Abstract
BackgroundBiochemical adrenal insufficiency induced by glucocorticoid treatment is prevalent, but data on the clinical implications are sparse. We investigated clinical consequences of glucocorticoid-induced adrenal insufficiency after oral glucocorticoid cessation.MethodsWe conducted a Danish population-based self-controlled case series utilizing medical registries. In this design each individual serves as their own control allowing event rates to be compared as a function of time and treatment. Clinical indicators of adrenal insufficiency were defined as diagnoses of gastrointestinal symptoms, hypotension, cardiovascular collapse, syncope, hyponatremia, and hypoglycaemia. We included 286,680 persons who discontinued long-term (≥ 3 months) oral glucocorticoid treatment. We defined five risk periods and a reference period (before treatment): period 0 (on treatment), withdrawal period (1 month before and after cessation), followed by three consecutive 2 month-risk periods after withdrawal (periods 2–4).ResultsMedian age at cessation was 69 years and 57% were female. Median treatment duration was 297 days and median cumulative dose was 3000 mg prednisolone equivalents. The incidence rates of hypotension, gastrointestinal symptoms, hypoglycemia and hyponatremia were increased in the withdrawal period compared to before treatment started (reference period). Incidence rate ratios comparing the withdrawal period with the reference period were 2.5 [95% confidence interval (CI): 1.4–4.3] for hypotension, 1.7 (95% CI: 1.6–1.9) for gastrointestinal symptoms, 2.2 (95% CI: 0.7–7.3) for hypoglycemia, and 1.5 (95% CI: 1.1–2.0) for hyponatremia. During 7 months of follow up, the rates of hypotension and gastrointestinal symptoms remained elevated compared to the reference period. Risk factors included use of antibiotics, increasing average daily dose of glucocorticoids, cumulative dose, and age.ConclusionOral glucocorticoid withdrawal was associated with adverse outcomes attributable to adrenal insufficiency. Our study underscores the need for future research to establish evidence-based clinical guidance on management of patients who discontinue oral glucocorticoids.
Highlights
Primary adrenal insufficiency and secondary adrenal insufficiency due to a pituitary disorder are rare but serious conditions necessitating appropriate replacement therapy [1,2,3]
Biochemical adrenal insufficiency induced by glucocorticoid treatment is prevalent, but data on the clinical implications are sparse
The incidence rates of hypotension, gastrointestinal symptoms, hypoglycemia and hyponatremia were increased in the withdrawal period compared to before treatment started
Summary
Primary adrenal insufficiency and secondary adrenal insufficiency due to a pituitary disorder are rare but serious conditions necessitating appropriate replacement therapy [1,2,3]. Glucocorticoid treatment suppresses the hypothalamic-pituitary-adrenal (HPA) axis, which may compromise endogenous cortisol secretion in response to stress and induce a state of relative adrenal insufficiency [1, 2]. A recent meta-analysis estimated a 50% pooled risk of biochemical adrenal insufficiency among oral glucocorticoid users [4]. This is noteworthy, considering that the annual prevalence of systemic glucocorticoid use is 3% in the Danish population [16]. We conducted a population-based self-controlled case series analysis of clinical indicators of adrenal insufficiency during and after withdrawal of oral glucocorticoids. We investigated clinical consequences of glucocorticoid-induced adrenal insufficiency after oral glucocorticoid cessation
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