Once-Daily Prednisolone Shows Metabolic Advantages Over Standard Hydrocortisone in Adrenal Insufficiency: JAMA

A recent clinical trial published in the Journal of the American Medical Association found once-daily low-dose prednisolone as a safe alternative to standard regimens of hydrocortisone to treat adrenal insufficiency, which may have better cardiovascular outcomes.

Patients with adrenal insufficiency rely on hydrocortisone taken several times a day to replace missing cortisol. An alternative approach using low-dose prednisolone once daily has existed for years, but direct comparisons between the two therapies have been limited. This study conducted between 2019 and 2023 looked in to whether simpler, once-daily steroid therapy could match, or outperform the traditional multi-dose regimen for patients with Adrenal insufficiency.

This study involved 46 adults diagnosed with adrenal insufficiency. These participants were alternated between a standard hydrocortisone taken 3-times daily and a once-daily morning dose of prednisolone (2–5 mg), with placebo tablets mimicking additional doses. Each treatment phase lasted 4 months to directly compare outcomes within the same individuals.

The primary focus of this study was bone health, which assessed through markers of bone turnover. Prednisolone significantly slowed bone turnover when compared to hydrocortisone. Major biomarkers including osteocalcin levels and indicators of bone breakdown were consistently lower during the prednisolone phase. Slower bone turnover may indicate reduced long-term risk of bone loss, which was a major concern for patients on chronic steroid therapy.

The participants lost an average of nearly 2 kilograms while on prednisolone when compared to hydrocortisone. This weight reduction was accompanied by improvements in body mass index (BMI), waist circumference, and blood sugar control, measured by HbA1c levels. These findings suggest that once-daily prednisolone may offer advantages in reducing cardiovascular and metabolic risk factors.

Surveys measuring quality of life (general health and disease-specific assessments) showed no significant differences between the two treatments. Safety outcomes were also comparable, indicating that prednisolone did not introduce additional risks over the study period.

While the findings are promising, longer-term studies are imperative to determine whether these metabolic and bone-related improvements translate into reduced rates of fractures, cardiovascular disease, or mortality. Overall, a once-daily regimen could simplify treatment for patients, potentially improving adherence while offering measurable health benefits. 

Reference:

Choudhury, S., Lazarus, K., Sharma, A., Narula, K., Go, C., Cro, S., Thaventhiran, T., Khoo, B., Tan, T., & Meeran, K. (2026). Prednisolone once daily vs hydrocortisone thrice daily in hypoadrenalism: A randomized clinical trial: A randomized clinical trial. JAMA Network Open, 9(3), e262982. https://doi.org/10.1001/jamanetworkopen.2026.2982