Extended-release Hydrocortisone Formulations—Is There a Clinically Meaningful Benefit?

Abstract

Despite best practice replacement therapy with corticosteroids, patients with adrenal insufficiency report diminished quality of life and face increased mortality and morbidity. Conventional formulations of hydrocortisone have short half-lives (about 90 minutes) requiring multiple dosing during the day. Since 2011, extended-release hydrocortisone (ER-HC) formulations have been available enabling once-, sometimes twice-daily dosing. Most studies comparing ER-HC formulations with conventional hydrocortisone therapy report reduction in body weight, blood pressure and glucose levels, and improved quality of life. However, it is still unclear if the reported beneficiary effects are due to differences in cortisol exposure or alterations in pharmacokinetics. Here, we review studies comparing conventional and ER-HC treatment in adrenal insufficiency and discuss whether these novel formulations are safe and offer clinically significant benefits.

Background

The revolution in treatment of adrenal insufficiency (AI) was the introduction of cortisone replacement in the late 1940s. This transformed AI from a lethal to a treatable disorder in which patients could live near-normal lives (1). Cortisone acetate (CA) and hydrocortisone (HC) have since been the mainstay of glucocorticoid replacement therapy in all forms of AI. However, treatment with CA and HC have several shortcomings. The diurnal rhythm of cortisol with the late night and early morning rise followed by declining levels throughout the day with multiple superimposed pulses (2) is impossible to replicate with the tablets containing cortisone or hydrocortisone (Fig. 1). Moreover, the adrenals do not respond to stress by increasing cortisol production, requiring the patient to take extra doses. Both drugs have a half-life of only 90 minutes, requiring multiple dosing to cover the daily need. Thus, both the number and timing of cortisol pulses become unphysiological on oral replacement therapy, which may explain the increased mortality, morbidity, and reduced quality of life observed in these patients (3, 4).

Figure 1.

Cortisol profiles in healthy subjects and during replacement therapy. (A) Cortisol and adrenocorticotropic hormone profiles in blood of a healthy subject revealing circadian and ultradian rhythmicity (modified from Lightman and Conway-Campbell, Nature Review Neuroscience, 11, 710-18, 2010). (B) Serum cortisol during trice daily immediate release hydrocortisone (mean of 64 patients, dosing interval 20-40 mg per day, modified from Johannsson et al, J Clin Endocrinol Metabol, 97(2):473-81). (C) Serum cortisol profiles during treatment with once daily Plenadren in the morning (mean of 64 patients, dosing interval 20-40 mg per day, modified from Johannsson et al, J Clin Endocrinol Metabol, 97(2):473-81). (D) Serum cortisol profiles during twice daily Chronocort, 20 mg at 23:00 hours and 10 mg at 07:00 hours (modified from DeBono et al J Clin Endocrinol Metabol, 94(5):1548-54). Reproduced with permission from the copyright owners and authors.

These disadvantages spurred the development of extended-release formulations of hydrocortisone (ER-HC), and now 2 different preparations are available. In 2011 the extended-release formulation Plenadren was given marked authorization for adrenal insufficiency for once daily administration in the morning by the European Medicines Agency. In 2021 Efmody (formerly called Chronocort) was approved by the European Medicines Agency for replacement therapy in congenital adrenal hyperplasia (CAH) for twice daily administration, combining delayed and extended release. Both drugs are significantly more expensive, which raises the question: Is there a clinical meaningful benefit?

Standard Glucocorticoid Replacement and its Shortcomings

Cortisol, regulated by ACTH from the pituitary, follows a distinct diurnal rhythm, with levels starting to increase around 2:00 to 4:00 Am, peaking shortly after awakening, and gradually declining throughout the day (5). This rhythm is controlled by the central endogenous clock of the hypothalamic-pituitary-adrenal axis (HPA), centered in the hypothalamic suprachiasmatic nucleus, which lead to the release of corticotropin-releasing hormone. Superimposed on this diurnal variation are pulses of cortisol creating ultradian pulses with high peaks in the morning and lower, almost undiscernible, peaks in the late evening, brought about by the HPA axis positive feed-forward and negative feed-back system (Fig. 1A) (6).

