Endocrine Abstracts

Importance: Adrenal insufficiency is a life-threatening condition complicating heterogenous disorders across various disciplines, with challenging diagnosis and a notable drug-induced component.

Objective: To describe the spectrum and main features of drug-induced adrenal insufficiency through adverse drug event reports received by the Food and Drug Administration (FDA).

Design: We conducted a retrospective disproportionality analysis within one of the largest publicly accessible spontaneous reporting systems.

Setting: The FDA Adverse Event Reporting System (FAERS) collecting more than 15 million reports since 2004.

Participants: Adverse event reports extracted from FAERS over the past 2 decades, with a focus on the 2015-2020 period.

Main Outcomes and Measures: We assessed the reporting trend of drug-induced adrenal insufficiency through descriptive statistics. Cases were selected if they contained any of the preferred terms in the Medical Dictionary for Regulatory Activities describing adrenal hypofunctions. We computed the reporting odds ratio (ROR) with relevant 95% confidence interval (CI) using Bonferroni correction to identify signals of disproportionate reporting for drugs recorded in at least 10 cases as primary suspect.

Results: We identified 8496 cases of adrenal insufficiency, 97.5% serious and 41.1% requiring hospitalization. Adrenal insufficiency showed an exponential increase throughout the years, with 5282 (62.2%) cases in 2015-2020. Among 164 drugs, we identified 56 compounds associated with significant disproportionality within various pharmacological classes: glucocorticoids (n=1971), monoclonal antibodies (n=1644, of which 1330 associated with immune checkpoint inhibitors, reaching 76% in 2020), hormone therapy (n=291), anti-infectives (n=252), drugs used for hypercortisolism or adrenocortical cancer diagnosis and/or treatment (n=169), protein kinase inhibitors (n=138). Cases of adrenal insufficiency by glucocorticoids were stable in each 5-year period (22-27%), whereas those by monoclonal antibodies peaked from 13% in 2010-2015 to 33% in 2015-2020.

Conclusions and Relevance: Our study provides a comprehensive insight into the evolution of drug-induced adrenal insufficiency, highlighting the heterogeneous spectrum of culprit drugs classes, the consolidated role of topical and systemic corticosteroids, and the emerging increased reporting of immune checkpoint inhibitors. Our data claim for an urgent identification of predictive factors of drug-induced adrenal insufficiency, and the establishment of screening protocols and educational programs for patients and caregivers.