ENDO 2021 Roundup: COVID-19 Risk With Adrenal Insufficiency, Cushing’s Death Risk, Jatenzo Liver Data, and More

Some of the latest research advancements in the field of endocrinology presented at the Endocrine Society’s virtual ENDO 2021 meeting included quantifying diabetic ketoacidosis readmission rateshyperglycemia as a severe COVID-19 predictor, and semaglutide as a weight loss therapy. Below are a few more research highlights:

More Safety Data on Jatenzo

In a study of 81 men with hypogonadism — defined as a serum testosterone level below 300 ng/dL — oral testosterone replacement therapy (Jatenzo) was both safe and effective in a manufacturer-sponsored study.

After 24 months of oral therapy, testosterone concentration increased from an average baseline of 208.3 ng/dL to 470.1 ng/dL, with 84% of patients achieving a number in the eugonadal range.

And importantly, the treatment also demonstrated liver safety, as there were no significant changes in liver function tests throughout the 2-year study — including alanine aminotransferase (28.0 ± 12.3 to 26.6 ± 12.8 U/L), aspartate transaminase (21.8 ± 6.8 to 22.0 ± 8.2 U/L), and bilirubin levels (0.58 ± 0.22 to 0.52 ± 0.19 mg/dL).

Throughout the trial, only one participant had elevation of liver function tests.

“Our study finds testosterone undecanoate is an effective oral therapy for men with low testosterone levels and has a safety profile consistent with other approved testosterone products, without the drawbacks of non-oral modes of administration,” said lead study author Ronald Swerdloff, MD, of the Lundquist Research Institute in Torrance, California, in a statement.

In addition, for many men with hypogonadism, “an oral option is preferred to avoid issues associated with other modes of administration, such as injection site pain or transference to partners and children,” he said. “Before [testosterone undecanoate] was approved, the only orally approved testosterone supplemental therapy in the United States was methyltestosterone, which was known to be associated with significant chemical-driven liver damage.”

Oral testosterone undecanoate received FDA approval in March 2019 following a rocky review history.

COVID-19 Risk With Adrenal Insufficiency

Alarming new data suggested that children with adrenal insufficiency were more than 23 times more likely to die from COVID-19 than kids without this condition (relative risk 23.68, P<0.0001). This equated to 11 deaths out of 1,328 children with adrenal insufficiency compared with 215 deaths out of 609,788 children without this condition (0.828% vs 0.035%).

These young patients with adrenal insufficiency also saw a much higher rate of sepsis (RR 21.68, P<0.0001) and endotracheal intubation with COVID-19 infection (RR 25.45, P<0.00001).

Data for the analysis were drawn from the international TriNetX database, which included patient records of children ages 18 and younger diagnosed with COVID-19 from 60 healthcare organizations in 31 different countries.

“It’s really important that you take your hydrocortisone medications and start stress dosing as soon as you’re sick,” study author Manish Raisingani, MD, of the University of Arkansas for Medical Sciences and Arkansas Children’s in Little Rock, explained during a press conference. “This will help prevent significant complications due to COVID-19 or any other infections. A lot of the complications that we see in kids with adrenal insufficiency are due to inadequate stress dosing of steroids.”

And with kids starting to return back to in-person schooling, “parents should also be reeducated about using the emergency injections of hydrocortisone,” Raisingani added. He noted that the COVID-19 complication rates were likely so high in this patient population because many had secondary adrenal insufficiency due to being on long-term, chronic steroids. Many also had comorbid respiratory illnesses, as well.

Cushing’s Death Risk

In a systematic review and meta-analysis of 87 studies — including data on 17,276 patients with endogenous Cushing’s syndrome — researchers found that these patients face a much higher death rate than those without this condition.

Overall, patients with endogenous Cushing’s syndrome faced a nearly three times higher mortality ratio (standardized mortality ratio 2.91, 95% CI 2.41-3.68, I2=40.3%), with those with Cushing’s disease found to have an even higher mortality risk (SMR 3.27, 95% CI 2.33-4.21, I2=55.6%).

And those with adrenal Cushing’s syndrome also saw an elevated death risk, although not as high as patients with the disease (SMR 1.62, 95% CI 0.08-3.16, I2=0.0%).

The most common causes of mortality among these patients included cardiac conditions (25%), infection (14%), and cerebrovascular disease (9%).

“The causes of death highlight the need for aggressive management of cardiovascular risk, prevention of thromboembolism, and good infection control, and emphasize the need to achieve disease remission, normalizing cortisol levels,” said lead study author Padiporn Limumpornpetch, MD, of the University of Leeds in England, in a statement.

