Novel agents to treat adrenal insufficiency: findings of preclinical and early clinical trials

ABSTRACT

Introduction

Adrenal insufficiency currently affects over 300/million population, with higher morbidity and mortality compared to the general population. Current glucocorticoid replacement therapy is limited by a lack of reliable biomarkers to guide dosing, inter-patient variation in metabolism and narrow therapeutic window. Increased morbidity and mortality may relate to unappreciated under- or over-exposure to glucocorticoids and impaired cortisol circadian rhythm. New agents are required to emulate physiological cortisol secretion and individualize glucocorticoid dosing.

Areas covered

History of glucocorticoid therapy, current limitations, and novel chronotherapeutic glucocorticoid delivery mechanisms. Literature search incorporated searches of PubMed and Embase utilizing terms such as adrenal insufficiency, Chronocort, Plenadren, continuous subcutaneous hydrocortisone infusion (CHSI), and glucocorticoid receptor modulator.

Expert opinion

Glucocorticoid chronotherapy is necessary to optimize glucocorticoid exposure and minimize complications. Current oral chronotherapeutics provide improved dosing functionality, but are modifiable only in specific increments and cannot accommodate ultradian cortisol variation. Current data show improvement in quality of life but not morbidity or mortality outcomes. CHSI has significant potential for individualized glucocorticoid dosing, but would require a suitable biomarker of glucocorticoid adequacy to be implementable. Avenues for future research include determining a glucocorticoid sufficiency biomarker, development of interstitial or systemic cortisol monitoring, or development of glucocorticoid receptor modulators.

KEYWORDS:

• Adrenal insufficiency
• adrenal crisis
• chronocort
• chronotherapy
• continuous hydrocortisone infusion
• glucocorticoid
• plenadren

Article highlights

• Current glucocorticoid therapy for adrenal insufficiency is limited by individual variations in glucocorticoid metabolism, the lack of biomarkers of adrenal sufficiency, and inability to mimic circadian and ultradian cortisol patterns.

• Chronotherapeutic agents such as a continuous subcutaneous hydrocortisone infusion and two delayed-release agents Plenadren and Chronocort attempt to reduce total glucocorticoid exposure by producing more physiological circadian plasma cortisol concentrations.

• Plenadren is the most researched agent and has been associated with minor improvements in weight, glycemia, quality of life, and immune function. It is unclear whether these benefits are due to the ~20% reduction in hydrocortisone exposure with direct 1:1 transition to Plenadren from hydrocortisone.

• Chronocort has primarily been assessed in congenital adrenal hyperplasia. It is administered twice daily and is associated with improvements in plasma androgen and 17-hydroxyprogestoerone concentrations, although limited long-term outcome data are available.

• Continuous subcutaneous hydrocortisone infusion has the most potential for individualization of circadian and ultradian cortisol patterns. It has the potential to be combined with continuous Holter cortisol monitoring analogous to type 1 diabetes mellitus; however, currently there are very limited studies assessing parameters of morbidity and mortality.

• The use of glucocorticoid receptor modulators, molecules that selectively exaggerate certain glucocorticoid effects and not others, may circumvent dosing-related issues associated with chronotherapeutic agents. Currently, phase 2 human trials exist for use of these agents in rheumatoid arthritis; however, no human data exist for adrenal insufficiency.

Declaration of interest

The authors have no relevant affiliation or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.