Adrenal Suppression in Duchenne Muscular Dystrophy: Management Strategies Incorporating Novel Steroid Vamorolone

Abstract

Adrenal suppression is an iatrogenic form of adrenal insufficiency that occurs secondary to exogenous glucocorticoids (GCs) and is a documented cause of premature mortality among individuals with Duchenne muscular dystrophy (DMD). Adrenal suppression in DMD necessitates awareness and careful management, given that GCs are currently the mainstay of therapy for individuals living with DMD. Vamorolone, a novel GC that has recently been approved in some regions worldwide for the treatment of DMD, has also been reported to place individuals at high risk of adrenal suppression in a dose-dependent fashion, requiring health care professional awareness. Vamorolone is a mineralocorticoid receptor antagonist, which differentiates it from classic GCs, and this characteristic impacts the approach to adrenal suppression management. This contemporary perspective provides insights into the mechanisms underlying adrenal suppression due to both classic GCs and novel vamorolone therapy, followed by an overview of adrenal suppression management with a particular focus on the unique aspects of providing care for individuals treated with vamorolone. It also emphasizes the importance of educating the DMD community and health care providers about the recognition and management of adrenal suppression and outlines critical concepts for clinicians managing adrenal suppression risk, tapering GCs, and transitioning from classic GC therapy to vamorolone. The key principles of managing adrenal suppression due to classic GCs and novel vamorolone therapy highlighted in this perspective are expected to enhance clinical practice, mitigate mortality, and optimize health outcomes for individuals with DMD.

Duchenne muscular dystrophy (DMD) is an X-linked disorder characterized by the absence of functional dystrophin, leading to progressive skeletal and cardiac muscle degeneration, loss of ambulation, and cardiorespiratory failure [1]. Long-term, high-dose, classic glucocorticoid (GC) therapies (prednisone, prednisolone, and deflazacort) slow disease progression but are associated with significant adverse effects, including growth failure, reduced serum bone turnover markers, and high rates of vertebral and long bone fractures in DMD [1-3]. Prolonged use of GCs (greater than 2-3 weeks) may cause adrenal suppression, an iatrogenic form of adrenal insufficiency [4, 5]. Symptoms and signs of adrenal insufficiency due to exogenous GCs are typically nonspecific and may include weakness, fatigue, nausea, vomiting, headache, myalgia, arthralgia, and/or poor growth [4]. Because weakness and fatigue are often the only symptoms of adrenal suppression, they can be mistaken for DMD disease progression. If adrenal suppression goes unrecognized, there is a risk for an adrenal crisis. An adrenal crisis may include cardiovascular collapse, hypoglycemia, and/or altered mental status; if not identified or managed properly, it may lead to premature death, including in DMD [4, 6]. Individuals treated with GCs are also at risk of GC withdrawal syndrome, a distinct entity with signs and symptoms of adrenal insufficiency that can occur during GC tapering but is typically not life-threatening [7].

Vamorolone is a novel GC that retains the anti-inflammatory benefits of classic GCs via nuclear factor kappa B inhibition while reducing side effects by selectively modulating GC receptor activity, thus dissociating trans-repression from transactivation and resulting in less adverse effects on growth and bone health [8, 9]. However, like classic GCs, vamorolone causes dose-dependent adrenal suppression [9, 10]. Vamorolone also acts as a mineralocorticoid antagonist, a unique property differentiating it from classic GCs (hydrocortisone, deflazacort, or prednisone/prednisolone) [11, 12]. Vamorolone was approved in 2023 in the USA for individuals with DMD ages 2 and older and subsequently approved in the European Union (EU), the United Kingdom (UK), China, and Canada for individuals with DMD ages 4 years and older [13, 14]. A commentary discussed vamorolone as an alternative to classic GCs in DMD; however, it did not include the risk of adrenal suppression from vamorolone or strategies to reduce morbidity and mortality secondary to this iatrogenic risk [15]. This perspective addresses this gap by describing the similarities and differences between vamorolone and classic GC use in DMD, highlighting key principles of adrenal suppression management.

