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.

Figure 1.

Study flow diagram and outcome identification. Eligibility inclusion criteria were a minimum of 1 year of registration in the CPRD practice, consent to data linkage, age ≥18 years, and a diagnosis of inflammatory bowel disease, systemic lupus erythematosus, polymyalgia rheumatica, giant cell arteritis, rheumatoid arthritis, and/or vasculitis before or during the study period (1 January 1998 to 15 March 2017). During periods of nonglucocorticoid exposure, 102 patients had adrenal insufficiency and 94 patients had Cushing syndrome diagnosed at a median of 52 [interquartile range (IQR): 31 to 79] d and 42 (IQR: 30 to 63) d, respectively, following glucocorticoid discontinuation. ADI, adrenal insufficiency; CS, Cushing syndrome; GC, glucocorticoid.

Figure 2.

Definition of time-variant oral glucocorticoid exposure variables. Inclusion criteria included a diagnosis of inflammatory bowel disease, systemic lupus erythematosus, polymyalgia rheumatica, giant cell arteritis, rheumatoid arthritis, and/or vasculitis before or during the study period (1 January 1998 to 15 March 2017). GC, glucocorticoid; PED, prednisolone equivalent dose.

Figure 3.

Time-variant cumulative and current dose-related oral glucocorticoid hazard ratios with 95% CIs for adrenal dysfunction by type of chronic inflammatory disease. (A) Adrenal insufficiency. (B) Cushing syndrome. Estimates are adjusted for prescribed inhaled, intra-articular, intramuscular, nasogastric, topical, and rectal glucocorticoids. HR, hazard ratio; IBD, inflammatory bowel disease; PMR/GCA, polymyalgia rheumatica and/or giant cell arteritis; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; VAS, vasculitis.

Figure 4.

Time-variant cumulative and current dose-related oral glucocorticoid hazard ratios for death by type of chronic inflammatory disease. Estimates are adjusted for prescribed inhaled, intra-articular, intramuscular, nasogastric, topical, and rectal glucocorticoids; baseline asthma; cancer; heart failure; chronic kidney disease; and inflammatory diseases (time-variant). All estimates were obtained among glucocorticoid users during the study period. HR, hazard ratio; IBD, inflammatory bowel disease; PMR/GCA, polymyalgia rheumatica and/or giant cell arteritis; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; VAS, vasculitis.