Proceedings of the American Thoracic Society

Many patients with chronic obstructive pulmonary disease (COPD) also suffer from other disorders that are considered to be comorbidities and that may have a major impact on morbidity and mortality. So far, it is not clear if these diseases in the context of COPD need specific drugs or if patients diagnosed with COPD should receive certain medications to prevent the development of systemic effects of COPD. Cachexia may be caused by many contributing factors and thus may prove to be very difficult to reverse. For the treatment of osteoporosis in patients with COPD, treatment recommendations have been published. COPD is associated with reduced systemic levels of vitamin D, which has not only calcemic, but also extracalcemic effects that may play a role in the development of COPD and its consequences. Available evidence suggests that statins have a high potential, although definitive studies have not been published yet. Physical inactivity may be a major cause for systemic inflammation. In turn, exercise training may be an effective form of therapy. Although smoking cessation is very effective, it is not successful in the majority of cases.

Chronic obstructive pulmonary disease (COPD) is primarily characterized by chronic airflow limitation, inflammation of the airways, and destruction of the lung parenchyma. However, in many patients affected by COPD, other disorders can be found that may have a major impact on morbidity and mortality. Although it is possible that these diseases are simply caused by the same risk factor(s) as COPD, it is hypothesized that they are causally related to the lung disease. Cachexia and weight loss, muscle atrophy and weakness, osteoporosis, cardiovascular disorders, lung cancer, metabolic syndrome, depression, and anxiety are assumed to be mediated by systemic inflammatory processes in COPD, although direct relationships still need to be proven. Spill-over of the local inflammatory process is hypothesized as the driver of this systemic inflammatory response, although studies reported no relationships between local and systemic inflammatory changes (15). Current insights suggest that physical inactivity, as well as body composition, can be involved in this systemic inflammatory process. Reported interventions largely focus on treatment of disabling conditions related to COPD, such as cachexia or osteoporosis. Future interventions must focus not only on treatment of end points in the natural history of COPD, but also on considering an integrated approach including behavioral interventions, such as smoking cessation and improvement of physical activity, combined with optimal management of intermediary risk factors, such as hypertension, obesity, metabolic syndrome, and diabetes. Smoking is considered the most important risk factor for COPD. However, along with physical inactivity, unhealthy diets, and excessive alcohol consumption, smoking forms an antecedent cluster of behavioral risk factors associated with an increased risk of a spectrum of noncommunicable diseases, such as COPD and cardiovascular disorders (Figure 1) (6).

Current knowledge on the treatment of some of these disorders is discussed subsequently here.

Cachexia in patients with COPD may be caused by a variety of mechanisms. These range from energy imbalance (increased work of breathing, inefficient metabolism, anorexia), disuse atrophy of muscles, hypoxemia, active proteolysis, sympathetic activation, accelerated aging, and systemic inflammation (TNF-α, IL-1β and IL-6, C-reactive protein [CRP], reactive oxygen species) to hormonal insufficiency (growth hormone, testosterone, insulin-like growth factor, leptin) (7). With this complex background, it is not surprising that, so far, no major breakthroughs have been achieved regarding the treatment of cachexia.

Several concepts have been tested. Among them are:

Ghrelin

Ghrelin is a growth hormone–releasing peptide and an endogenous ligand for the growth hormone secretagogue receptor. It may induce beneficial effects on muscle strength and energy metabolism, and induces a positive energy balance and weight gain by decreasing fat utility and stimulating food intake. In addition, it acts directly on the central nervous system to decrease sympathetic nerve activity, and attenuates energy expenditure. In rats with heart failure, it has been shown to improve cachexia (8). Nagaya and colleagues (8) performed an open-label pilot study with ghrelin in a small sample of patients with cachexia and COPD (n = 7). The patients received 2 μg/kg body weight of ghrelin twice daily for 3 weeks. Comparing data obtained before and after therapy, there was a significant increase of food intake, body weight, lean body mass, Karnofsky index, and 6 minute walk distance. Based on these preliminary findings, a randomized controlled trial with ghrelin was performed. The study has been completed, but not yet been published.

Anabolic Steroids

The anabolic steroid, nandrolone, has been evaluated in a small sample (n = 16) in a randomized controlled trial. Nandrolone and placebo were given for 16 weeks. There were no relevant effects on body weight, lean body mass, maximum work load, or 6-minute walk distance (9). Unfortunately, the baseline characteristics of the two groups were not well balanced—the patients in the nandrolone group had higher body weight and better lung function.

