Glucagon-Like Peptide-1 Receptor Agonists in Asthma and Obesity-Associated Asthma: A Systematic Review of Clinical Outcomes and Translational Mechanisms.

Abstract

Obesity and metabolic dysfunction are increasingly recognized as important modifiers of asthma risk, severity, and treatment response. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), widely used for type 2 diabetes and obesity, have been associated with improved respiratory outcomes, but the underlying clinical and biological mechanisms remain incompletely defined. To systematically review and synthesize clinical, translational, and preclinical evidence evaluating the effects of GLP-1RAs on asthma outcomes, with particular attention to weight-dependent, metabolic, and airway-intrinsic mechanisms. We conducted a systematic review of human observational studies, clinical trials, and preclinical investigations assessing associations between GLP-1RA exposure and asthma-related outcomes. Data extraction included study design, population characteristics, respiratory outcomes, mechanistic findings, and risk-of-bias assessments using validated tools appropriate to study type. Across observational human studies, GLP-1RA use was consistently associated with reduced asthma exacerbations and health care utilization, predominantly in populations with obesity and/or type 2 diabetes. Several studies reported associations that persisted after adjustment for body mass index or glycemic markers. Preclinical models demonstrated reductions in airway inflammation, hyper-responsiveness, and epithelial cytokine signaling, though these findings were subject to substantial risk of bias and species-specific differences in GLP-1 receptor expression. Overall, evidence supporting airway-intrinsic effects remains largely preclinical, whereas human data are limited by confounding and population selection. Current evidence suggests that GLP-1RAs may improve asthma outcomes through mechanisms that extend beyond weight loss, potentially involving metabolic and airway-relevant pathways. However, uncertainty remains regarding benefits in the absence of metabolic dysfunction. Ongoing randomized controlled trials will be critical to clarifying causality, defining responsive asthma phenotypes, and determining the clinical role of GLP-1RAs in broader asthma populations.