Similarities and Differences between Novel GC Vamorolone and Classic GCs Used in DMD

Vamorolone is a novel anti-inflammatory GC that lacks a hydroxyl group at the C11 position of the steroid skeleton. This structural modification prevents the formation of a hydrogen bond with the Asn564 residue in the GC receptor [16]. Consequently, the vamorolone-GC receptor complex has reduced affinity for coactivator proteins compared to prednisone or deflazacort, making it a significantly weaker activator of gene transcription associated with some GC-related side effects [8]. However, the vamorolone-GC receptor complex retains a high affinity for co-repressors and has significant gene trans-repression activity, responsible for its anti-inflammatory effects. Therefore, vamorolone is classified as a dissociative ligand for the GC receptor [8]. Additionally, the absence of the hydroxyl group at C11 prevents a hydrogen bond with the N770 residue of the mineralocorticoid receptor, giving vamorolone mineralocorticoid antagonist properties, unlike prednisone and deflazacort [11]. Furthermore, vamorolone is not a substrate for 11β-hydroxysteroid dehydrogenases (HSD) I and II due to the absence of the C11 hydroxyl group. This is significant because 11β-HSD-1 was shown to mediate some adverse effects of classic GCs, including the negative impact on bone turnover [17].

The recommended vamorolone dose of 6 mg/kg/day (2 mg/kg/day for hepatic impairment) stems from reported clinical trials [9, 18-21]. Efficacy data up to 24 weeks in a randomized, blinded, placebo-controlled trial of previously GC-naïve boys with DMD showed that vamorolone 6 mg/kg/day had similar efficacy to prednisone 0.75 mg/kg/day on motor outcomes [9]. Efficacy was maintained at 48 weeks in an extension study and was demonstrated to be comparable to historical GC regimens (including both prednisone and deflazacort) in a 30-week open-label trial [18, 19]. In the 24-week study, linear growth was not suppressed in the vamorolone group compared to prednisone, and deceleration of growth and decline in serum bone biomarkers were also reversed after crossover from prednisone to vamorolone 6 mg/kg/day [9]. Similarly, improved height velocity was demonstrated in the 30-week open-label trial compared to classic GC regimens [18]. In summary, vamorolone is effective in improving motor outcomes for up to 30 months in ambulatory boys with DMD and has a more favorable effect on linear growth and serum bone turnover markers compared to classic GCs [9, 18, 19].

Despite improvements in some GC-associated adverse events [9, 18], excess weight gain was reported with vamorolone and, importantly, vamorolone caused adrenal suppression similar to prednisone [9, 18, 19]. In the randomized controlled trial of vamorolone vs prednisone and placebo in boys with DMD, adrenocorticotropic hormone (ACTH) stimulation testing after 24 weeks demonstrated adrenal suppression (peak cortisol < 400 nmol/L) in 19/21 (90.5%) of subjects treated with vamorolone 6 mg/kg/day, 9/19 (47.5%) of subjects treated with vamorolone 2 mg/kg/day, and 23/25 (92%) of subjects treated with prednisone 0.75 mg/kg/day [10]. Vamorolone also caused a dose-dependent decrease in morning cortisol and ACTH-stimulated peak cortisol concentrations after 48 weeks in an extension study [10] with virtually all subjects on 6 mg/kg/day demonstrating an impaired peak cortisol response. While most participants had adrenal suppression at 48 weeks, adrenal suppression increased in those who switched from prednisone to vamorolone 6 mg/kg/day and decreased in those who switched to vamorolone 2 mg/kg/day [10].

Adrenal Suppression and Stress Steroid Coverage in DMD Treated with Vamorolone and Classic GCs

Mechanisms underlying adrenal suppression due to exogenous GCs involve disruption of the feedback loop of the hypothalamic-pituitary-adrenal (HPA) axis. Normally, the hypothalamus secretes corticotropin-releasing hormone (CRH), stimulating the pituitary gland to release ACTH. ACTH then signals the adrenals to produce cortisol. When cortisol levels rise, they feed back to the hypothalamus and pituitary gland, inhibiting further release of CRH and ACTH, downregulating cortisol production [22]. During physiological stress, the HPA axis is upregulated, stimulating the adrenals to increase cortisol production to prevent hypotension and hypoglycemia. This upregulation is referred to as a stress response [22]. Supraphysiological GC doses (>10 mg/m²/day hydrocortisone equivalent) [23] exert similar inhibitory effects on the HPA axis as endogenous cortisol. If supraphysiological GCs are administered over the long term, chronic HPA axis suppression leads to atrophy of cortisol-producing cells in the adrenals [22]. Unlike other side effects related to GCs, GC suppression of CRH and ACTH is mediated through trans-repression of the CRH and pro-opiomelanocortin genes [24]. Since the vamorolone-GC receptor complex maintains trans-repression [8], it is not surprising that adrenal suppression occurs with vamorolone.