Community-Based Management Program

Recently, the results of a community-based management program (interdisciplinary community-based COPD lifestyle program [INTERCOM]) have been published. In a randomized controlled trial, patients underwent a 4-month multidisciplinary rehabilitation program followed by 20 months of maintenance. In comparison to usual care, after 4 months there was a statistically significant change in favor of the management program with regard to health related quality of life (St. George's Respiratory Questionnaire) and fat-free mass index (10). A subpopulation of the sample was cachectic (n = 36). Aside from the rehabilitation program, they received a protein-rich dietary supplement (564 kcal/day) or usual care. After 4 months, the group with protein supplementation had a statistically significantly higher body mass index, fat-free mass index, and 6-minute walk distance (11).

The following concept has been recommended for the management of patients with COPD and osteoporosis or a high risk for osteoporosis: screening of high-risk patients (i.e., smoking history, advanced COPD, high-dose inhaled corticosteroids, systemic steroids); calcium (1,000–1,500 mg/d); vitamin D (400–800 IU/d); lifestyle modification and rehabilitation; risendronate (5 mg/d) or alendronate (5 or 10 mg/d); and screening for metabolic/hormonal abnormalities (2). Although this concept is sensible, relevant studies in this area are scarce (12). Smith and colleagues (13) performed a randomized controlled trial in patients with asthma and/or COPD plus a low bone mineral density. All patients received calcium, one group alendronate, the other placebo, for 16 weeks. Endpoint was the change in bone mineral density evaluated by a dual energy X-ray absorptiometry-scan. In the intention-to-treat population, there was no significant difference between the groups, whereas, in the per-protocol population, there was a significant difference in favor of alendronate in the lumbar spine region, but not in the femur.

Vitamin D may be of great relevance for COPD, not only with regard to bone metabolism, but also because of its potential extracalcemic effects. Vitamin D may have a significant impact on tumor cell proliferation and angiogenesis, macrophage antimicrobial peptides, interaction between dendritic cells and T cells, CD4 T cell activation, insulin secretion, renin synthesis, and skeletal muscle strength—all effects that may play a role in the context of COPD pathogenesis and systemic effects of COPD (14). With this as a background, studies that evaluate vitamin D levels in COPD are highly relevant: Janssens and colleagues (15) analyzed 25-hydroxy vitamin D serum levels in a sample of 414 smokers and ex-smokers, ranging from individuals with normal spirometry to GOLD (Global Initiative for Chronic Obstructive Lung Disease) 4 COPD. They found a GOLD stage–dependent reduction of vitamin D levels. In parallel, the percentage of patients with severely decreased vitamin D levels (<20 ng/ml) increased stepwise from healthy smokers to patients with GOLD 4 COPD. Interestingly, the observed correlation between vitamin D and lung function is not restricted to patients with COPD—it has also been described in a population-based study (Third National Health and Nutrition Examination Survey). People (n = 14,091) over 20 years of age had undergone spirometry and measurements of serum 25-hydroxy vitamin D levels. The authors compared the highest with the lowest vitamin D level quintile. They found highly significant differences in favor of the highest quintile with regard to FEV1 (106 ml) and FVC (142 ml) (16). Based on these findings, it would be worthwhile to perform a trial that evaluates vitamin D supplementation in patients with COPD.

β-Blockers

It has been known for some time that β-blockers may have a positive impact on mortality in patients with myocardial infarction and COPD (17). More recently, evidence was presented that this is also the case for patients with significant peripheral arterial disease and COPD (18). However, the use of β-blockers is frequently withheld, because clinicians fear that β-blockers will provoke bronchospasm (19). It is generally recommended to use cardioselective β-blockers in patients with COPD. A recent study that compared the effects of the cardioselective β-blockers, bisoprolol and metoprolol succinate, with the nonselective β-blocker, carvedilol, in a crossover design, supports that concept (20). Positive effects of β-blockers on mortality do not seem to be limited on stable disease states. In a study at the University of Alabama, 825 COPD exacerbations were analyzed. It was found that the risk for in-hospital mortality was reduced more than 60% in the patient sample that had been treated with β-blockers (21).

Statins

Statins inhibit endogenous cholesterol synthesis in hepatocytes. In addition, evidence from animal and human studies has shown that statins have strong effects on a variety of mechanisms that may be of relevance for COPD—these are inhibition of cytokine production (TNF-α, IL-6, IL-8), inhibition of neutrophil infiltration, inhibition of fibrotic activity, antioxidant and anti-inflammatory effects on skeletal muscle, reduction of inflammatory response to pulmonary infection, and inhibition of epithelial–mesenchymal transition (lung cancer) (22).

