Deciphering the Benefits and Risks of Single-Inhaler Triple Therapy in COPD.
10 affiliations
- 1Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia.
- 2Institute for Pulmonary Diseases of Vojvodina, 21204 Sremska Kamenica, Serbia.
- 3Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia.
- 4Clinic for Pulmonology, University Clinical Center of Serbia, 11000 Belgrade, Serbia.
- 5Medical Faculty of the Military Medical Academy, University of Defense in Belgrade, 11000 Belgrade, Serbia.
- 6Clinic for Pulmonology, Military Medical Academy, 11000 Belgrade, Serbia.
- 7Faculty of Medicine, University of Kragujevac, 34000 Kragujevac, Serbia.
- 8Clinic for Pulmonology, University Clinical Center of Kragujevac, 34000 Kragujevac, Serbia.
- 9Faculty of Medicine, University of Nis, 18000 Nis, Serbia.
- 10Clinic for Pulmonology, University Clinical Center of Nis, 18000 Nis, Serbia.
Abstract
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.
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BibTeX
@article{kopitovic2026deciphering,
title = {{Deciphering the Benefits and Risks of Single-Inhaler Triple Therapy in COPD.}},
author = {Ivan Kopitovic and Sanja Dimic-Janjic and Mihailo Stjepanovic and Sanja Hromis and Biljana Zvezdin and Miroslav P Ilic and Violeta Kolarov and Rade Milic and Ivan Cekerevac and Vojislav Cupurdija and Ivana Buha and Jelena Jankovic and Maja Omcikus and Nikola Trboljevac and Ivana Stankovic and Marija Vukoja},
journal = {Advances in respiratory medicine},
year = {2026},
month = sep,
doi = {10.3390/arm94050070},
url = {https://europepmc.org/article/MED/42930048},
note = {CC BY},
}
RIS
TY - JOUR
TI - Deciphering the Benefits and Risks of Single-Inhaler Triple Therapy in COPD.
AU - Ivan Kopitovic
AU - Sanja Dimic-Janjic
AU - Mihailo Stjepanovic
AU - Sanja Hromis
AU - Biljana Zvezdin
AU - Miroslav P Ilic
AU - Violeta Kolarov
AU - Rade Milic
AU - Ivan Cekerevac
AU - Vojislav Cupurdija
AU - Ivana Buha
AU - Jelena Jankovic
AU - Maja Omcikus
AU - Nikola Trboljevac
AU - Ivana Stankovic
AU - Marija Vukoja
PY - 2026
DA - 2026/09/30
JO - Advances in respiratory medicine
DO - 10.3390/arm94050070
UR - https://europepmc.org/article/MED/42930048
AB - 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.
SN - 2451-4934
SN - 2543-6031
ER -