Effectiveness of metformin in preventing asthma exacerbations: a self-controlled case series and inverse propensity score weighting analysis

Background: Obesity and type-2 diabetes (T2DM) are prevalent in people with asthma. Metformin, the first-line medication for T2DM, has shown anti-inflammatory and airway remodeling properties in murine lungs, suggesting a potential preventive effect on asthma exacerbations.

Objectives: To determine whether metformin is associated with a decreased risk of asthma exacerbations among adults with T2DM.

Methods: Using UK nationwide electronic healthcare records from the Clinical Practice Research Datalink (2004 to 2021), linked to secondary care and mortality data, we drew a cohort of adult (>17 years) asthma patients that had not used metformin at cohort entry (new-users, NU). We then applied two different approaches to determine the association between metformin and exacerbations: a self-controlled case series (SCCS) and an inverse probability treatment weighted (IPTW) Cox proportional hazard model. For the SCCS, we ensured assumptions were not violated by excluding people with the outcome in a 12-month period before SCCS entry and included a 1-month pre-exposure period. Age-adjusted conditional Poisson regression was used to derive the effect estimates and risk period was divided into three periods (0-90 days, 91-180 days and 181-365 days). For the IPTW model, patients were censored on the first outcome event, treatment discontinuation or addition of other diabetes drugs, or the end of the 1-year follow-up period. Propensity scores were derived using logistic regression and the potential confounders including age, sex, socioeconomic deprivation, body mass index, smoking, comorbidities, asthma mediation, HbA1c. Asthma exacerbations (outcome) were defined as a short course of oral corticosteroids, an A&E visit, hospital admission, or death.

Results: In the SCCS, 4,395 NU were identified (62% female, mean age 52.3 years [SD 14.0]). Metformin was significantly associated with fewer exacerbations (Incidence Rate Ratio 95%CI: 0-90 days=0.65 (0.58-0.73); 91-180 days=0.70 (0.62-0.79); 181-365 days=0.74 (0.65-0.84).
In the IPTW-Cox model, 8,625 NU were identified with 6,027 NU and 2,598 non-users; 57% were women, mean age 59.6 years [SD 14.2], 90% were obese/overweight and 28% experienced exacerbations in the year before the study start. Metformin was again found to be associated with fewer exacerbations during the 12-month follow-up, and with a similar magnitude of effect (Hazard Ratio=0.77, 95%CI 0.68-0.86).

Conclusions: In this real-world UK study, using two different methodological approaches, we consistently found that metformin reduced the risk of an asthma exacerbation by around 40%. These results suggest that metformin, an affordable and easily available drug, could be an innovative option for managing asthma in a high-risk group.