Metyrapone Benefits Blood Pressure in Mild Hypercortisolism

Posted on November 7, 2025 by MaryO

TOPLINE:

A notable proportion of patients with mild hypercortisolism achieved blood pressure (BP) control with low-dose evening metyrapone, without requiring the intensification of antihypertensive therapy. The treatment was particularly beneficial for those with higher baseline systolic BP and was well tolerated, with no adverse events reported.

METHODOLOGY:

  • This prospective observational study assessed the impact of low-dose evening metyrapone on 24-hour ambulatory BP, glucose metabolism, and the cortisol circadian rhythm in 20 patients with mild hypercortisolism (median age, 70.5 years; 65% women).
  • Eligible patients had cortisol levels > 1.8 μg/dL after a 1-mg dexamethasone suppression test on at least two separate occasions, fewer than two specific Cushing syndrome‑related symptoms, and either hypertension or impaired glucose metabolism.
  • Patients received evening metyrapone 250 mg/d, with dose adjustments on the basis of clinical response and cortisol secretion; in 12 patients who showed no signs of hypoadrenalism after week 12, an additional 250-mg afternoon dose was given.
  • The primary endpoint was BP control, defined as a reduction in mean 24-hour systolic BP of ≥ 5 mm Hg without increasing antihypertensive medication; ambulatory BP monitoring was done at baseline and weeks 12 and 24.

TAKEAWAY:

  • At 24 weeks, 40% of patients had a clinically significant improvement in BP control without escalation of therapy, with reductions in both daytime and nighttime systolic BP; benefits were more pronounced in those with elevated baseline systolic BP.
  • Glucometabolic control improved in four patients at 24 weeks; those with poorly controlled type 2 diabetes at baseline achieved the most pronounced glycaemic benefits.
  • Salivary cortisol levels remained unchanged from baseline; no significant changes in hormonal, metabolic, or anthropometric parameters were observed from baseline, except for testosterone levels in women.
  • The treatment was well tolerated, with no side effects or reports of adrenal insufficiency.

IN PRACTICE:

“Our findings support the notion that metyrapone may offer clinical benefits in patients with mH [mild hypercortisolism], particularly those with uncontrolled comorbidities. The observed improvements in BP and glycaemic control, despite minimal changes in UFC [urinary free cortisol] levels, underscore the need to re-evaluate traditional therapeutic targets and to adopt a more holistic approach to disease management,” the authors of the study wrote.

SOURCE:

This study was led by Antonio Musolino, University of Milan, Milan, Italy. It was published online on October 16, 2025, in the European Journal of Endocrinology.

LIMITATIONS:

This study was limited by its relatively short treatment duration, potential adherence bias, and an older cohort age, which may have limited generalisability. The sample size, although adequate for the primary endpoint, was limited. The absence of a control group restricted the ability to definitively attribute improvements to metyrapone therapy.

DISCLOSURES:

This study received financial support through an investigator-initiated study grant from ESTEVE (formerly HRA RD). Two authors reported receiving speaker or consultancy fees or honoraria from Corcept Therapeutics.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication

https://www.medscape.com/viewarticle/metyrapone-benefits-blood-pressure-mild-hypercortisolism-2025a1000szc?form=fpf

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Levoketoconazole Treatment in Endogenous Cushing’s Syndrome

Posted on November 9, 2022 by MaryO

Objective: This extended evaluation (EE) of the SONICS study assessed effects of levoketoconazole for an additional 6 months following open-label, 6-month maintenance treatment in endogenous Cushing’s syndrome.

Design/Methods: SONICS included dose-titration (150–600 mg BID), 6-month maintenance, and 6-month EE phases. Exploratory efficacy assessments were performed at Months 9 and 12 (relative to start of maintenance). For pituitary MRI in patients with Cushing’s disease, a threshold of ≥2 mm denoted change from baseline in largest tumor diameter.

Results: Sixty patients entered EE at Month 6; 61% (33/54 with data) exhibited normal mean urinary free cortisol (mUFC). At Months 9 and 12, respectively, 55% (27/49) and 41% (18/44) of patients with data had normal mUFC. Mean fasting glucose, total and LDL-cholesterol, body weight, body mass index, abdominal girth, hirsutism, CushingQoL, and BDI-II scores improved from study baseline at Months 9 and 12. Forty-six patients completed Month 12; 4 (6.7%) discontinued during EE due to adverse events. The most common adverse events in EE were arthralgia, headache, hypokalemia, and QT prolongation (6.7% each). No patient experienced ALT or AST >3× ULN, QTcF interval >460 msec, or adrenal insufficiency during EE. Of 31 patients with tumor measurements at baseline and Month 12 or follow-up, largest tumor diameter was stable in 27 (87%) patients, decreased in 1, and increased in 3 (largest increase 4 mm).

