Prednisone may have bone and cardiovascular benefits compared to hydrocortisone therapy in adrenal insufficiency

1. Prednisolone therapy is well tolerated, may have better bone and cardiovascular outcomes compared to hydrocortisone, and poses lower medication burden compared to hydrocortisone therapy in adult patients with adrenal insufficiency (AI).

Evidence Rating Level: 1 (Excellent)

Study Rundown: Glucocorticoid replacement is an essential, lifesaving treatment of AI. Current standard management is 3 doses of hydrocortisone daily, with the largest dose upon waking to mimic the normal physiological cortisol circadian rhythm. However, even with appropriate therapy, patients with adrenal insufficiency have a shorter life expectancy by 12 years. This may be due to excess replacement, particularly later in the day, which is associated with increased bone loss, risk of cardiovascular deaths, and reduced quality of life. Prednisolone has a longer half-life and has been shown to give adequate glucocorticoid replacement while mimicking the circadian cortisol rhythm in a once-daily dose. No studies have compared the effects of once-daily prednisolone vs multiple daily doses of hydrocortisone on bone turnover.

This 2-arm, 2-period, double-blind, crossover randomized clinical trial was conducted in London, UK, from September 3, 2019, to December 14, 2023. Participants included adults aged 18-70 years with primary or secondary AI on stable glucocorticoid replacement therapy for the preceding 3 months. Participants were randomized 1:1 to receive prednisolone or hydrocortisone replacement therapy in the first 120-day study period, followed by the alternative treatment in the second 120-day study period. There was a minimum 2-week washout period. Corticosteroid dose was determined by the pretrial regimen already used by each participant.

Overall, this study found that prednisolone was associated with significantly slower bone turnover compared to hydrocortisone. Prednisolone was also significantly associated with greater reductions in weight, body mass index, and HbA1c. There were no significant differences in adverse events or subjective health outcomes.

Click here to read this study in JAMA Network Open

Relevant reading: Prednisolone Replacement Therapy Mimics the Circadian Rhythm More Closely Than Other Glucocorticoids

In-Depth [randomized clinical trial]:

Glucocorticoid replacement, an essential treatment of AI, is conventionally daily multiple-dose hydrocortisone. Clinical trials comparing this standard with once-daily prednisolone, which better mimics the physiological cycle of cortisol, are lacking. This randomized controlled trial compared metabolic outcomes in patients with AI receiving hydrocortisone vs. prednisolone. The primary outcome was bone turnover, measured by changes in multiple bone markers.

46 patients were randomized to receive prednisolone first (n = 24; median [IQR] age, 51.5 [42.8-63.2] years; 41.7% female) or hydrocortisone first (n = 22; median [IQR] age, 57.5 [48.2-62.0] years; 54.5% female). Compared with hydrocortisone, prednisolone was associated with significantly lower levels of multiple bone markers, including carboxylated osteocalcin (−1.22 ng/mL; 95% CI, −2.35 to −0.10 ng/mL; P = .04), undercarboxylated osteocalcin (−1.38 ng/mL; 95% CI, −2.32 to −0.44 ng/mL; P = .005), urinary N-terminal telopeptide (−9.34 nmol/mmol; 95% CI, −15.40 to −3.29 nmol/mmol; P = .002), and procollagen type 1 N-terminal propeptide (−13.80 ng/mL; 95% CI, −22.20 to −5.49 ng/mL; P < .001). Prednisolone was also associated with significantly greater reductions in weight (−1.87 kg; 95% CI, −3.02 to −0.72 kg; P = .002) and HbA1c (−0.12% [−1.23 mmol/mol; 95% CI, −1.95 to −0.51 mmol/mol]; P = .001). There were no significant differences in fasting glucose, insulin, lipids, or blood pressure. There were also no significant differences in subjective health outcomes, as measured by the Addison’s Disease-Specific Quality of Life Questionnaire, or in the incidence of adverse events.

Image: PD

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