Hydrocortisone is the synthetic equivalent of cortisol and is therefore the pharmacologic GC that most closely mimics the basal secretion of cortisol, at an equivalency of approximately 8 to 10 mg/m²/day [23, 25] (Table 1). Higher doses (stress dosing) are required during times of moderate and severe physiological stress (including critical illness) to mimic the cortisol “stress response” (Table 1). Deflazacort and prednisone are approximately 3 and 4 times more potent than hydrocortisone, respectively, in terms of their anti-inflammatory properties [26]. The potencies in hydrocortisone equivalents related to adrenal suppression are not fully understood for most classic GCs, but anti-inflammatory equivalencies are typically considered equal to adrenal suppression equivalencies and are used in clinical practice [27]. Although GC replacement potencies in hydrocortisone equivalents are unknown for vamorolone, its adrenal suppression potencies compared to prednisone are dose dependent: the therapeutic vamorolone dose (6 mg/kg/day) causes slightly more suppression compared to a therapeutic prednisone dose (0.75 mg/kg/day), while the subtherapeutic vamorolone dose (2 mg/kg/day) causes less compared to a therapeutic prednisone dose [10]. Therapeutic doses of deflazacort and prednisone are several times greater than a physiological hydrocortisone equivalent dose, even if a lower treatment dose is prescribed [1, 28] (Table 1). Even at these supraphysiologic doses, adrenal suppression can be dangerous when the body would be triggered to produce a cortisol “stress response,” and can occur on prednisone, deflazacort, and vamorolone due to their variable half-lives and durations of action [22, 26, 28]. Additionally, adrenal suppression risk must be managed with an appropriate stress steroid with mineralocorticoid agonistic properties since signaling through the mineralocorticoid receptor helps to maintain blood pressure (Table 1) [22, 26, 28, 29]. While hydrocortisone, prednisolone, and prednisone can be used for moderate illness stress dosing since they are mineralocorticoid agonists, it is unknown if deflazacort is safe for stress dosing because of its short half-life [26].

Table 1.

Glucocorticoids used in the treatment of individuals with DMD

Glucocorticoid	Physiologic (maintenance)a	Duration of action (hours)b	DMD treatment dosec	Mineralocorticoid receptor activity	Acceptable for stress coverage	Moderate stress dosing (enteral)d	Severe stress dosing (intravenous or intramuscular)d
Hydrocortisone	8-10 mg/m2/d	8 to 12	N/A	Agonist	Yes	30-50 mg/m2/d divided every 6-8 hours (max 60 mg daily) OR Weight-based dosinge  10-25 kg: 5 mg every 6-8 hours  26-50 kg: 10 mg q 6-8 hours > 50 kg: 15 mg q 6-8 hours	100 mg/m2 (max 100 mg) × 1 followed by 50-100 mg/m2/d divided every 4-6 hours
Prednisolone	2-3 mg/m2/d	12 to 36	0.75 mg/kg/d (max dose 30-40 mg)	Agonist	Yes	8-12 mg/m2/d divided every 12 hours (max 15 mg daily) OR Weight-based dosinge  10-25 kg: 2.5 mg q 12 hours  26-50 kg: 5 mg q 12 hours  > 50 kg: 7.5 mg q 12 hours	N/A
Prednisone	2-3 mg/m2/d	12 to 26	0.75 mg/kg/d (max dose 30-40 mg)	Agonist	Yes	8-12 mg/m2/d divided every 12 hours (max 15 mg daily) OR Weight-based dosinge  10-25 kg: 5 mg every 6-8 hours  26-50 kg: 10 mg q 6-8 hours  > 50 kg: 15 mg q 6-8 hours	N/A
Deflazacort	2.6 mg/m2/d	4 to 24	0.9 mg/kg/d (max dose 36 mg)	Weak agonist	Unknownf	Unknownf	N/A
Vamorolone	Unknown	24	6 mg/kg/d (max dose 300 mg USA, 240 mg EU)	Antagonist	No	N/A	N/A

Abbreviations: DMD, Duchenne muscular dystrophy; EU, European Union; max, maximum; N/A, not applicable.

