Antidiabetic Medication and Asthma Attacks

Importance Elevated body mass index (BMI) and type 2 diabetes are prevalent in asthma and are associated with an increase in the risk of asthma attacks. In experimental studies, the diabetes medications metformin and glucagon-like peptide-1 receptor agonists (GLP-1RA) have mitigated airway inflammation, hyperresponsiveness, and remodeling. However, epidemiological evidence is limited. Objective To estimate the association of metformin and add-on antidiabetic medications (GLP-1RA, dipeptidyl peptidase-4 inhibitors, sulphonylureas, sodium-glucose cotransporter-2 inhibitors, and insulin) with asthma attacks. Design, Setting, and Participants The study used data from the UK Clinical Practice Research Datalink (CPRD) Aurum linked hospital admissions and mortality data from 2004 to 2020. A triangulation approach was used that applied 2 distinct approaches to enhance robustness: a self-controlled case series (SCCS) and a metformin new user cohort with inverse probability of treatment weighting (IPTW). Eligible participants were new users of metformin with type 2 diabetes. To evaluate the association between metabolic phenotypes (BMI, glycemic control) and asthma phenotypes (type 2 inflammation, asthma severity), interaction analyses were conducted. Negative control analyses were conducted to assess for bias. Exposure The primary exposure was metformin; secondary exposures included add-on antidiabetic medications. Main Outcomes The primary outcome was first asthma exacerbation (short course of oral corticosteroids, unscheduled asthma-related hospital attendance, or death) during 12-month follow-up. Incidence rate ratios (IRRs) with 95% CIs were estimated using fixed-effect conditional Poisson models in the SCCS, and hazard ratios (HRs) were estimated using weighted Cox proportional hazards models in the cohort. Results Of more than 2 million adults with asthma, 4278 patients (2617 women [61.2%]; mean [SD] age, 52.9 [13.6] years) were identified for the SCCS and 8424 patients (4690 women [55.7%]; unexposed: mean [SD] age, 61.6 [13.2] years; exposed: mean [SD] age, 59.7 [13.7] years) for the IPTW cohort. Metformin was found to be associated with fewer asthma attacks of similar magnitude in both approaches (SCCS: IRR, 0.68; 95% CI, 0.62-0.75; IPTW: HR, 0.76; 95% CI, 0.67-0.85). Negative control analyses did not find evidence of significant bias. Hemoglobin A 1c levels, BMI, blood eosinophil cell counts, and asthma severity did not modify the association. The only add-on antidiabetic medication to have an additive association was GLP-1RA (SCCS: IRR, 0.60; 95% CI, 0.49-0.73). Conclusions and Relevance The results of this cohort study suggest that metformin was associated with a lower rate of asthma attacks, with further reductions with the use of GLP-1RA. This appeared to be associated with mechanisms other than through glycemic control or weight loss and occurred across asthma phenotypes.