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 [email protected]Key Words 1
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COPD and comorbidities
Marc Decramer and Wim Janssens
Respiratory Division, University of Leuven, Belgium
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
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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 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
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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 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
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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 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.
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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
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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%. 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
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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
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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.
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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.
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.
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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.
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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
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