Cushing Death Rate ‘Unacceptable,’ Triple That of General Population

Excess mortality among people with endogenous Cushing syndrome (CS) has declined in the past 20 years yet remains three times higher than in the general population, new research finds.

Among more than 90,000 individuals with endogenous CS, the overall proportion of mortality ― defined as the ratio of the number of deaths from CS divided by the total number of CS patients ― was 0.05, and the standardized mortality rate was an “unacceptable” three times that of the general population, Padiporn Limumpornpetch, MD, reported on March 20 at ENDO 2021: The Endocrine Society Annual Meeting.

Excess deaths were higher among those with adrenal CS compared to those with Cushing disease. The most common causes of death among those with CS were cardiovascular diseases, cerebrovascular accident, infection, and malignancy, noted Limumpornpetch, of Songkla University, Hat Yai, Thailand, who is also a PhD student at the University of Leeds, Leeds, United Kingdom.

“While mortality has improved since 2000, it is still significantly compromised compared to the background population…. The causes of death highlight the need for aggressive management of cardiovascular risk, prevention of thromboembolism, infection control, and a normalized cortisol level,” she said.

Asked to comment, Maria Fleseriu, MD, told Medscape Medical News that the new data show “we are making improvements in the care of patients with CS and thus outcomes, but we are not there yet…. This meta-analysis highlights the whole spectrum of acute and life-threatening complications in CS and their high prevalence, even before disease diagnosis and after successful surgery.”

She noted that although she wasn’t surprised by the overall results, “the improvement over time was indeed lower than I expected. However, interestingly here, the risk of mortality in adrenal Cushing was unexpectedly high despite patients with adrenal cancer being excluded.”

Fleseriu, who is director of the Pituitary Center at Oregon Health and Science University, Portland, Oregon, advised, “Management of hyperglycemia and diabetes, hypertension, hypokalemia, hyperlipidemia, and other cardiovascular risk factors is generally undertaken in accordance with standard of clinical care.

“But we should focus more on optimizing more aggressively this care in addition to the specific Cushing treatment,” she stressed.

In addition, she noted, “Medical therapy for CS may be needed even prior to surgery in severe and/or prolonged hypercortisolism to decrease complications…. We definitely need a multidisciplinary approach to address complications and etiologic treatment as well as the reduced long-term quality of life in patients with CS.”

Largest Study in Scale and Scope of Cushing Syndrome Mortality

Endogenous Cushing syndrome occurs when the body overproduces cortisol. The most common cause of the latter is a tumor of the pituitary gland (Cushing disease), but another cause is a usually benign tumor of the adrenal glands (adrenal Cushing syndrome). Surgery is the mainstay of initial treatment of Cushing syndrome. If an operation to remove the tumor fails to cause remission, medications are available.

Prior to this new meta-analysis, there had been limited data on mortality among patients with endogenous CS. Research has mostly been limited to single-cohort studies. A previous systematic review/meta-analysis comprised only seven articles with 780 patients. All the studies were conducted prior to 2012, and most were limited to Cushing disease.

“In 2021, we lacked a detailed understanding of patient outcomes and mortality because of the rarity of Cushing syndrome,” Limumpornpetch noted.

The current meta-analysis included 91 articles that reported mortality among patients with endogenous CS. There was a total of 19,181 patients from 92 study cohorts, including 49 studies on CD (n = 14,971), 24 studies on adrenal CS (n = 2304), and 19 studies that included both CS types (n = 1906).

Among 21 studies that reported standardized mortality rate (SMR) data, including 13 CD studies (n = 2160) and seven on adrenal CS (n = 1531), the overall increase in mortality compared to the background population was a significant 3.00 (range, 1.15 – 7.84).

This SMR was higher among patients with adrenal Cushing syndrome (3.3) vs Cushing disease (2.8) (= .003) and among patients who had active disease (5.7) vs those whose disease was in remission (2.3) (< .001).

The SMR also was worse among patients with Cushing disease with larger tumors (macroadenomas), at 7.4, than among patients with very small tumors (microadenomas), at 1.9 (= .004).

The proportion of death was 0.05 for CS overall, with 0.04 for CD and 0.02 for adrenal adenomas.

Compared to studies published prior to the year 2000, more recent studies seem to reflect advances in treatment and care. The overall proportion of death for all CS cohorts dropped from 0.10 to 0.03 (P < .001); for all CD cohorts, it dropped from 0.14 to 0.03; and for adrenal CS cohorts, it dropped from 0.09 to 0.03 (P = .04).

Causes of death were cardiovascular diseases (29.5% of cases), cerebrovascular accident (11.5%), infection (10.5%), and malignancy (10.1%). Less common causes of death were gastrointestinal bleeding and acute pancreatitis (3.7%), active CS (3.5%), adrenal insufficiency (2.5%), suicide (2.5%), and surgery (1.6%).

Overall, in the CS groups, the proportion of deaths within 30 days of surgery dropped from 0.04 prior to 2000 to 0.01 since (P = .07). For CD, the proportion dropped from 0.02 to 0.01 (P = .25).

Preventing Perioperative Mortality: Consider Thromboprophylaxis

Fleseriu told Medscape Medical News that she believes hypercoagulability is “the least recognized complication with a big role in mortality.” Because most of the perioperative mortality is due to venous thromboembolism and infections, “thromboprophylaxis should be considered for CS patients with severe hypercortisolism and/or postoperatively, based on individual risk factors of thromboembolism and bleeding.”

Recently, Fleseriu’s group showed in a single retrospective study that the risk for arterial and venous thromboembolic events among patients with CS was approximately 20%. Many patients experienced more than one event. Risk was higher 30 to 60 days postoperatively.

The odds ratio of venous thromoboembolism among patients with CS was 18 times higher than in the normal population.

“Due to the additional thrombotic risk of surgery or any invasive procedure, anticoagulation prophylaxis should be at least considered in all patients with Cushing syndrome and balanced with individual bleeding risk,” Fleseriu advised.

A recent Pituitary Society workshop discussed the management of complications of CS at length; proceedings will be published soon, she noted.

Limumpornpetch commented, “We look forward to the day when our interdisciplinary approach to managing these challenging patients can deliver outcomes similar to the background population.”

Limumpornpetch has disclosed no relevant financial relationships. Fleseriu has been a scientific consultant to Recordati, Sparrow, and Strongbridge and has received grants (inst) from Novartis and Strongbridge.

ENDO 2021: The Endocrine Society Annual Meeting: Presented March 20, 2021

Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape. Other work of hers has appeared in the Washington Post, NPR’s Shots blog, and Diabetes Forecast magazine. She can be found on Twitter @MiriamETucker.

From https://www.medscape.com/viewarticle/949257

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

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

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

Adrenal Insufficiency Associated With Increased CVD and Cerebrovascular Disease

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 comorbiditiesJ 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/

Increased Mortality Risk in Patients With Primary and Secondary Adrenal Insufficiency

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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