Plasma pharmacometabolomics of inhaled corticosteroid-related adrenal suppression in asthma

Abstract

Background: Inhaled corticosteroids (ICSs) are frequently prescribed medications for asthma symptoms, but higher doses can increase risks of adrenal insufficiency through suppression of endogenous cortisol production. Understanding which patients may be at increased risk for developing adrenal suppression related to ICS use may help providers improve treatment regimens for asthmatic patients; however, the mechanisms underlying ICS-related adrenal insufficiency have not been clarified.

Objective: We sought to identify metabolite signatures and biochemical pathways associated with ICS-related adrenal insufficiency in asthmatic patients.

Methods: Global metabolite profiling (metabolomics) was integrated with electronic medical records data including the development of adrenal suppression in 2 independent asthma cohorts. The discovery cohort (Pharmacogenomics of Adrenal Suppression with Inhaled Corticosteroids) included 711 adult asthmatic patients on ICSs. Untargeted metabolomic profiling identified 1397 metabolites, of which 810 were selected for further analysis. Using plasma cortisol as a biomarker for adrenal status (outcome), linear regression models were used to identify associations between metabolites and plasma cortisol, adjusted for potential confounders. In the validation cohort (Omics Determinant of Longitudinal Lung Function in Asthma Study), metabolite associations were validated in 575 patients on ICSs. Pathway and network analyses were performed using bioinformatic approaches to identify altered metabolic pathways related to the outcome.

Results: Of 810 endogenous metabolites, 12 demonstrated significant associations with adrenal insufficiency after correction for multiple comparisons. In the validation cohort, 3 of these 12 replicated, including 2 steroid metabolites (tetrahydrocortisol glucuronide and tetrahydrocortisol glucuronide (5)) and homocitrulline. Pathway and network analyses revealed alterations in biochemical pathways related to the metabolism of steroids, bile acids, urea cycle, and long-chain polyunsaturated fatty acids.

Conclusions: We have identified specific metabolites within steroid and nonsteroid metabolic pathways that are associated with adrenal insufficiency with ICS use.

Keywords: Asthma; adrenal suppression; inhaled corticosteroids; metabolomics.