1 INTRODUCTION

Chronic obstructive pulmonary disease (COPD) is a chronic lung disease characterized by persistent respiratory symptoms due to abnormalities in the airways and/or alveoli, resulting in persistent, often progressive, airflow obstruction.¹ According to the latest Chinese Pulmonary Health study, the incidence of COPD is as high as 13.7% among individuals over 40 years of age.² Currently, COPD is the third leading cause of death in China, thereby inducing a considerable economic and societal burden.³ With aging and continued exposure to risk factors, the prevalence of COPD is expected to increase over the next 40 years, with more than 5.4 million deaths annually estimated from COPD and related diseases by 2060 worldwide.⁴

In recent years, the focus has shifted from the prevention and treatment of COPD to early prevention, early treatment, and disease stabilization, primarily to relieve clinical symptoms and reduce the number of acute exacerbations. Strategies for COPD management include smoking cessation, pharmacological therapy, pulmonary rehabilitation, treatment of comorbidities, influenza, and pneumococcal immunization, and long-term oxygen therapy. Pharmacological therapy is the cornerstone of COPD treatment.⁵ Treatment should be individualized for each patient depending on symptom severity, airflow restriction, and acute exacerbation, as well as the availability, cost, and clinical response to medication considering side effects.¹ According to the latest Global Initiative for Chronic Obstructive Lung Disease (GOLD) report,¹ patients should be divided into groups A, B, and E instead of the traditional ABCD group to highlight the clinical relevance of exacerbations (Table 1).

Patients with stable COPD are frequently treated with bronchodilators and inhaled corticosteroids (ICSs). Each drug regimen should be guided individually based on symptom severity, risk of acute exacerbation, adverse reactions, comorbidities, drug availability, and cost, patient response, preference, and the ability to use various drug delivery devices. We have summarized the different drug groups below:

2 BRONCHODILATORS

Bronchodilators are the core of COPD therapy. Inhaled bronchodilators include two classes, namely, β2 agonists and anticholinergics, which can be divided into short-acting (short-acting β2 agonists and short-acting anticholinergic agents) and long-acting (long-acting β2 agonists [LABAs] and long-acting anticholinergic agents) based on the duration of drug efficacy (Table 2). Typically, short-acting bronchodilators act for 4–6 h and are used to relieve respiratory symptoms when necessary. Conversely, long-acting bronchodilators should be used daily as maintenance drug therapy for individuals with moderate to very severe disease, with long-term benefits, including reduced dyspnea, improved exercise performance, and decreased frequency of attacks.

Long-acting muscarinic antagonists (LAMAs) are superior to LABAs for preventing disease progression. In a randomized controlled trial (RCT) including 7376 patients with COPD from multiple countries, patients were randomly assigned to receive 18 mg tiotropium once daily or 50 mg salmeterol twice daily. Compared with salmeterol, tiotropium could significantly extend the time to the first onset of moderate or severe deterioration. The proportion of serious adverse events in the two groups was similar.⁶

A synergistic effect has been observed between β2 agonists and muscarinic agonists. Considering one potential mechanism underlying the observed synergistic effect, muscarinic agonists poorly inhibit potassium channel opening, leading to airway smooth muscle relaxation, which, in turn, activates intracellular signaling pathways to promote β2-mediated smooth muscle relaxation.⁷ Clinical studies have revealed that combined therapy with LABA/LAMA is superior to monotherapy with either drug in terms of reducing the number of acute exacerbations and improving quality of life, symptom score, and lung function.^8-11 Considering safety outcomes and severe exacerbations, no statistically significant differences between LABA/LAMA combined therapy and monotherapy were observed.¹² The Early MAXimization (EMAX) study was a randomized, multicenter, parallel trial conducted between 2017 and 2018.¹³ Patients with moderate-to-severe COPD were randomly assigned to the umeclidinium/vilanterol, umeclidinium, or salmeterol groups. At week 24 of treatment, the forced expiratory volume in 1 s (FEV₁) from baseline increased by 66 mL (95% confidence interval [CI]: 43–89) and 141 mL (95% CI: 118–164) in patients treated with dual bronchodilators when compared with those treated with umeclidinium and salmeterol, respectively.

