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Once-daily glucocorticoid therapy improves immune, metabolic function in adrenal insufficiency
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Patients with primary or secondary adrenal insufficiency assigned to once-daily hydrocortisone therapy for 24 weeks experienced fewer infections and improved metabolic control and reported a higher quality of life vs. patients prescribed conventional therapy, according to findings from an Italian study.
“It is generally accepted that conventional treatment of adrenal insufficiency is far from ideal,” Andrea M. Isidori, MD, PhD, associate professor of endocrinology in the department of experimental medicine at Sapienza University of Rome, and colleagues wrote. “Patients taking multiple, divided daily doses of glucocorticoids are advised to take the last dose no later than 4 to 6 hours before bedtime. In reality, patients will often take hydrocortisone late in the evening. Experimental studies have shown that nighttime exposure to glucocorticoids contributes to their detrimental effects on metabolism, independently of the cumulative 24-hour dose.”
Isidori and colleagues analyzed data from 89 patients with primary or secondary adrenal insufficiency taking conventional glucocorticoid therapy (hydrocortisone or cortisone two or three times per day plus daily fludrocortisone as needed) for at least 3 months, and a group of age- and sex-matched healthy volunteers (controls) matched in a 1:4 ratio. All participants were recruited between March 2014 and June 2016. Researchers randomly assigned patients to once-daily, modified-release hydrocortisone tablet (n = 46) or to continue with conventional therapy (n = 43) for 24 weeks. Patients in the once-daily group were advised to take the dose upon waking. Primary outcome was change in body weight from baseline to 24 weeks; secondary outcomes included changes in metabolic and immune profile from baseline to 24 weeks, as well as quality-of-life changes as measured by the Addison’s disease-specific quality-of-life questionnaire.
Within the cohort, 44 patients had primary adrenal insufficiency, and 45 patients had secondary adrenal insufficiency.
At 24 weeks, patients in the once-daily treatment group saw a greater reduction in body weight vs. those on conventional therapy (mean, –2.1 kg vs. 1.9 kg), for an estimated difference of –4 kg after adjustment. Researchers found that body weight had a treatment-by-time interaction (P = .001) in the once-daily group, starting at week 12 and improving through week 24.
Patients in the once-daily group saw improvements in other metabolic parameters vs. those using conventional therapy. The estimated treatment difference between groups at week 24 was –1.7 kg/m² for BMI (95% CI, –3 to –0.5), –2.5 cm for waist circumference (95% CI, –4.3 to –0.5) and –0.3% for HbA1c (95% CI, –0.5 to –0.1).
Additionally, the number of proinflammatory monocytes was reduced by nearly 50% at 24 weeks in the once-daily group vs. the conventional therapy group, and the once-daily group reported fewer mild infections and fewer influenza or influenza-like events vs. the conventional therapy group. Researchers observed a higher number of recurrent respiratory tract infections in the conventional treatment group vs. the once-daily therapy group (38 vs. 17; P = .016).
“The trial demonstrates that even small doses of glucocorticoids, if taken multiple times a day in the late afternoon or evening, can disrupt important endogenous circadian functions, metabolism and immune defense,” Isidori told Endocrine Today. “Shifting to a once-daily administration of the modified-release hydrocortisone can overcome these complications and improve the quality of life of patients with adrenal insufficiency. This is among the very few trials in endocrinology to explore clinical outcomes related to chronopharmacology. Contrary to the common belief, we showed that glucocorticoids, when taken without respecting the circadian rhythm of cortisol, are proinflammatory, rather than anti-inflammatory, and exhaust the immune function, specifically of the natural killer cells, the first line of defense against viral infections and malignancies.”
In commentary accompanying the study, Gudmundur Johannsson, MD, of the Sahlgrenska Academy Institute of Medicine in Gothenburg, Sweden, wrote that the findings suggest that conventional cortisol replacement therapy might promote atherosclerosis directly, and not only through conventional CV risk factors.
“Therefore, the outcome of this study could help elucidate the effect of cortisol on proinflammation in general and in patients with atherosclerosis specifically,” Johannsson wrote. – by Regina Schaffer
For more information:
Andrea M. Isidori, MD, PhD, can be reached at Sapienza University of Rome, Department of Experimental Medicine, Piazzale Aldo Moro, 5, 00185 Roma RM, Italy; email: andrea.isidori@uniroma1.it.
Disclosures: The Italian Ministry of University and Research funded this study. Isidori reports he receives grants and personal fees from Ipsen, Menarini, Novartis, Otsuka and Shire. Johannsson reports he receives consulting or lecture fees from AstraZeneca, Eli Lilly, Merck Serono, Novartis, Novo Nordisk, Otsuka, Pfizer and Shire. Please see the study for the other authors’ relevant financial disclosures.
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