{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T22:46:32Z","timestamp":1791499592563,"version":"4.3.4"},"reference-count":24,"publisher":"Georg Thieme Verlag KG","issue":"12","license":[{"start":{"date-parts":[[2022,11,7]],"date-time":"2022-11-07T00:00:00Z","timestamp":1667779200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Exp Clin Endocrinol Diabetes"],"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>\n          Objective To assess safety, tolerability, pharmacokinetics, and\n                    pharmacodynamics of treatment with the selective 11beta-hydroxysteroid\n                    dehydrogenase-1 (11beta-HSD1) inhibitor BI 187004 in male and female patients\n                    with type 2 diabetes and overweight or obesity.<\/jats:p><jats:p>\n          Methods Randomized, double-blind, parallel-group, placebo-controlled\n                    multiple rising dose study, with 10\u2013360\u2009mg BI 187004 once daily\n                    over 14 days in 71 patients. Assessments included 11beta-HSD1 inhibition in the\n                    liver and subcutaneous adipose tissue ex vivo (clinical trial registry number\n                    NCT01874483).<\/jats:p><jats:p>\n          Results BI 187004 was well tolerated and safe in all tested dose groups.\n                    The incidence of drug-related adverse events was 51.8% (n=29)\n                    for BI 187004 and 35.7% (n=5) for placebo. There were no\n                    clinically relevant deviations in laboratory or electrocardiogram parameters\n                    besides one patient on 360\u2009mg discontinuing treatment due to moderate\n                    supraventricular tachycardia.<\/jats:p><jats:p>BI 187004 was rapidly absorbed within 2\u2009h; exposure increased\n                    non-proportionally. The oral clearance was low, apparent volume of distribution\n                    was moderate to large, and terminal half-life with 106\u2013124\u2009h was\n                    rather long. Urinary tetrahydrocortisol\/tetrahydrocortisone ratio\n                    decreased, indicating liver 11beta-HSD1 inhibition. Median inhibition of\n                    11beta-HSD1 in subcutaneous adipose tissue biopsies was\n                    87.9\u201399.4% immediately after the second dose and\n                    73.8\u201397.5% 24\u2009h after the last dose of BI 187004.<\/jats:p><jats:p>\n          Conclusions BI 187004 was safe and well tolerated over 14 days and could\n                    be dosed once daily. Targeted 11beta-HSD1 enzyme inhibition\n                    of\u226580% could be shown for BI 187004 doses\u226540\u2009mg.\n                    This dose should be targeted in further studies to test blood glucose lowering\n                    in patients with type 2 diabetes and overweight or obesity.<\/jats:p>","DOI":"10.1055\/a-1932-3136","type":"journal-article","created":{"date-parts":[[2022,11,7]],"date-time":"2022-11-07T23:48:38Z","timestamp":1667864918000},"page":"773-782","source":"Crossref","is-referenced-by-count":5,"title":["Selective Inhibition of 11beta-Hydroxysteroiddehydrogenase-1 with BI\n                    187004 in Patients with Type 2 Diabetes and Overweight or Obesity: Safety,\n                    Pharmacokinetics, and Pharmacodynamics After Multiple Dosing Over 14\n                    Days"],"prefix":"10.1055","volume":"130","author":[{"given":"Susanna","family":"Bianzano","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim International GmbH, Ingelheim,\n                    Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cornelia","family":"Schepers","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim,\n                    Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Wolff","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach,\n                    Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Heise","sequence":"additional","affiliation":[{"name":"Profil, Neuss, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leona","family":"Plum-Moerschel","sequence":"additional","affiliation":[{"name":"Profil, Neuss, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"194","published-online":{"date-parts":[[2022,11,7]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"2692","DOI":"10.1210\/jc.2009-0370","article-title":"Clinical review: The pathogenetic role of cortisol in the metabolic syndrome: A\n                    hypothesis","volume":"94","author":"P Anagnostis","year":"2009","journal-title":"J