Compared with long-acting bronchodilator monotherapy, double bronchodilators (LABA/LAMA) can improve lung function, dyspnea symptoms, and quality of life in affected patients. Patients in groups B and above can be initially treated with double bronchodilators (Table 1).

3 ANTI-INFLAMMATORY DRUGS

ICSs have anti-inflammatory effects that can reduce airway and systemic inflammation. Therefore, ICSs are suitable for a few patients, especially those with eosinophilia in the peripheral blood. Studies have shown that ICS therapy alone does not modify lung function or reduce mortality.¹⁴ ICSs should not be used alone for treatment but should be combined with long-acting bronchodilators in COPD.

The GOLD guidelines present differing views on the need for combination therapy with ICS for the initial treatment of COPD. Strongly supported: moderate acute exacerbations occurring ≥2 times/year, hospitalization due to acute exacerbations, blood eosinophils ≥300 cells/μL, current asthma, or previous history of asthma; favors use: one previous moderate acute exacerbation per year, blood eosinophils of 100–300 cells/μL; not supported: repeat pneumonia, blood eosinophils < 100 cells/μL, mycobacterium tuberculosis infection. Notably, ICS can induce several potential adverse effects, including pneumonia, nontuberculous mycobacterium infection in the lungs, and an elevated risk for oral candidiasis. Clinicians should periodically evaluate the risks and benefits of maintenance therapy with ICS in patients with COPD, as well as determine whether to increase or withdraw ICS during follow-up based on the patient's frequency of deterioration, adverse reactions, and blood eosinophil counts.

In addition, the potential impact of ICS on the development of lung tumors remains controversial. Several studies assessing patients with COPD have reported inconsistent findings. Considering a cohort study of 63,276 individuals with COPD, the results revealed that the adjusted risk rate associated with ICS was 1.01 (95% CI: 0.94–1.08), and the risk rate associated with longer ICS use (>4 years) was 0.92 (95% CI: 0.83–1.03), while the risk rate of average ICS daily high dose (>1000 μg fluticasone equivalent) was 1.36 (95% CI: 1.03–1.81), suggesting that ICS are not associated with a reduced incidence of lung cancer in patients with COPD.¹⁵ A few studies have also reported an increased risk of lung cancer in patients who used ICS when compared with those who did undergo ICS treatment.^{16, 17} In addition, studies have suggested that increasing cumulative ICS dose was associated with decreasing lung cancer risk and this may be dose-dependent.^{18, 19} Based on available data, whether ICS increases the risk of lung cancer warrants further confirmation.

Notably, the latest GOLD guidelines do not recommend the use of LABA + ICS for COPD treatment; LABA + LAMA + ICS is superior to LABA + ICS and is the preferred choice.¹ Recent large RCTs have revealed that triple therapy can decrease the frequency of moderate/severe acute exacerbations^{20, 21} and a series of clinically important endpoints.^{22, 23} Additionally, triple therapy was found to be superior to the other two types of dual therapy (ICSs/LABAs or LAMAs/LABAs) and did not increase the incidence of adverse events. The TRIBUTE (extrafine inhaled triple therapy versus dual bronchodilator therapy in chronic obstructive pulmonary disease) study²¹ compared the efficacy and safety of triple therapy (beclomethasone, formoterol, glycopyrronium) with a double bronchodilator (glycopyrronium/indacaterol). Compared with double bronchodilation, triple therapy could significantly reduce the incidence of moderate-to-severe acute exacerbations without increasing the risk of pneumonia in symptomatic patients with COPD experiencing severe or very severe airflow restriction. The FULFIL trial,²² a randomized, double-blind study, compared triple therapy (fluticasone/umeclidinium/vilanterol) with ICS/LABA therapy (budesonide/formoterol). Compared with ICS/LABA therapy, triple therapy can significantly reduce the rate of moderate/severe exacerbation, delay lung function decline, and improve COPD symptoms. Recently, two large RCTs, IMPACT (the informing the pathway of COPD treatment),²⁰ and ETHOS (the efficacy and safety of triple therapy in obstructive lung disease),²⁴ provided evidence that triple therapy can reduce all-cause mortality when compared with other dual or single treatments.²⁵

Extensive ICS/LAMA/LABA combinations have been examined in recent years, with no difference observed between different ICS/LAMA/LABA combinations in reducing the time of acute exacerbations, COPD-related mortality, and all-cause mortality.²⁶ This finding indicates that the shortcomings and advantages of the ICS/LAMA/LABA are equivalent.

