Comparison of Various Glucocorticoid Replacement Regimens Used in Chronic Adrenal Insufficiency: A Systematic Review

Abstract

Objective: Patients with adrenal insufficiency require life-long glucocorticoid replacement therapy. Hydrocortisone (15–30 mg/day) and prednisolone (3–7.5 mg/day) are the preferred agents used although there is a lack of consensus among endocrinologists regarding the impact of different steroid regimens on quality of life, bone metabolism, cardiometabolic outcomes, adrenal crisis and infections. We carried out a retrospective systematic review of the literature to compare the efficacy and side effects of various glucocorticoid replacement regimens in patients with chronic adrenal insufficiency. Methods: We searched PubMed, Cochrane Reviews and Google Scholar databases up to March 14, 2019, for studies evaluating various clinical outcomes with glucocorticoid replacement therapy. The abstracts and full studies were appraised and data extracted from the eligible studies. The quality of evidence was evaluated and risk of bias carried out. Results: A total of 47 studies including 9 randomised controlled trials (RCTs) and 38 observational studies were evaluated in this systematic review. Prednisolone therapy was observed to be safe as well as efficacious as hydrocortisone although a higher dose was associated with an increased risk of cardiovascular (CV) disease. A lower hydrocortisone dose (15–20 mg/day) was associated with a reduction of blood pressure and improved clinical outcomes although this observation was based on a solitary RCT. Modified release hydrocortisone was observed to reduce the risk of CV disease based upon results from 2 of the RCTs. However, there was no conclusive evidence of benefit of modified release hydrocortisone and continuous subcutaneous hydrocortisone infusion in improving subjective health status. Conclusion: Prednisolone therapy remains a safe and efficacious alternative to hydrocortisone although there are concerns of dyslipidaemia and CV disease with higher doses. There is limited level I evidence suggestive of a positive effect of modified release hydrocortisone on CV and metabolic outcomes, particularly weight reduction.

Corticosteroid Replacement Therapy

“…Hydrocortisone is the most commonly administered glucocorticoid therapeutic agent for adrenal insufficiency. Clinic data from the UK revealed 72% of patients were managed with hydrocortisone, 26% with prednisolone and 2% with modified release hydrocortisone [9]. Data from the European Adrenal Insufficiency Registry.…”

“…In clinical practice the use of hydrocortisone or prednisolone are often preferable due to their more predictable pharmacokinetics compared to their precursor hormones cortisone and prednisone [9]. The normal functioning adrenal glands are thought to produce 5-10 mg cortisol per m 2 body surface area/per day; this equates to an oral hydrocortisone dose of 15-25 mg/per day for an adult [11].…”

“…It can be considered an alternative for patients who continue to feel unwell on conventional therapy, given typically at a dose of 15-25 mg daily. Evidence from 2 randomized-controlled trials (RCTs) has shown a reduction in CV disease risk parameters with modified release hydrocortisone compared to conventional therapy [9]. Though Plenadren® carries a significantly higher cost basis to the other traditional therapeutic glucocorticoid medications and carries a higher vulnerability to malabsorption during intercurrent gastrointestinal illness [16].…”

Latent Adrenal Insufficiency: From Concept to Diagnosis

“…The mean replacement dose reported in their study was 7.6 ± 3.5 mg/m2, reflecting daily endogenous cortisol production (72). A recent systematic review of 47 studies reported that although prednisolone therapy increased risk of dyslipidemia and cardiovascular disease, it was as safe and efficacious as hydrocortisone (73). It also suggested that lower doses of hydrocortisone (less than 20 mg/day) had better clinical outcomes, and failed to conclusively demonstrate an added benefit of modified release hydrocortisone or continuous subcutaneous hydrocortisone infusion using insulin pumps (73).…”

“…A recent systematic review of 47 studies reported that although prednisolone therapy increased risk of dyslipidemia and cardiovascular disease, it was as safe and efficacious as hydrocortisone (73). It also suggested that lower doses of hydrocortisone (less than 20 mg/day) had better clinical outcomes, and failed to conclusively demonstrate an added benefit of modified release hydrocortisone or continuous subcutaneous hydrocortisone infusion using insulin pumps (73). Current available regimens fail to replicate both circadian and ultradian rhythmicity of cortisol, potentially explaining the persistently low quality of life that patients with AI often complain about.…”