Cortisol Pumps May Be Viable Option to Reduce Adrenal Crisis in Severe Adrenal Insufficiency

The use of an insulin pump to deliver continuous pulsatile cortisol may be a viable treatment option in patients with severe adrenal insufficiency who are unresponsive to oral corticosteroids, according to study results presented at the 28th Annual Congress of the American Association of Clinical Endocrinologists, held April 24 to 28, 2019, in Los Angeles, California.

According to the investigators, increasing oral steroid doses may be required to prevent adrenal crisis in patients with adrenal insufficiency. However, in light of the associated side effects of long-term use of steroids, an alternative treatment method is needed. Insulin pumps, typically used to treat patients with diabetes, can be used to deliver steroids and may provide symptom control, prevent adrenal crisis, and lower required corticosteroid dose.

The current study enrolled patients with adrenal insufficiency who could not absorb oral corticosteroid treatment or were not responding to treatment. Of 118 patients with adrenal insufficiency, 6 patients were switched to pump treatment.

The results indicated that the use of cortisol pumps was associated with a 78.5% risk reduction for adrenal crisis compared with oral corticosteroids. As hydrocortisone dose was gradually tapered using the cortisol pump, there was a mean dose reduction of 62.77 mg compared with oral corticosteroid therapy.

The researchers noted that in addition to reducing the number of adrenal crises, use of a cortisol pump was found to be associated with better symptom control and quality of life.

“Continuous pulsatile cortisol replacement via pump is an option for management of severe adrenal insufficiency in patients unresponsive to oral therapy,” concluded the researchers.

Reference

Khalil A, Ahmed F, Alzohaili O. Insulin pump for adrenal insufficiency, a novel approach to the use of insulin pumps to deliver corticosteroids in patients with poor cortisol absorption. Presented at: American Association of Clinical Endocrinologists 28th Annual Scientific & Clinical Congress; April 24-28, 2019; Los Angeles, CA.

From https://www.endocrinologyadvisor.com/home/conference-highlights/aace-2019/cortisol-pumps-may-be-viable-option-to-reduce-adrenal-crisis-in-severe-adrenal-insufficiency/

Cyclic Cortisol Production May Lead to Misdiagnosis in Cushing’s

Increased cortisol secretion may follow a cyclic pattern in patients with adrenal incidentalomas, a phenomenon that may lead to misdiagnosis, a study reports.

Since cyclic subclinical hypercortisolism may increase the risk for heart problems, researchers recommend extended follow-up with repeated tests to measure cortisol levels in these patients.

The study, “Cyclic Subclinical Hypercortisolism: A Previously Unidentified Hypersecretory Form of Adrenal Incidentalomas,” was published in the Journal of Endocrine Society.

Adrenal incidentalomas (AI) are asymptomatic masses in the adrenal glands discovered on an imaging test ordered for a problem unrelated to adrenal disease. While most of these benign tumors are considered non-functioning, meaning they do not produce steroid hormones like cortisol, up to 30% do produce and secrete steroids.

Subclinical Cushing’s syndrome is an asymptomatic condition characterized by mild cortisol excess without the specific signs of Cushing’s syndrome. The long-term exposure to excess cortisol may lead to cardiovascular problems in these patients.

While non-functioning adenomas have been linked with metabolic problems, guidelines say that if excess cortisol is ruled out after the first evaluation, patients no longer need additional follow-up.

However, cortisol secretion can be cyclic in Cushing’s syndrome, meaning that clinicians might not detect excess amounts of cortisol at first and misdiagnose patients.

In an attempt to determine whether cyclic cortisol production is also seen in patients with subclinical Cushing’s syndrome and whether these patients have a higher risk for metabolic complications, researchers in Brazil reviewed the medical records of 251 patients with AI — 186 women, median 60 years old — followed from 2006 to 2017 in a single reference center.

Cortisol levels were measured after a dexamethasone suppression test (DST). Dexamethasone is used to stop the adrenal glands from producing cortisol. In healthy patients, this treatment is expected to reduce cortisol levels, but in patients whose tumors also produce cortisol, the levels often remain elevated.

Patients were diagnosed with cyclic subclinical Cushing’s syndrome if they had at least two normal and two abnormal DST tests.

From the 251 patients, only 44 performed the test at least three times and were included in the analysis. The results showed that 20.4% of patients had a negative DST test and were considered non-functioning adenomas.

An additional 20.4% had elevated cortisol levels in all DST tests and received a diagnosis of sustained subclinical Cushing’s syndrome.

