Two hundred and eighty nine patients with a recorded diagnosis of adrenal insufficiency were identified; 135 with a previous prescription for oral hydrocortisone were excluded, leaving 154 cases and 870 controls who contributed a median of 4.9 (IQR 2.5–8.5) years and 5.3 (IQR 2.6–8.5) years of data prior to the index date. The mean (SD) age of the cases was 53 (21) years and 64 (42%) were male. Patients with adrenal insufficiency were more likely than controls to have asthma or COPD but were of similar body mass index and smoking status (table 1).
Table 1Demographic details of cases and controls
Of the cases and controls, 58 (38%) and 59 (7%) had been prescribed an oral corticosteroid, 31 (20%) and 78 (9%) had been prescribed an inhaled corticosteroid, and 92 (60%) and 764 (88%) had no recorded prescriptions for either an inhaled or oral corticosteroid. Of those prescribed an oral corticosteroid, cases and controls received a median of 2 (IQR 0.4–5.5) and 0.5 (IQR 0.2–1.2) courses of oral corticosteroid per year, respectively. Of the people prescribed an inhaled corticosteroid within 90 days of the index date (22 cases and 40 controls), the mean (SD) daily dose was 1054 (774) μg for cases and 667 (367) μg for controls (data missing for one control) in the 90 days prior to the index date. The mean (SD) daily dose of beclometasone dipropionate, budesonide, and fluticasone propionate for cases was 1116 (885) μg, 444 μg (based on one case) and 890 (545) μg, respectively, and for controls was 678 (385) μg, 467 (277) μg and 500 (192) μg, respectively. There were no prescriptions for mometasone furoate.
Univariate analysis showed that a prescription for at least one course of oral corticosteroids was associated with an increased risk of adrenal insufficiency with an OR of 8.6 (95% CI 5.5 to 13.5). This increased risk was dose related with an OR of 2.0 (95% CI 1.6 to 2.5) per course of oral corticosteroids per year. After adjusting for the mean daily dose of inhaled corticosteroid prescribed in the past 90 days, this OR was almost unchanged at 1.9 (95% CI 1.5 to 2.4).
Univariate analysis also showed that at least one prescription for an inhaled corticosteroid was associated with adrenal insufficiency with an OR of 2.5 (95% CI 1.6 to 4.0). After adjusting for the number of courses of oral corticosteroids prescribed per year as a continuous variable, this OR was reduced to 1.3 (95% CI 0.8 to 2.3). Before adjusting for the impact of oral corticosteroids, a prescription for an inhaled corticosteroid within 90 days of the index date was associated with an increase in the risk of adrenal insufficiency with an OR of 3.4 (95% CI 1.9 to 5.9) while a prescription for an inhaled corticosteroid before this time point was not associated with an increased risk (OR 1.6, 95% CI 0.7 to 3.4). After adjusting for the number of courses of oral corticosteroids prescribed per year, the equivalent ORs were 1.6 (95% CI 0.8 to 3.2) and 1.0 (95% CI 0.4 to 2.3), respectively (table 2).
Table 2Association between individual inhaled corticosteroids and adrenal insufficiency
The increased risk of adrenal insufficiency in people taking an inhaled corticosteroid was dose related (table 3, p for trend <0.001) and, although this relationship was attenuated, it remained significant at the 5% level after adjusting for courses of oral corticosteroids (p for trend
Table 3Association between mean daily dose of inhaled corticosteroid and adrenal insufficiency
The increase in risk of adrenal insufficiency differed between inhaled corticosteroids although the confidence intervals were wide and overlapped. The ORs for a prescription within 90 days of the index date for beclometasone dipropionate and fluticasone propionate after adjusting for oral corticosteroid exposure were 1.1 (95% CI 0.5 to 2.7) and 4.6 (95% CI 1.3 to 17.0), respectively; there were insufficient data for budesonide (table 2).