Effects of Budesonide and Fluticasone on 24-Hour Plasma Cortisol

Donnelly, Richard; Williams, Kayon; Baker, A. B.; Badcock, CA; Day, Richard O.; Seale, J. Paul

doi:10.1164/ajrccm.156.6.9703003

Cited by 75 publications

(39 citation statements)

References 18 publications

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“…Unfortunately, most studies have assessed morning cortisol levels. This is recognised as a screening test for adrenocortical excess but is an insensitive measure and poor predictor of adrenal suppression [11,12]. In contrast, dynamic stimulation tests assess adrenal reserve and give an estimation of the capacity of the HPA axis to respond to stress.…”

Section: Methodological Issuesmentioning

confidence: 99%

“…This is an insensitive and variable measure for detecting adrenal suppression [10,11]. Other limitations have included the study of healthy volunteers rather than subjects with asthma [12] and studies in which subjects were not randomised to different doses, but were sequentially administered ICS in increasing doses [13]. These limitations are reflected in the conclusions of the most recent Cochrane meta-analyses [14,15], which state that data on the effect of ICS on adrenal function are limited and that the clinical significance of the findings is unclear.…”

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confidence: 99%

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Inhaled fluticasone propionate and adrenal effects in adult asthma: systematic review and meta-analysis

Masoli¹,

Weatherall²,

Holt³

et al. 2006

Eur Respir J

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The dose-response relationship of inhaled fluticasone propionate (FP) for adrenal suppression in adults with asthma is not clear.The current authors carried out a systematic review and meta-analysis of placebo-controlled randomised dose-response studies of o4 weeks' duration, which assessed the adrenal effects of FP by cosyntropin stimulation tests in adult asthma. The main outcome measure was the proportion of subjects with adrenal function below the lower limit of the normal range.Five studies, with a total of 732 subjects with asthma, met the inclusion criteria. Data on daily doses .1,000 mg were limited to one study. The proportion of subjects with adrenal function below the lower limit of the normal range on placebo was 3.9%; for a 500-mg per day increase in FP dose the odds of an abnormality increased by 1.38 (95% confidence interval 1.01-1.59). The continuous secondary outcome measures showed an inverse linear relationship with the FP dose up to 2,000 mg?day -1 .In conclusion, for routine prescribing within the established therapeutic dose-response range (50-500 mg?day -1 ), fluticasone propionate has minimal effects on adrenal function. This conclusion is limited by the paucity of long-term studies of daily doses of fluticasone propionate .1,000 mg and by the considerable individual variability in the response.

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Section: Methodological Issuesmentioning

confidence: 99%

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confidence: 99%

Inhaled fluticasone propionate and adrenal effects in adult asthma: systematic review and meta-analysis

Masoli¹,

Weatherall²,

Holt³

et al. 2006

Eur Respir J

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“…A progressive reduction in adrenal function can be observed with increasing doses of ICS over relatively short periods [102,184,185]. For example 5 days of treatment with high doses of fluticasone and budesonide caused near-complete reduction of the 24-h plasma cortisol profile [185].…”

Section: Systemic Side Effectsmentioning

confidence: 99%

Inhaled corticosteroids as combination therapy with β-adrenergic agonists in airways disease: present and future

Chung

Caramori

Adcock

2009

Eur J Clin Pharmacol

123

106

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International audienceInhaled corticosteroid (ICS) therapy in combination with long-acting β-adrenergic agonists represents the most important treatment for chronic airways diseases such as asthma and chronic obstructive pulmonary disease (COPD). ICS therapy forms the basis for treatment of asthma of all severities, improving asthma control, lung function and preventing exacerbations of disease. Use of ICS has also been established in the treatment of COPD, particularly symptomatic patients, who experience useful gains in quality of life, likely from an improvement in symptoms such as breathlessness and in reduction in exacerbations, and an attenuation of the yearly rate of deterioration in lung function. The addition of long-acting β-agonist (LABA) therapy with ICS increases the efficacy of ICS effects in moderate-to-severe asthma. Thus, a 800 μg daily dose of the ICS budesonide reduced severe exacerbation rates by 49% compared to a low dose of 200 μg daily, and addition of the LABA formoterol to budesonide (800 μg) led to a 63% reduction. In COPD, the effects of ICS are less prominent but there are beneficial effects on the decline in FEV and the rate of exacerbations. A reduction in the rate of decline in FEV of 16 ml/year with a 25% reduction in exacerbation rate has been reported with the salmeterol and fluticasone combination. A non-significant 17.5% reduction in all-cause mortality rate with ICS and LABA is reported. Chronic inflammation is a feature of both asthma and COPD, although there are site and characteristic differences. ICS targets this inflammation although this effect of ICS is less effective in patients with severe asthma and with COPD; however, addition of LABA may potentiate the anti-inflammatory effects of ICS. An important consideration is the presence of corticosteroid insensitivity in these patients. Currently available ICS have variably potent binding activities to specific glucocorticoid receptors, leading to inhibition of gene expression by either binding to DNA and inducing anti-inflammatory genes or by repressing the induction of pro-inflammatory mediators. Local side effects of ICS include oral candidiasis, hoarseness and dysphonia, while systemic side effects, such as easy bruising and reduction in growth velocity or bone mineral densitometry, are usually restricted to doses above maximally recommended doses. Use of LABA alone in patients with asthma increases the risk of asthma-related events including deaths, but this is less observed with the combination of ICS and LABA. Therefore, use of LABA alone is not recommended for asthma therapy. Future progress in ICS development will be characterised by the introduction of ICS with greater efficacy with a limited side-effect profile, and by longer-acting ICS that can be used in combination with once-daily LABAs. Other agents that could improve the efficacy of corticosteroids or reverse corticosteroid insensitivity may be added to ICS. ICS in combination with LABAs will continue to remain the main focus of treatment of airways diseases