Normal functioning adrenal glands produce 5 to 10 mg of cortisol per m² body surface area in a day (7). Allowing for incomplete intestinal absorption and the first-pass effect in the liver, this is considered equivalent to an oral replacement dose of 15 to 25 mg HC or 20-30 mg CA per day for an adult. In children, an optimal dose based on body surface area is 8 to 10 mg/m² per day. Given the restraints of the short half-life, most adults take 2 or 3 daily doses of HC, but some prefer 4 or more doses (8). In children, 4 daily doses are recommended (9). To mimic the diurnal variation, the first and largest dose should be taken as soon as the patient is awake, and the last dose not later than 4 to 6 hours before bedtime to avoid sleep disturbances. Evening HC dosing has been associated with insulin resistance and should be avoided (10).

Despite modern best practice glucocorticoid replacement therapy, patients still report reduced quality of life (QoL) and employment (11, 12), indicating that the failure of the currently used regimes to mimic the normal physiology is of importance. Glucocorticoid replacement doses that are too low can increase the risk of a life-threatening acute adrenal crisis in the event of stress. On the contrary, excess glucocorticoid doses can lead to Cushingoid and metabolic side effects such as obesity, hypertension, glucose intolerance, infections, and osteoporosis (4, 13-16). At the group level, both patients with primary adrenal insufficiency (PAI) and secondary adrenal insufficiency (SAI) have increased mortality (3, 17, 18). Many of the studies comparing regular (short-acting) immediate release HC (IR-HC) to ER-HC formulations claim to reduce these side effects and improve quality of life.

Pharmacokinetics of Extended-release Formulations

Plenadren is a once-daily ER-HC tablet, based on an immediate-release coating and an extended-release core. This provides a rapid rise in cortisol equivalent to the regular HC tablet, while the core contains a matrix that ensures delayed release with a declining cortisol curve throughout the day reaching almost undetectable levels in the evening (Fig. 1C). Absorption is rapid in the fasting state, inducing an adequate increase in morning cortisol levels with a peak concentration time comparative to conventional HC (Fig. 1B and 1C). Pharmacokinetic studies have found that the 24-hour area-under-the-curve (AUC) cortisol profile drops by 20% when an equivalent dose of IR-HC is substituted with Plenadren (19, 20). Furthermore, in comparison with trice-daily HC, Plenadren users have lower urinary excretion of cortisol and metabolites, corroborating the notion of less cortisol exposure (21). However, comparing the 24-hour cortisol profiles of conventional HC and Plenadren to healthy controls, neither treatment regimens are optimal and conventional HC may even resemble the cortisol rhythm in healthy subjects better than Plenadren because it has more pulses (22, 23).

Efmody is an ER-HC formulation consisting of a multiparticulate HC core and a delayed-release coating (24). The pharmacokinetic profile is very different from Plenadren in that the absorption of the HC is delayed. Administration of 5 and 30 mg Efmody resulted in peak concentrations of 6.4 µg/dL (176.6 nmol/L) and 24.9 µg/dL (687.0 nmol/L), with Tmax values of 8.25 and 7.17 hours, respectively (25). Twice daily dosing is recommended, with two thirds of the daily dose given in the evening mimicking the physiological predawn cortisol rise and enabling the patient to wake up with near normal cortisol levels. The morning dose is typically one third of the daily dose, to ensure sufficient cortisol levels throughout the day (Fig. 1D). This so-called toothbrush regime (at bedtime and in the morning) has been shown to achieve lower levels of androstenedione and 17-hydroxy-progesterone in CAH patients (26, 27).

Plenadren for Treatment of Primary Adrenal insufficiency

Metabolic effects

The marked authorization of Plenadren was based on an open-label crossover study comparing Plenadren and trice daily HC in 64 patients with PAI (19). Twelve weeks of treatment resulted in a modest reduction in weight (0.7 kg) and systolic (5.5 mm Hg) and diastolic (2.3 mm Hg) blood pressure. In a subgroup with type 1 diabetes, HbA1c was reduced by 0.6% (19, 28-30). In an 18-month extension of the study a weight difference of 1.4 kg in favor of Plenadren was observed, but no additional improvement in blood pressure or HbA1c (28). Other studies have largely replicated these results (21, 29-41) (Table 1).

