Triple Therapy in Focus: The Importance of a Proactive Approach

Millions of Americans live with COPD, a leading cause of morbidity, mortality, and cardiopulmonary events. There is also evidence linking COPD, exacerbations and the increased risk of cardiopulmonary events. Despite these findings, many patients with COPD may be unrecognized or undertreated. At the 2025 American Thoracic Society (ATS) International Conference, pulmonologist Sanjay Sethi from the University at Buffalo, The State University of New York, USA, discussed clinical trials and real-world studies supporting the use of triple therapy containing the long-acting β2-agonist (LABA), formoterol fumarate (FORM), the long-acting muscarinic antagonist (LAMA), glycopyrrolate (GLY), and budesonide (BUD), an inhaled corticosteroid (ICS; BUD/GLY/FORM), delivered as a fixed dose combination via a pressurized metered-dose inhaler (MDI). RCTs of BUD/GLY/FORM involving symptomatic patients with moderate-to-very severe COPD include ETHOS, where patients were required to have ≥1 moderate-to-severe exacerbation in the previous year, and KRONOS, where such prior exacerbation history was not required. In ETHOS, moderate-to-severe COPD exacerbations over 52 weeks were both lower with BUD/GLY/FORM compared with GLY/FORM and BUD/FORM MDIs. All-cause mortality was also assessed as a pre-defined secondary endpoint. In KRONOS, forced expiratory volume in 1 second (FEV1) area under the curve from 0–4 hours (AUC0–4) improved with BUD/GLY/FORM, and was significantly different at Week 24 compared to a BUD/FORM MDI and an improvement in change from baseline in morning pre-dose trough FEV1 versus GLY/FORM. Most common adverse reactions (incidence ≥2%) were upper respiratory tract infection, pneumonia, back pain, dysphonia, oral candidiasis, influenza, muscle spasms, urinary tract infection, cough, sinusitis, and diarrhea. Real-world studies also evaluated the timing of initiation of BUD/GLY/FORM in rates of moderate-to-severe exacerbations and in healthcare resource utilization.