GLP-1 receptor agonists and obstructive lung disease: Beyond metabolic control to respiratory outcomes

Abstract

Chronic obstructive pulmonary disease (COPD) and asthma are increasingly recognized as systemic conditions shaped by metabolic comorbidities, particularly obesity and type 2 diabetes mellitus (T2DM). Beyond traditional airway-directed therapies, increasing attention has turned to whether metabolic interventions may influence respiratory outcomes. In this context, glucagon-like peptide-1 receptor agonists (GLP-1RAs), widely used for the treatment of T2DM and obesity, have emerged as unexpected candidates with potential relevance for obstructive lung disease control. The aim of this review is to synthesize emerging clinical, real-world, and mechanistic evidence linking GLP-1RA therapy to respiratory outcomes in COPD and asthma.

Accumulating real-world evidence from population-based cohorts, comparative effectiveness studies, and recent meta-analyses consistently associates GLP-1RA use with reduced rates of moderate and severe exacerbations in patients with COPD or asthma and comorbid T2DM, particularly when compared with sulfonylureas and dipeptidyl peptidase-4 inhibitors. Notably, these associations appear most pronounced among patients with obesity, frequent exacerbations, or high healthcare utilization. In contrast, randomized cardiovascular outcome trials of GLP-1RAs have generally shown neutral effects on respiratory endpoints, a finding that likely reflects the absence of prespecified pulmonary outcomes and limited event capture rather than a true absence of biological effect. Importantly, recent proof-of-principle disease-focused randomized trials in obesity-related COPD have begun to report respiratory-specific benefits, complementing large real-world and nationwide observational data.

From a mechanistic perspective, the observed respiratory signal may reflect a combination of indirect metabolic effects, such as weight loss, improved glycemic control, and reduced systemic inflammation, together with direct airway and immune-modulatory actions mediated by GLP-1R expression in airway smooth muscle and immune cells. Importantly, recent proof-of-principle and disease-focused randomized trials in obesity-related asthma and COPD are now specifically designed to interrogate these pathways and address limitations inherent to observational data. Although the current evidence base remains largely observational and subject to residual confounding, its consistency across diverse settings supports that GLP-1RAs may act as systemic metabolic modulators with potential respiratory relevance. Prospective RCTs with prespecified respiratory endpoints will be important to establish causality and define the role of GLP-1RAs beyond metabolic control, toward clinically meaningful respiratory outcomes in obstructive lung disease.