Table 1.

Overview of studies of Plenadren

Authors (ref.)	Study design	Subjects (no)	ER-HC treatment length	Outcome/results
Johannsson et al, 2012 (19)	Open, randomized, crossover	PAI (64)	12 weeks + 24 weeks’ extension	Decrease 24-h cortisol exposure (∼20%) with ER-HC. Significant decrease of body weight, HbA1c, and blood pressure.
Ceccato et al, 2016 (36)	Prospective, observational	PAI (18), controls (43)	26 weeks	Improvement of salivary cortisol profile with ER-HC.
Quinkler et al, 2015 (31)	Open, prospective	PAI (26), SAI (18), CAH (6)	Median 202 days (85-498)	Improvement of BMI, HbA1c, total cholesterol with ER-HC. No differences in HDL cholesterol, LDL cholesterol, and triglycerides levels. No between treatment difference in QoL, but QoL reduction over time in the HC group.
Giordano et al, 2016 (32)	Prospective, crossover	PAI (19)	12 months	Improvement of waist circumference, HbA1c, total cholesterol, LDL cholesterol, and ACTH level with ER-HC. Improvement of the QoL.
Isidori et al, 2018 (30)	Prospective, crossover	PAI (44), SAI (45)	6 months	Decreased body weight with ER-HC. Decreases susceptibility to infection. More physiological profile of immune cells.
Mongioì et al, 2018 (33)	Prospective, crossover	PAI (10), SAI (9)	12 months	Reduced HbA1c and improvement of glycometabolic profile in PAI, opposite in SAI. Improvement of the QoL in all patients.
Guarnotta et al, 2018 (29)	Retrospective	PAI (13), SAI (36)	36 months	Improvement of insulin sensitivity in prediabetes with ER-HC. Reduced BMI, waist circumference, and HbA1c.
Ceccato et al, 2018 (36)	Prospective, observational	PAI (18), controls (43)	6 months	Decrease of total cholesterol and HbA1c levels with ER-HC.
Guarnotta et al, 2019 (34)	Prospective, observational, real-world	PAI (44), SAI (56)	48 months	Reduced BMI, waist circumference, diastolic blood pressure, total and LDL cholesterol, HbA1c with ER-HC.
Guarnotta et al, 2019 (35)	Observational, retrospective	AI (45)	12 months	Improvement of hepatic steatosis index and of insulin sensitivity with ER-HC.
Guarnotta et al, 2024 (42)	Randomized, open	PAI (43), SAI (43)	10 years	Conventional GC treatment (HC or cortisone acetate) was associated with a worsening of weight, metabolic, insulin-sensitivity, cardiac, and bone outcomes, compared to ER-HC, in treatment-naive AI.
Dineen et al, 2023 (21)	Prospective, crossover	AI (51), controls (60)	12 months	Reduction in urinary cortisol and total GC metabolite excretion after switch from IR-HC to DR-HC. The enhanced glucocorticoid activation in adipose tissue was ameliorated by treatment with DR-HC.
Jørgensen et al, 2024 (37)	Prospective, crossover	SAI (27)	16 months	Lower evening salivary cortisol, total and abdominal fat mass and HbA1c with ER-HC. Osteocalcin decreased, whereas sclerostin increased.
Hasenmajer et al, 2024 (43)	Prospective, crossover	AI (89)	24 weeks	Sexual dysfunction is common in AI patients. No difference with ER-HC.
Dineen et al, 2021 (39)	Prospective, crossover	AI (51)	12 weeks	ER-HC decreased blood pressure, weight and BMI, significant improvements in QoL. Patient preference for ER-HC.
Krekeler et al, 2021 (40)	Prospective	AI (36)	4 weeks	Improved sleep and cognitive function with ER-HC.
Estpiard et al, 2021 (41)	Randomized, crossover	PAI (50), controls (124)	12 weeks	Toward normalization with ER-HC.
Frara et al, 2018 (44)	Retrospective, observational	SAI (14)	104 weeks	Improved lumbar spine and femoral neck BMD, improved fasting glucose.
Guarnotto et al, 2022 (45)	Prospective, crossover	PAI (70)	60 weeks	Improved BMD.
Hasenmajer et al, 2023 (38)	Prospective, crossover	AI (32)	72 weeks	BMD and bone markers remained stable.

