Dose Dependency of Iatrogenic Glucocorticoid Excess and Adrenal Insufficiency and Mortality: A Cohort Study in England

Abstract

Context Adrenal insufficiency and Cushing syndrome are known adverse events of glucocorticoids. However, no population estimates of dose-related risks are available. Objective To investigate dose-related risks of adrenal dysfunction and death in adults with six chronic inflammatory diseases treated with oral glucocorticoids. Design and setting Retrospective, record-linkage, open-cohort study spanning primary and hospital care in England. Patients A total of 70,638 oral glucocorticoid users and 41,166 nonusers aged ≥18 years registered in 389 practices in 1998 to 2017. Main outcome measures Incidence rates and hazard ratios (HRs) of diagnosed adrenal dysfunction and death. Results During a median follow-up of 5.5 years, 183 patients had glucocorticoid-induced adrenal insufficiency and 248 had glucocorticoid-induced Cushing syndrome. A total of 22,317 (31.6%) and 7544 (18.3%) deaths occurred among glucocorticoid users and nonusers, respectively. The incidence of all outcomes increased with higher current daily and cumulative doses. For adrenal insufficiency, the increases in HRs were 1.07 (95% CI: 1.04 to 1.09) for every increase of 5 mg per day and 2.25 (95% CI: 2.15 to 2.35) per 1000 mg of cumulative prednisolone-equivalent dose over the past year. The respective increases in HRs for Cushing syndrome were 1.09 (95% CI: 1.08 to 1.11) and 2.31 (95% CI: 2.23 to 2.40) and for mortality 1.26 (95% CI: 2.24 to 1.28) and 2.05 (95% CI: 2.04 to 2.06). Conclusion We report a high glucocorticoid dose-dependent increased risk of adrenal adverse events and death. The low observed absolute risk of adrenal insufficiency highlights a potential lack of awareness and a need for increased physician and patient education about the risks of adrenal dysfunction induced by glucocorticoids.

High prescription rate of oral glucocorticoids in children and adults: A retrospective cohort study from Western Sweden

“…Indeed, overtreatment with GCs is a serious health problem. A recent article showed that GC‐induced Cushing syndrome is more common than tertiary adrenal insufficiency although the author concludes that the low absolute risk of adrenal insufficiency highlights a potential lack of awareness …”

Novel medications inducing adrenal insufficiency

“…However, iatrogenic suppression of the hypothalamicpituitary-adrenal (HPA) axis is an increasing challenge for clinicians 2 . One important factor is the widespread use of novel steroid medications to manage chronic diseases in an ageing society 1,3 . Novel drugs targeting common disorders (for example, hypertension or cancer) interfere with adrenal steroid synthesis or metabolism and have the potential to induce adrenal suppression.…”

Endogenous urinary glucocorticoid metabolites and mortality in prednisolone‐treated renal transplant recipients

“…To our knowledge, there are no studies in RTR which investigated the association of urinary cortisol metabolism and mortality long‐term after kidney transplantation. However, there are studies in other populations, such as patients with rheumatoid arthritis, pituitary adenoma, acromegaly, and alcoholic hepatitis, showing that treatment with higher doses of corticosteroids is associated with an increased risk of mortality.…”