Clin Endocrinol Metab"},{"key":"ref2","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.mce.2009.09.024","article-title":"Obesity and corticosteroids: 11beta-hydroxysteroid type 1 as a cause and\n                    therapeutic target in metabolic disease","volume":"316","author":"N M Morton","year":"2010","journal-title":"Mol Cell Endocrinol"},{"key":"ref3","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1053\/beem.2000.0119","article-title":"Cortisol metabolism and the role of 11beta-hydroxysteroid dehydrogenase","volume":"15","author":"J W Tomlinson","year":"2001","journal-title":"Best Pract Res Clin Endocrinol Metab"},{"key":"ref4","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1055\/s-0030-1254134","article-title":"Repeated measurements of 11beta-HSD-1 activity in subcutaneous adipose tissue\n                    from lean, abdominally obese, and type 2 diabetes subjects \u2013 no change\n                    following a mixed meal","volume":"42","author":"M Sjostrand","year":"2010","journal-title":"Horm Metab Res"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"1954","DOI":"10.1038\/oby.2007.233","article-title":"11Beta-HSD type 1 expression in human adipose tissue: Impact of gender, obesity,\n                    and fat localization","volume":"15","author":"S K Paulsen","year":"2007","journal-title":"Obesity (Silver Spring)"},{"key":"ref6","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1016\/j.bbrc.2016.06.015","article-title":"Inhibition of 11beta-hydroxysteroid dehydrogenase type 1 ameliorates\n                    obesity-related insulin resistance","volume":"478","author":"S Shao","year":"2016","journal-title":"Biochem Bioph Res Co"},{"key":"ref7","doi-asserted-by":"crossref","first-page":"46","DOI":"10.2337\/db08-0969","article-title":"Cortisol release from adipose tissue by 11\u03b2-hydroxysteroid dehydrogenase\n                    type 1 in humans","volume":"58","author":"R H Stimson","year":"2009","journal-title":"Diabetes"},{"key":"ref8","doi-asserted-by":"crossref","first-page":"720","DOI":"10.2337\/db10-0726","article-title":"Increased whole-body and sustained liver cortisol regeneration by\n                    11beta-hydroxysteroid dehydrogenase type 1 in obese men with type 2 diabetes\n                    provides a target for enzyme inhibition","volume":"60","author":"R H Stimson","year":"2011","journal-title":"Diabetes"},{"key":"ref9","doi-asserted-by":"crossref","first-page":"1418","DOI":"10.1210\/jcem.86.3.7453","article-title":"Tissue-specific dysregulation of cortisol metabolism in human obesity","volume":"86","author":"E Rask","year":"2001","journal-title":"J Clin Endocrinol Metab"},{"key":"ref10","doi-asserted-by":"crossref","first-page":"14","DOI":"10.2337\/db08-1404","article-title":"Selective inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 for patients\n                    with metabolic syndrome: Is the target liver, fat, or both?","volume":"58","author":"P M Stewart","year":"2009","journal-title":"Diabetes"},{"key":"ref11","doi-asserted-by":"crossref","first-page":"1516","DOI":"10.2337\/dc09-2315","article-title":"The 11b-hydroxysteroid dehydrogenase type 1 inhibitor INCB13739 improves\n                    hyperglycemia in patients with type 2 diabetes inadequately controlled by\n                    metformin monotherapy","volume":"33","author":"J Rosenstock","year":"2010","journal-title":"Diabetes Care"},{"key":"ref12","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/s40842-021-00130-x","article-title":"Safety, tolerability, pharmacokinetics and pharmacodynamics of single oral doses\n                    of BI 187004, an inhibitor of 11beta-hydroxysteroid dehydrogenase-1, in healthy\n                    male volunteers with overweight or obesity","volume":"7","author":"S Bianzano","year":"2021","journal-title":"Clin Diabetes Endocrinol"},{"key":"ref13","first-page":"786","article-title":"Pharmacokinetics, pharmacodynamics and tolerability of multiple oral doses of\n                    linagliptin, a dipeptidyl peptidase-4 inhibitor in male type 2 diabetes\n                    patients. Diabetes Obes","volume":"11","author":"T Heise","year":"2009","journal-title":"Metabolism"},{"key":"ref14","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1111\/dom.12635","article-title":"Safety, pharmacokinetics and pharmacodynamics of BI 135585, a selective\n                    11beta-HSD1 inhibitor in humans: Liver and adipose tissue 11beta-HSD1 inhibition\n                    