NEW YORK (Reuters Health) – In patients with adrenal insufficiency, a once-daily, modified-release glucocorticoid regimen may reduce the recurrent infections and metabolic effects that can occur with multiple daily doses, researchers in Italy say.
“Since infections are the most common trigger of adrenal crisis, and today there are no effective ways to prevent their occurrence, reducing the frequency of infections seems the only way to address one of the most worrisome and unmet needs in the treatment of adrenal insufficiency,” Dr. Andrea Isidori of Sapienza University of Rome told Reuters Health.
“This 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,” he said by email.
“Shifting to a once-daily administration of modified-release hydrocortisone can overcome these complications and improve the quality of life of patients with adrenal insufficiency,” he said.
The single-blind randomized DREAM study involved 89 patients with adrenal insufficiency who were stable for at least three months on conventional glucocorticoid therapy. About half had primary adrenal insufficiency.
As reported online December 8 in The Lancet Diabetes-Endocrinology, 43 patients continued on standard treatment and 46 were switched to a once-daily, modified-release hydrocortisone pill, taken before getting out of bed in the morning. Twenty-five controls were also recruited.
At baseline, the two intervention groups were similar, whereas the control group had lower mean body mass index and lipid concentrations. Patients and controls had similar full blood counts, but the patients had higher T lymphocyte (CD3+) and B lymphocyte (CD19+) counts, higher numbers of classic pro-inflammatory monocytes (CD14+CD16–), and fewer CD16+CD14– cells and CD16+ natural killer cells. Patients also had higher concentrations of soluble CD16 and ADAM17 at baseline compared to the control group.
At 24 weeks, with adjustment for covariates, weight reduction was significantly better in the switch treatment group than in the standard treatment group, with a significant treatment-by-time interaction in the switch group, starting from week 12 and improving further at week 24.
The once-daily regimen also improved waist circumference and HbA1c concentration, according to the report.
At week 24, patients in the switch group had more normal immune cell profiles and fewer infections, and their number of mild infections was only slightly higher than that reported by the control group.
Similarly, the frequency of flu or flu-like events decreased from baseline to 24 weeks in the switch group compared to the standard therapy or control groups. An increase in the Addison’s disease-specific quality of life score was observed only in the switch group.
No differences in the frequency or severity of adverse events were observed between the two intervention groups, although the switch group had fewer recurrent upper respiratory tract infections.
Most adverse events were mild. Three serious adverse events occurred in each group; one (arthritis) in the switch group could be considered drug-related.
“This is among the very few trials in endocrinology to explore clinical outcomes related to chronopharmacology,” Dr. Isidori said. “Contrary to the common belief, we showed that glucocorticoids taken without respecting the circadian rhythm of cortisol are pro-inflammatory, rather than anti-inflammatory, and exhaust immune function – specifically of the natural killer cells, the first line of defense against viral infections and malignancies.”
“Current guidelines still recommend treating adrenal-insufficient patients with multiple doses divided during the day,” he noted. “Reducing the frequency of infections and improving the quality of life of these patients are valid arguments to encourage a change in clinical practice.”
“We show the value of using adrenal insufficiency as a model to study the importance of cortisol rhythm in the same year as the Nobel Prize in Physiology and Medicine was awarded to the discoverers of circadian rhythms,” Dr. Isidori added.
“The next step will be to look outside adrenal insufficiency,” he said. “A vast amount of people are receiving corticosteroids, often given at night, for respiratory (asthma or COPD), rheumatic or neoplastic diseases.”
“Further studies are needed to explore whether the same molecular mechanisms we documented in the DREAM trial works outside adrenal insufficiency,” Dr. Isidori concluded.
Dr. Gudmundur Johannsson of the University of Gothenburg, Sweden, author of a related editorial, told Reuters Health that the new findings support his group’s previous studies “showing the importance of the circadian cortisol profile for health in patients with adrenal insufficiency, but also in general.”
Like Dr. Isidori, he pointed to the 2017 Nobel Prize, and called the current study “very exciting.”
“In a much wider perspective, the DREAM study demonstrates the importance of a normal circadian cortisol profile for metabolism and the immune system in general,” Dr. Johannsson concludes, “and (suggests) that an abnormal circadian cortisol profile may be one of the mechanisms explaining the health burden in shift workers; sleep and stress-related disorders; and the development of obesity and type 2 diabetes.”
SOURCE: http://bit.ly/2zxy7VN and http://bit.ly/2zyIrwO
Lancet Diabetes Endocrinol 2017.
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