^aAvailable data for relative hypothalamic-pituitary-adrenal suppression potency is limited and variable.

^bDeflazacort has a half-life of 1.1 to 1.9 hours is shorter than both hydrocortisone (3 hours) and prednisone (6.2 hours).

^cTypical starting doses, may differ across clinical practice. Recommended dose for vamorolone is 2 mg/kg/d (max dose 100 mg/d) in people with moderate hepatic impairment. Safety in individuals with severe hepatic impairment has not been established.

^dSuggested stress dosing. Refer to the PJ Nicholoff protocol or other more comprehensive document for further details.

^eAs per British Society for Paediatric Endocrinology and Diabetes consensus guidance.

^fInsufficient data to inform dosing frequency for stress steroid coverage.

Intravenous or intramuscular steroid stress coverage has commonly been given during times of severe illness or surgery in DMD, but enteral stress steroid plans for prednisone- or deflazacort-treated individuals for moderate illnesses or post-bisphosphonates are not consistently provided. Reported concerns for severe acute phase reaction associated with bisphosphonates in DMD [30] have led clinicians to provide stress coverage for this indication. This approach was driven by recognizing that deflazacort may not provide adequate stress steroid coverage due to its short duration of action, and that prednisone may not last beyond 12 hours, consequently providing inadequate stress coverage in some situations [26, 31, 32].

All individuals with DMD on daily GCs, including vamorolone, must be presumed to have adrenal suppression and require a stress steroid plan for illness, injury, or surgery [4, 6, 22, 29, 33]. Vamorolone cannot be used for stress dosing because it blocks the mineralocorticoid receptor. This unique physiologic property of vamorolone was confirmed to occur in a study where healthy adult males were randomized to receive vamorolone (20 mg/kg), eplerenone (200 mg), or no treatment, followed by a fludrocortisone challenge [12]. Vamorolone reversed the reduction of the urinary sodium/potassium ratio induced by fludrocortisone and showed a natriuretic effect similar to eplerenone, with no evidence of potassium retention. Single doses of vamorolone 20 mg/kg were well tolerated. In the VISION-DMD trial, boys with DMD treated with vamorolone (2 or 6 mg/kg/day) showed increases in serum renin, klotho, and calcium carrier proteins consistent with mineralocorticoid receptor antagonism. These biomarker changes were specific to vamorolone and not observed with prednisone or placebo [12]. While no electrolyte disturbances with vamorolone in DMD have been reported, its mineralocorticoid antagonism could potentially cause hypotension, hyponatremia, or hyperkalemia at high doses. Clinicians should monitor electrolytes during periods of stress, particularly in individuals with DMD and heart failure or on renin-angiotensin-aldosterone inhibitors. No studies have examined concurrent use of vamorolone with eplerenone or other mineralocorticoid antagonists [13, 14, 34, 35]. It is reasonable to monitor serum electrolytes after starting a combination of vamorolone and a mineralocorticoid antagonist, and in cases of hyperkalemia, there should be a mineralocorticoid antagonist dose reduction. Since vamorolone has only been studied as an anti-inflammatory agent and not for GC replacement, it is unknown if vamorolone provides the physiological effects of cortisol or of a classic GC. Individuals treated with vamorolone must receive stress doses of hydrocortisone or prednisone/prednisolone during periods of physiological stress in addition to their usual vamorolone dose.

