Endocrinologists in Europe and the United States have come together to produce joint guidance to help clinicians manage patients who have, or are a at risk for, glucocorticoid-induced adrenal insufficiency (GC-AI).
Publication of the guidance marks the first time that the European Society of Endocrinology (ESE) and the Endocrine Society have cooperated in producing a guideline.
The guideline "Diagnosis and therapy of glucocorticoid-induced adrenal insufficiency" is published in the May 2024 issues of the societies respective journals, the European Journal of Endocrinology and The Journal of Clinical Endocrinology & Metabolism.
Felix Beuschlein, PhD, from the ESE, who cochaired the clinical committee, told Medscape Medical News: "You would hope that this leads to a common ground for a very large number of patients."
The risk for GC-AI is dependent on the dose, duration, and potency of the glucocorticoid; route of administration; as well as susceptibility of the individual patient. Once it develops or is suspected, careful education and management of affected patients is required.
Glucocorticoids Commonly Prescribed
"Glucocorticoid-induced adrenal insufficiency is actually a potential concern for a lot of patients," coauthor Tobias Else, MD, from the Department of Internal Medicine at the University of Michigan, Ann Arbor, Michigan, explained to Medscape Medical News. "Roughly 1% of all people are being treated with glucocorticoids at any given time."
"That's a tremendous number, and it gives the scale of the situation," added Beuschlein, who is director of the Department of Endocrinology, Diabetology and Clinical Nutrition at University Hospital Zürich, Zürich, Switzerland. "Now, fortunately, only a very small proportion of patients who are treated with glucocorticoids do have endocrine problems, and this is what this guideline is actually concentrating on."
Glucocorticoids are effective agents for treating autoimmune and inflammatory disorders. However, they can cause adverse reactions, particularly when administered at high doses and/or for a prolonged period.
Some studies have reported that even low-dose glucocorticoid use, such as prednisone at 2.5-7.5 mg/d, can increase the risk for cardiovascular disease, severe infections, hypertension, diabetes, osteoporosis, and fractures, as well as increase overall mortality with concurrent type 2 diabetes.
Tapering glucocorticoids can be challenging when symptoms of glucocorticoid withdrawal develop, which overlap with those of adrenal insufficiency, the guidelines stated. In general, tapering of glucocorticoids can occur more rapidly within a supraphysiological range, followed by a slower taper when on physiological glucocorticoid dosing.
The degree and persistence of hypothalamic-pituitary-adrenal (HPA) axis suppression after glucocorticoid therapy is stopped depends on overall exposure and recovery of adrenal function. "This is a quite individual situation, as you can imagine, because it's about sex, age, and comorbidities, the kind of glucocorticoid or other medications that you're giving," said Beuschlein. To cover contingencies, the paper presents tables to explain management covering various eventualities.
Leonie van Hulsteijn, MD,from the Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, Netherlands, said: "There are so many other specialties prescribing glucocorticoids; so especially the rheumatologist, the pulmonologist, the general practitioners."
Asked by Medscape Medical News whether the guidelines might dissuade some clinicians from offering glucocorticoids, van Hulsteijn, who contributed to the guidance, said, "I don't think it will keep them from prescribing it, but I really hope it will make them aware if somebody, after using long-term glucocorticoids, presents with complaints of adrenal insufficiency, that they will be aware and take immediate action."
Evidence Gaps
The review team took around 2.5 years to draw up the guidance amid some concerns about the quality of the evidence base, which they mainly rated as "low" or "very low." "I think we all, going through the literature, were quite astonished at how bad the evidence is for a problem as global as that," said Beuschlein. "But that's how it is — sometimes, even in the absence of strong evidence, you have to give some kind of guidance."
Nevertheless, the authors have called for more research to establish risk factors contributing to the development of and susceptibility to adrenal insufficiency, a greater understanding of glucocorticoid withdrawal, and identification of glucocorticoids retaining immunosuppressive and anti-inflammatory properties that have less effect on HPA axis suppression and an improved adverse effect profile.
Patient-facing materials on GC-AI are also in development and will be made available via the ESE Patient Zone this month.
Next year, the societies plan to publish a joint guideline on diabetes in pregnancy. That will be followed in 2026 by guidance on arginine vasopressin resistance and arginine vasopressin deficiency and a guideline on male hypogonadism in 2027.
Funding for the development of joint guidelines was provided by the societies and did not involve support from other bodies.
Beuschlein declared funding from the German Research Funding Agency, the Swiss National Science Foundation, University Medicine Zürich, the Vontobel Foundation, the Swiss Heart Foundation, and consultancy work for Bayer AG. Else declared membership of the advisory board of Merck and Company. van Hulsteijn declared no conflicts of interest.