Comparative Effectiveness and Safety of LAMA-LABA Inhalers in Chronic Obstructive Pulmonary Disease

Importance: Dual bronchodilator therapy with a long-acting muscarinic antagonist (LAMA) and a long-acting β2-agonist (LABA) is recommended for most patients with symptomatic chronic obstructive pulmonary disease (COPD). Fixed-dose LAMA-LABA therapies are available in metered-dose, dry powder, and soft mist inhalers. However, metered-dosed inhalers are associated with greater greenhouse gas emissions than either dry powder or soft mist inhalers, and questions persist about potential intraclass differences among LAMA-LABAs given variability in their active ingredients, dosing schedules, and delivery devices. Objective: To evaluate the comparative effectiveness and safety of once-daily umeclidinium-vilanterol dry powder inhalers, twice-daily glycopyrrolate-formoterol metered-dosed inhalers, and once-daily tiotropium-olodaterol soft mist inhalers. Design, Setting, and Participants: This observational active-comparator study analyzed claims of patients (≥40 years) newly treated with LAMA-LABA inhalers and continuously enrolled in a large commercial health insurance or Medicare Advantage plan during the 183-day baseline period. Patients were propensity score matched 1:1 into 3 cohorts with index dates ranging from May 1, 2016, to February 28, 2025. Data were analyzed from July to August 2025. Exposures: Patients treated with umeclidinium-vilanterol, glycopyrrolate-formoterol, or tiotropium-olodaterol fixed-dose inhalers. Main Outcomes and Measures: Time to the first moderate or severe COPD exacerbation, major adverse cardiovascular event, urinary tract infection, and pneumonia hospitalization. Results: The cohorts included 9479 matched pairs of patients receiving umeclidinium-vilanterol vs glycopyrrolate-formoterol (mean age, 68.9 [SD, 9.0] years; 10 319 women [54.4%]; 8636 men [45.6%]), 9598 receiving tiotropium-olodaterol vs glycopyrrolate-formoterol (mean age, 69.2 [SD, 8.7] years; 10 513 women [54.8%]; 8680 men [45.2%]), and 36 740 receiving umeclidinium-vilanterol vs tiotropium-olodaterol (mean age, 71.5 [SD, 8.4] years; 39 429 women [53.7%]; 34 044 men [46.3%]). Umeclidinium-vilanterol was associated with a 14% lower hazard of a first moderate or severe COPD exacerbation than glycopyrrolate-formoterol (hazard ratio [HR], 0.86; 95% CI, 0.81-0.91; number needed to treat [NNT], 17) and was associated with a 3% lower hazard than tiotropium-olodaterol (HR, 0.97; 95% CI, 0.94-0.99; NNT, 100). Tiotropium-olodaterol was associated with a 6% lower hazard of a first moderate or severe COPD exacerbation than glycopyrrolate-formoterol (HR, 0.94; 95% CI, 0.89-1.00). Similar risks of first major adverse cardiovascular event, urinary tract infection, and pneumonia hospitalization were observed among patients in all 3 cohorts. Conclusions and Relevance: This cohort study found that umeclidinium-vilanterol was associated with improved clinical outcomes compared with glycopyrrolate-formoterol and tiotropium-olodaterol. Patients, prescribers, and health systems may consider once-daily umeclidinium-vilanterol dry powder inhalers over alternatives among new users of LAMA-LABA therapy.