Triple therapy versus dual inhaler therapy for moderate-to-severe asthma: an updated systematic review and meta-analysis.

Background: Long-acting muscarinic antagonists (LAMA) are commonly added to inhaled corticosteroids (ICS) and long-acting beta-agonists (LABA) for asthma management.

Objective: To systematically synthesize the benefits and harms of triple therapy (ICS/LABA/LAMA) compared to dual therapy (ICS/LABA) for asthma management across key subpopulations as part of developing linked AAAAI/ACAAI guidelines.

Methods: We searched MEDLINE, Embase, CENTRAL, and ICTRP from January 1, 2020 to February 1, 2025, for randomized trials comparing inhaled triple therapy to dual therapy for asthma to update our previous systematic review. Paired reviewers independently screened citations, extracted data, and assessed risk of bias. Random-effects meta-analyses assessed asthma control (ACQ-7; 0-6), asthma-related quality of life (AQLQ; 1-7), pre-bronchodilator FEV1, severe exacerbations, and serious adverse events. The GRADE approach informed the certainty of evidence. Open Science Framework Registration (https://osf.io/u8t4q/).

Results: Twenty-six trials randomized 12,431 participants. Compared to dual therapy, triple therapy reduces severe exacerbations in patients at high risk for future exacerbation (relative risk 0.83, 95%CI 0.76 to 0.90; risk difference 5.3% fewer; high certainty), with trivial improvement in asthma control (mean difference [MD] -0.04, 95%CI -0.07 to 0.00, moderate certainty; lower better), quality of life (MD 0.05, 95%CI -0.03 to 0.14, moderate certainty; higher better), and pre-bronchodilator FEV1 (MD 0.07, 95%CI 0.05 to 0.09; high certainty), without increase in serious adverse events (moderate certainty). Effects were consistent across age, body mass index, and exacerbation history.

Conclusion: In patients with moderate-to-severe asthma, triple therapy, compared to dual therapy, reduces severe exacerbations in patients at high risk for future exacerbation with minimal harm.