From https://www.medpagetoday.com/meetingcoverage/endo/91808

Estrogen receptor α plays an important role in Cushing’s syndrome during pregnancy

Abstract

Cushing’s syndrome (CS) during pregnancy is very rare with a few cases reported in the literature.

Of great interest, some cases of CS during pregnancy spontaneously resolve after delivery. Most studies suggest that aberrant luteinizing hormone (LH)/human chorionic gonadotropin (hCG) receptor (LHCGR) seems to play a critical role in the pathogenesis of CS during pregnancy.

However, not all women during pregnancy are observed cortisol hypersecretion. Moreover, some cases of adrenal tumors or macronodular hyperplasia with LHCGR expressed, have no response to hCG or LH.

Therefore, alternative pathogenic mechanisms are indicated. It has been recently reported that estrogen binding to estrogen receptor α (ERα) could enhance the adrenocortical adenocarcinoma (ACC) cell proliferation.

Herein, we hypothesize that ERα is probably involved in CS development during pregnancy.

Better understanding of the possible mechanism of ERα on cortisol production and adrenocortical tumorigenesis will contribute to the diagnosis and treatment of CS during pregnancy.

Read the entire article here: https://www.sciencedirect.com/science/article/pii/S0306987720303893?via%3Dihub

Steroids! Scientists Hail Dexamethasone as ‘Major Breakthrough’ in Treating Coronavirus

 

Dexamethasone, a cheap and widely used steroid, has become the first drug shown to be able to save lives among Covid-19 patients in what scientists hailed as a “major breakthrough”.

Results of trials announced on Tuesday showed dexamethasone, which is used to reduce inflammation in other diseases, reduced death rates by around a third among the most severely ill Covid-19 patients admitted to hospital.

The results suggest the drug should immediately become standard care in patients with severe cases of the pandemic disease, said the researchers who led the trials.

“This is a result that shows that if patients who have Covid-19 and are on ventilators or are on oxygen are given dexamethasone, it will save lives, and it will do so at a remarkably low cost,” said Martin Landray, an Oxford University professor co-leading the trial, known as the RECOVERY trial.

“It’s going to be very hard for any drug really to replace this, given that for less than 50 pounds ($63.26), you can treat eight patients and save a life,” he told reporters in an online briefing.

His co-lead investigator, Peter Horby, said dexamethasone was “the only drug that’s so far shown to reduce mortality – and it reduces it significantly.”

“It is a major breakthrough,” he said. “Dexamethasone is inexpensive, on the shelf, and can be used immediately to save lives worldwide.”

There are currently no approved treatments or vaccines for Covid-19, the disease caused by the new coronavirus which has killed more than 431,000 globally.

Saving ‘countless lives’

The RECOVERY trial compared outcomes of around 2,100 patients who were randomly assigned to get the steroid, with those of around 4,300 patients who did not get it.

The results suggest that one death would be prevented by treatment with dexamethasone among every eight ventilated Covid-19 patients, Landray said, and one death would be prevented among every 25 Covid-19 patients that received the drug and are on oxygen.

Among patients with Covid-19 who did not require respiratory support, there was no benefit from treatment with dexamethasone.

“The survival benefit is clear and large in those patients who are sick enough to require oxygen treatment, so dexamethasone should now become standard of care in these patients,” Horby said.

Nick Cammack, a expert on Covid-19 at the Wellcome Trust global health charity, said the findings would “transform the impact of the Covid-19 pandemic on lives and economies across the world”.

“Countless lives will be saved globally,” he said in a statement responding to the results.

The RECOVERY trial was launched in April as a randomised clinical trial to test a range of potential treatments for Covid-19, including low-dose dexamethasone and the malaria drug hydoxycholoroquine.

The hydroxychloroquine arm was halted earlier this month after Horby and Landray said results showed it was “useless” at treating Covid-19 patients.

Global cases of infection with the novel coronavirus have reached over 8 million, according to a Reuters tally, and more than 434,000 people have died after contracting the virus, the first case if which was reported in China in early January.

From https://www.cnbc.com/2020/06/16/steroid-dexamethasone-reduces-deaths-from-severe-covid-19-trial.html

Patients on Steroids With COVID-19 Might Need Rescue Steroids

 

Endocrinologists have underlined the importance that physicians consider “a stress dose” of glucocorticoids in the event of severe COVID-19 infection in endocrine, and other, patients on long-term steroids.

 

People taking corticosteroids on a routine basis for a variety of underlying inflammatory conditions, such as asthma, allergies, and arthritis, are at elevated risk of being infected with, and adversely affected by, COVID-19.

