Metabolic Effects of Modified-Release Hydrocortisone Versus Short Acting Conventional Oral Glucocorticoids in Adrenal Insufficiency: A Systematic Review and Meta-Analysis.

OBJECTIVE

Adrenal insufficiency's (AI) lifelong replacement therapy by conventional glucocorticoid (GC) regimens poorly mimics physiological cortisol, leading to poor adherence and metabolic abnormalities. Modified-release hydrocortisone (MR-HC) provides a more physiological cortisol replacement with potentially enhanced outcomes. This study assessed comparative evidence of MR-HC versus GC in patients with AI.

DESIGN

Systematic review and meta-analysis.

METHODS

Comparative articles published until July 2025 were searched in PubMed, Scopus and Web of Science. Glucose metabolism, anthropometrics, lipid profile and blood pressure were the primary outcomes; bone health parameters and safety and tolerability measures were secondary outcomes.

RESULTS

Across six included studies (n = 400), MR-HC was associated with significant reductions in BMI (mean difference -1.1, 95% CI -2.11 to -0.1) and waist circumference (-5.03, 95% CI-8.54 to -1.51), without significant changes in body weight. MR-HC lowered total cholesterol (-10.64, 95% CI -19.86 to -1.42), systolic blood pressure (-6.03, 95% CI -10.95 to -1.1) and diastolic blood pressure (-4.35, 95% CI -7.37 to -1.34). Glucose metabolic outcomes (fasting glucose and HbA1c) did not differ significantly between the groups, but sensitivity analysis suggested a potential HbA1c benefit with MR-HC. Bone health results favoured MR-HC for lumbar spine T-score (0.69, 95% CI 0.16 to 1.22), and femoral neck T-score (0.64, 95% CI 0.16 to 1.12). Safety measures favoured MR-HC for Infection score (-1.7, 95% CI -2.6 to -0.8), and flu-like events (-1.0, 95% CI -1.6 to -0.4), but not vertebral fractures (0.20, 95% CI 0.03 to 1.55), or AddiQol score (4.00, 95% CI -0.68 to 8.68).

CONCLUSIONS

MR-HC demonstrated improved effects on anthropometric measures, lipid profile, blood pressure, bone mineral density, and safety and tolerability compared to conventional GC with no apparent differences in glucose metabolism. These findings validate MR-HC as a better regimen, but await larger long-term trials for confirmation.

TRIAL REGISTRATION: This study was prospectively registered on PROSPERO (CRD420251074980). Available at: https://www.crd.york.ac.uk/PROSPERO/view/CRD420251074980.