Deciphering the Benefits and Risks of Single-Inhaler Triple Therapy in COPD

Single-inhaler triple therapy (SITT) combines an inhaled corticosteroid (ICS; for example, fluticasone furoate, budesonide, or beclometasone dipropionate), a long-acting β2-agonist (LABA; for example, vilanterol or formoterol fumarate), and a long-acting muscarinic antagonist (LAMA; for example, umeclidinium or glycopyrronium bromide) in one device. Triple pharmacological therapy reduces exacerbations in selected patients with chronic obstructive pulmonary disease (COPD), but its effects on mortality and cardiovascular outcomes remain uncertain. This structured narrative review summarizes randomized trials, observational comparative-effectiveness studies, target trial emulations, systematic reviews, and health technology assessments published between 2015 and 2026. We grouped the evidence by comparator: LABA/LAMA, ICS/LABA, multiple-inhaler triple therapy (MITT), and ICS continuation versus withdrawal, because each comparison addresses a different clinical question. Pivotal trials and evidence syntheses consistently showed fewer moderate-to-severe exacerbations with triple therapy, with reported rate ratios of approximately 0.69-0.93. Mortality signals from IMPACT and ETHOS are clinically important, but previous ICS use and ICS withdrawal among participants assigned to ICS-free comparators make these findings difficult to interpret. Observational cardiovascular findings are also uncertain because residual confounding, treatment selection, exposure misclassification, outcome misclassification, and differences in baseline disease severity limit causal interpretation. Compared with MITT, the main advantages of SITT are simpler treatment and possible improvements in adherence and persistence, not greater pharmacological potency. Treatment decisions should consider exacerbation history, repeated blood eosinophil counts, pneumonia risk, cardiovascular disease, previous ICS exposure and response, inhaler technique, device suitability, and patient preference. Trials in patients with documented absence of previous ICS use and well-designed target trial emulations are needed to determine whether the observed mortality and cardiovascular associations are causal.