 

This also applies to a rarer group of patients with adrenal insufficiency and uncontrolled Cushing syndrome, as well as secondary adrenal insufficiency occurring in hypopituitarism, who also rely on glucocorticoids for day-to-day living.

 

In the event of COVID-19, all of these individuals may be unable to mount a normal stress response, and “in the case of adrenal suppression…such patients may run into severe difficulties, particularly if on intensive care units,” warns Paul Stewart, MD, University of Leeds, UK, and editor-in-chief of the Journal of Clinical Endocrinology & Metabolism (JCEM).

 

As such, it is vitally important to recognize that “Injectable supplemental glucocorticoid therapy in this setting can reverse the risk of potentially fatal adrenal failure and should be considered in every case,” Stewart and colleagues emphasize in a newly published editorial in JCEM.

 

They note this advice must be considered alongside World Health Organization (WHO) guidance against prescribing therapeutic glucocorticoids to treat complications of COVID-19, based on prior experience in patients with acute respiratory distress syndrome, as well as those affected by severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS).

 

The key difference here is not to use pharmacologic doses of glucocorticoids as treatment for COVID-19 (where they have no effect), but rather to prevent death from adrenal failure by using “stress” doses of replacement glucocorticoid, Stewart explained to Medscape Medical News.

 

“No patient with a history of prior exposure to chronic glucocorticoid therapy (> 3 months)…should die without consideration” for a stress dose of replacement glucocorticoid therapy.

“The intent here is to ensure that no patient with a history of prior exposure to chronic glucocorticoid therapy (> 3 months) by whatever route should die without consideration for parenteral glucocorticoid therapy,” the editorialists write.

 

He advises using physiological stress doses of hydrocortisone (50-100 mg intravenously tid).

 

Specific Advice for Adrenal Insufficiency: Follow Sick Day Rules

 

separate statement by the American Association of Clinical Endocrinologists (AACE) also emphasizes that it is particularly important for patients with adrenal insufficiency to follow advice from the Centers for Disease Control and Prevention (CDC) or similar guidance on preventing COVID-19 infection, including social distancing and frequent hand washing.

 

Such patients should continue to take medications as prescribed and ensure they have appropriate supplies of oral and injectable steroids, ideally for 90 days, AACE advises.

And if there is a shortage of hydrocortisone, the statement advises patients ask a pharmacist or physician about replacement hydrocortisone with different doses that might be available.

Stewart agrees that patients with adrenal insufficiency need to be hypervigilant, but says that “if they do become ill, for the most part they are well counseled to respond appropriately to intercurrent infections.”

Nevertheless, it is “invaluable to reiterate ‘sick day rules'” for suspected COVID-19 infection.

“Any patient who develops a dry continuous cough and fever should immediately double their daily oral glucocorticoid dose and continue on this regimen until the fever has subsided.”

If a patient still deteriorates on this regimen, develops diarrhea or vomiting, or is unable to take oral glucocorticoids for other reasons, they should contact their physicians or seek urgent medical care to receive parenteral treatment with a glucocorticoid.

J Clin Endocrinol Metab. Published online March 31, 2020. Position statement

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From https://www.medscape.com/viewarticle/928072?nlid=134869_3901&src=wnl_newsalrt_200404_MSCPEDIT&uac=295048SY&impID=2335560&faf=1&fbclid=IwAR1zZe6fqDS3tKuHUYoFpbvBMkQYJ4JN59RzC93xdzVcGGkJIz5bnmmE4LY

Update on Coronavirus (COVID-19)

Along with all of you, NADF is monitoring this outbreak by paying close attention to CDC and FDA updates. We have also asked our Medical Advisor to help answer your important questions as they come up.

We asked Medical Director Paul Margulies, MD, FACE, FACP to help us with this question:

Question: Does Adrenal Insufficiency cause us to have a weakened immune system and therefore make us more susceptible?

Response: Individuals with adrenal insufficiency on replacement doses of glucocorticoids do not have a suppressed immune system. The autoimmune mechanism that causes Addison’s disease does not cause an immune deficiency that would make one more likely to get an infection. The problem is with the individual’s ability to deal with the stress of an infection once it develops. Those with adrenal insufficiency fall into that category. When sick with a viral infection, they can have a more serious illness, and certainly require stress dose steroids to help to respond to the illness. If someone with adrenal insufficiency contracts the coronavirus, it is more likely to lead to the need for supportive care, including hospitalization.

This information from the CDC Website provides important information regarding Prevention & Treatment.  You can find this information here: https://www.cdc.gov/coronavirus/2019-ncov/about/prevention-treatment.html

 

From https://www.nadf.us/

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