Dobler and colleagues (23) conducted a systematic review of studies that reported effects of statin treatment in COPD. Outcomes included decreased all-cause mortality in three out of four studies (odds ratio [OR]/hazard ratio [HR], 0.48–0.67 in three studies; OR, 0.99 in one study), decreased COPD-related mortality (OR, 0.19–0.29), reduction in incidence of respiratory-related urgent care (OR, 0.74), fewer COPD exacerbations (OR, 0.43), fewer intubations for COPD exacerbations (OR, 0.1), and reduced decline in pulmonary function. The greatest weight in this systematic review belongs to the study by Mancini and colleagues (24). They tested the effects of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and statins on cardiovascular events and pulmonary mortality/morbidity in a case–control study with two population-based retrospective cohorts (n = 6,214): COPD–high risk (COPD + coronary revascularization) and COPD–low risk (COPD without myocardial infarction). Endpoints were COPD hospitalization, myocardial infarction, and all-cause mortality. The drugs reduced both cardiovascular and pulmonary outcomes, with the largest benefits occurring with the combination of statins and either ACE inhibitors or angiotensin receptor blockers, not only in the high-risk, but also in the low-risk cohort. Statin use also reduced mortality in a group of patients with COPD and significant peripheral arterial disease (25). Lee and colleagues (26) performed a prospective, randomized, placebo-controlled trial in which they evaluated the effects of 6 months of therapy with pravastatin on exercise capacity and high-sensitivity CRP. They found significant changes in exercise time and high sensitive CRP in the pravastatin group. Currently, a major (n > 1,000) randomized, placebo-controlled long-term trial (up to 37 mo) (statins in COPD exacerbations [STATCOPE]) is underway sponsored by the National Heart, Lung, and Blood Institute, evaluating the effects of simvastatin (40 mg/d). Patients with moderate to severe COPD that are prone to exacerbations and that do not have other indications for COPD treatment are included. Primary endpoint is the frequency of COPD exacerbations (www.clinicaltrials.gov).

Physical Activity

The physical activity of patients with COPD declines with increasing severity of the airflow limitation (27). In parallel, patients with COPD with a higher degree of systemic inflammation seem to be more limited regarding their physical activity than patients with less inflammation (28). Thus, the conclusion would be logical that COPD may affect physical activity via a high degree of systemic inflammation. However, there are data that support an alternative concept. Namely, that physical inactivity and obesity, which can be found in a high percentage of patients with COPD (29), may induce systemic inflammation (30, 31).

It has been shown that exercise training may improve outcomes in COPD. The most recent study by Troosters and colleagues (32) demonstrated that resistance training in patients hospitalized because of a COPD exacerbation improved quadriceps force and 6-minute walking distance. Muscle biopsies performed during the study showed a more anabolic status of the muscle in the patients undergoing resistance training.

Interestingly, a transcriptional coactivator, peroxisome proliferator–activated receptor-γ coactivator 1α (PGC1α, has been identified that may mediate the positive effects of training. Physical activity determines the amount of PGC1α in skeletal muscle—the more activity, the more PGC1α. PGC1α may induce repression of forkhead box O3 activity, increased vascularization, increased detoxification of reactive oxygen metabolites, reduced systemic inflammation, and increased gene expression of mitochondrial, metabolic, “exercise,” and neuromuscular junction genes (30). In addition, skeletal muscle has recently been identified as an endocrine organ that expresses and releases cytokines. These cytokines are called myokines. The first identified and most studied myokine is IL-6. IL-6 increases up to 100-fold in the circulation during exercise, and exerts its effects in the muscle and several organs in a hormone-like fashion (e.g., in the skeletal muscle, it increases glucose intake and fat oxidation; in the liver, glucose production; and in the adipose tissue, lipolysis [33]). Thus, IL-6 released by the muscle during exercise may contribute to the beneficial effects of training.

Although not successful in the majority of cases, sustained quitting of patients with COPD has been shown to have a positive impact on mortality caused not only by the respiratory disease, but also by coronary heart disease, cerebrovascular disease, and lung cancer (35). Therefore, novel concepts are mandatory in order to improve long-term smoking cessation rates.

Further research is needed to better understand critical pathways in the pathogenesis of different systemic components of COPD in order to develop better targeted therapy to improve the burden of the disease. Effective management of known modifiable risk factors can immediately be implemented to prevent additional future burden of noncommunicable diseases, such as COPD.

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Correspondence and requests for reprints should be addressed to Claus F. Vogelmeier, M.D., Department of Respiratory Medicine, University of Marburg, Baldingerstrasse, 35043 Marburg, Germany. E-mail:

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