Abbreviations: BMD, bone mineral density; BMI, body mass index; ER-HC, extended-release hydrocortisone; GC, glucocorticoid; HDL, high-density lipoprotein; LDL, low-density lipoprotein; PAI, primary adrenal insufficiency; QoL, quality of life; SAI, secondary adrenal insufficiency; 17-OHP, 17-hydroxyprogesterone.

As shown in the original study by Johannsson and coworkers, the effects on weight and body mass index (BMI) are overall modest (30, 46), with a more pronounced effect in obese subjects (39). In a similar 12-week crossover trial also including patients with SAI, a weight reduction of 1.2 kg was observed (39). The SAI group had a more pronounced weight reduction, but they were also more obese (average BMI 31.5, compared to 26.8 in the PAI group). The DREAM study compared Plenadren and conventional HC in a randomized parallel trial and found that the Plenadren group lost 2 kg of body weight. A study of 10 participants who switched from IR-HC to Plenadren showed no weight reduction after 3 months but a significant reduction in fat mass and a corresponding increase in lean body mass (46). A 10-year follow-up study on treatment-naive AI showed that conventional glucocorticoid treatment (HC or cortisone acetate) was associated with increased weight (from 67.1 kg to 72.5 kg), whereas ER-HC did not change weight significantly from the baseline (from 68.8 kg to 66.1 kg) (42). The mean starting dose of glucocorticoids (mg/day) was significantly higher for the conventional treatment, than the ER-HC treatment group, indicating higher glucocorticoid exposure in this group.

Overall, switching to Plenadren seems to reduce weight, BMI, and waist circumference, but to a minor degree. The studies are in general small and of mixed quality, often including a mixture of PAI and SAI patients, and without estimation of cortisol exposure (equipotent dosing) with a few exceptions (20, 32).

Are there other potential cardiometabolic effects? Blood pressure is either slightly reduced (19, 39, 47) or unchanged after switching from IR-HC to Plenadren (37). A slight reduction of HbA1c has also been observed in nondiabetic patients in most (29, 33, 34, 36), but not all studies (30). The reduction is more pronounced in diabetes patients, but very few diabetes patients have been studied (19, 32). A few trials have also looked at fasting blood glucose, insulin or homeostatic assessment for insulin resistance and found small, inconsistent changes (29, 35, 44).

The effect of switching from IR-HC to Plenadren on lipid levels have revealed a mixed picture. Several studies report a slight decrease of all the major classes of cholesterol (32, 36), whereas others show no change or a worsening of the lipid profile after switching (19, 31, 33). For instance, in the DREAM study low-density lipoprotein cholesterol showed a slight increase from 123 to 129 mg/dL on Plenadren (30).

Effects on bone

The adverse effect of glucocorticoids on bone mineral density (BMD) is well known (48). Studies of PAI patients have shown normal to decreased BMD (9, 49) and a negative association between BMD and glucocorticoid dose (16), suggesting that overall cortisol exposure may be as important as type of treatment. Recent longitudinal studies have suggested that Plenadren-treated patients have less decline in trabecular bone score but in general the effects were small and bone markers relatively unchanged (37, 38, 45).

Immunological effects

Corticosteroids have diverse immunological effects and have an immunosuppressive capacity when administered in high doses. The DREAM study investigated the effects of glucocorticoid replacement regimes on peripheral immune cells and made several interesting observations. Patients on IR-HC had a proinflammatory profile compared to healthy subjects with higher percentage of T and B lymphocytes, lower levels of natural killer cells, and a higher ratio of proinflammatory CD14+ CD16– compared to CD14-CD16+ monocytes. Switching to Plenadren restored this ratio to that found in healthy subjects (30). Moreover, when expression of clock genes were assayed an abnormal relative expression of CLOCK, PER3, and TIMELESS was seen, that converged toward levels in healthy subjects when treatment was switched from IR-HC to Plenadren (50). Although these results fit well with the notion that Plenadren is a more physiological mode of replacement, there are several caveats to consider. The immune cell profiling (gene expressions) was determined at a single time point 2 hours after intake of the morning medication and other expression levels might be found at other time points. Considering the pharmacokinetic profiles of IR- HC and Plenadren 2 hours after intake (19), cortisol levels was probably higher in the Plenadren-treated group since release from the core had started. Thus, the differences could perhaps be explained by differences in cortisol levels, not by differences in pharmacokinetics. Thus, we believe that further studies of the dynamics of gene expression is needed to assess the immune effects of different cortisol preparations.

