Roflumilast: a review of its use in the treatment of COPD

Abstract

COPD is a progressive condition involving chronic inflammation and parenchymal destruction with resulting airflow limitation. COPD is associated with worsening airflow limitation over time and increased frequency of COPD exacerbations, leading to increased mortality and morbidity. The effects of COPD extend beyond the lungs, as multiple comorbidities may occur with COPD, including cardiovascular disease, diabetes mellitus, osteoporosis, depression, and pneumonia. COPD exacerbations are associated with a rapid worsening of baseline symptoms that requires prompt management and may necessitate hospitalization in the case of a severe episode. Patients with COPD exacerbations require urgent management of symptoms to prevent further worsening, and preventative steps may be taken to help reduce the number and frequency of future exacerbations. Roflumilast is a potent and selective inhibitor of the enzyme phosphodiesterase-4 that targets the systemic inflammation associated with COPD. Roflumilast has a variety of anti-inflammatory effects including decreasing inflammatory mediators and the expression of cell surface markers and inhibition of apoptosis. Several clinical trials evaluating roflumilast in the treatment of COPD have demonstrated significant improvements from baseline versus placebo in lung function, including increases in mean pre- and postbronchodilator forced expiratory volume in 1 second and forced vital capacity. Data suggest that roflumilast reduces moderate to severe exacerbations with the benefit most well established in patients with severe disease. Given this evidence, roflumilast, as part of a combination regimen with long-acting bronchodilators, appears to be a reasonable treatment option for patients with severe to very severe COPD associated with chronic bronchitis and a history of exacerbations.

Keywords: COPD; chronic bronchitis; exacerbations; phosphodiesterase-4 inhibitors; roflumilast.

Figure 1

Schematic of the frequent exacerbator phenotype. Notes: Reproduced from BioMed Central. © 2013 Wedzicha et al; licensee BioMed Central Ltd. Wedzicha JA, Brill SE, Allinson JP, Donaldson GC. Mechanisms and impact of the frequent exacerbator phenotype in chronic obstructive pulmonary disease. BMC Med. 2013;11:181. Creative Commons license and disclaimer available from: http://creativecommons.org/licenses/by/4.0/legalcode. Abbreviations: CRP, C-reactive protein; FEV₁, forced expiratory volume in 1 second; IL-6, interleukin-6.

Figure 2

Effect of roflumilast on the mean rate of moderate or severe exacerbations with or without a LABA. Notes: Reproduced with permission of the European Respiratory Society^©. Eur Respir J, September 2011 38(3):553–560; doi:10.1183/09031936.00178710. Bateman ED, Rabe KF, Calverley PM, et al. Roflumilast with long-acting β₂-agonists for COPD: influence of exacerbation history. Eur Respir J. 2011;38(3):553–560. Abbreviations: CI, confidence interval; LABA, long-acting β₂-agonist.

Figure 3

Mean rate of serious exacerbations or exacerbations leading to hospital admission per patient per year in the REACT study. Notes: Reprinted from The Lancet, Vol. 385, number 9971, Martinez FJ, Calverley PM, Goehring UM, Brose M, Fabbri LM, Rabe KF. Effect of roflumilast on exacerbations in patients with severe chronic obstructive pulmonary disease uncontrolled by combination therapy (REACT): a multicentre randomised controlled trial, Pages 857–866, Copyright (2015), with permission from Elsevier. Abbreviation: CI, confidence interval.

Figure 4

Changes in mean glycated hemoglobin (HbA_1c) levels over 12 weeks in patients with newly diagnosed, treatment-naïve type 2 diabetes mellitus. Notes: Bars represent confidence intervals. Republished with permission of the Endocrine Society, from Effect of the phosphodiesterase 4 inhibitor roflumilast on glucose metabolism in patients with treatment-naive, newly diagnosed type 2 diabetes mellitus. Wouters EF, Bredenbroker D, Teichmann P, et al. J Clin Endocrinol Metab. 2012;97(9):E1720–E1725. Copyright 2012; permission conveyed through Copyright Clearance Center, Inc.

Figure 5

Pooled analysis of the incidence rate of the composite of MACE (nonfatal MI, nonfatal stroke, and CV death) for patients receiving roflumilast (n=6,563) or placebo (n=5,491). Notes: Adapted with permission from the American College of Chest Physicians. White WB, Cooke GE, Kowey PR, et al. Cardiovascular safety in patients receiving roflumilast for the treatment of COPD. Chest. 2013;144(3):758–765. Abbreviations: CV, cardiovascular; MACE, major adverse cardiovascular events; MI, myocardial infarction.