4 PHOSPHODIESTERASE (PDE)-4 INHIBITORS

PDE 4 inhibitors can block the metabolism of cyclic adenosine phosphate and inhibit the release of inflammatory mediators, thereby clarifying their application in treating airway inflammation. Roflumilast is a PDE-4 inhibitor, and multiple RCT trials and meta-analyses have shown that it can reduce the risk of acute exacerbation in patients with moderate-to-severe COPD.^27-30 Roflumilast can be used as an adjunct to combination therapy with ICS and long-acting bronchodilators to further improve outcomes in patients with severe COPD and reduce the rate of acute exacerbation. Considering patients in the GOLD E group with refractory symptoms, selective PDE-4 inhibitors should be considered. Traditional oral PDE-4 inhibitors have been associated with several adverse reactions, including gastrointestinal disorders, weight loss, and nausea due to systemic exposure. Inhaled PDE-4 inhibitors have been developed, exhibiting positive results in early clinical trials and adequate safety. Further trials are required to determine the efficacy of PDE-4 inhibitors.³¹

5 METHYLXANTHINES

The precise treatment efficacy of methylxanthine in COPD remains controversial. Multiple RCTs have revealed that aminophylline does not minimize the risk of acute COPD exacerbation or other primary clinical endpoints and may even increase the hospitalization rate and long-term mortality.³² In a randomized, three-arm, double-blind, placebo-controlled study conducted at 37 centers in China, symptomatic patients with moderate-to-severe COPD were randomly assigned to one of three groups (placebo, low-dose theophylline, and low-dose theophylline and prednisone). Compared with the placebo, low doses of theophylline alone or combined with prednisone did not reduce the rate of acute COPD exacerbations.³³ The theophylline with inhaled corticosteroids (TWICS) trial demonstrated that low-dose theophylline did not reduce the number of COPD exacerbations over a 1-year period. These results do not support the use of low-dose theophylline as an adjunctive therapy to ICS to prevent COPD exacerbations.³⁴

Adverse reactions associated with aminophylline and theophylline, narrow treatment windows, limited benefits, and the need to monitor patients receiving these drugs restrict their application in patients with COPD. Therefore, the GOLD management strategy guidelines do not recommend theophylline unless other long-term therapeutic bronchodilators are unavailable or unaffordable. However, GOLD guidelines support the use of aminophylline and theophylline in patients with severe refractory symptoms. If patients do not respond after a few weeks of treatment, the treatment should be discontinued.

6 BETA-BLOCKERS

According to multiple observational studies, beta-blockers reduce the risk of acute exacerbation and death in patients with moderate-to-severe COPD^35-38; however, these results have not been confirmed in RCTs.^{39, 40} The beta-blockers for the Prevention of Acute Exacerbations of COPD study was a prospective, multicenter RCT that recruited 532 patients with COPD, randomly assigned to a metoprolol group or placebo group to evaluate the effectiveness of metoprolol in preventing acute exacerbations of moderate-to-severe COPD. In patients with moderate or severe COPD, metoprolol was not associated with an increased duration of the first acute exacerbation when compared with the placebo, with no clear indication of beta-blocker use. However, metoprolol was associated with a higher risk of hospitalization than the placebo.⁴¹ Therefore, selective beta-1 blockers are recommended only for treating COPD with cardiovascular indications and not solely for preventing acute COPD exacerbation.

