ORF32-03 - Cardiometabolic and Patient-Reported Outcomes of Low-Dose Once-Daily Prednisolone Versus Standard Divided-Dose Hydrocortisone in Adrenal Insufficiency: A Multicentre Crossover Study (HYPER-AID Study)

Background:
Prednisolone (prednisone) has a longer biological half-life and greater glucocorticoid (GC) receptor affinity, allowing once-daily dosing and more sustained daytime GC exposure compared with conventionally divided-dose hydrocortisone, typically administered three times daily. This may better approximate physiological diurnal cortisol activity, reduce peak–trough variability, and improve adherence in adrenal insufficiency (AI).

Methods:
This prospective, multicentre, open-label crossover observational study enrolled adults aged 18–85 years with primary or secondary AI receiving stable GC replacement for at least four months. Participants were assessed on their usual regimen and then switched to the alternative GC, with follow-up assessments performed after at least four months. Outcomes included cardiometabolic measures, routine biochemical and bone turnover markers, and quality of life assessed using a modified SF-36 questionnaire, with within-participant comparisons performed.

Results:
A total of 213 participants completed the study visits (mean age 56.3 years; 63% female; 27% primary AI). Switching from hydrocortisone to prednisolone (n=194; median daily prednisolone dose 4 mg [IQR 3–4 mg]) resulted in significant reductions in body weight (−2.01 kg; p< 0.001), BMI (−0.51 kg/m²; p=0.005), systolic blood pressure (−5.32 mmHg; p< 0.001), diastolic blood pressure (−2.52 mmHg; p=0.002), and HbA1c (−0.79 mmol/mol; p=0.001). Participants with baseline HbA1c ≥48 mmol/mol experienced a greater reduction (−4.59 mmol/mol; p< 0.001). The total cholesterol–HDL ratio decreased by 0.18 (p=0.006). Routine biochemical and bone turnover markers remained unchanged. Improvements were seen in patient-reported SF-36 scores for general health (+4.5; p=0.031), energy (+9.2; p< 0.001), and wellbeing (+4.6; p=0.017); nausea scores remained unchanged (+2.4; p=0.13).
Participants switching from prednisolone to hydrocortisone (n=19) experienced weight gain (+2.15 kg; p=0.005), with increased triglycerides (+0.68 mmol/L; p=0.037) and reduced HDL cholesterol (−0.19 mmol/L; p=0.003). Other parameters remain unchanged.

Conclusions:
Low-dose once-daily prednisolone was associated with improved cardiometabolic profiles and better patient-reported wellbeing compared with hydrocortisone. These findings support prednisolone as an effective and potentially preferable GC replacement strategy for adults with AI.