Carolyn J Petersons1, Brenda L Mangelsdorf, Campbell H Thompson, Morton G Burt. 1. Faculty of Health Sciences (C.J.P., C.H.T., M.G.B.), Flinders University, Adelaide SA 5042, Australia; Southern Adelaide Diabetes and Endocrine Services (C.J.P., B.L.M., M.G.B.), Repatriation General Hospital, Adelaide 5041, Australia; and Discipline of Medicine (C.H.T.), University of Adelaide, Adelaide SA 5005, Australia.
Abstract
CONTEXT: Higher hydrocortisone doses are associated with increased overall and cardiovascular mortality in ACTH-deficient patients. The mechanisms underlying this association have not been fully defined. OBJECTIVE: The aim of the study was to determine whether increasing hydrocortisone (or equivalent) to 30 mg/d in ACTH-deficient patients increased cardiovascular risk and whether a reduction in insulin sensitivity and attenuation of insulin's hemodynamic effects was responsible for this effect. DESIGN: We conducted an open interventional study between 2011 and 2013. SETTING: The study was performed in the Endocrine Research Unit, Repatriation General Hospital, Adelaide, Australia. PATIENTS: Seventeen ACTH-deficient subjects taking hydrocortisone (≤20 mg/d) for at least 6 months were studied. INTERVENTION: Subjects were studied before and after a 7-day increase in hydrocortisone to 30 mg/d. MAIN OUTCOME MEASURE: The primary outcome was the change in pulse wave velocity, both fasting and after a 75-g oral glucose load. RESULTS: Fasting and post-glucose load pulse wave velocities were not significantly different on the higher glucocorticoid dose. Fasting augmentation index (24.9 ± 2.7 vs 22.6 ± 2.6%; P = .04) and reactive hyperemia index (2.3 ± 0.2 vs 2.0 ± 0.2; P = 0.04) were lower on the higher glucocorticoid dose, with no significant difference in the post-glucose load changes in these variables. There were no significant changes in insulin sensitivity or secretion on the higher glucocorticoid dose. CONCLUSIONS: Endothelial dysfunction may contribute to the increased cardiovascular mortality associated with higher glucocorticoid doses. This may be a direct glucocorticoid effect, not mediated by insulin resistance. ACTH-deficient patients should thus be prescribed the lowest safe glucocorticoid replacement dose.
CONTEXT: Higher hydrocortisone doses are associated with increased overall and cardiovascular mortality in ACTH-deficient patients. The mechanisms underlying this association have not been fully defined. OBJECTIVE: The aim of the study was to determine whether increasing hydrocortisone (or equivalent) to 30 mg/d in ACTH-deficient patients increased cardiovascular risk and whether a reduction in insulin sensitivity and attenuation of insulin's hemodynamic effects was responsible for this effect. DESIGN: We conducted an open interventional study between 2011 and 2013. SETTING: The study was performed in the Endocrine Research Unit, Repatriation General Hospital, Adelaide, Australia. PATIENTS: Seventeen ACTH-deficient subjects taking hydrocortisone (≤20 mg/d) for at least 6 months were studied. INTERVENTION: Subjects were studied before and after a 7-day increase in hydrocortisone to 30 mg/d. MAIN OUTCOME MEASURE: The primary outcome was the change in pulse wave velocity, both fasting and after a 75-g oral glucose load. RESULTS: Fasting and post-glucose load pulse wave velocities were not significantly different on the higher glucocorticoid dose. Fasting augmentation index (24.9 ± 2.7 vs 22.6 ± 2.6%; P = .04) and reactive hyperemia index (2.3 ± 0.2 vs 2.0 ± 0.2; P = 0.04) were lower on the higher glucocorticoid dose, with no significant difference in the post-glucose load changes in these variables. There were no significant changes in insulin sensitivity or secretion on the higher glucocorticoid dose. CONCLUSIONS: Endothelial dysfunction may contribute to the increased cardiovascular mortality associated with higher glucocorticoid doses. This may be a direct glucocorticoid effect, not mediated by insulin resistance. ACTH-deficient patients should thus be prescribed the lowest safe glucocorticoid replacement dose.
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