7 BIOLOGICAL ACTIVE AGENTS

Patients with COPD and eosinophilia have a high risk of acute exacerbations and hospitalization rates; hence, this subgroup may benefit from targeting eosinophil inflammation. Interleukin (IL)-5 is a key cytokine in eosinophilic inflammation, and anti-IL-5 therapy was effective in treating severe eosinophilic asthma.⁴² Anti-IL-5 biological agents include mepolizumab, benralizumab, and reslizumab. Several RCTs have explored the efficacy and safety of anti-IL-5 therapy in patients with severe COPD and eosinophilia. GALATHEA (benralizumab efficacy in moderate to very severe chronic obstructive pulmonary disease with exacerbation history) and TERRANOVA (efficacy and safety of benralizumab in moderate to very severe chronic obstructive pulmonary disease with exacerbation history)⁴³ are two Phase II trials that evaluated the effectiveness of benralizumab in preventing exacerbations in patients with moderate-to-severe COPD. Compared with the placebo, benralizumab did not reduce the annual rate of acute exacerbations in patients with COPD. Mepolizumab has also been examined in two Phase III randomized controlled studies in patients with COPD (METREO and METREX studies).⁴⁴ The primary endpoint of these two studies was the annual rate of moderate or severe exacerbations. Mepolizumab reduced the annual rate of acute exacerbations in the METREX study; however, this was not replicated in the METREO study. The overall results of METREX/METREO suggested that mepolizumab may play a role in reducing the risk of deterioration in patients with COPD and eosinophilia. Based on clinical trial results for mepolizumab and benralizumab, additional clinical trial data are required to determine the feasibility of IL-5 targeted therapy for COPD.

8 POTENTIAL TREATMENTS IN DEVELOPMENT

The occurrence and development of COPD are complex pathological processes. Inflammation, oxidative stress, and protease-antiprotease imbalance are the predominant causes of COPD. Currently, a series of new molecular-targeted therapeutic drugs have been developed to target key molecules involved in signal transduction to prevent the progression of COPD. Sirtuin 1 (SIRT1) is an important molecule that regulates oxidative stress in COPD rats.⁴⁵ Reportedly, SIRT1 can resist oxidative stress and inflammatory responses caused by cigarette smoke.⁴⁶ Resveratrol is a natural SIRT1 agonist that can alleviate lung inflammation and airway remodeling in COPD rats, affording a potential candidate for treating COPD.⁴⁷ Numerous studies have also examined other pathogeneses, including inflammation and antiprotease imbalance, and a series of new therapeutic targets have been identified, including p38 mitogen-activated protein kinase inhibitor,^{48, 49} phosphoinositide 3-kinase inhibitors,^{50, 51} and matrix metalloproteinase-9 inhibitor.⁵² These small-molecule substances have been shown to exhibit notable anti-inflammatory and anti-emphysema effects in a smoking-induced animal model of COPD. In recent years, studies have shown that troxerutin plays a crucial protective role in the pathogenesis of COPD, regulating multiple signal transduction pathways, such as inflammation,^{53, 54} oxidative stress,⁵⁵ and protease imbalance.⁵⁶ Troxerutin can inhibit the occurrence and development of COPD through diverse mechanisms and may be an important drug for treating COPD in the future.

9 CONCLUSIONS AND PROSPECTS

Management strategies for stable COPD should be based on presenting symptoms and a history of exacerbations. Double bronchodilator therapy is the cornerstone of drug therapy for COPD. Triple inhalation therapy is recommended for patients with an increased eosinophil count or asthma. PDE inhibitors may act as an adjunct to combination therapy with ICS and long-acting bronchodilators in patients at a high risk of severe acute exacerbation. Additional clinical trials are needed to verify the efficacy and safety of biologics and other targeted drugs among this patient population.

AUTHOR CONTRIBUTIONS

Ruirui Duan reviewed the literature and wrote the manuscript. Baicun Li and Ting Yang revised the manuscript.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interest. Professor Ting Yang is a member of Chronic Diseases and Translational Medicine editorial board and is not involved in the peer review process of this article.

ETHICS STATEMENT

Not applicable.