after acute and multiple administrations over 2 weeks","volume":"18","author":"S Freude","year":"2016","journal-title":"Diabetes Obes Metab"},{"key":"ref15","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1007\/s00125-014-3228-6","article-title":"Tissue-specific dysregulation of cortisol regeneration by 11betaHSD1 in obesity:\n                    Has it promised too much?","volume":"57","author":"A Stomby","year":"2014","journal-title":"Diabetologia"},{"key":"ref16","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1210\/en.2010-0957","article-title":"Hexose-6-phosphate dehydrogenase contributes to skeletal muscle homeostasis\n                    independent of 11beta-hydroxysteroid dehydrogenase type 1","volume":"152","author":"N M Semjonous","year":"2011","journal-title":"Endocrinology"},{"key":"ref17","doi-asserted-by":"crossref","first-page":"3236","DOI":"10.1210\/en.2012-1019","article-title":"Lack of significant metabolic abnormalities in mice with liver-specific\n                    disruption of 11beta-hydroxysteroid dehydrogenase type 1","volume":"153","author":"G G Lavery","year":"2012","journal-title":"Endocrinology"},{"key":"ref18","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1046\/j.1365-2265.1996.00853.x","article-title":"Urinary free cortisone and the assessment of 11 beta-hydroxysteroid\n                    dehydrogenase activity in man","volume":"45","author":"M Palermo","year":"1996","journal-title":"Clin Endocrinol (Oxf)"},{"key":"ref19","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1111\/dom.12317","article-title":"Safety, efficacy and weight effect of two 11beta-HSD1 inhibitors in\n                    metformin-treated patients with type 2 diabetes","volume":"16","author":"T Heise","year":"2014","journal-title":"Diabetes Obes Metab"},{"key":"ref20","first-page":"60","article-title":"Pharmacodynamic effects of AZD4017, a selective 11beta-HSD1 inhibitor, in liver\n                    and adipose tissue","author":"M Sj\u00f6strand","year":"2011","journal-title":"Diabetes"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1210\/jc.2007-1912","article-title":"Modulation of 11beta-hydroxysteroid dehydrogenase (11betaHSD) activity\n                    biomarkers and pharmacokinetics of PF-00915275, a selective 11betaHSD1\n                    inhibitor","volume":"93","author":"R Courtney","year":"2008","journal-title":"J Clin Endocrinol Metab"},{"key":"ref22","first-page":"A2255","article-title":"Endocrine homeostasis with inhibition of tissue-specific cortisone reductase\n                    activity in healthy volunteers and obese insulin resistant subjects following\n                    oral INCB13739 11beta-HSD1 inhibitor therapy","volume":"56","author":"W V Williams","year":"2007","journal-title":"Diabetes"},{"key":"ref23","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1177\/0091270010374470","article-title":"Population pharmacokinetic\/pharmacodynamic model of subcutaneous adipose\n                    11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) activity after oral\n                    administration of AMG 221, a selective 11beta-HSD1 inhibitor","volume":"51","author":"J P Gibbs","year":"2011","journal-title":"J Clin Pharmacol"},{"key":"ref24","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.ejphar.2014.10.053","article-title":"Pharmacological characterization of the selective 11beta-hydroxysteroid\n                    dehydrogenase 1 inhibitor, BI 135585, a clinical candidate for the treatment of\n                    type 2 diabetes","volume":"746","author":"B S Hamilton","year":"2015","journal-title":"Eur J Pharmacol"}],"container-title":["Experimental and Clinical Endocrinology &amp; Diabetes"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.thieme-connect.de\/products\/ejournals\/pdf\/10.1055\/a-1932-3136.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T11:48:29Z","timestamp":1672832909000},"score":1,"resource":{"primary":{"URL":"http:\/\/www.thieme-connect.de\/DOI\/DOI?10.1055\/a-1932-3136"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,7]]},"references-count":24,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2022,12,15]]},"published-print":{"date-parts":[[2022,12]]}},"URL":"https:\/\/doi.org\/10.1055\/a-1932-3136","archive":["Portico","CLOCKSS"],"relation":{},"ISSN":["0947-7349","1439-3646"],"issn-type":[{"value":"0947-7349","type":"print"},{"value":"1439-3646","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,7]]}}}