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“…It is now well established that inhaled corticosteroids are absorbed into the systemic circulation, that their absorption is affected by lung function and that measureable dose-related systemic biological effects can occur [9][10][11][12][13]. Taken together with other data including the case reports and case-control studies, there is indeed evidence that inhaled corticosteroid use is associated with adrenal insufficiency, although the absolute risk is low and the association is dominated by the effects of systemic corticosteroid therapy.…”

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confidence: 99%

Getting risks right on inhaled corticosteroids and adrenal insufficiency

Watkins

Soriano²,

Mortimer

2013

Eur Respir J

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@ERSpublications Adrenal insufficiency should be considered in patients on inhaled corticosteroids presenting with suggestive symptoms http://ow.ly/kskjU As Thomas Addison observed in his famous monograph written in 1855, the adrenal glands are ''objects of deep interest'' and so they remain [1]. In the monograph he described several patients who presented with generalised weakness and in whom abnormalities of the adrenal glands were found at post mortem. Addison had discovered primary hypoadrenalism, the disease that would later take his name. He observed that ''the disease is by no means of very rare occurrence, and that were we better acquainted with its symptoms and progress, we should probably succeed in detecting many cases'' [1].With Addison's words ringing in our ears we reflect on the paper by LAPI et al. [2] in this issue of the European Respiratory Journal. LAPI et al.[2] describe a nested case-control study examining the association between inhaled corticosteroids and adrenal insufficiency conducted within a cohort of patients treated for respiratory conditions over a 15-year period, starting in 1990, in Quebec, Canada. They identified 392 cases of adrenal insufficiency from 368 238 prevalent users of respiratory medicines from the Régie de l'assurance médicale du Québec database. They did not find, as per their primary objective, an increased risk of adrenal insufficiency among current users of inhaled corticosteroids. However, they did report an increased risk in relation to the use of a current high dose (o52000 mg beclomethasone dipropionate (BDP)-units per day, equivalent to 1000 mg fluticasone per day) of inhaled corticosteroids (OR51.84; 95% CI: 1.16-2.90). They concluded that high doses of inhaled corticosteroids are an independent risk factor for adrenal insufficiency although the risk was much smaller than that seen with oral corticosteroids.This study provides interesting new data, and will add fuel to the debate, about the risk of adrenal insufficiency in patients prescribed inhaled corticosteroids. In our view the conclusion that high doses of inhaled corticosteroids alone increase the risk of adrenal insufficiency is not fully supported by the data presented. Although cases were more likely than controls to be users of high doses of inhaled corticosteroids, the lack of a clear dose-response relationship across the three tertiles of cumulative inhaled corticosteroid dose in the current users and, if anything, the protective effect of recent or past use, as depicted in table 2, casts some doubt on the assertion that there is an independent dose-related impact of inhaled corticosteroids on adrenal insufficiency. A critical issue overall is the overwhelming influence of oral corticosteroid therapy; there was an order of magnitude difference in the cumulative dose of oral corticosteroids in cases versus controls (547.4 mg versus 42.5 mg). Although the authors adjusted for the effect of oral corticosteroids, it is a difficult task to completely adjust for these strong effects. Residual confou...

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Effects of Budesonide and Fluticasone on 24-Hour Plasma Cortisol

Cited by 75 publications

References 18 publications

Inhaled fluticasone propionate and adrenal effects in adult asthma: systematic review and meta-analysis

Inhaled fluticasone propionate and adrenal effects in adult asthma: systematic review and meta-analysis

Inhaled corticosteroids as combination therapy with β-adrenergic agonists in airways disease: present and future

Getting risks right on inhaled corticosteroids and adrenal insufficiency

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