The present study is the first prospective crossover study comparing the effects of high-dose inhaled budesonide with fluticasone on adrenal suppression, in patients with moderate to severe COPD. The results indicate that there is no significantly different effect of either steroid formulation, on adrenal function, when measured by overnight urinary cortisol level and cortisol-creatinine ratio.
Tests for adrenal function include basal tests for adrenocortical activity and dynamic stimulation tests to check adrenocortical reserve. Integrated 24-hour plasma-free cortisol and urinary cortisol excretion is a very sensitive basal test for adrenal function.[10
] Measurement of an overnight or early morning urinary cortisol-creatinine excretion is as sensitive as an integrated 24-hour urinary cortisol collection and more sensitive than a 9 am cortisol assay.[11
] It is a simple and accurate test for within patient comparison of adverse effects on adrenal function. Hence, it was chosen as primary surrogate marker of adrenal suppression in this study.
The systemic effects of inhaled budesonide and fluticasone, in terms of adrenal suppression, have been investigated in asthmatic patients in a number of studies[12
] with conflicting results. Ringdal et al
] compared the effects of both steroids on hypothalamic-pituitary-adrenal (HPA) axis in a randomized, double blind, multicenter crossover trial. They compared budesonide 1 600 μg daily with fluticasone propionate 1 500 μg daily and found no clinically significant effects on HPA axis in moderate to severe asthma population. In contrast, Clark and Lipworth[14
] found significantly greater adrenal suppression (measured by both plasma and urinary cortisol) at three different doses, with fluticasone as compared to budesonide in asthmatic children as well as adults. They conclude that fluticasone may exert greater adrenal suppression due to enhanced receptor potency, prolonged tissue retention, and longer half-life. Fluticasone propionate is a trifluorinated glucocorticoid that is 300-fold lipophilic than budesonide, resulting in faster association with glucocorticoid receptor and slower dissociation, resulting in a half-life of >10 hours.[16
] The greater lipophilicity of fluticasone results in greater binding in systemic tissues with consequently increased volume of distribution and prolonged airway and systemic retention.[17
] Recently, Derom et al
] conducted first placebo-controlled, crossover study evaluating the systemic effects of ICS (Ciclesonide and Fluticasone) on cortisol secretion, bronchial hyper-responsiveness, and bone markers in ICS-dependent asthmatic patients. They found a significantly greater suppression of adrenal function and bone formation markers with fluticasone in comparison with ciclesonide. This could largely be explained by the difference in half-life of 3 hours and 7-14 hours in case of ciclesonide and fluticasone, respectively.
In a randomized double blind, crossover study, Dalby et al
] evaluated systemic bioavailability and airway clearance of fluticasone and budesonide in combination with LABA in 28 patients with severe COPD (Mean FEV1 37% predicted) and 27 healthy controls. Plasma concentration of ICS over 10 hours post-inhalation and sputum concentration of steroid over 6 hours were measured. The relative systemic bioavailability of the steroid formulation was similar in COPD patients and healthy subjects supporting our finding of the similar adrenal effects of these drugs. In a double blind, randomized crossover study[20
] evaluating pharmacokinetics of fluticasone in COPD and healthy controls, fluticasone caused less HPA suppression in COPD patients than healthy subjects. This difference was thought to be likely to be due to the altered pharmacokinetics of fluticasone propionate in COPD with the Cmax
and Area under the curve being substantially lower in comparison with controls. This suggests that adrenal response to inhaled steroids is blunted in patients with COPD, making significant adrenal suppression less likely.
The inhaler design may have a differential effect on drug absorption and bioavailability. We compared the two steroid formulations used via turbohaler (budesonide) and accuhaler (fluticasone). It is impossible in our current study to determine the relative contributions of differences in drug deposition or differences in pharmacological properties that contribute to our findings.
The findings of our study are interesting in terms of failure to show any significantly different effect on adrenal function with either formulation, and are in contrast to many studies conducted in patients with asthma. There could be a number of potential explanations for these findings. Patients with COPD, in particular with emphysema, have lung damage secondary to smoking with consequent reduction in steroid absorption in comparison with asthmatics that may have greater tendency to have systemic adverse effects. This mechanism is supported by the reduced gas transfer of 57% of predicted seen in our patients and evidence of extensive emphysema in those in whom thoracic CT scan had been performed. Alternatively, the adrenal response to high-dose ICS in COPD patients may be blunted due to the systemic effects of nicotine on HPA axis as there is evidence of impaired Adrenocorticotropic Hormone (ACTH) and cortisol stimulation in response to insulin-induced hypoglycemia and lysin-8-vasopressin test in smokers when compared with nonsmokers.[21
] We do not know whether the patients with moderate to severe COPD have significant basal adrenal suppression because of the confounding effect of preceding frequent administration of oral corticosteroids.
In our opinion, the present study has certain limitations. First, we do acknowledge the small number of participants and a high dropout rate in the study. Second, the doses of budesonide and fluticasone studied in this investigation might not be equipotent and may have a differential effect on adrenal function. However, the decision of comparison of 1 000 μg of fluticasone with 800 μg of budesonide per day was based on these doses being the recommended doses in moderate to severe COPD. Evaluation of adrenal suppression at different doses of ICS may enhance our understanding of effects of corticosteroids on HPA axis. Finally, this study was conducted at a single center and multicenter collaboration with a larger sample size may highlight the effects of inhaled steroids on adrenal function in greater detail.