The remaining 59.2% had discordant results in their tests, with 18.3% having at least two positive and two negative test results, matching the criteria for cyclic cortisol production, and 40.9% having only one discordant test, being diagnosed as possibly cyclic subclinical Cushing’s syndrome.

Interestingly, 20 of the 44 patients had a normal cortisol response at their first evaluation. However, 11 of these patients failed to maintain normal responses in subsequent tests, with four receiving a diagnosis of cyclic subclinical Cushing’s syndrome and seven as possibly cyclic subclinical Cushing’s.

Overall, the findings suggest that patients with adrenal incidentalomas should receive extended follow-up with repeated DST tests, helping identify those with cyclic cortisol secretion.

“Lack of recognition of this phenomenon makes follow-up of patients with AI misleading because even cyclic SCH may result in potential cardiovascular risk,” the study concluded.

From https://cushingsdiseasenews.com/2019/04/11/cyclic-cortisol-production-may-lead-to-misdiagnosis-in-cushings-study-finds/

The Incidence Of Cushing’s Disease: A Nationwide Swedish Study

In: Pituitary, ISSN 1386-341X, E-ISSN 1573-7403, Vol. 22, no 2, p. 179-186Article in journal (Refereed) Published

Abstract [en]

Background: Studies on the incidence of Cushing’s disease (CD) are few and usually limited by a small number of patients. The aim of this study was to assess the annual incidence in a nationwide cohort of patients with presumed CD in Sweden.

Methods: Patients registered with a diagnostic code for Cushing’s syndrome (CS) or CD, between 1987 and 2013 were identified in the Swedish National Patient Registry. The CD diagnosis was validated by reviewing clinical, biochemical, imaging, and histopathological data.

Results: Of 1317 patients identified, 534 (41%) had confirmed CD. One-hundred-and-fifty-six (12%) patients had other forms of CS, 41 (3%) had probable but unconfirmed CD, and 334 (25%) had diagnoses unrelated to CS. The mean (95% confidence interval) annual incidence between 1987 and 2013 of confirmed CD was 1.6 (1.4-1.8) cases per million. 1987-1995, 1996-2004, and 2005-2013, the mean annual incidence was 1.5 (1.1-1.8), 1.4 (1.0-1.7) and 2.0 (1.7-2.3) cases per million, respectively. During the last time period the incidence was higher than during the first and second time periods (P<0.05).

Conclusion: The incidence of CD in Sweden (1.6 cases per million) is in agreement with most previous reports. A higher incidence between 2005 and 2013 compared to 1987-2004 was noticed. Whether this reflects a truly increased incidence of the disease, or simply an increased awareness, earlier recognition, and earlier diagnosis can, however, not be answered. This study also illustrates the importance of validation of the diagnosis of CD in epidemiological research.

Place, publisher, year, edition, pages

SPRINGER , 2019. Vol. 22, no 2, p. 179-186

Keywords [en]

Cushing’s syndrome, Epidemiology, Incidence, Validation

National Category

Endocrinology and Diabetes

Identifiers

URN: urn:nbn:se:uu:diva-380429DOI: 10.1007/s11102-019-00951-1ISI: 000461291200010PubMedID: 30799512OAI: oai:DiVA.org:uu-380429DiVA, id: diva2:1300822

From http://uu.diva-portal.org/smash/record.jsf?aq2=%5B%5B%5D%5D&c=1&af=%5B%5D&searchType=LIST_LATEST&sortOrder2=title_sort_asc&query=&language=en&pid=diva2%3A1300822&aq=%5B%5B%5D%5D&sf=all&aqe=%5B%5D&sortOrder=author_sort_asc&onlyFullText=false&noOfRows=50&dswid=-3880

 

Osilodrostat Continues to Show Promise for Cushing’s Disease

NEW ORLEANS — The investigational drug osilodrostat (Novartis) continues to show promise for treating Cushing’s disease, now with new phase 3 trial data.

The data from the phase 3, multicenter, double-blind randomized withdrawal study (LINC-3) of osilodrostat in 137 patients with Cushing’s disease were presented here at ENDO 2019: The Endocrine Society Annual Meeting by Beverly M.K. Biller, MD, of the Neuroendocrine & Pituitary Tumor Center at Massachusetts General Hospital, Boston.

“Osilodrostat was effective and shows promise for the treatment of patients with Cushing’s disease,” Biller said.

Osilodrostat is an oral 11β-hydroxylase inhibitor, the enzyme that catalyzes the last step of cortisol biosynthesis in the adrenal cortex. Its mechanism of action is similar to that of the older Cushing’s drug metyrapone, but osilodrostat has a longer plasma half-life and is more potent against 11β-hydroxylase.

