Dataset Information

Dose dependency of iatrogenic glucocorticoid excess and adrenal insufficiency and mortality: a cohort study in England.

ABSTRACT: CONTEXT:Adrenal insufficiency and Cushing's 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:70,638 people oral glucocorticoid-users and 41,166 non-users aged ?18 years registered in 389 practices in 1998-2017. 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 glucocorticoid-induced Cushing's syndrome. A total of 22,317 (31.6%) and 7,544 (18.3%) deaths occurred amongst glucocorticoid users and non-users, respectively. Incidence of all outcomes increased with higher current daily and cumulative doses. For adrenal insufficiency, the increases in HRs were of 1.07 (95% CI 1.04-1.09) for every increase of 5mg per day and of 2.25 (95% CI 2.15-2.35) per 1000mg of cumulative prednisolone-equivalent dose over the past year. The respective increases in HRs for Cushing's syndrome were of 1.09 (95% CI 1.08-1.11) and 2.31 (95% CI 2.23-2.40) and for mortality of 1.26 (95% CI 2.24-1.28) and 2.05 (95% CI 2.04-2.06). 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.

SUBMITTER: Mebrahtu TF

PROVIDER: S-EPMC6656418 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Publications

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

Mebrahtu Teumzghi F TF Morgan Ann W AW Keeley Adam A Baxter Paul D PD Stewart Paul M PM Pujades-Rodriguez Mar M

The Journal of clinical endocrinology and metabolism 20190901 9

<h4>Context</h4>Adrenal insufficiency and Cushing syndrome are known adverse events of glucocorticoids. However, no population estimates of dose-related risks are available.<h4>Objective</h4>To investigate dose-related risks of adrenal dysfunction and death in adults with six chronic inflammatory diseases treated with oral glucocorticoids.<h4>Design and setting</h4>Retrospective, record-linkage, open-cohort study spanning primary and hospital care in England.<h4>Patients</h4>A total of 70,638 or ...[more]

PMID: 31009052

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Project description:ObjectivesThe aim of this systematic literature review was to summarize the current knowledge regarding the prevalence of, time to recovery from, and influence of glucocorticoid dose and duration on glucocorticoid-induced adrenal insufficiency (AI).MethodsEligible studies were original research articles, which included adult patients with an indication for glucocorticoids and measured adrenal function following exposure to systemic glucocorticoids. Searches were performed in Web of Science and MEDLINE, with further articles identified from reference lists. Screening was performed in duplicate. Data were extracted for each group of glucocorticoid-exposed patients within eligible studies. The reported proportion of patients with AI was summarized as median and inter-quartile range. Results were then stratified by daily dose, cumulative dose, duration of exposure and time since last glucocorticoid use. The risk of bias within and across studies was considered: for randomised controlled trials risk of bias was assessed using the tool developed by the Cochrane Collaboration.ResultsOverall, 73 eligible studies were identified out of 673 screened. The percentage of patients with AI ranged from 0% to 100% with a median (IQR) = 37.4% (13-63%). Studies were small-median (IQR) group size 16 (9-38)-and heterogeneous in methodology. AI persisted in 15% of patients retested 3 years after glucocorticoid withdrawal. Results remained widely distributed following stratification. AI was demonstrated at <5mg prednisolone equivalent dose/day, <4 weeks of exposure, cumulative dose <0.5g, and following tapered withdrawal.ConclusionsThe heterogeneity of studies and variability in results make it difficult to answer the research questions with confidence based on the current literature. There is evidence of AI following low doses and short durations of glucocorticoids. Hence, clinicians should be vigilant for adrenal insufficiency at all degrees of glucocorticoid exposure.

Project description:Increased morbidity and mortality associated with conventional glucocorticoid replacement therapy for primary adrenal insufficiency (primary AI; estimated prevalence 93-140/million), secondary AI (estimated prevalence, 150-280/million, respectively) or congenital adrenal hyperplasia (estimated prevalence, approximately 65/million) may be due to the inability of typical glucocorticoid treatment regimens to reproduce the normal circadian profile of plasma cortisol. A once-daily modified-release formulation of hydrocortisone has been developed to provide a plasma cortisol profile that better mimics the daytime endogenous profile of cortisol. Here, we describe the protocol for the European Adrenal Insufficiency Registry (EU-AIR), an observational study to assess the long-term safety of modified-release hydrocortisone compared with conventional glucocorticoid replacement therapies in routine clinical practice (ClinicalTrials.gov identifier: NCT01661387).Patients enrolled in EU-AIR have primary or secondary AI and are receiving either modified-release or conventional glucocorticoid replacement therapy. The primary endpoints of EU-AIR are the incidence of intercurrent illness, adrenal crisis and serious adverse events (SAEs), as well as the duration of SAEs and dose changes related to SAEs. Data relating to morbidity, mortality, adverse drug reactions, dosing and concomitant therapies will be collected. Patient diaries will record illness-related dose changes between visits. All decisions concerning medical care are made by the registry physician and patient. Enrolment is targeted at achieving 3600 patient-years of treatment (1800 patient-years per group) for the primary analysis, which is focused on determining the non-inferiority of once-daily modified-release replacement therapy compared with conventional glucocorticoid therapy.Recruitment began in August 2012 and, as of March 2014, 801 patients have been enrolled. Fifteen centres are participating in Germany, the UK and Sweden, with recruitment soon to be initiated in the Netherlands.EU-AIR will provide a unique opportunity not only to collect long-term safety data on a modified-release preparation of glucocorticoid but also to evaluate baseline data on conventional glucocorticoid replacement. Such data should help to improve the treatment of AI.

Dataset Information

Dose dependency of iatrogenic glucocorticoid excess and adrenal insufficiency and mortality: a cohort study in England.

Publications

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

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