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Background Dual-release hydrocortisone (DR-HC) improves metabolism in patients with adrenal insufficiency. The aims of this study were to compare the cardiovascular and metabolic effects of conventional glucocorticoids (GCs) vs. DR-HC and of high vs. low doses of GCs, after 48 months of observation. Methods We selected 27 patients on hydrocortisone (mean dose 17.5 ± 4.2 mg/day) and 20 patients on cortisone acetate (mean dose 37.5 ± 12.1 mg/day) who maintained this treatment (group A) and 53 patients switched to DR-HC (mean dose 22 ± 4.8 mg/day) (group B). At baseline and after 48 months, clinical and metabolic parameters and Framingham Risk Score (FRS) were obtained. Results After 48 months, patients in group A had a significant increase from baseline in BMI (P P = 0.001), systolic blood pressure (P = 0.001), LDL cholesterol (P = 0.018), HbA1c (P = 0.020) and FRS (P = 0.002). By contrast, patients in group B had a significant decrease in BMI (P = 0.002), waist circumference (P = 0.015), diastolic blood pressure (P = 0.031), total (P = 0.006) and LDL cholesterol (P = 0.005), HbA1c (P P = 0.015) compared to baseline. No significant differences between high and low doses of both conventional GCs and DR-HC were observed. Conclusions DR-HC is associated with an improvement of metabolic parameters and cardiovascular risk compared to conventional GCs, which are associated with a worsening of these parameters, regardless of the dose used.