hoeks SE, Sin DD et al. COPD and cancer mortality: the influence of statins. Thorax 2009; 64:963-967.

33