Quality of life

Studies comparing Plenadren to IR-HC have shown improved QoL with Plenadren. In the first study by Johannsson and coworkers, patients on Plenadren had a better total score and positive well-being as assessed by the Psychological General Well-Being questionnaire, but no difference in Short Form-36 scores (19). Others have found QoL improvement with the PAI-specific QoL questionnaire AddiQoL in patients switching to Plenadren, with an increase of up to 4 points in total score (AddiQoL range 30-120 points) (30, 32), an effect that was maintained over time (33). In comparison, QoL seems to decrease over time when treated with IR-HC (51). None of the QoL assessments have been blinded, leaving some uncertainty. Furthermore, a statistically significant difference in QoL score may not be clinically meaningful at the group level.

Efmody Treatment in Congenital Adrenal Hyperplasia

Several trials have compared IR-HC and Efmody treatment in CAH. An initial trial tested once-daily Efmody in the evening, which led to an early morning cortisol peak but lower cortisol and higher androstenedione levels in the afternoon (52). However, twice daily Efmody revealed lower androstenedione AUC despite taking a lower HC dose equivalent compared to conventional therapy (24, 53, 54). All studies using a twice daily dosing regimen have consistently demonstrated improvements in 17-OHP concentrations (24, 53, 54) (Table 2).

Table 2.

Overview of studies of Efmody

Authors (ref.)	Study design	Subjects (no.)	ER-HC treatment length	Outcome/results
Verma et al, 2010 (52)	Open, crossover	CAH (14)	4 weeks	Once-daily dosing resulted in an early morning cortisol peak. Reduced afternoon cortisol exposure was associated with elevated 17OHP, androstenedione, and ACTH.
Jones et al, 2017 (54)	Open, cross-sectional	CAH (55), controls (60)	26 weeks	Efmody appeared superior in controlling androgen synthesis via alternative pathways through attenuation of their major substrate, 17OHP.
Mallapa et al, 2015 (24)	Open, prospective, crossover	CAH (16)	26 weeks	Twice-daily Efmody approximates physiologic cortisol secretion and was well tolerated and effective in controlling androgen excess.
Merke et al, 2021 (55)	Prospective, crossover	CAH (122)	26 weeks, extension	Improved biochemical disease control in adults with reduction in steroid dose over time and patient-reported benefit.
Tschaidse et al, 2023 (53)	Data from Merke et al (55)	CAH adults (83)	26 weeks	Reduction in renin on Efmody.

Abbreviations: CAH, congenital adrenal hyperplasia; PAI, primary adrenal insufficiency; SAI, secondary adrenal insufficiency; 17OHP, 17-hydroxyprogesterone.

In a follow-up study of 122 adult patients, Efmody treatment resulted in a reduced androstenedione AUC, lower 24-hour 17OHP, and reduced morning 17OHP AUC, although the primary endpoint was not achieved as both groups achieved better hormonal control compared to baseline. QoL and metabolic parameters such as weight, body composition, blood pressure, and HbA1c did not change, but 8 patients reported restored menstrual cycles compared to 1 person on standard therapy (55).

Safety of Extended-release Formulations

The current literature on efficacy and safety of ER-HC is summarized in Table 1 (Plenadren) and Table 2 (Efmody). Both ER-HC formulations have demonstrated noninferiority to conventional HC for adrenal crisis and side effects, although for Efmody these results are currently limited to CAH patients (55).

Is There a Clinical Meaningful Benefit of ER-HC?

