BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a progressive disease associated with substantial morbidity and mortality. Acute COPD exacerbations are a primary driver of significant burden and contribute to disease progression. METHODS: This retrospective, observational cohort study used the Optum Clinformatics Data Mart database to identify patients with COPD who were classified as Global Initiative for Chronic Obstructive Lung Disease (GOLD) A/B0 or A/B1 based on exacerbation history (i.e., they had either 0 [GOLD A/B0] or 1 [GOLD A/B1] moderate exacerbation and 0 severe exacerbations in a 12-month baseline period). Patients were required to be aged ≥ 40 years and to have newly initiated inhaled maintenance therapy for COPD from January 2016 to June 2023. The rates of and time to progression to GOLD E (defined in the claims data as experiencing 2 moderate exacerbations within a 12-month period or 1 severe exacerbation) were estimated using the Kaplain-Meier method. Predictors of progression to GOLD E were analyzed using multivariable Cox proportional hazard models. RESULTS: Of the 156,462 included patients, the largest proportion of patients (46.6%) were initiated on long-acting beta-agonists/inhaled corticosteroids. The majority of patients progressed to GOLD E over 5 years. The risk of progressing to GOLD E was approximately 3 times higher in the GOLD A/B1 versus GOLD A/B0 group (hazard ratio [HR] 2.92; 95% CI 2.84-3.00; P < 0.001). The strongest predictor of progressing to GOLD E was history of having a moderate exacerbation. Other independent predictors included older age, having Medicare versus commercial insurance, and the presence of Elixhauser comorbidities. CONCLUSIONS: Despite use of inhaled maintenance treatments for COPD, most patients still progressed to a frequent or severe exacerbator phenotype. New therapies are needed to modify the disease trajectory in COPD.