Once-daily low-dose prednisolone outperformed the current standard treatment of multiple daily doses of hydrocortisone for bone turnover and cardiometabolic markers in a small randomized clinical trial of patients with adrenal insufficiency.

“The take-home message is that a very cost-effective drug has a new use, with prednisolone causing fewer of the side effects of glucocorticoid replacement than traditional hydrocortisone,” Karim Meeran, MD, professor of endocrinology at Imperial College London in London, England, and the study’s corresponding author, told Medscape Medical News.

The findings were published in JAMA Network Open.

Crossover Comparison of Prednisolone and Hydrocortisone

The trial included 46 participants, who were randomly assigned to receive either 4 months of once-daily morning prednisolone with placebo tablets at noon and in the afternoon, or hydrocortisone administered at the same times. Participants then crossed over to the alternate treatment for an additional 4 months.

Meeran and colleagues reported that bone turnover appeared to slow during prednisolone treatment compared with hydrocortisone, as reflected by significantly lower level of multiple markers, including carboxylated osteocalcin (mean treatment difference [MTD], -1.22 ng/mL; P = .04), undercarboxylated osteocalcin (MTD, -1.38 ng/mL; P = .005), urinary N-terminal telopeptide (MTD, -9.34 nmol/mmol; P = .002), and procollagen type 1 N-terminal propeptide (MTD, -13.8 ng/mL; P < .001).

Compared with baseline measurements, prednisolone treatment was also associated with greater reductions in body weight (MTD, -1.87 kg; P = .002) and A1c levels (MTD, -0.12%; P = .001) than hydrocortisone.

No significant differences were observed between groups in safety measures or subjective health outcomes, including scores on the 36-Item Short-Form Health Survey and Addison Disease-Specific Quality-of-Life Questionnaire.

Meeran said these findings were reassuring because the metabolic improvements were not accompanied by signs of glucocorticoid deficiency.

Cost Concerns Prompt Consideration of Prednisolone

Meeran said the study evolved from concerns about the rising costs of hydrocortisone, long considered the standard treatment for adrenal insufficiency.

Meeran said he became aware of the dramatic pricing increase while treating a patient from the US who was paying out of pocket because he was not covered by the UK National Health Service. That experience prompted him to reconsider prednisolone, which remained inexpensive, as an alternative.

He noted that prednisolone’s chemical structure includes a double bond that slows degradation and prolongs its half-life, allowing for once-daily dosing, whereas hydrocortisone’s short half-life typically requires three daily doses.

Meeran and colleagues emphasized that further studies are needed to assess longer-term mortality and morbidity outcomes with prednisolone. They identified the reliance on biomarkers rather than clinical event outcomes as a major limitation of their study.

Expert Commentary

In an invited commentary accompanying the paper, Mira Emilova Boyanova, MD, of Acibadem City Clinic Tokuda Hospital in Sofia, Bulgaria, highlighted the challenges of conducting trials in rare diseases such as adrenal insufficiency, where studies often involve relatively small numbers of participants.

“In adrenal insufficiency, clinical judgment has always been and will remain the mainstay of deciding whether disease control is optimal rather than the level of any corticosteroid preparation measured by tandem mass spectrometry,” Boyanova wrote.

She also questioned aspects of the study design and interpretation, asking whether some participants’ adrenal insufficiency had already been well controlled before treatment.

Katie B. Guttenberg, MD, endocrinologist and associate professor of medicine at The University of Texas Health Science Center at Houston, also raised concerns about the study’s use of slightly different dosing approaches between hydrocortisone and prednisolone.

“There appears to have been a tendency toward possible over-replacement with hydrocortisone and possible under-replacement with prednisolone for at least some of the participants,” she told Medscape Medical News in an email.

Guttenberg also questioned the inclusion of both primary adrenal insufficiency (16 patients) and secondary adrenal insufficiency (30 patients) in the same analysis. Current Endocrine Society guidelines recommend different dosing approaches for these conditions, as patients with primary adrenal insufficiency typically require higher hydrocortisone doses than those with secondary adrenal insufficiency, in which the adrenal gland remains intact and patients often have partial adrenocorticotropic hormone deficiency, she said.

She additionally noted that participants’ use of bone antiresorptive therapy may have affected the bone marker findings. In the study, 13% of participants received such therapy, including 8.3% of those initially assigned to prednisolone and 18.2% of those initially assigned to hydrocortisone.

“This is potentially a confounder since these medications impact the markers of bone health assessed in this study,” Guttenberg said. “I would like to see an analysis specifically excluding patients taking antiresorptive medication.”

Still, she added, “we should remain cognizant of bone health in patients with adrenal insufficiency and do our best to optimize their clinical outcomes.”

Meeran and coauthors reported no relevant financial conflicts of interest. Guttenberg disclosed serving as an advisor for Crinetics Pharmaceuticals.

Kerry Dooley Young is a freelance journalist based in Washington, DC. She has covered medical research and healthcare policy for more than 20 years.