Glucagon-like Peptide 1 Receptor Agonists and Asthma Exacerbations: Which Patients Benefit Most?

RATIONALE:While recent evidence suggested glucagon-like peptide 1 receptor agonists (GLP1RA) may reduce the risk of asthma exacerbations, it remains unclear which subpopulations might derive the most benefit from GLP1RA treatment. OBJECTIVE:To identify characteristics of patients with asthma that predict who might benefit the most from GLP1RA treatment using real-world data. METHODS:We implemented an active-comparator, new-user design analysis using commercially insured patients ages 18-65 from Marketscan data 2007-2019 and identified two cohorts: GLP1RA vs thiazolidinediones and GLP1RA vs sulfonylureas. The outcome was acute exacerbation of asthma (hospital admission or emergency department (ED) visit for asthma) within 180 days after initiation. We applied iterative causal forest (iCF), a novel causal machine learning subgrouping algorithm, to assess HTE. In identified subgroups, we predicted propensity score, conducted propensity score trimming, and then estimated adjusted risk differences (aRD) for the effect of GLP1RA relative to comparators on asthma exacerbation using inverse probability treatment weighting in propensity score trimmed subpopulation. RESULTS:Among 10,989 patients initiating GLP1RA or thiazolidinediones and 17,088 patients initiating GLP1RA vs sulfonylurea, GLP1RA initiators had fewer exacerbations with an aRD of -0.5% (95% CI -1.1% to 0.1%) and -1.6% (95% CI -2.2% to -1.1%), respectively. In the GLP1RAvsSUcohort where we observed beneficial effect, our iCF analysis identified 5 subgroups with different treatment effects, defined by number of ED visits, number of prescriptions of short-acting beta2-agonsit (SABA), number of prescriptions of inhaled steroid (ICS) and long-acting beta-agonists (LABA) (either combination therapy or concurrent use), and aged 50+. Among these, patients with 2+ ED visits during 12-month baseline period had the largest absolute exacerbation risk reduction, with a decrease of 2.8% for GLP1RA (95% CI: -4.8% to -0.9%). CONCLUSIONS:GLP1RA demonstrated beneficial effect on reducing asthma exacerbation relative to sulfonylureas. Asthma patients with 2+ ED visits (a proxy for disease severity) benefit most from GLP1RA. ED visit frequency, and number of maintenance and reliever inhalers, and age may help individualize prediction of the short-term benefit from GLP1RA on asthma exacerbation.