ECE2022 Rapid Communications Rapid Communications 2: Adrenal and Cardiovascular Endocrinology 1 (8 abstracts)
Improved biochemical control with modified-release hydrocortisone overturns the impaired fludrocortisone effect in salt-wasting CAH patients
Lea Tschaidse 1 , Nicole Reisch 2 , Wiebke Arlt 3 , Aude Brac De La Perriere 4 , Angelica Linden Hirschberg 5 , Anders Juul 6 , Ashwini Mallappa 7 , Deborah P Merke 8 , John DC Newell-Price 9 , Colin Graham Perry 10 , Alessandro Prete 3 , Aled Rees 11 , Monica Stikkelbroeck 12 , Phillippe A Touraine 13 , Helen Coope 14 , John Porter 14 , Richard John M Ross 14 & Marcus Quinkler 15
1Klinikum der Universität München, Standort Großhadern, München, Germany; 2Endokrinologie, Nephrologie und weitere Sektionen - Medizinische Klinik und Poliklinik IV - Campus Innenstadt, München, Germany; 3University of Birmingham, United Kingdom; 4Louis Pradel Hospital, Bron, France; 5Karolinska Institute, Sweden; 6Rigshospitalet, København, Denmark; 7AstraZeneca, Gaithersburg, United States; 8NIH Clinical Center, Bethesda, United States; 9The University of Sheffield, United Kingdom; 10Queen Elizabeth University Hospital, United Kingdom; 11Cardiff University, United Kingdom; 12Radboud University Nijmegen, Nijmegen, Netherlands; 13University Hospitals Pitié Salpêtrière - Charles Foix, Paris, France; 14Diurnal, United Kingdom; 15Endocrinology in Charlottenburg, Berlin, Germany
Background: Patients with salt-wasting congenital adrenal hyperplasia (CAH) due to classic 21-hydroxylase deficiency require glucocorticoid (GC) and mineralocorticoid (MC) replacement therapy. Recently, it was shown that twice daily modified-release hydrocortisone hard capsules (MRHC, Efmody®, Diurnal Ltd) improved control of CAH with most patients showing good disease control versus standard GC therapy. However, no data has been reported on the renin-angiotensin-aldosterone (RAA) system in these patients. This is of clinical relevance because 17-hydroxyprogesterone (17-OHP) is a known MC-receptor antagonist, and poorly controlled salt-wasting CAH patients often require higher fludrocortisone doses than patients with primary adrenal insufficiency. The aim of this study was to investigate the RAA system in patients on MRHC.
Methods: Data was analyzed from the 6-month, phase 3 study1. Patients with salt-wasting CAH (5 excluded; 83 included; 34.9% male, median age 35.3 yrs) were randomized to either MRHC twice daily (n=42) or standard GC (n=41; 4.9% dexamethasone, 39% prednisolone, 56.1% HC). MC replacement therapy with fludrocortisone remained stable and unchanged throughout the study. Blood pressure, potassium, sodium, plasma-renin-activity (PRA) serum androgen precursors 17-OHP and androstenedione were analyzed at baseline, 4, 12 and 24 weeks.
Results: Both groups improved hormonal control (17-OHP and androstenedione) on intensive monitoring and with stable GC doses on MRHC (median 25.0 to 25.0 mg/d, P= 0.062) and increased doses on standard GC (25.0 to 31.3 mg/d, P= 0.001) at 24 weeks. However, the serum 17-OHP was significantly lower on MRHC compared to standard GC at 24 weeks (2,5 nmol/l vs 10,5 nmol/l, P= 0.001). PRA decreased significantly from baseline to 24 weeks in patients on MRHC (0.83 ng/l/s to 0.48 ng/l/s, P=0.012) but not in patients on standard GC therapy (0.53 ng/l/s to 0.52 ng/l/s, P=0.613). In line with these changes, serum sodium concentrations increased from baseline to 24 weeks in patients on MRHC (138.8±1.9 mmol/l to 139.3±1.8 mmol/l, P=0.047), but remained unchanged on standard GC (139.8±1.6 mmol/l to 139.3±1.9 mmol/l, P=0.135). No significant changes were seen in systolic and diastolic blood pressure and serum potassium levels.
Conclusion: Six months of MRHC therapy decreased PRA and increased sodium levels indicating a better MC effect of the unchanged fludrocortisone dose. This might be due to the significantly decreased levels of the MC-receptor antagonist 17-OHP owing to the improved control of precursor excess by MRHC, indicating lower fludrocortisone efficacy in poorly controlled salt-wasting CAH patients.
References: Merke DP. JCEM 2021 106 e2063-e2077.
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Endocrine Abstracts
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