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

Posted on March 29, 2021 by MaryO

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 rates, hyperglycemia 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

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Severe COVID-19 risks greatly increased for children with adrenal insufficiency

Posted on March 24, 2021 by MaryO

Adrenal insufficiency increases the risk for severe outcomes, including death, 23-fold for children who contract COVID-19, according to a data analysis presented at the ENDO annual meeting.

“Adrenal insufficiency in pediatrics does increase risk of complications with COVID-19 infections,” Manish Gope Raisingani, MD, assistant professor in the department of pediatrics in the division of pediatric endocrinology at Arkansas Children’s Hospital, University of Arkansas for Medical Sciences, told Healio. “The relative risk of complications is over 20 for sepsis, intubation and mortality, which is very significant.”

Adrenal transparent _Adobe
Source: Adobe Stock

Using the TriNetX tool and information on COVID-19 from 54 health care organizations, Raisingani and colleagues analyzed data from children (aged 0-18 years) with COVID-19; 846 had adrenal insufficiency and 252,211 did not. The mortality rate among children with adrenal insufficiency was 2.25% compared with 0.097% for those without, for a relative risk for death of 23.2 (P < .0001) for children with adrenal insufficiency and COVID-19. RRs for these children were 21.68 for endotracheal intubation and 25.45 for sepsis.

“Children with adrenal insufficiency should be very careful during the pandemic,” Raisingani said. “They should take their steroid medication properly. They should also be appropriately trained on stress steroids for infection, other significant events.”

From https://www.healio.com/news/endocrinology/20210321/severe-covid19-risks-greatly-increased-for-children-with-adrenal-insufficiency

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Adrenal Insufficiency Associated With Increased CVD and Cerebrovascular Disease

Posted on March 15, 2021 by MaryO

Patients with adrenal insufficiency may have higher rates of cardiovascular events due to the presence of cardiovascular comorbidities, shows a study published in The Journal of Clinical Endocrinology and Metabolism.

Led by Kanchana Ngaosuwan, MD, PhD, of Imperial College London, UK, the authors of this population-based matched cohort study also found that cerebrovascular events were independently increased in patients with secondary adrenal insufficiency, particularly in those treated with irradiation therapy. Cardiovascular mortality, specifically from ischemic heart disease, was higher regardless of having secondary adrenal insufficiency or primary adrenal insufficiency (Addison’s disease).

Adrenal insufficiency occurs when the adrenal glands fail to produce adequate glucocorticoids. In Addison’s disease, it arises from the adrenal glands, but in secondary adrenal insufficiency, it occurs as a result of a pituitary or hypothalamic condition. Glucocorticoid replacement therapy is usually the first line of defense, but the treatment is associated with a number of adverse events, such as cardiovascular disease. Ischemic heart disease is the leading cause of death for patients with Addison’s disease.

Data from this study was sourced from the Clinical Practice Research Datalink which collected information from 15,354,125 individuals living in the United Kingdom between 1987 and 2017. Data from patients prescribed glucocorticoid prescriptions for adrenal insufficiency (primary: n=2,052; secondary: n=3,948) and random age and gender matched controls (primary: n=20,366; secondary: n=39,134) were assessed for comorbidities and clinical outcomes.

Patients and controls had previous cardiovascular disease (17.5% vs 11.2%), diabetes (10.4% vs 4.8%), hypertension (22.1% vs 13.6%), dyslipidemia (20.5% vs 5.0%), and 19.6% and 4.9% of patients and controls were taking statins, respectively.

Composite cardiovascular events occurred at a rate of 31.4 (95% CI, 29.6-33.3) per 1,000 person-years among the patients and 24.4 (95% CI, 23.9-24.9; P <.0001) per 1,000 person years among the controls. Stratified by adrenal insufficiency subtype, after correcting for cofounders, patients with primary (adjusted hazard ratio [aHR], 1.08; 95% CI, 0.96-1.22) and secondary (aHR, 1.10; 95% CI, 1.01-1.19) adrenal insufficiency were at marginally increased risk for composite cardiovascular events.

