To the Editors:
We read with great interest the recent review article by Barnes and Celli 1 outlining the systemic manifestation of chronic obstructive pulmonary disease (COPD) and the potential benefits of statin therapy in the management of COPD. In this article, the authors propose that statins may have a dual role in reducing pulmonary and systemic inflammation, through inhibition of cell signalling molecules (Ras, Rho and Rac). Attenuation of pulmonary inflammation would result from inhibition of inflammatory cell migration and associated cytokine release into lung tissue. Attenuation of systemic inflammation would result from a reduction in pulmonary inflammation (reduced “spill over” into the systemic circulation) and inhibition of interleukin (IL)-6 and C-reactive protein synthesis from the liver and other tissues 2. We suggest the pharmacological and clinical benefits of statins in COPD 3 may be even greater than described in this review.
With respect to the possible inhibition of pulmonary inflammation, a recent systematic review of observational studies showed that patients with COPD taking statins had consistently better outcomes than those not taking statins 4. Benefits included less COPD exacerbations (30% reduction), lower mortality from chest infections (40–50% reduction), a slower decline in forced expiratory volume in 1 s (FEV1) and lower all-cause mortality (50% reduction). In addition to these findings, we have shown that three large observational studies consistently show a reduced risk of lung cancer in those taking statins (30–50% reduction) 3. The latter benefit is of considerable importance as lung cancer accounts for the greatest proportion of deaths (33%) in patients with COPD 5. Moreover, along with other studies, we have recently shown that as many as 70% of patients with lung cancer have pre-existing COPD 6. If statins confer a chemopreventive action as suggested, then widespread use of statins in patients with COPD might, along with reduced smoking rates, reduce the incidence of lung cancer in the near and long term. The mechanism for this chemopreventive effect has been elucidated in studies showing that statins not only inhibit the pulmonary inflammatory and remodelling processes underlying COPD 1, 3, but also inhibit (or even reverse) subsequent epithelial mesenchymal transition, recognised in pre-clinical studies as the precursor to lung malignant transformation 7, 8.
The second important implication from this review article stems from the hypothesis that systemic inflammation in patients with COPD (“spill over” effect) is associated with the development of coronary artery disease (CAD) and can be modified by statin therapy 1. The former would explain why reduced FEV1 has been shown to be a strong predictor of CAD, comparable to cholesterol level and independent of smoking history 3. Given the strong relationship between COPD and CAD, and that CAD is a common cause of death in patients with COPD (23%) 5, it could be argued that COPD patients might benefit from statin therapy for this reason alone. In our review we showed that about 20–30% of patients with COPD are currently taking statins 3, although many more may benefit from this therapy.
Lastly, in their review, Barnes and Celli 1 voice concerns that statins may have a detrimental effect on skeletal muscle. However, elevated IL-6 is an important factor underlying skeletal and respiratory muscle dysfunction or wasting 9. As statins inhibit IL-6 synthesis in both the liver and other tissues (including inflammatory cells in the lung), then they could potentially improve muscle function. Such a finding was reported in a small randomised control trial where exercise tolerance in patients with COPD was improved by >50% in those receiving statin therapy for 6 months compared with placebo 10.
We conclude that the recently published review by Barnes and Celli 1 highlights the need to look beyond the lungs in treating patients with COPD 1. Specifically, they suggest that addressing co-existing systemic inflammation may result in a considerable improvement in morbidity and mortality. In contrast, limiting COPD treatment to symptom control with bronchodilators might appear analogous to limiting treatment of CAD to sublingual glyceryl trinitrate. We suggest that considerable clinical and pre-clinical data exist to show that statins inhibit pulmonary inflammation through mechanisms that explain all of the respiratory benefits reported to date. Although randomised control trials are needed to confirm and quantify these pulmonary effects, there is no doubt that statins reduce systemic inflammation, reduce mortality and, thus, have potential in the management of COPD.
Statement of interest
None declared.
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