Role of Inhaled Therapies in COPD Progression and Exacerbation Prevention: A Critical Review

Abstract

Background: Chronic Obstructive Pulmonary Disease (COPD) management lacks universal consensus on triple inhaled therapy, comprising a long-acting muscarinic antagonist (LAMA), a long-acting β2-adrenoceptor agonist (LABA), and an inhaled corticosteroid (ICS). Current guidelines, such as GOLD, primarily reserve triple therapy for very severe cases (Group D), while other international guidelines advocate for broader use, including in patients with frequent exacerbations or asthma-COPD overlap syndrome (ACOS). This divergence leads to varied real-world prescribing practices, often driven by clinical empiricism rather than strict phenotypic stratification. Emerging evidence suggests therapeutic advantages in specific subgroups, such as those with ACOS, eosinophilic inflammation, or a history of frequent exacerbations, who may benefit from intensified bronchodilator treatment.
Aim: This review aims to critically examine the rationale for triple inhaled therapy in COPD by integrating data from various clinical trials, exploring its clinical effectiveness and safety profiles, and considering future trends in COPD management.
Methods: A comprehensive literature review was conducted, synthesizing data from clinical trials investigating the simultaneous use of LAMA, LABA, and ICS. The review focused on the pharmacologic rationale, anti-inflammatory effects, and evidence from key clinical trials, including studies on fixed-dose combinations and novel pharmacological approaches. Safety considerations, particularly regarding pneumonia risk and mortality, were also examined.
Results: Triple inhaled therapy demonstrates synergistic bronchodilation and anti-inflammatory effects, particularly beneficial in patients with high exacerbation risk, eosinophilic inflammation, or poor symptom control. Clinical trials show improvements in lung function and reductions in exacerbations, though the universal benefit is debated. ICS withdrawal may be feasible in select patients without compromising exacerbation control. Fixed-dose combinations enhance adherence and convenience. Safety concerns include increased pneumonia risk with ICS, especially fluticasone, and historical mortality signals with tiotropium Respimat®, though large trials have largely allayed these concerns. Novel bifunctional molecules like MABAs and PDE4 inhibitors are emerging, offering potential for improved efficacy and simplified regimens.
Conclusion: Triple inhaled therapy is a valuable option for specific COPD phenotypes, emphasizing the need for personalized medicine. Future research should focus on identifying biomarkers for ICS responsiveness and assessing long-term safety. Optimal use depends on robust clinical evidence tailored to diverse patient populations.