Cerebrovascular disease occurred at a rate of 10.4 (95% CI, 9.5-11.5) per 1.000 person years among the patients and 7.2 (95% CI, 7.0-7.5; P <.0001) per 1,000 person years among the controls. Only patients with secondary adrenal insufficiency were at increased risk for cerebrovascular disease (aHR, 1.53; 95% CI, 1.34-1.74).

All patients had increased risk for hospitalization due to cardiovascular diseases (aHR, 1.41; 95% CI, 1.28-1.55) and only the patients with secondary adrenal insufficiency were more likely to be hospitalized with cerebrovascular disease (aHR, 1.63; 95% CI, 1.28-2.08).

Patients had increased rates of cardiovascular mortality compared with controls (9.9 vs 6.4 per 1,000 person years; P <.0001). Both patients with primary (aHR, 1.58; 95% CI, 1.19-2.10) and secondary (aHR, 1.23; 95% CI, 0.99-1.52) insufficiency were at increased risk for cardiovascular mortality. Risk for cerebrovascular mortality was elevated for patients with secondary insufficiency (aHR, 1.14; 95% CI, 0.78-1.67).

Stratified by secondary insufficiency, age, and sex, women (aHR, 1.18; 95% CI, 1.04-1.31; P =.016) and patients who were less than 50 years old (aHR, 1.58; 95% CI, 1.22-2.03; P <.0001) were at increased risk for composite cardiovascular events. Similarly, patients 50 years old or younger were at increased risk for cerebrovascular disease (aHR, 3.67; 95% CI, 2.60-5.17; P <.0001).

These data may be limited by the cohort imbalance of disease risk factors, although the investigators corrected for these features, some residual biases may remain.

While further study is needed to assess changes in treatment approaches, the authors suggested that “these findings support further optimization of glucocorticoid replacement in conjunction with cardio protective interventions in patients with adrenal insufficiency.”

Reference

Ngaosuwan K, Johnston D G, Godsland I F, et al. Cardiovascular disease in patients with primary and secondary adrenal insufficiency and the role of comorbidities. J Clin Endocrinol Metab. 2021;dgab063. doi:10.1210/clinem/dgab063.

From https://www.endocrinologyadvisor.com/home/topics/cardiovascular-and-metabolic-disorders/adrenal-insufficiency-associated-with-increased-cvd-and-cerebrovascular-disease/

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Increased Mortality Risk in Patients With Primary and Secondary Adrenal Insufficiency

Posted on February 21, 2021 by MaryO
A retrospective cohort study was performed to compare mortality risk and causes of death in adrenal insufficiency with an individually-matched reference population. Researchers examined 6,821 patients with adrenal insufficiency (primary, 2052; secondary, 3948) and 6,7564 individually-matched controls (primary, 20366; secondary, 39134).
It was shown that in adrenal insufficiency, mortality was elevated, particularly primary, even with individual matching, and was found early in the disease course. The data demonstrated that cardiovascular disease was the major cause but mortality from infection was also high. The adrenal crisis was a common contributor.
The outcomes suggested that early education for prompt treatment of infections and avoidance of adrenal crisis hold the potential to decrease mortality.
The Journal of Clinical Endocrinology & Metabolism, dgab096, https://doi.org/10.1210/clinem/dgab096

Abstract

Context

Mortality data in patients with adrenal insufficiency are inconsistent, possibly due to temporal and geographical differences between patients and their reference populations.

Objective

To compare mortality risk and causes of death in adrenal insufficiency with an individually-matched reference population.

Design

Retrospective cohort study.

Setting

UK general practitioner database (CPRD).

Participants

6821 patients with adrenal insufficiency (primary, 2052; secondary, 3948) and 67564 individually-matched controls (primary, 20366; secondary, 39134).

