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, ßblockers 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
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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
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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
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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 nonsmokers 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 agematched 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 dyslipidemia 16, or
metabolic syndrome17;18. Several studies found an enhanced prevalence of diabetes in COPD
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patients7;9;17;19;20, , but the odds ratio of having diabetes was reduced in older patients 19. 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 arteriosclerosis 10;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.
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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 cap 18. 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 hyperreactivity 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
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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 3337.
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
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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 selfrenewal 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 diagnosis 58. A
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retrospective 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 proinflammatory 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 resection 63;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
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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 breathing84. 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 involved 85;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
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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 IL1, 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
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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 ß2agonists104. Three recent studies advanced new arguments in support of the use of ßblockers. 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
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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 healthrelated 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 FEV 1 (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 salmeterol 120, 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
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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%. Shortterm 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.
(1) (2) (3)
% of total mortality
80%
(4)
60%
Lung cancer
40%
Cardiovascular disease
20%
Respiratory failure
20%
40%
60%
80%
mean FEV1%pred
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
Figure 2.
inactivity
smoking
Lung oxidative
stress inflammation
Airway
remodelling +
Emphysema
COPD
exacerbations
poor diet
Systemic oxidative
stress inflammation
aging
genetics
Endothelial
dysfunction + Vascular
inflammation
Arterial hypertension
Obesity
Diabetes
Hypercholesterolemia
Arteriosclerosis
Plaque
rupture
AMI/Stroke
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
Figure 3.
COPD
Smokers with “normal”
lung function
Lung cancer
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
Figure 4.
smoking
Bronchial epithelial cell
CSC
Epi/Genomic
alterations
Tumor cells
EMT
genetics
aging
Bronchial epithelial cell
Epigenetic
modifications
Lung inflammation
Oxidative stress
Small airways disease
Alveolar destruction
Tumor growth
Metastasis
COPD
Lung cancer
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
Figure 5.
smoking
Lung oxidative
stress inflammation
Airway remodelling
Emphysema
COPD
exacerbations
Systemic oxidative
stress inflammation
aging
genetics
dyspnea - hypoxia
anorexia
Cachexia
inactivity
Muscle weakness
Osteoporosis
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
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
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