Significantly more patients randomized to osilodrostat maintained a mean urinary free cortisol (mUFC) response versus placebo at 34 weeks following a 24-week open-label period plus 8-week randomized phase, with rapid and sustained mUFC reduction in most patients.

Patients also experienced improvements in clinical signs of hypercortisolism and quality of life. The drug was generally well-tolerated and had no unexpected side effects.

Asked to comment, session comoderator Julia Kharlip, MD, associate medical director of the Pituitary Center at the University of Pennsylvania, Philadelphia, told Medscape Medical News, “This drug is incredibly exciting because over 80% of people were controlled fairly rapidly. People could get symptom relief but also a reliable response. You don’t have to wonder when you’re treating a severely affected patient if it’s going to work. It’s likely going to work.”

However, Kharlip cautioned that it remains to be seen whether osilodrostat continues to work long-term, given that the older drug metyrapone — which must be given four times a day versus twice daily for osilodrostat — is known to become ineffective over time because the pituitary tumor eventually overrides the enzyme blockade.

“Based on how osilodrostat is so much more effective at smaller doses, there’s more hope that it will be effective long term…If the effectiveness and safety profile that we’re observing now continues to show the same performance years in a row, then we’ve got our drug.”

Osilodrostat Potentially Addresses an Unmet Medical Need

Cushing’s disease is a rare disorder of chronic hypercortisolism with significant burden, increased mortality, and decreased quality of life. Pituitary surgery is the recommended first-line treatment for most patients, but not all patients remit with surgery and some require additional treatment.

Pasireotide (Signifor, Novartis), an orphan drug approved in the United States and Europe for the treatment of Cushing’s disease in patients who fail or are ineligible for surgical therapy, is also only effective in a minority of patients.

“There hasn’t been a medicine effective for long-term treatment, so a lot of patients end up getting bilateral adrenalectomy, thereby exchanging one chronic medical disease for another,” Kharlip explained.

Biller commented during the question-and-answer period, “I think because not all patients are placed in remission with surgery initially and because other patients subsequently recur — a problem that is more common than we used to believe — we do need medical therapies.”

She continued, “I think it’s important to have a large choice of medical therapies that work in different places in the hypothalamic-pituitary-adrenal axis.

“Even though surgery is the right initial therapy for everyone, I think in terms of subsequent medical therapy we have to tailor that to the individual circumstances of the patient in terms of the goals of treatment, and perhaps what other medicines they’re on, the degree of cortisol excess [and other factors].”

Highly Significant Normalization in Mean UFC Versus Placebo

In a prior 22-week phase 2 study (LINC-2), osilodrostat normalized mUFC in most patients. Results of the extension phase were reported by Medscape Medical News 2 years ago.

The current phase 3 study, LINC-3, was conducted on the basis of that proof-of-concept study, Biller said.

The trial was conducted in 19 countries across four continents in patients with persistent or recurrent Cushing’s disease screened for mUFC > 1.5 times the upper limit of normal and other entry criteria. In total, 137 patients were enrolled and randomized.

Participants were a median age of 40 years, 77% were female, and 88% had undergone prior pituitary surgery. Nearly all (96%) had received at least one previous treatment for Cushing’s.

At baseline, patients’ mean mUFC (364 µg/24 hours) was 7.3 times the upper limit of normal, which is “quite significant hypercortisolemia,” Biller noted.

All patients initially received osilodrostat, with a rapid dose uptitration every 2 weeks from 2 to 30 mg orally twice daily until they achieved a normal UFC.

They continued on open-label medication until week 24, when urine samples were collected. Patients who had an mUFC less than the upper limit of normal and had not had a dose increase in the prior 12 weeks were eligible for the double-blind phase. Those who were ineligible continued taking open-label drug.

The 70 eligible patients were randomized to continue taking osilodrostat (n = 36) or were switched to placebo (n = 34) for another 8 weeks. After that, the patients taking placebo were switched back to osilodrostat until week 48. A total of 113 patients completed the 48 weeks.

The primary efficacy endpoint was mUFC at 34 weeks (the end of the 8-week randomized phase).

For those randomized to continue on the drug, mUFC remained in the normal range in 86.1% of patients versus just 29.4% of those who had been switched to placebo for the 8 weeks. The difference was highly significant (odds ratio, 13.7; P < .001), Biller reported.

A key secondary endpoint, proportion of patients with an mUFC at or below the ULN at 24 weeks without up-titration after week 12, was achieved in 53%.

The mean dose at 48 weeks was 11.0 mg/day, “a fairly low dose,” she noted.

