LAMA/LABA vs ICS/LABA in the treatment of COPD in Japan based on the disease phenotypes

International Journal of COPD Dovepress open access to scientific and medical research Review International Journal of Chronic Obstructive Pulmonary Disease downloaded from https://www.dovepress.com/ by 37.59.46.207 on 12-Jul-2018 For personal use only. Open Access Full Text Article LAMA/LABA vs ICS/LABA in the treatment of COPD in Japan based on the disease phenotypes This article was published in the following Dove Press journal: International Journal of COPD 10 June 2015 Number of times this article has been viewed Nobuyuki Hizawa Department of Pulmonary Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan Abstract: In the combined use of bronchodilators of different classes, ie, long-acting β2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs), bronchodilation is obtained both directly, through LABA-mediated stimulation of β2-adrenergic receptors, and indirectly, through LAMA-mediated inhibition of acetylcholine action at muscarinic receptors. The clinical trial data for LABAs/LAMAs in the treatment of chronic obstructive pulmonary disease (COPD) continue to be promising, and these combinations will provide the convenience of delivering the two major bronchodilator classes, recommended as first-line maintenance options in COPD treatment guidelines. COPD is a complex condition that has pulmonary and extrapulmonary manifestations. These clinical manifestations are highly variable, and several are associated with different responses to currently available therapies. The concept of a COPD phenotype is rapidly evolving from one focusing on the clinical characteristics to one linking the underlying biology to the phenotype of the disease. Identification of the peculiarities of the different COPD phenotypes will permit us to implement a more personalized treatment in which the patient’s characteristics, together with his or her genotype, will be key to choosing the best treatment option. At present in Japan, fixed combinations of inhaled corticosteroids (ICSs) and LABAs are frequently prescribed in the earlier stages of COPD. However, ICSs increase the risk of pneumonia. Notably, 10%–30% of patients with COPD with or without a history of asthma have persistent circulating and airway eosinophilia associated with an increased risk of exacerbations and sensitivity to steroids. Thus, sputum or blood eosinophil counts might identify a subpopulation in which ICSs could have potentially deleterious effects as well as a subpopulation that benefits from ICSs. In this review, I propose one plausible approach to position ICSs and LABAs/LAMAs in clinical practice, based on both the extent of airflow obstruction and the presence of an asthma component or airway eosinophilic inflammation. This approach is a tentative move toward personalized treatment for COPD patients, and with progress in knowledge and developments in physiology, lung imaging, medical biology, and genetics, identification of COPD phenotypes that provide prognostic and therapeutic information that can affect clinically meaningful outcomes is an urgent medical need. Keywords: COPD phenotype, LAMA/LABA combination, ICS LAMA/LABA in the treatment of COPD Correspondence: Nobuyuki Hizawa Department of Pulmonary Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan Email 1093 submit your manuscript | www.dovepress.com International Journal of COPD 2015:10 1093–1102 Dovepress © 2015 Hizawa. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php http://dx.doi.org/10.2147/COPD.S72858 Powered by TCPDF (www.tcpdf.org) Two key classes of bronchodilators have been developed in chronic obstructive pulmonary disease (COPD): β2-agonists and muscarinic antagonists. Long-acting bronchodilators, such as tiotropium, formoterol, and salmeterol, are proven to provide long-term improvements in lung function and quality of life and preventing exacerbations in patients with COPD.1–3 Long-acting bronchodilators also reduce lung hyperinflation and dyspnea and increase exercise endurance.4,5 Airway smooth muscle relaxation (leading to bronchodilation) can be achieved via two main routes: inhibition of acetylcholine signaling via muscarinic M3 receptors Dovepress International Journal of Chronic Obstructive Pulmonary Disease downloaded from https://www.dovepress.com/ by 37.59.46.207 on 12-Jul-2018 For personal use only. Hizawa on airway smooth muscle with a muscarinic antagonist or stimulation of β2-adrenoceptors with a β2-agonist.6 The interaction between the two systems has yet to be fully elucidated; however, β2-agonists can amplify the bronchial smooth muscle relaxation directly induced by muscarinic antagonists by decreasing the release of acetylcholine via modulation of cholinergic neurotransmission. Additionally, in preclinical models, muscarinic antagonists have been demonstrated to augment β2-agonist-stimulated bronchodilation by reducing the bronchoconstrictor effects of acetylcholine. Theoretically, targeting these two mechanisms of bronchoconstriction has the potential to maximize the bronchodilator response without increasing the dose of either component and would help to overcome the inter- and intrapatient variability in response to individual agents seen in COPD. The regional distribution and relative proportion of muscarinic acetylcholine receptor (mAChR) and β-adrenoceptor subtypes were evaluated in the human bronchus and lung parenchyma.7 The M3 subtype predominantly occurred in the bronchus, but the density decreased from the segmental to subsegmental bronchus and was absent in the lung parenchyma. β2-adrenoceptors were increased along the airways, and their densities in the subsegmental bronchus and lung parenchyma were approximately twofold higher than those of mAChRs in the same region. These differential distributions of the receptors may also underlie the increased efficacy of combined usage of long-acting β2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) in patients with COPD. A study conducted on airways of patients without histories of chronic airway diseases also suggested that combining LABA and LAMA in the treatment of COPD might have a rationale by providing synergistic benefit on airway smooth muscle relaxation of both the medium and the small human airways.8 These proposed pharmacologic interactions of LAMA and LABA are supported by clinical evidence suggesting that improvements in lung function (forced (...truncated)