Transitioning from Classic GCs to Vamorolone and GC Tapering

Clinicians and individuals should be aware of the risk of adrenal insufficiency and GC withdrawal symptoms during GC tapering or transition. GC withdrawal symptoms such as fatigue, nausea, and muscle or joint pain may resemble those of adrenal insufficiency but can occur even on supraphysiological GC doses; these are usually not life-threatening, although the risk of adrenal insufficiency increases during physiological stress or when tapering below a physiological dose. If GC withdrawal symptoms occur despite supraphysiological dosing, the taper should be slowed [7, 33]. Because the physiological dose of vamorolone is unknown, adrenal insufficiency symptoms should be considered throughout a vamorolone taper. Once GCs are discontinued or reduced to a physiological dose, the HPA axis function should be assessed with a morning cortisol and/or an ACTH stimulation test. If cortisol deficiency is detected, stress steroid doses and, in some cases, daily physiologic replacement may be required. Endocrinology involvement is recommended during both tapering and evaluation of HPA axis recovery.

Careful attention to the adrenal axis is required when transitioning from classic GCs to vamorolone. Individuals being transitioned from prednisone or deflazacort should ideally be directly started on vamorolone 6 mg/kg/day (maximum dose 300 mg in the USA, 240 mg in the EU, UK, China, and Canada) without interruption to reduce the risk of GC withdrawal and adrenal insufficiency [13, 14]. Individuals and caregivers must be educated on adrenal insufficiency symptoms and advised to begin stress dosing and contact their provider if symptoms occur during the transition to vamorolone, even at a dose of 6 mg/kg/day. In cases where symptomatic adrenal suppression develops, stress doses of GCs must be initiated in addition to vamorolone. If transitioning individuals from prednisone/prednisolone or deflazacort to a vamorolone dose less than 6 mg/kg/day, the theoretical risk of symptomatic GC withdrawal or adrenal insufficiency is higher [10], and as such, consider treating these individuals with physiologic hydrocortisone replacement for 4 weeks at initiation of vamorolone for a safe transition. Intermittent dosing, such as weekend-only high-dose vamorolone, has not been investigated and is not advised.

Ongoing Education for Individuals with DMD to Minimize the Risk of Adrenal Suppression

Minimizing adrenal suppression risks in DMD requires a multifaceted approach. At vamorolone or classic GC initiation, healthcare providers must teach individuals and caregivers about the risks of life-threatening adrenal suppression, emphasize adherence to their regularly prescribed GC therapy, and provide stress dosing education. This includes training on intramuscular hydrocortisone for emergencies and providing written instructions [29, 32, 36]. Individuals should wear a form of medical identification stating they are steroid-dependent, and their electronic medical records should identify this risk [22]. Stress dosing plans, prescriptions, and education should be reviewed annually and during care transitions.

Conclusions

Adrenal suppression poses a significant challenge in the management of individuals with DMD treated with GCs, necessitating proactive recognition, prevention, and management strategies. Endocrinologists and other health care providers must be informed that vamorolone is a novel GC being used in DMD. Although vamorolone reduces certain side effects of traditional GCs, such as growth suppression, it still causes adrenal suppression comparable to classic GCs, necessitating careful management to avoid morbidity and mortality. Importantly, vamorolone cannot be used for stress steroid coverage due to its mineralocorticoid antagonistic properties. By integrating these clinical considerations into practice, healthcare providers will be able to safely and effectively initiate vamorolone therapy in DMD.

Abbreviations

ACTH

adrenocorticotropic hormone

CRH

corticotropin-releasing hormone

DMD

Duchenne muscular dystrophy

GC

glucocorticoid

HPA

hypothalamic-pituitary-adrenal

Funding

This work was supported by Parent Project Muscular Dystrophy, Parent Project APS, and The Nicholoff Family. L.M.W. is supported by a Tier 1 Research Chair in Pediatric Bone Disorders from The University of Ottawa, The Children’s Hospital of Eastern Ontario Department of Pediatrics, and The Children’s Hospital of Eastern Ontario Research Institute. Drs. Phung and Halloun are supported by Parent Project Muscular Dystrophy and Defeat Duchenne Canada Clinical Research Fellowships.