Most of the data presented here point to improvement of metabolic parameters when patients are switched from IR-HC to ER-HC, including weight and BMI reductions, possible increase in lean body mass and reduction of fat mass, improved glycemic control, and possibly lower catabolic impact on bone. QoL data also point in favor of ER-HC, and there might be beneficial immunological effects. The unanswered question is if these effects are due to reduced cortisol exposure or altered kinetics. An equivalent dose Plenadren generates about 80% of the cortisol exposure of an equivalent dose of HC, which can well explain all the reported beneficial effects.

Although many investigators claim that Plenadren results in a more physiological replacement of HC, we tend to disagree. Plenadren might be more physiological in the sense that the cortisol exposure is closer to the physiological range during daytime, but it is clearly less physiological when it comes to replicating normal cortisol pulsatility. A normal cortisol profile consists of repetitive pulses of cortisol throughout the day (Fig. 1A), and there is convincing evidence that this pulsatility is important for the effects of glucocorticoids on gene expression (2). A continuous glucocorticoid exposure results in a totally different gene expression pattern than pulsatile exposure, which enables cortisol to bind and dissociate from its receptor in repetitive cycles (56). Thus, the 2 or 3 pulses of cortisol generated by conventional IR-HC treatment are arguably more physiological than the single peak produced by Plenadren.

Efmody has the advantage of being the only oral glucocorticoid formulation mimicking the late night and early morning rise in cortisol which possibly can ameliorate the early morning fatigue experienced by many PAI patients. This is so far the only oral HC preparation with the potential for restoring the full 24-hour circadian cortisol rhythm in AI, without more technically complicated treatments such as infusion of HC subcutaneously with a pump (57, 58), although the pulses are lacking. Whether Efmody is superior to conventional HC or Plenadren in patients with PAI and SAI remains to be seen.

The new formulations have some obvious shortcomings. There exists no clear protocol for adjustment of the daily dose in stressful conditions (eg, fever, infection, vomiting, diarrhea). Thus, the patients are normally equipped with regular HC or CA tablets as well. Moreover, patients with malabsorption or a short transit time of nutrients through the small intestine are unable to take up sufficient HC before the tablet passes to the colon.

To conclude, based on the available literature, we tend say there is not enough evidence to claim a clinical meaningful benefit for ER-HC. Statistical significance is not the same as clinical significance, which requires a more sustained and obvious effect on hard endpoints such as mortality and morbidity.

Future Perspectives

To come closer to a definite answer, we need well-powered placebo-controlled trials with enough patients and comparative trials where between-treatment cortisol exposure is equal. With current technologies, we can already measure cortisol levels within their target tissues, over a day, providing valuable insights into the body's natural rhythms (59). Furthermore, subcutaneous infusion of HC has emerged as a potential alternative treatment. This involves administering a HC solution subcutaneously via an insulin pump, allowing for the recreation of the circadian (60, 61), and potentially also ultradian variation in cortisol levels. Preliminary studies on pump therapy have indicated minimal complications and improvements in quality of life (57, 58, 62). Although there are acknowledged cognitive and emotional benefits of replicating the ultradian rhythm, the long-term benefits remain uncertain.

Looking ahead, there's exciting potential for further innovation. Imagine a future in which real-time monitoring of tissue cortisol becomes a reality, akin to the continuous glucose monitoring systems available today. This could enable more precise and personalized dosing strategies, optimizing hormone levels towards physiological pharmacokinetics and improved patient outcomes.

Abbreviations

AI

adrenal insufficiency

AUC

area under the curve

BMD

bone mineral density

BMI

body mass index

CA

cortisone acetate

CAH

congenital adrenal hyperplasia

ER-HC

extended-release formulation of hydrocortisone

GC

glucocorticoid

HC

hydrocortisone

HPA

hypothalamic-pituitary-adrenal axis

IR-HC

immediate release hydrocortisone

PAI

primary adrenal insufficiency

QoL

quality of life

SAI

secondary adrenal insufficiency

Funding

S.S. is supported by a grant from The National Programme for Clinical Therapy Research in the Specialist Health Services (KLINBEFORSK, grant no WBS F-12310-D10636).

Disclosures

S.D.S., M.Ø., A.P.J., and E.S.H. have nothing to declare.

Data Availability

Data sharing is not applicable to this article as no data sets were generated or analyzed during the present study.