Effectiveness and Safety of Budesonide/Formoterol in Asthma: A Systematic Review

Background/Objectives: Asthma's preventable burden is heavily driven by severe exacerbations (SE). Replacing standalone short-acting β2-agonists (SABAs), which risk reducing patient tolerance, with inhaled corticosteroid/long-acting β2-agonist combinations optimizes care through maintenance, reliever, and maintenance-and-reliever therapy (MART). This systematic review and meta-analysis evaluated the efficacy, effectiveness, and safety of Budesonide/Formoterol (B/F). Methods: PubMed, Cochrane, and Embase were searched for randomized controlled trials (RCTs) and non-randomized controlled trials (non-RCTs) through May 15, 2026. Bias was assessed via the Cochrane Risk of Bias tool version 2 (RoB 2) and the Risk ff Bias in Non-randomized Studies of Interventions (ROBINS-I) version 2.0. Primary outcomes (time to first SE, annual SE rate) were pooled using a random-effects meta-analysis, yielding hazard ratios (HRs) and rate ratios (RRs). Results: We included 19 studies (15 RCTs, 4 non-RCTs) comprising 104,600 patients (primarily aged ≥12 years with mild-to-severe asthma). Most RCTs had a low risk of bias, whereas the non-RCTs had a high risk of bias. B/F MART significantly delayed the first SE and reduced annual rates versus Budesonide + SABA (HR = 0.57; RR = 0.55), B/F + SABA (HR = 0.62; RR = 0.58), and Fluticasone/Salmeterol + SABA (HR = 0.75; RR = 0.72). As-needed B/F reduced first SE hazard and annual rates versus SABA alone (HR = 0.43; RR = 0.42). Compared with Budesonide + SABA, it delayed the first SE (HR = 0.85) but showed non-significant rate reductions (RR = 0.90). Adverse events were balanced between groups over 12-52 weeks. Conclusions: B/F MART demonstrates high efficacy in mitigating the risk of the first SE. However, limited trial data leave the evidence for maintenance or reliever regimens controversial. Across all regimens, B/F is well-tolerated within 6 to 12 months.