Prednisolone Once Daily vs Hydrocortisone Thrice Daily in Hypoadrenalism: A Randomized Clinical Trial.

Importance: Adrenal insufficiency is conventionally treated with daily multiple-dose hydrocortisone, and once-daily low-dose prednisolone is an alternative for glucocorticoid replacement. Clinical trials comparing once-daily low-dose prednisolone with thrice-daily hydrocortisone are lacking. Objective: To examine the differences in metabolism and bone turnover in patients receiving hydrocortisone vs prednisolone for adrenal insufficiency. Design, Setting, and Participants: This double-blind, crossover randomized clinical trial of multiple-daily standard-dose hydrocortisone vs once-daily low-dose prednisolone (2-5 mg), performed from September 3, 2019, to December 14, 2023, involved adults with adrenal insufficiency. Anthropometrics, biochemical data for cardiometabolic and bone health, and subjective health survey data were collected at days 1, 30, and 120 of each study period for both medications. Intervention: Individuals were randomized to receive 4 months of once-daily prednisolone in the morning (with placebos at noon and afternoon) or hydrocortisone at the same times. All participants were crossed over to the alternative treatment for an additional 4 months. Main Outcome and Measures: The primary outcome was assessment of bone turnover, detected by change in carboxylated and undercarboxylated osteocalcin between days 1 and 120 in each treatment period. Secondary outcomes included change in weight, body mass index, waist circumference, glycated hemoglobin, and subjective heath survey responses. Results: Forty-seven participants were randomized, with 46 participants included in the analysis (median [IQR] age, 55.0 [46.5-62.8] years; 24 [52.2%] male). Twenty-four received prednisolone first and 22 received hydrocortisone first. Bone turnover was significantly slowed with prednisolone compared with hydrocortisone as evidenced by a significantly lower level of multiple bone markers, including carboxylated osteocalcin (mean treatment difference, -1.22 ng/mL; 95% CI, -2.35 to -0.10 ng/mL; P = .04), undercarboxylated osteocalcin (mean treatment difference, -1.38 ng/mL; 95% CI, -2.32 to -0.44 ng/mL; P = .005) (to convert osteocalcin to micrograms per liter, multiply by 1), urinary N-terminal telopeptide (mean treatment difference, -9.34 nmol/mmol; 95% CI, -15.4 to -3.29 nmol/mmol; P = .002), and procollagen type 1 N-terminal propeptide (mean treatment difference, -13.8 ng/mL; 95% CI, -22.2 to -5.49 ng/mL; P < .001). The mean treatment group difference in weight reduction from baseline was -1.87 kg (95% CI, -3.02 to -0.72 kg; P = .002) for prednisolone treatment compared with hydrocortisone, and this was associated with concordant significantly greater reductions in body mass index (BMI; calculated as weight in kilograms divided by the square of height in meters; treatment difference, -0.522; 95% CI, -1.01 to -0.04; P = .04), waist circumference (treatment difference, -2.26 cm; 95% CI, -3.97 to -0.56 cm; P = .01), and HbA1c (treatment difference, -0.12% [-1.23 mmol/mol; 95% CI, -1.95 to -0.51 mmol/mol]; P = .001). There were no differences in safety measures or subjective health outcomes, including all 36-Item Short-Form Health Survey domains and Addison's Disease-Specific Quality of Life Questionnaire. Conclusions and Relevance: In this randomized clinical trial, once-daily low-dose prednisolone was associated with slower bone turnover and improvements in cardiometabolic health markers compared with multiple-dose hydrocortisone without compromising well-being. Studies assessing longer-term mortality and morbidity outcomes are needed. Trial Registration: ClinicalTrials.gov Identifier: NCT03936517.