Prednisolone once daily vs hydrocortisone thrice daily in hypoadrenalism: a randomized controlled trial

Importance: Adrenal insufficiency (AI) is conventionally treated with daily multiple-dose hydrocortisone. Once-daily low-dose prednisolone is an alternative for glucocorticoid replacement. This is the first ever clinical trial comparing once daily low-dose prednisolone with thrice-daily hydrocortisone. Objective: We investigate differences in metabolism and bone turnover with this comparative study of hydrocortisone versus prednisolone. Design, Setting and Participants: This double-blind randomised crossover trial of multiple-dose daily hydrocortisone versus once-daily low-dose prednisolone (2-5 mg), between September 2019 and December 2023, involved adults with AI. Anthropometrics, biochemical data for cardiometabolic and bone health, and subjective health survey data were collected at Day 1, 30 and 120 of each study period, on both medications. Intervention: Individuals were randomised to four months of once-daily prednisolone in the morning (placebos at noon and afternoon), or hydrocortisone at the same times. All participants were crossed over to the alternative treatment for a further four months. Main Outcome and Measures: The primary outcome was assessment of bone turnover, detected by change in carboxylated and under-carboxylated osteocalcin between Day 1 and Day 120 in each treatment period. Results: Forty-seven participants were randomised, 24 receiving prednisolone first and 23 for hydrocortisone first. Body weight fell by -1.04 kg [95%-CI -1.88 to -0.21] on prednisolone compared to an increase of 0.83 kg [-0.01 to 1.66] with hydrocortisone (treatment difference -1.87 kg, p=0.002). Waist circumference fell by -1.1 cm [95%-CI -2.4 to 0.1] on prednisolone and rose by 1.1 cm [95%-CI -0.1 to 2.4] on hydrocortisone (treatment difference -2.26 cm, p=0.01). HbA1c fell by -0.7 mmol/mol [95%-CI -1.2 to -0.2] on prednisolone and increased by 0.6 mmol/mol [95%-CI 0.1 to 1.1] on hydrocortisone (treatment difference -1.23 mmol/mol; p=0.001). Bone formation and resorption markers including osteocalcin, P1NP and urinary NTX were significantly lower on prednisolone compared to hydrocortisone. There were no differences in safety measures, or subjective health outcomes, including all SF36 domains and Addi-QoL questionnaire. Conclusions and Relevance: In this randomized clinical trial, once-daily low-dose prednisolone was associated with improvements in cardiometabolic health markers, in comparison to multiple-dose hydrocortisone, without compromising well-being. Studies assessing longer term mortality and morbidity outcomes are needed.