Main outcome measures

All-cause and cause-specific mortality; hospital admission from adrenal crisis.

Results

With follow-up of 40799 and 406899 person-years for patients and controls respectively, the hazard ratio (HR; [95%CI]) for all-cause mortality was 1.68 [1.58 – 1.77]. HRs were greater in primary (1.83 [1.66 – 2.02]) than in secondary (1.52 [1.40 – 1.64]) disease; (HR; primary versus secondary disease, 1.16 [1.03 – 1.30]). The leading cause of death was cardiovascular disease (HR 1.54 [1.32-1.80]), along with malignant neoplasms and respiratory disease. Deaths from infection were also relatively high (HR 4.00 [2.15 – 7.46]). Adrenal crisis contributed to 10% of all deaths. In the first two years following diagnosis, the patients’ mortality rate and hospitalisation from adrenal crisis were higher than in later years.

Conclusion

Mortality was increased in adrenal insufficiency, especially primary, even with individual matching and was observed early in the disease course. Cardiovascular disease was the major cause but mortality from infection was also high. Adrenal crisis was a common contributor. Early education for prompt treatment of infections and avoidance of adrenal crisis hold potential to reduce mortality.

PDF available at https://academic.oup.com/jcem/advance-article-abstract/doi/10.1210/clinem/dgab096/6141434?redirectedFrom=fulltext

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Hydrocortisone in Granule Form Effectively Treats Childhood Adrenal Insufficiency

Posted on October 17, 2020 by MaryO

The treatment of adrenal insufficiency with hydrocortisone granules in children with congenital adrenal hyperplasia (CAH) was associated with an absence of adrenal crises and normal growth patterns over a 2-year period, according to study findings published in The Journal of Clinical Endocrinology and Metabolism.

The study included a total of 17 children with CAH and 1 child with hypopituitarism. All included participants were <6 years old who were receiving current adrenocortical replacement therapy, including hydrocortisone with or without fludrocortisone. Hydrocortisone medications used in this population were converted from pharmacy compounded capsules to hydrocortisone granules without changing the dose.

These study participants were followed by study investigators for 2 years. Glucocorticoid replacement therapy was given three times a day for a median treatment duration of 795 days. Treatment was adjusted by 3 monthly 17-hydroxyprogesterone (17-OHP) profiles in children with CAH.

There were a 150 follow-up visits throughout the study. At each visit, participants underwent assessments that measured hydrocortisone dose, height, weight, pubertal status, adverse events, and incidence of adrenal crisis.

A total of 40 follow-up visits had changes in hydrocortisone doses based on salivary measurements (n=32) and serum 17-OHP levels (n=8).

At time of study entry, the median daily doses of hydrocortisone were 11.9 mg/m2 for children between the ages of 2 to 8 years, 9.9 mg/m2 for children between 1 month and 2 years, and 12.0 mg/m2 for children <28 days of age. At the end of the study, the respective doses for the 3 age groups were 10.2, 9.8, and 8.6.

The investigators observed no trends in either accelerated growth or reduced growth; however, 1 patient with congenital renal hypoplasia and CAH did show reduced growth. While 193 treatment-emergent adverse events, including pyrexia, gastroenteritis, and viral upper respiratory tract infection, were reported in 14 patients, there were no observed adrenal crises.

Limitations of this study included the small sample size as well as the relatively high drop-out rate of the initial sample.

The researchers concluded that “hydrocortisone granules are an effective treatment for childhood adrenal insufficiency providing the ability to accurately prescribe pediatric appropriate doses.”

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.

Reference

Neumann U, Braune K, Whitaker MJ, et al. A prospective study of children 0-7 years with CAH and adrenal insufficiency treated with hydrocortisone granules. Published online September 4, 2020. J Clin Endocrinol Metab. doi:10.1210/clinem/dgaa626

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