The study compared the efficacy and safety of two triple therapies in a single inhaler in patients with COPD: budesonide-glycopyrrolate-formoterol (twice daily) and fluticasone-umeclidinium-vilanterol (once daily). It included 20,388 pairs of new users aged 40+ years from US commercial data (2021-2023), balanced by propensity score. Main endpoints were first moderate or severe COPD exacerbation and first hospitalization with pneumonia. Patients on budesonide-glycopyrrolate-formoterol had a 9% higher risk of a first moderate or severe exacerbation (HR 1.09; 95% CI 1.04-1.14; NNH 38) compared with fluticasone-umeclidinium-vilanterol. The risk of a first moderate exacerbation was 7% higher (HR 1.07; 95% CI 1.02-1.12; NNH 54) and the risk of a severe exacerbation was 29% higher (HR 1.29; 95% CI 1.12-1.48; NNH 97). The risk of hospitalization with pneumonia was identical (HR 1.00; 95% CI 0.91-1.10). Sensitivity analyses confirmed the main findings.