Disclosures

A.M.S. has been a site investigator for vamorolone clinical trials funded by Reveragen and a consultant for Catalyst Pharmaceuticals. M-E.L. is a local site sub-investigator for the Duchenne Muscular Dystrophy Study PGN-EDO51. H.J.M. has consulted for Roche, Kye Pharma, Regenxbio, and Solid Biosciences. He has been a site principal investigator for clinical trials sponsored by Roche, Sarepta, Italfarmaco, Dyne Therapeutics, PepGen, Regenxbio, Pfizer, and Reveragen. K.A.S. has been a member of the advisory committee of Solid Bio, Roche, and Biogen; PI for the clinical trials of Italfarmico, Dyne, Argenx, Solid Bio, RegenxBio, and Santhera-Vamorolone; Honoraria for presentations/educational events for Novartis and Roche; SMA working group lead for CNDR. A.V. has been an ad hoc advisor/consultant for PTC Therapeutics, Novartis, Sarepta, Scholar Rock, Edgewise, UCB, Solid, Pfizer, RgenexBio, Avidity, Catalyst, Santhera, Dyne, Entrada, Lupin, Percheron, Capricor, Italfarmaco, Gruenthel, Quince, and Keros. D.R.W. has been a consultant for Catalyst, Inozyme, and Santhera. D.X.B. has no conflict of interest specific to this paper (Adrenal Suppression); D.X.B. has served as site investigator for Sarepta, Roche/Genentech; serves as DSMB/DSMC for BridgeBio (ASPA Therapeutics) in an unpaid capacity; has served on ad hoc advisory board committees for Sarepta, REGENXBIO, and Pfizer in an unpaid capacity; and has no financial interest in these companies. P.R.C. has grant support from NS Pharma, Sanofi, Spark Therapeutics, ReveraGen Biopharma, Amicus Therapeutics, NIH, and FDA. Consulting for TRiNDS. M.F. has received grant support from the University of Montreal, Azrieli Research Centre of CHU Sainte Justine, and Muscular Dystrophy Canada. N.M. has been on the advisory board for BioMarin, Catalyst, Pfizer, BridgeBio, Ascendis, Kyowa Kirin, and Alexion. L.M. has been a member of the advisory board for Kye therapeutics (DMD) and Acadia Pharmaceuticals (Rett Syndrome); PI for a clinical trial funded by Italfarmaco SpA (DMD) and Sub I clinical trial funded by Anavex Life Sciences (Rett Syndrome). S.N. received research funding from the American Neuromuscular Foundation, the Muscular Dystrophy Association, and the American Brain Foundation. M.M.R. has served as a consultant for Catalyst Pharmaceuticals Inc. M.S. has been an advisor/consultant for PPMD. P.N.S. has been an advisory board meeting for Santhera Pharmaceutical 2025 advisory board meeting for Cataylst 2024. J.T. has been a consultant for Catalyst Pharmaceuticals (Pediatric Endocrinology Advisory Board, May 2024). C.T. has been a site PI for clinical trials and studies sponsored by Avexis, BioHaven, BMS, Capricor, Catabasis, Fibrogen, Pfizer, PTC, Roche, Santhera, and Sarepta; and has been a consultant for Biogen, Catalyst, Entrada, Regenxbio, and Sarepta. L.M.W. has been a consultant to Amgen, Ultragenyx, Kyowa Kirin, Roche, Angitia, Santhera, Catalyst, BioMarin, and Ipsen, with funds to Dr. Ward's institution, and has participated in clinical trials with Alexion, QED, Ultragenyx, Edgewise, ReveraGen, Ascendis, Roche, and Catalyst, with funds to Dr. Ward's Institution. C.L.W. is an investigator for the GUARDIAN study (an open-label study to collect long-term safety and efficacy data from boys with DMD who have completed prior studies with vamorolone). She has received speaker fees from Pfizer and consultancy fees from PTC Therapeutics, Roche, and Pfizer. S.C.W. has been a consultant for Santhera, Roche, and Novartis; and has received speaker honoraria from Nutricia, Sandoz, Novo Nordisk, and Roche. A.A. has received honoraria for consultancy work from Reveragen, with funds to Dr. Ahmet's Institution. K.K., S.A., S.B. (Bharill), S.B. (Bansal), R.H., C.L., N.N., O.M.M.F., and K.P. have nothing to declare.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the course of this work.