Clinical Effectiveness and Safety of Dipeptidyl Peptidase-1 Inhibitors in Non-Cystic Fibrosis Bronchiectasis with Recurrent Exacerbations: A Systematic Review and Meta-Analysis

Background: Non-cystic fibrosis bronchiectasis is a chronic inflammatory airway disease characterized by impaired mucus clearance, recurrent pulmonary exacerbations and neutrophil-dominant airway injury. Dipeptidyl peptidase-1 (DPP-1) inhibition suppresses activation of neutrophil serine proteases and is a plausible targeted anti-inflammatory strategy. This review evaluates DPP-1 inhibitors as a class, rather than brensocatib alone, in adults with bronchiectasis and recurrent exacerbations. Methods: Randomized controlled trials comparing a DPP-1 inhibitor with placebo were systematically reviewed. Eligible studies enrolled adults with CT-confirmed non-cystic fibrosis bronchiectasis and recurrent exacerbations. Outcomes included annualized adjudicated pulmonary exacerbation rate, time to first exacerbation, FEV1, Quality of Life-Bronchiectasis Respiratory Symptoms Score (QOL-B RSS). High-dose versus low-dose estimates were presented as exploratory indirect comparisons because formal head-to-head dose-comparison covariance data were unavailable. Results: Four randomized trials were included: WILLOW, ASPEN, SAVE-BE and AIRLEAF. The trial denominators reported in the submitted baseline table sum to 2522 participants. Compared with placebo, high-dose DPP-1 inhibition did not significantly reduce annualized exacerbation rate (rate ratio 0.72, 95% CI 0.43-1.19) or time to first exacerbation (HR 0.61, 95% CI 0.33-1.14), but increased hyperkeratosis (RR 3.10, 95% CI 1.35-7.12). Lowdose therapy reduced annualized exacerbations (rate ratio 0.71, 95% CI 0.53-0.93) and time to first exacerbation (HR 0.64, 95% CI 0.41-0.99), without significant effects on FEV1or QOL-B RSS. Conclusion: DPP-1 inhibitors appear to reduce pulmonary exacerbations in selected patients with non-cystic fibrosis bronchiectasis, with the most consistent placebo-controlled efficacy signal in low-dose regimens. The apparent dose pattern should be interpreted cautiously because highdose versus low-dose evidence is indirect and trial-level.