Prospective evaluation of long-term safety of dual-release hydrocortisone replacement administered once daily in patients with adrenal insufficiency

Abstract

ObjectiveThe objective was to assess the long-term safety profile of dual-release hydrocortisone (DR-HC) in patients with adrenal insufficiency (AI).DesignRandomised, open-label, crossover trial of DR-HC or thrice-daily hydrocortisone for 3 months each (stage 1) followed by two consecutive, prospective, open-label studies of DR-HC for 6 months (stage 2) and 18 months (stage 3) at five university clinics in Sweden.MethodsSixty-four adults with primary AI started stage 1, and an additional 16 entered stage 3. Patients received DR-HC 20–40 mg once daily and hydrocortisone 20–40 mg divided into three daily doses (stage 1 only). Main outcome measures were adverse events (AEs) and intercurrent illness (self-reported hydrocortisone use during illness).ResultsIn stage 1, patients had a median 1.5 (range, 1–9) intercurrent illness events with DR-HC and 1.0 (1–8) with thrice-daily hydrocortisone. AEs during stage 1 were not related to the cortisol exposure-time profile. The percentage of patients with one or more AEs during stage 1 (73.4% with DR-HC; 65.6% with thrice-daily hydrocortisone) decreased during stage 2, when all patients received DR-HC (51% in the first 3 months; 54% in the second 3 months). In stages 1–3 combined, 19 patients experienced 27 serious AEs, equating to 18.6 serious AEs/100 patient-years of DR-HC exposure.ConclusionsThis long-term prospective trial is the first to document the safety of DR-HC in patients with primary AI and demonstrates that such treatment is well tolerated during 24 consecutive months of therapy.

Modified-release hydrocortisone decreases BMI and HbA1c in patients with primary and secondary adrenal insufficiency

“…This treatment proved to be safe and was well-tolerated during 24 consecutive months of therapy in patients with PAI (8). In the initial 3 months trial, this new modified release HC showed an improvement in cardiovascular risk factors, glucose metabolism, and HRQoL in comparison with conventional treatment with trice daily HC (7).…”

Steroid Therapy in Adrenal Insufficiency

“…Patients with hypopituitarism with partial/total ACTH deficiency and on suboptimal cortisol therapy may develop symptoms of cortisol deficiency upon initiation of growth hormone therapy due to inhibition of 11-betahydroxysteroid dehydrogenase-type-1 [6][7][8][9].…”

“…Nilsson AG et al [9] concluded favorable results on safety and tolerance of DR-HC during 24 months of therapy [9].…”

Improving glucocorticoid replacement in patients with adrenal insufficiency

“…The long-term safety data are reassuring and of great values as there was an indication of increased reporting of mild adverse events after the switch from conventional TID to DR-HC [10]. Careful analysis of the association between the pharmacokinetic profile and adverse event reporting suggested that this initial increase in number of adverse events was related to increased awareness among the patients during the therapeutic change and not due to the change in cortisol exposure or time exposure profile [12].…”

“…In 11 patients with concomitant diabetes mellitus (DM), a reduction in HbA1c was observed with DR-HC compared with TID. After the pivotal trial, patients entered a long-term prospective openlabelled safety trial that could show safe outcome with the use of the DR-HC [12]. The long-term safety data are reassuring and of great values as there was an indication of increased reporting of mild adverse events after the switch from conventional TID to DR-HC [10].…”