A new crossover study concluded that prednisolone is a noninferior alternative to hydrocortisone for treating both primary and secondary adrenal insufficiency. The results suggest that patients with this condition may benefit from a once-daily option that could improve treatment adherence.

Conducted at the National Hospital Kandy in Sri Lanka, the HYPER-AID study included 116 patients with adrenal insufficiency who were switched from hydrocortisone to equivalent low-dose prednisolone regimens. Patients taking 15-20 mg of hydrocortisone daily were switched to 3.75 mg prednisolone, whereas those on higher hydrocortisone doses (22.5-35 mg) received 5 mg prednisolone. Most patients tolerated the 3.75 mg dose well and did not require adjustment.

The researchers found that prednisolone provided comparable efficacy and patient well-being to hydrocortisone while offering practical advantages. Hydrocortisone’s short half-life typically requires multiple daily doses, whereas prednisolone’s longer half-life allows for once-daily dosing.

Findings from the HYPER-AID study were published in October in Endocrine Practice.

A More Convenient and Effective Approach

The authors noted that once-daily prednisolone may improve adherence, as it is easier to remember than hydrocortisone’s multi-dose schedule. It is also a less expensive steroid option, given that prednisolone is seven times more potent than hydrocortisone. However, they cautioned that long-term steroid-induced adverse effects remain a concern.

Richard Auchus, MD, PhD, professor of internal medicine in the Division of Metabolism, Endocrinology & Diabetes at the University of Michigan and chief of the Endocrinology & Metabolism Section at the Ann Arbor VA Medical Center, Ann Arbor, Michigan, said there has been an unmet need for a formal comparison of these two regimens.

Auchus, who was not involved in the study, explained that it has been difficult to design a study without knowing the equivalent doses and dosing schedules between hydrocortisone and once-daily prednisolone.

“Another difficulty is what to use for a primary endpoint to show that one regimen is better than the other,” Auchus told Medscape Medical News. “Also, the study had a mixture of patients with primary adrenal insufficiency and secondary adrenal insufficiency, and the latter group is often partial affected and requires less treatment than the former. Nevertheless, the data are relevant.” 

Among the 116 patients (mean age, 48.8 years), 101 continued prednisolone through the study period. Six patients were lost to follow-up and nine switched back to hydrocortisone within 2-8 weeks. In the final analysis, 89 patients were taking 3.75 mg prednisolone daily and 12 were on 5 mg.

Longer Follow-Up Studies Needed

Betul Hatipoglu, MD, professor of medicine at Case Western Reserve University School of Medicine, Cleveland, said the findings are clinically significant because they address a question commonly raised in clinical practice.

“We favor multiple doses to mimic physiologic fluctuation of circadian rhythm, which is not possible to do with long-acting formulation,” said Hatipoglu, who was not involved in the study. “However, the HYPER-AID study provides encouraging early evidence that once‐daily low‐dose prednisolone may be as effective as multiple‐dose hydrocortisone for adrenal insufficiency, with possible metabolic benefits and improved convenience.” 

Hatipoglu noted that the within-patient comparisons and real-world clinical setting strengthen the study’s relevance, although its short follow-up period of approximately 4 months and small sample sizes may limit generalizability.

Future studies are warranted to evaluate long-term outcomes such as bone mineral density, adrenal crises rates, and mortality. Hatipoglu said for certain patients with adrenal insufficiency, once-daily low-dose prednisolone may be a viable alternative to multi-dose hydrocortisone, offering convenience and potentially favorable early metabolic markers.

“Switching therapies should be done under physician supervision, individualized, and cannot be generalized to the entire adrenal insufficiency population,” Hatipoglu told Medscape Medical News. “Monitoring of cortisol adequacy, adrenal crisis risk, bone health, and cardiovascular/metabolic markers must be followed with other longer duration studies.”

Auchus advised that clinicians should not hesitate to consider once-daily prednisolone as an alternative for patients struggling with hydrocortisone’s multi-dose regimen. Prednisone, the pro-drug of prednisolone, is widely used in the US, inexpensive, and available in 1-mg tablets, however, its conversion to prednisolone can be incomplete at lower doses.

“The replacement dose of prednisolone should be about 3 mg per day in most adults, not 5 mg per day like many of us were taught,” Auchus noted.

He added that although prednisolone tablets remain costly in the US, methylprednisolone (4 mg tablets) and prednisolone liquid formulations are inexpensive and widely available, offering practical alternatives.

Auchus and Hatipoglu had no financial disclosures. The disclosures by the authors are listed on the original paper.