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Lipworth BJ. Systemic adverse effects of inhaled corticosteroid therapy. A systematic review and meta-analysis. Arch Intern Med. 1999 May 10; 159:941-55.
In patients with asthma, what are the systemic adverse effects of inhaled cor-ticosteroids (ICs)?
Studies were identified by searching MEDLINE, EMBASE/Excerpta Medica, and BIDS (1966 to July 1998) with 30 key terms and by scanning scientific abstracts in key respiratory and allergy journals and bibliographies.
Studies were selected if they provided sufficient data on patients, study design, quality, route of drug administration, end points, and analysis.
Data were extracted on patients; study design; drugs; end points; time of measurement; and outcomes for adrenal suppression, growth, bone density, and ocular and skin effects.
Adrenal suppression: 10 randomized, single- or double-blind, controlled trials (RCTs) evaluated 3 doses of ICs in adults (8 RCTs) and children (2 RCTs) with asthma. Adrenal cortisol suppression was shown in 7 of 8 RCTs on fluticasone (range 9% to 78%), 1 of 5 RCTs on budesonide (14% to 46%, depending on the test used to measure cortiol suppression), 2 of 2 RCTs on beclomethasone (6% and 36%), and 1 of 2 RCTs on triamcinolone (34%). An overall meta-analysis of 27 studies found equivalent adrenal suppression for prednisolone at 10 mg and flutica- sone at 1 mg and greater adrenal suppression with fluticasone compared with beclomethasone (1.9-fold), triamcinolone (3.7-fold), and budesonide (4.3-fold).
Growth: 6 double-blind RCTs evaluated the effect of ICs on growth. A reduction in growth was found for beclo-methasone compared with placebo (2 RCTs; mean reduction 1.0 cm/y at 7 mo, P < 0.001; 1.08 cm/y at 12 mo, P < 0.05), for salmeterol at 12 months (1 RCT; 1.4 cm/y, P < 0.01), and for theophylline at 12 months (1 RCT; 1.6 cm/y, P = 0.001). No effect was seen for fluticasone (1 RCT) at 12 months or for the addition of budesonide to albuterol at 22 months (1 RCT). 2 studies showed that final adult height in persons who used ICs in childhood was not adversely affected.
Bone mineral density (BMD): 7 cross-sectional and 3 longitudinal studies examined the effect of inhaled cortico- steroids on BMD. 2 longitudinal studies (1 of middle-aged persons for 12 mo and 1 of children for 6 mo) on beclometh-asone and 1 study (of middle-aged persons for 2 y) on budesonide, beclo-methasone, or both showed no effect on BMD.
Ocular and skin effects: 1 review and 4 studies examined ocular effects, and 3 studies examined skin effects. 2 studies showed a strong association between high-dose, IC use and posterior subcapsular cataracts, and the review showed an association between increased risk for cataracts and IC dose, age, and ethnic origin. 1 study showed a weak association between high doses of ICs and increased risk for ocular hypertension or open-angle glaucoma. 3 studies showed an association between ICs (especially beclomethasone) and skin bruising.
In patients with asthma, high doses of inhaled corticosteroids increase the risk for adrenal suppression (particularly with fluticasone), growth reduction (during the short to medium term), posterior subcapsular cataracts, ocular hypertension and glaucoma, and skin bruising. Longitudinal studies show no effects on bone mineral density.
Source of funding: None.
For correspondence: Not available.
Abstract and Commentary also published in ACP Journal Club. 1999;131:78.
Lipworth's review shows that all ICs exhibit dose-dependent adverse systemic effects. Most guidelines on asthma, including the U.S. National Heart, Lung, and Blood Institute guidelines, emphasize the importance and benefits of ICs for patients whose asthma cannot be managed by the use of as-needed inhaled b-agonists alone (1). This review confirms the important safety considerations articulated in product labeling, much of which is class labeling for ICs (e.g., hypothalamicpituitaryadrenocortical [HPA] axis effects and growth velocity effects in children).
Care should be taken in attempts to use these data to compare the relative systemic effects of the various ICs. The literature contains differing methods for assessment of systemic effects. For example, HPA axis effects are quantified by using many end points, ranging from spot plasma cortisol measurements and 24-hour urinary cortisol collections to serial, timed plasma cortisol assessments. All of these measures offer different sensitivities and clinical interpretability. More important, as Lipworth appropriately points out, these studies do not provide information on the relative therapeutic index of each drug. This can be accomplished only by comparing the ICs at equivalent doses in a single study, which is a daunting task.
What message should the practitioner who manages patients with asthma take from these findings? Asthma prevalence and mortality continue to increase, and the benefits of ICs are indisputable. This review reaffirms that after asthma has been stabilized with ICs, it is always desirable to titrate to the lowest effective dose to reduce the possibility of systemic effects and optimize the benefitrisk ratio for these drugs.
Peter K. Honig, MD, MPH
U.S. Food and Drug Administration
Rockville, Maryland, USA
1. National Asthma Education and Prevention Program (National Heart, Lung, and Blood Institute). Bethesda, MD: U.S. Department of Health and Human Services; 1997. Pub no. 97-4051.
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