Conclusion: In the first long-term levoketoconazole study, continued treatment through 12-month maintenance period sustained the early clinical and biochemical benefits in most patients completing EE, without new adverse effects.

Read the whole article at https://eje.bioscientifica.com/configurable/content/journals$002feje$002faop$002feje-22-0506$002feje-22-0506.xml?t%3Aac=journals%24002feje%24002faop%24002feje-22-0506%24002feje-22-0506.xml&body=pdf-45566

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Osilodrostat normalizes urinary free cortisol in Cushing’s disease for most at 72 weeks

Posted on September 19, 2022 by MaryO

More than 80% of adults with Cushing’s disease receiving osilodrostat had normalized mean urinary free cortisol levels at 72 weeks of treatment, according to findings from the LINC 3 study extension.

“Cushing’s disease is a chronic condition, and many patients require prolonged pharmacological treatment. Therefore, evaluating long-term efficacy and safety of drug therapies in clinical trials is essential,” Maria Fleseriu, MD, FACE, professor of medicine and neurological surgery and director of the Pituitary Center at Oregon Health & Science University in Portland and a Healio | Endocrine Today co-editor, told Healio. “Our findings build on the positive results of the LINC 3 study core phase, and it was reassuring to see that continued treatment with osilodrostat for over 72 weeks provided long-term normalization of cortisol levels. Furthermore, continued treatment with osilodrostat also led to sustained improvements in clinical signs and physical manifestations of hypercortisolism, as well as health-related quality of life, which are all important factors in the management of these patients.”

Fleseriu and colleagues enrolled 106 adults with Cushing’s disease who were responders to osilodrostat (Isturisa, Recordati) at 48 weeks during the LINC 3 core study to enter the extension phase of the trial. Participants continued to receive open-label osilodrostat until 72 weeks or treatment discontinuation. Mean urinary free cortisol was collected every 12 weeks. Physical manifestations of hypercortisolism were rated at 48 and 72 weeks. Participants completed the Cushing’s Quality of Life questionnaire and Beck Depression Inventory II at 48 and 72 weeks. Adults were deemed to have completely responded to treatment if mean urinary free cortisol was less than the upper limit of normal and partially responded to treatment if mean urinary free cortisol was above the upper limit of normal but decreased more than 50% from baseline.

The findings were published in the European Journal of Endocrinology.

Of the 106 participants in the extension study, 98 completed 72 weeks of treatment. At 72 weeks, 81.1% of participants were complete responders to treatment, and reductions in mean urinary free cortisol from the core phase were maintained during the extension.

Improvements in most cardiovascular and metabolic-related parameters from the core study were maintained or improved in the extension phase. The cohort also had increases in quality of life score and improvements in Beck Depression Inventory II scores.

The proportion of participants with improvements in physical manifestation of hypercortisolism were maintained or improved in all areas at 72 weeks. For hirsutism in women, 86.4% had an improved or stable severe score at 72 weeks. Improved scores were observed in participants with mild, moderate and severe physical manifestations at baseline with few adults experiencing worse manifestations at the end of the extension study.

There were no new safety signals reported in the extension study. Of the extension study participants, 11.3% discontinued osilodrostat due to adverse events, a similar percentage to the 10.9% discontinuation rate during the core phase of the study.

Several hormone concentrations, including mean adrenocorticotropic hormone, 11-deoxycortisol and plasma aldosterone, stabilized during the extension phase after changes were observed in the core study compared with baseline. Mean testosterone in women decreased from 2.6 nmol/L at 48 weeks to 2.1 nmol/L at 72 weeks. There were no changes observed in mean testosterone levels for men.

“Patients should be regularly monitored and osilodrostat dose titrated as necessary, alongside adjustment of concomitant medications, to optimize outcomes,” the researchers wrote. “Taken together, these findings support osilodrostat as an effective and well-tolerated long-term treatment option for patients with Cushing’s disease.”

For more information:

Maria Fleseriu, MD, FACE, can be reached at fleseriu@ohsu.edu.

From https://www.healio.com/news/endocrinology/20220914/osilodrostat-normalizes-urinary-free-cortisol-in-cushings-disease-for-most-at-72-weeks

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Results Reinforce Efficacy of Recordati’s Isturisa in Cushing’s Disease

Posted on June 22, 2022 by MaryO

Recordati Rare Diseases, a US biopharma that forms part of the wider Italian group, has presented multiple positive data sets on Isturisa (osilodrostat) at the annual ENDO 2022 meeting in Atlanta, Georgia.

