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

## TL;DR

A clinical trial found that once-daily prednisolone slows bone turnover and improves cardiometabolic markers compared to thrice-daily hydrocortisone in adrenal insufficiency patients.

## Contribution

This study provides the first direct comparison of once-daily prednisolone and multiple-dose hydrocortisone on bone and cardiometabolic outcomes in adrenal insufficiency.

## Key findings

- Prednisolone significantly reduced bone turnover markers compared to hydrocortisone.
- Prednisolone led to greater reductions in weight, BMI, waist circumference, and HbA1c.
- No differences were observed in subjective health outcomes or safety measures between the two treatments.

## Abstract

Are there differences in bone turnover between once-daily low-dose prednisolone and multiple-daily standard-dose regimens of hydrocortisone on cardiometabolic outcomes in patients with adrenal insufficiency?

In this randomized clinical trial of 46 adults with adrenal insufficiency, bone turnover was slowed with prednisolone treatment, which was also associated with reductions in body weight, waist circumference, and glycated hemoglobin. Bone formation and resorption markers were elevated with hydrocortisone treatment, despite no detectable differences in subjective health outcomes.

These results suggest that once-daily low-dose prednisolone is a safe alternative to standard regimens of hydrocortisone for treatment of adrenal insufficiency, which may have better cardiovascular outcomes.

This randomized clinical trial investigates how bone turnover in patients with adrenal insufficiency is affected by once-daily prednisolone compared with multiple-dose hydrocortisone treatment.

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.

To examine the differences in metabolism and bone turnover in patients receiving hydrocortisone vs prednisolone for adrenal insufficiency.

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.

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.

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.

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.

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.

ClinicalTrials.gov Identifier: NCT03936517