Background <p>Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are among the most rapidly growing drug classes in contemporary medicine, approved for type 2 diabetes mellitus (T2DM) and obesity management. Although gastrointestinal adverse effects are well characterised, the pulmonary safety profile of GLP-1 RAs remains incompletely defined, representing an important evidence gap given the scale of global prescribing.</p> Objective <p>This systematic review aims to synthesise published evidence on respiratory adverse events temporally associated with GLP-1 RA therapy in adults, characterise their patterns and severity, appraise the risk of bias using validated design-appropriate tools, describe proposed pathophysiological mechanisms, and grade the certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. Given the heterogeneity of the included evidence—spanning case reports, pharmacovigilance analyses, and observational cohorts—this review is framed primarily as a signal-detection and evidence-mapping exercise rather than a causal-inference analysis.</p> Eligibility criteria <p>Adults (≥ 18 years) receiving any approved GLP-1 RA for any indication. Eligible study designs included randomised controlled trials (RCTs), retrospective and prospective observational cohorts, pharmacovigilance disproportionality analyses, and case reports or series. Studies were excluded if they enrolled paediatric populations, involved animal or in vitro experiments, reported only metabolic or cardiovascular outcomes without respiratory adverse-event data, or were narrative reviews, editorials, or commentaries without primary data.</p> Methods <p>A systematic review was conducted following PRISMA 2020 guidelines (PROSPERO: CRD420261305875). PubMed, Embase, and Scopus were searched from inception to January 2026. Risk of bias was assessed using the Cochrane Risk of Bias 2 (RoB2) tool for RCTs, the Newcastle-Ottawa Scale (NOS) for cohort studies, and Joanna Briggs Institute (JBI) checklists for case reports, case series, and pharmacovigilance studies. GRADE was applied at the outcome-domain level; evidence from uncontrolled designs (case reports, case series, pharmacovigilance analyses) was initially rated very low certainty, as these designs are inherently uncontrolled and start below the lowest GRADE tier. Given substantial heterogeneity, meta-analytic pooling was not performed; a pre-specified narrative synthesis following the Synthesis Without Meta-Analysis (SWiM) reporting guideline was conducted.</p> Results <p>Nineteen studies met inclusion criteria: four RCTs (<i>n</i> = 1,884 participants), five retrospective cohort studies (<i>n</i> = 1,122,653 participants), three pharmacovigilance analyses (<i>n</i> = 498,892 spontaneous adverse-event reports), and seven case reports or case series (<i>n</i> = 13 patients). Spontaneous reports do not represent unique exposed individuals and were not pooled with participant counts. Risk of bias: all four RCTs were rated low risk by RoB2 (with some concerns for open-label outcome ascertainment in three trials, a domain-specific issue that does not alter the overall RoB2 category from low); three of five cohort studies were rated moderate and one high risk by NOS (one cohort study rating not reported, classified as not reported/unable to rate); all three pharmacovigilance studies were rated high risk by JBI; and case reports were rated as methodologically adequate by JBI, though these instruments cannot overcome the inherent anecdotal nature and very limited generalisability of single-case designs. Upper respiratory tract infections (URTIs) were the most frequently reported adverse event (8 of 12 reporting studies, 66.7%), occurring at rates comparable to controls across RCTs (GRADE: MODERATE certainty). Pharmacovigilance analyses identified disproportionate reporting signals for dyspnoea and asthma-like events, particularly with exenatide, using the reporting odds ratio (ROR 2.14, 95% CI 1.88–2.43; Cazzola 2024); these signals are hypothesis-generating only and do not establish causality or incidence. Serious adverse events reported in temporal association with GLP-1 RA exposure included anaphylaxis with bronchospasm (<i>n</i> = 4 cases), acute eosinophilic pneumonia (<i>n</i> = 1), perioperative aspiration pneumonitis or pneumonia (multiple perioperative cases across two cohort studies and one case series), acute respiratory distress syndrome (ARDS; <i>n</i> = 2, one fatal requiring extracorporeal membrane oxygenation [ECMO]), and spontaneous pneumomediastinum (<i>n</i> = 1). A large global retrospective cohort study (<i>n</i> = 331,863 matched patients; Henney 2024) demonstrated a potentially meaningful reduction in incident pneumonia with GLP-1 RAs compared with dipeptidyl peptidase-4 (DPP-4) inhibitors (hazard ratio [HR] 0.60, 95% confidence interval [CI] 0.58–0.62; GRADE: LOW certainty); this finding should be interpreted cautiously given the retrospective design, active and non-inert comparator, and likelihood of residual confounding. Evidence certainty for serious respiratory events was very low, driven by sparse case reports and high-risk pharmacovigilance data.</p> Conclusion <p>GLP-1 RA therapy has a respiratory safety profile that is neither uniformly benign nor hazardous, stratified by mechanism, agent subclass, and clinical context. Common upper airway symptoms are mild and comparable to controls. Rare but clinically consequential events—including anaphylaxis, eosinophilic pneumonia, perioperative aspiration, and ARDS—have been reported in temporal association with GLP-1 RA exposure, predominantly in case reports and pharmacovigilance data of very low certainty; these signals are hypothesis-generating and should not be interpreted as confirmed causal risks. Exendin-4-based agents (exenatide and lixisenatide) appear to carry the highest reported risk of hypersensitivity reactions, attributable to their non-human structural origin. Clinicians should maintain heightened awareness for aspiration risk in perioperative settings; individualised, extended pre-procedural fasting intervals calibrated to the specific agent’s pharmacokinetic profile should be considered. Prospective, standardised, and adequately powered studies with pre-specified respiratory endpoints are required to move from signal detection to causal inference.</p>