Isturisa is a cortisol synthesis inhibitor indicated for the treatment of adult patients with Cushing’s disease for whom pituitary surgery is not an option or has not been curative.

Among the data presented, the Phase III LINC 4 study demonstrated that Isturisa maintained normal mean urinary free cortisol long-term in patients with Cushing’s disease while the Phase III LINC 3 study found adrenal hormone levels changed during early treatment with the drug while stabilizing during long-term treatment.

The ILLUSTRATE study also showed patients treated with a prolonged titration interval tended to have greater persistence with therapy.

Mohamed Ladha, president and general manager for North America, Recordati Rare Diseases, said: “The data from these studies reinforces the efficacy and safety of Isturisa as a treatment for patients with Cushing’s disease.

“We are pleased to share these data with the endocrine community and are excited to provide patients with a much-needed step forward in the management of this rare, debilitating, and potentially life-threatening condition.”

Cushing’s disease is a rare, serious illness caused by a pituitary tumor that leads to overproduction of cortisol by the adrenal glands. Excess cortisol can contribute to an increased risk of morbidity and mortality. Treatment for the condition seeks to lower cortisol levels to a normal range.

Isturisa, which was approved by the US Food and Drug Administration in March 2020, works by inhibiting 11-beta-hydroxylase, an enzyme responsible for the final step of cortisol biosynthesis in the adrenal gland.

From https://www.thepharmaletter.com/article/results-reinforce-efficacy-of-recordati-s-isturisa-in-cushing-s-disease

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Sparrow Pharmaceuticals Presents New Clinical Trial Data Analyses on HSD-1 Inhibitor SPI-62 at the 24th European Congress of Endocrinology

Posted on June 1, 2022 by MaryO

Clinical trial analyses focus on the human body’s homeostatic response to potent HSD-1 inhibition by SPI-62

Results highlight that urinary free cortisol is distinct from intracellular cortisol that causes symptoms in patients with Cushing’s syndrome or autonomous cortisol secretion

PORTLAND, Ore.–(BUSINESS WIRE)–Sparrow Pharmaceuticals, an emerging, clinical-stage biopharmaceutical company developing novel, targeted therapies for disorders of glucocorticoid excess, today presented new pharmacological data during a poster session and a Rapid Communications session titled, “HPA axis modulation by a potent inhibitor indicates 11β-hydroxysteroid dehydrogenase type 1 (HSD-1) is a main source of cortisol that can bind intracellular receptors” at the 24th European Congress of Endocrinology (ECE 2022). Sparrow scientists examined the steroid hormone changes after administration of its lead therapeutic candidate, SPI-62, an HSD-1 inhibitor, to healthy adults.

“Normalized urinary free cortisol, or UFC, is a standard therapeutic target for patients with Cushing’s syndrome,” said David A. Katz, Ph.D., CSO at Sparrow Pharmaceuticals, “But that biomarker doesn’t measure the cortisol that can access intracellular receptors and cause symptoms. UFC normalization has been shown not to correlate with clinical endpoints in patients with Cushing’s syndrome. Many patients with autonomous cortisol secretion have normal UFC, yet substantial cortisol morbidity. As we conduct clinical trials for patients with those diseases, we’re in search of better ways to measure the cortisol that makes patients ill.”

The study analyzed historical clinical trial data to better characterize how SPI-62 impacts cortisol levels and the body’s homeostatic response to those changes.

Conclusions of the study include:

  • Half of hepatocellular cortisol with access to intracellular receptors is generated in healthy adults by HSD-1.
  • ACTH increase compensates for the effect of HSD-1 inhibition on systemic cortisol levels.
  • Secondary increases of androgen levels have not been associated to date with clinical consequences.
  • Large changes of the amount of cortisol that can bind intracellular receptors, and thus cause cortisol-related morbidity, can occur independently of urinary free cortisol levels.

HSD-1 converts cortisone to cortisol in tissues in which cortisol excess is associated with morbidity including liver, adipose, bone, and brain. SPI-62 is a potent HSD-1 inhibitor in clinical development for treatment of Cushing’s syndrome and autonomous cortisol secretion, and as adjunctive therapy to prednisolone in polymyalgia rheumatica. In Phase 1 clinical trials SPI-62 was generally well tolerated and associated with maximal liver and brain HSD-1 inhibition.

To register and view the abstracts, visit ECE’s website here.

From https://www.businesswire.com/news/home/20220524005465/en/Sparrow-Pharmaceuticals-Presents-New-Clinical-Trial-Data-Analyses-on-HSD-1-Inhibitor-SPI-62-at-the-24th-European-Congress-of-Endocrinology

 

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