Clinical features were also improved at week 48, including systolic and diastolic blood pressure (percentage change –6.8 and –6.6, respectively), weight (–4.6), waist circumference (–4.2), fasting plasma glucose (–7.1), and HbA1c (–5.4).

Scores on the Cushing Quality of Life scale improved by 52.4 points, and Beck Depression Inventory scores dropped by 31.8 points.

Most Adverse Events Temporary, Manageable

The most commonly reported adverse events were nausea (41.6%), headache (33.6%), fatigue (28.5%), and adrenal insufficiency (27.7%), and 10.9% of patients overall discontinued because of an adverse event.

Adverse events related to hypocortisolism occurred in 51.1% of patients overall, with 10.2% being grade 3 or 4.  However, most of these were single episodes of mild-to-moderate intensity and mainly occurred during the initial 12-week titration period. Most patients responded to dose reduction or glucocorticoid supplementation.

Adverse events related to accumulation of adrenal hormone precursors occurred in 42.3% of patients overall, with the most common being hypokalemia (13.1%) and hypertension (12.4%).

No male patients had signs or symptoms related to increased androgens or estrogens. However, 12 female patients experienced hirsutism, most of those patients also had acne, and one had hypertrichosis. None discontinued because of those symptoms.

Kharlip commented, “What’s really inspiring was that even though half of the patients had symptoms related to adrenal insufficiency, it sounded as if they were quickly resolved with treatment and none discontinued because of it.”

“And it may have been related to study design where the medication was titrated very rapidly. There is probably a way to do this more gently and get the good results without the side effects.”

Kharlip also praised the international consortium that devised the protocol and collaborated in the research effort.

“It’s incredibly exciting and gratifying to see the world come together to get these data. It’s such a rare disease. To be able to have something like that in the field is a dream, to have a working consortium. The protocol was effective in demonstrating efficacy. It’s just a win on so many levels for a disease that currently doesn’t have a good therapy…I struggle with these patients all the time so I’m thrilled that there is hope.”

An ongoing confirmatory phase 3 study, LINC-4, is evaluating patients up to 48 weeks.

Biller is a consultant for and has received grants from Novartis and Strongbridge. Kharlip has  reported no relevant financial relationships.

For more diabetes and endocrinology news, follow us on Twitter and on Facebook.

From https://www.medscape.com/viewarticle/910864#vp_1

Cushing’s Disease Stresses Your Heart and Your Mental Health

Written by Kathleen Doheny

With Oskar Ragnarsson, MD, PHD, and Tamara Wexler, MD, PhD

Adults with Cushing’s syndrome, also called hypercortisolism, have a three-fold higher risk of dying from heart disease compared to the general population,1 according to findings reported by a Swiss research team. Although the researchers found that the risk drops when patients are under care, receiving treatment, and are in remission, the risks don’t disappear completely.  For some perspective, heart disease is common in the United States, affectingone in four adults, regardless of health status.2

Patients with Cushing’s disease have excess mortality [risk],” says Oskar Ragnarsson, MD, PhD, associate professor and a senior consultant in internal medicine and endocrinology at Sahlgrenska University Hospital in Gothenburg, Sweden. He is the author of the study, which appears in the Journal of Clinical Endocrinology & Metabolism.

Having Cushing’s Requires Vigilance Beyond Disease Symptoms

Still, the news is not all bleak, he says. Simple awareness of the increased risks can help individuals reduce their risk, just as following your doctor’s treatment plan so remain in remission, Dr. Ragnarsson tells EndocrineWeb. In addition, patients who received growth hormone replacement appear to have better overall outcomes.1

Cushing’s syndrome occurs when your body is exposed to high levels of the hormone cortisol over a long period of time. This can be caused either by taking corticosteroid medicine orally, or if your body just makes too much cortisol. Common symptoms of this condition include: having a fatty hump between the shoulders, a rounded face, and stretch marks with pink or purple coloring on the skin. Complications, if Cushing’s disease goes untreated, may include bone loss (leading to increased risk of fractures and osteoporosis), high blood pressure, type 2 diabetes, and other problems. Usual treatment includes medication and surgery that are aimed to normalize cortisol levels.3

Increased Risks Are Cause for Concern in Cushing’s Disease

The researchers analyzed data from 502 men and women, all of whom were diagnosed with Cushing’s disease between 1987 and 2013 as indicated in a Swedish health database.1 The average age of these patients at diagnosis was 43 years, and, 83% of these individuals were in remission. During a median follow up of 13 years—half followed for longer, half followed for less time—the researchers noted 133 deaths, more than the 54 that had been anticipated in this patient population.

