Stopping Inhaled Corticosteroids or LAMA in COPD Linked to Early Exacerbations

A new study demonstrated the association between inhaled corticosteroid discontinuation and a transient increase in moderate-to-severe exacerbations during the first quarter among patients with chronic obstructive pulmonary disease (COPD) .1

“This study reveals for the first time that [long-acting muscarinic antagonists (LAMA)] discontinuation results in potent withdrawal effects on exacerbations, while also reinforcing evidence of [inhaled corticosteroid] withdrawal effects,” wrote study investigator Alexander G. Mathioudakis, MD, PhD, from the biology department at The University of Manchester, and colleagues.1

COPD affected approximately 480 million adults worldwide in 2020 and ranks as the 5th leading cause of years lost due to disability-adjusted life expectancy.2 By 2050, this number is projected to reach 600 million, driven by an aging population and increased exposure to air pollution and biomass.

Medication adherence in COPD is low, with only 20–30% of patients following prescribed treatments.2 Low medication adherence exacerbates disease progression, increases hospitalization risk, and worsens symptoms and quality of life. Poor adherence often leads to treatment discontinuation.

Discontinuing inhaled corticosteroids can trigger withdrawal effects and, consequently, a transient increase in exacerbations. Investigators performed a post-hoc analysis of the 52-week double-blind trial, Effect of Indacaterol Glycopyrronium versus Fluticasone Salmeterol on COPD Exacerbations (FLAME), which compared the long-acting beta-2 agonist (LABA) plus long-acting muscarinic antagonists (LAMA) with LAMA plus inhaled corticosteroids in 3362 patients with moderate-to-severe COPD and exacerbation history.1

The trial stratified participants by baseline use of these therapies and compared outcomes between the first and subsequent quarters among those who continued versus discontinued each treatment. Multivariable mixed-effects models were used to evaluate differences in exacerbation rates, with temporal variations in treatment effects suggesting potential withdrawal effects.1

The study found that discontinuing LAMA was associated with a transient increase in moderate-to-severe exacerbations during the first quarter versus subsequent quarters (P =.001; rate ratio up to 2.2 (95% confidence interval [CI], 1.2 to 4.1) in the subgroup least influenced by concomitant ICS use. The study did not confirm this observation for only severe exacerbations, likely due to the low number of events.1

However, the study found that discontinuing inhaled corticosteroids was associated with a significantly earlier increase in severe exacerbations (P = .023), though the difference in moderate-to-severe events was not statistically significant. Due to the insignificant data, the study could not demonstrate the inhaled corticosteroid withdrawal effect on moderate to severe exacerbations. The analysis saw consistent inhaled corticosteroid withdrawal effects regardless of baseline blood eosinophil count.1

“These early peaks in exacerbations likely reflect withdrawal effects from LAMA and ICS, respectively,” investigators wrote.1

The study observed a potentially strong LAMA withdrawal effect among patients who were only receiving LAMA (risk ratio, 2.7 to 3.7) or inhaled corticosteroids (risk ratio, 0.23 to 0.33) at baseline.1 Additionally, investigators said that inhaled corticosteroid withdrawal effects persisted beyond 4 weeks.

A sensitivity analysis, which only included participants who completed ≥ 300 days of trial treatment, also showed early peaks in exacerbations, although this was a less pronounced finding.1

“Our results indicate that both LAMA and ICS have a potential treatment withdrawal effect on exacerbations that needs to be prospectively validated,” investigators concluded.1 “These findings emphasize the critical role of monitoring treatment adherence at every clinical visit and increasing awareness among both patients and healthcare professionals about the risks associated with intermittent use of maintenance COPD therapies. Finally, our study highlights the importance of accounting for potential withdrawal effects when evaluating treatment efficacy or effectiveness in clinical research.”

References

1. Mathioudakis AG, Bate S, Chatzimavridou-Grigoriadou V, et al. Disproportionate increase in COPD exacerbation risk for 3 months after discontinuing LAMA or ICS: insights from the FLAME trial. Thorax. Published online December 15, 2025. doi:10.1136/thorax-2025-223282

2. Medication adherence as the keystone in COPD management success. Acarepro. Accessed January 14, 2026. https://acarepro.abbott.com/articles/general-topics/medication-adherence-copd-management-success/