{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T05:10:25Z","timestamp":1794028225277,"version":"4.8.0"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,4,7]],"date-time":"2021-04-07T00:00:00Z","timestamp":1617753600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Cushing\u2019s syndrome (CS) is associated with numerous comorbidities, including diabetes mellitus (DM). Levoketoconazole, an orally administered ketoconazole stereoisomer, is in clinical trials for the treatment of CS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>SONICS, a prospective, open-label, phase 3 study in adults with confirmed CS and mean 24-h urinary free cortisol (mUFC) \u22651.5\u00d7 ULN, included dose-titration, 6-month maintenance, and 6-month extension phases. This subanalysis evaluated the efficacy of levoketoconazole in patients with DM (n = 28) or without DM (n = 49) who entered the maintenance phase. Safety was evaluated in the overall population (N = 94) during the dose-titration and maintenance phases.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Normalization of mUFC at the end of maintenance phase (EoM), without a dose increase during maintenance (SONICS primary endpoint) was observed in 46% of patients with DM (95% CI, 28 to 66%; <jats:italic>P<\/jats:italic> = 0.0006 <jats:italic>vs<\/jats:italic> null hypothesis of \u226420%) and 33% of patients without DM (95% CI, 20 to 48%; <jats:italic>P<\/jats:italic> = 0.0209). At EoM, mean HbA1c decreased from 6.9% at baseline to 6.2% in patients with DM and from 5.5 to 5.3% in patients without DM. Mean fasting blood glucose decreased from 6.85 mmol\/L (123.4 mg\/dl) to 5.82 mmol\/L (104.9 mg\/dl) and from 5.11 mmol\/L (92.1 mg\/dl) to 4.66 mmol\/L (84.0 mg\/dl) in patients with and without DM, respectively. Adverse events that were more common in patients with DM included nausea (58.3%), vomiting (19.4%), and urinary tract infection (16.7%); none prompted study drug withdrawal.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Treatment with levoketoconazole led to sustained normalization of mUFC and improvement in glycemic control that was more pronounced in patients with DM.<\/jats:p><\/jats:sec><jats:sec><jats:title>Clinical Trial Registration<\/jats:title><jats:p>(<jats:ext-link>ClinicalTrials.gov<\/jats:ext-link>), NCT01838551.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2021.595894","type":"journal-article","created":{"date-parts":[[2021,4,7]],"date-time":"2021-04-07T06:15:39Z","timestamp":1617776139000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":27,"title":["Levoketoconazole in the Treatment of Patients With Cushing\u2019s Syndrome and Diabetes Mellitus: Results From the SONICS Phase 3 Study"],"prefix":"10.3389","volume":"12","author":[{"given":"Rosario","family":"Pivonello","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atanaska","family":"Elenkova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Fleseriu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard A.","family":"Feelders","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Przemyslaw","family":"Witek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yona","family":"Greenman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eliza B.","family":"Geer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Perotti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonard","family":"Saiegh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fredric","family":"Cohen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgio","family":"Arnaldi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,4,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(18)30155-4","article-title":"Advances in the medical treatment of Cushing\u2019s syndrome","volume":"7","author":"Feelders","year":"2019","journal-title":"Lancet Diabetes Endocrinol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(14)61375-1","article-title":"Cushing\u2019s syndrome","volume":"386","author":"Lacroix","year":"2015","journal-title":"Lancet"},{"key":"B3","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1210\/er.2013-1048","article-title":"The treatment of Cushing\u2019s disease","volume":"36","author":"Pivonello","year":"2015","journal-title":"Endocr Rev"},{"key":"B4","doi-asserted-by":"publisher","first-page":"77","DOI":"10.4158\/EP14126.OR","article-title":"Burden of illness, annual healthcare utilization, and costs associated with commercially insured patients with Cushing disease in the United States","volume":"21","author":"Broder","year":"2015","journal-title":"Endocr Pract"},{"key":"B5","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1097\/HJH.0000000000000415","article-title":"The hypertension of Cushing\u2019s syndrome: controversies in the pathophysiology and focus on cardiovascular complications","volume":"33","author":"Isidori","year":"2015","journal-title":"J Hypertens"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(16)00086-3","article-title":"Complications of Cushing\u2019s syndrome: state of the art","volume":"4","author":"Pivonello","year":"2016","journal-title":"Lancet Diabetes Endocrinol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2265.2011.04055.x","article-title":"Metabolic and cardiovascular outcomes in patients with Cushing\u2019s syndrome of different aetiologies during active disease and 1 year after remission","volume":"75","author":"Giordano","year":"2011","journal-title":"Clin Endocrinol (Oxf)"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-11-0272","article-title":"The European Registry on Cushing\u2019s syndrome: 2-year experience. 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