The Changing Face of Drug-induced Adrenal Insufficiency in the Food and Drug Administration Adverse Event Reporting System

Abstract

Context Adrenal insufficiency (AI) is a life-threatening condition complicating heterogenous disorders across various disciplines, with challenging diagnosis and notable drug-induced component. Objective To describe the spectrum of drug-induced AI through adverse drug event reports received by the Food and Drug Administration (FDA). Design Retrospective disproportionality analysis. Setting FDA Adverse Event Reporting System (FAERS) (>15,000,000 reports since 2004). Participants Adverse event reports extracted from FAERS over the past 2 decades. Interventions 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. Main Outcomes and Measures Reporting trend of drug-induced AI. Results 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. Conclusions 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.

Adrenal Insufficiency with Anticancer Tyrosine Kinase Inhibitors Targeting Vascular Endothelial Growth Factor Receptor: Analysis of the FDA Adverse Event Reporting System

“…In the FAERS database, AEs are classified according to the Medical Dictionary for Regulatory Activities (MedDRA) terminology in terms of signs/symptoms, called preferred terms (PTs). AEs of interest were identified using PTs under the high-level term “adrenal cortical hypofunctions”, in line with a recent study [ 20 ].…”

“…We also analyzed three mAbs targeting VEGF (bevacizumab, ranibizumab, ramucirumab) and the fusion protein aflibercept. Immune checkpoint inhibitors (ICIs) served as a positive control, considering their recognized association with AI [ 20 , 21 ]. Cyclin-Dependent Kinase (CDK)-TKIs (abemaciclib, palbociclib, ribociclib) and Janus Kinase (JAK)-TKIs (upadacitinib, ruxolitinib, tofacitinib, baricitinib) served as negative controls.…”

“…If an imbalance in the number of cases vs. non-cases emerges, a disproportionality signal can be claimed, thus informing physicians to proactive monitoring [ 23 ]. We calculated two different disproportionality measures to reduce the likelihood of false positives: the frequentist reporting odds ratio (ROR), deemed statistically significant by the lower limit of the 95% of the Confidence Interval (CI) >1, with at least five cases, using the Bonferroni correction to reduce the likelihood of detecting spurious associations related to multiple testing [ 20 ]. the Bayesian Information Component (IC), deemed significant by the 95% credibility interval, IC0 25 > 0, which is more accurate in case of low number of cases [ 24 ].…”

“…the frequentist reporting odds ratio (ROR), deemed statistically significant by the lower limit of the 95% of the Confidence Interval (CI) >1, with at least five cases, using the Bonferroni correction to reduce the likelihood of detecting spurious associations related to multiple testing [ 20 ].…”

Trends in hospital admissions for adrenal insufficiency in adolescents and young adults in the 21st century

“…Alternatively, their AI diagnosis may be seen as a secondary problem relative to other reasons for admission, such as management of fertility and genitourinary issues. Admissions for a principal diagnosis of “drug-induced AI” were also very uncommon, despite drug-related iatrogenic AI being considered a common, often undiagnosed, and potentially increasing cause of AI in populations ( 30 ). It is possible that, in this dataset of hospital admissions, some patients coded as having an AC or another subtype of AI may have had drug-induced AI, thereby leading to an underestimate of the true rate of admissions for this category of AI.…”