From this data,1 Dr. Ragnarsson and his team calculated that people with Cushing’s disease were about 2.5 times more likely to die than the general population. The most common reason, with more than a 3-fold increased risk, was attributed to events associated with cardiovascular disease, encompassing both heart disease and stroke. This group also appeared to have a higher risk of death from infectious and respiratory diseases, and conditions related to gastrointestinal problems.

Fortunately, just being in disease remission helps to reduce the risk of all-cause mortality,1 the researchers’ report, with both men and women whose Cushing’s disease is well-managed having a two-fold lower risk of death during the follow-up period.1 Those in remission who were receiving growth hormone had an even lower risk of death than those on other forms of treatment.

In addition, the researchers looked at the 55 patients with Cushing’s disease who were in remission and also had diabetes, finding that their risks remained the same. In other words, despite a strong relationship between diabetes and increased heart disease, the risks of death were not increased in this group of patients.1

In considering the impact that treatments may have, the researchers found:

  • 3 in 4 of these patients (75%) had undergone pituitary surgery
  • 28% had undergone radiotherapy
  • 1 in 4 (24%) had had both adrenal glands removed

Those who had their adrenal glands removal experienced a 2.7-fold higher risk of death, while those who were treated with radiotherapy or had pituitary surgery did not have an increased risk associated with cardiovascular events. When glucocorticoid therapy was added, it did not affect results, according to Dr. Ragnarsson and his research team.

Bottom line? “Even though patients in remission have a better prognosis than patients not in remission, they still have more than a 2-fold increased mortality [risk],” he says. The study, he says, is the first to uncover a high rate of death from suicide in Cushing’s patients. It has been reported before, but the numbers found in this study were higher than in others.

The findings, he says, emphasize the importance of treating Cushing’s with a goal of remission. Ongoing surveillance and management are crucial, he says. “Also, evaluation and active treatment of cardiovascular risk factors and mental health is of utmost importance,” Dr. Ragnarsson tells EndocrineWeb.

Remission Reduces But Doesn’t Eliminate Serious Risks 

The study findings underscore the message that ”the priority for patients is to achieve biochemical remission,” says Tamara L. Wexler, MD, PhD, director of the NYU Langone Medical Center Pituitary Center, in reviewing the findings for EndocrineWeb.

“One question raised by the study findings is whether patients listed as being in remission were truly in (consistent) remission,” Dr. Wexler says. “One or more of several testing methods may have been used, and the data were based on medical record reviews so we can’t be certain about the status of these patients’ remission. In addition, we don’t know how much excess cortisol patients were exposed over time, which may change their risks.”

I have another concern about the findings, she says. While the method of analysis used in the study suggests that the length of time from diagnosis to remission is not associated with increased death risk, ”it may be that the total exposure to excess cortisol—the amplitude as well as duration—is related to morbidity [illness] and mortality [death] risk.” And, she adds, any negative effects experienced by patients with Cushing’s disease may be reduced further as remission status continues.

In addition, Dr. Wexler considers the authors’ comments that sustained high cortisol levels may impact the cardiovascular system in a way that is chronic and irreversible ”may be overly strong.” She believes that the total cortisol exposure and the duration of remission may both play important roles in patients’ ongoing health.

She does agree, however, with the researchers’ recommendation of the need to treat heart disease risk factors more aggressively in patients with a history of Cushing’s disease. Equally important, is for patients to be warned that there is an increased concern about suicide, she says, urging anyone with Cushing’s disease to raise all of these concerns with your health practitioner.

Overall, the study findings certainly suggest that it is important for you to know that if you have Cushing’s syndrome, you are at increased risk for not just heart disease but also mental health disorders and other ailments than the general population, she says, and that the best course of action is to work closely with your doctor to achieve remission and stick to your overall treatment plan.

Steps to Take to Reduce Your Risks for Heart Disease and Depression

Dr. Ragnarsson suggests those with Cushing’s disease make adjustments as needed to achieve the following risk-reducing strategies:

  • Be sure your food choices meet the parameters of a heart-healthy diet
  • You are getting some kind of physical activity most every day
  • You see your doctor at least once a year to have annual checks of your blood pressure, blood sugar, and other heart disease risk factors.

For those of you receiving cortisone replacement therapy, you should be mindful of the need to have a boost in your medication dose with your doctors’ supervision when you’re are sick or experiencing increased health stresses.

From https://www.endocrineweb.com/news/adrenal-disorders/61675-cushings-disease-stresses-your-heart-your-mental-health

%d bloggers like this: