The changing face of drug-induced adrenal insufficiency in the Food and Drug Administration Adverse Event Reporting System

Adrenal insufficiency (AI) is a life-threatening condition complicating heterogenous disorders across various disciplines, with challenging diagnosis and notable drug-induced component. To describe the spectrum of drug-induced AI through adverse drug event reports received by the Food and Drug Administration (FDA). Retrospective disproportionality analysis. FDA Adverse Event Reporting System (FAERS) (>15,000,000 reports since 2004). Adverse event reports extracted from FAERS over the past 2 decades. Cases containing any of the preferred terms in the Medical Dictionary for Regulatory Activities describing AI. Signals of disproportionate reporting for drugs recorded in ≥10 cases as primary suspect. Reporting trend of drug-induced AI. We identified 8,496 cases of AI, 97.5% serious, 41.1% requiring hospitalization. AI showed an exponential increase throughout the years, with 5,282 (62.2%) cases in 2015-2020. We identified 56 compounds associated with significant disproportionality: glucocorticoids (N=1971), monoclonal antibodies (N=1644, of which N=1330 associated with immune checkpoint inhibitors - ICIs), hormone therapy (N=291), anti-infectives (N=252), drugs for hypercortisolism or adrenocortical cancer diagnosis/treatment (N=169), protein kinase inhibitors (N=138). Cases of AI by glucocorticoids were stable in each 5-year period (22-27%), whereas those by monoclonal antibodies, largely ICIs, peaked from 13% in 2010-2015 to 33% in 2015-2020. We provided a comprehensive insight into the evolution of drug-induced AI, highlighting the heterogeneous spectrum of culprit drug classes and the emerging increased reporting of ICIs. We claim for urgent identification of predictive factors for drug-induced AI, and establishment of screening and educational protocols for patients and caregivers.