Improving glucocorticoid replacement in patients with adrenal insufficiency

Abstract

The outcome among patients with adrenal insufficiency (AI) is not as excellent as was previously thought [1]. Recent studies have observed increased mortality both in patients with primary and secondary AI that are explained by both cardiovascular and infectious diseases, suggesting that both the maintenance dose and the rescue therapy during an intercurrent illness are inadequate [2].The aim of glucocorticoid replacement is to obtain physiological cortisol exposure, both in terms of the dose and the time exposure profile in order to mimic the normal diurnal variation in serum cortisol. Also during increased need, such as during physical and mental stress, e.g., during an infection, the dose needs to be increased. Based on small studies on cortisol production rate in the resting state, it is clear that a dose above 20 mg per day is too high for most patients. Therefore, several attempts have been done to reduce the overall cortisol exposure during the replacement therapy. Three previous open prospective studies have reduced the dose of conventional hydrocortisone (HC) replacement by 30-50 % (approximately 30 to 20-15 mg of HC per day) and found an increase in bone formation markers and a small reduction in body weight, but with no impact on blood pressure or glucose metabolism [3][4][5]. In addition, one open study which randomised patients to two different regimens of glucocorticoid replacement using doses between 15 and 30 mg of HC per day was unable to show an impact of dose on QoL [6].Based on the pharmacokinetic properties of conventional oral immediate-release HC formulations, it is impossible to achieve a physiological serum cortisol profile as there is a rapid increase in serum cortisol after an oral administration and a rapid decrease reaching low unphysiological troughs in between each dose [7,8]. The early morning rise in serum cortisol before awakening will not be mimicked using conventional HC.Giordano and colleagues in this issue of the Journal have reported data from a clinical intervention study using a newly developed drug, a dual-release oral HC (DR-HC) formulation for glucocorticoid replacement. It has an outer layer of immediate-release HC allowing a peak serum cortisol concentration in the morning after an oral administration in the fasting state, and an inner core with modified-release HC that mimics the serum cortisol profile throughout the day and evening [9]. In the pivotal trial comparing DR-HC with three times daily conventional hydrocortisone tablets (TID) in a 2 9 3-month randomised cross-over trial in patients with Addison's disease, it was shown that the cortisol exposure was higher during the first 4 h after the intake of the DR-HC, whereas the exposure was markedly reduced thereafter due to the absence of the second and third cortisol peaks after TID [10]. The total 24-h exposure was on average 20 % lower with the DR-HC compared with the same daily dose of HC administered as TID due to the serum cortisol peaks associated with TID, but also due to the non-proportional dose-exposur...

MANAGEMENT OF ENDOCRINE DISEASE: Risk of overtreatment in patients with adrenal insufficiency: current and emerging aspects

“…Conventional hydrocortisone replacement regimens in the management of AI cannot provide the physiological (43,143,144), although their relative high cost and the limited availability in some countries do not yet permit the universal use of these drugs for treatment of AI. Interestingly, the more physiological serum cortisol resulting from this innovative treatment profile was accompanied by an improvement in several clinical outcomes of patients with primary and secondary AI (72, 73,143,144,145,146,147).…”

“…Conventional hydrocortisone replacement regimens in the management of AI cannot provide the physiological (43,143,144), although their relative high cost and the limited availability in some countries do not yet permit the universal use of these drugs for treatment of AI. Interestingly, the more physiological serum cortisol resulting from this innovative treatment profile was accompanied by an improvement in several clinical outcomes of patients with primary and secondary AI (72, 73,143,144,145,146,147). In fact, the use of dualrelease hydrocortisone was associated with reductions in body weight, glycated hemoglobin, and blood pressure and improvements in bone formation markers and QoL as compared to conventional therapeutic regimen either in head-to-head studies (72, 147) or in prospective evaluations performed in patients who were switched from conventional hydrocortisone replacement treatment to the dual-release hydrocortisone formulation (72, 73).…”