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In the 2\u2010year carcinogenicity study with the SGLT2 inhibitor empagliflozin in CD\u20101 mice, an increased incidence of renal tubular adenomas and carcinomas was identified in the male high\u2010dose group but was not observed in female mice. An integrated review of available nonclinical data was conducted to establish a mode\u2010of\u2010action hypothesis for male mouse\u2010specific tumorigenesis. Five key events were identified through systematic analysis to form the proposed mode\u2010of\u2010action: (1) Background kidney pathology in CD\u20101 mice sensitizes the strain to (2) pharmacology\u2010related diuretic effects associated with SGLT2 inhib ition. (3) In male mice, metabolic demand increases with the formation of a sex\u2010 and species\u2010specific empagliflozin metabolite. These features converge to (4) deplete oxidative stress handling reserve, driving (5) constitutive cellular proliferation in male CD\u20101 mice. The proposed mode of action requires all five key events for empagliflozin to present a carcinogenicity risk in the CD\u20101 mouse. Considering that empagliflozin is not genotoxic in the standard battery of genotoxicity tests, and not all five key events are present in the context of female mice, rats, or humans, nor for other osmotic diuretics or other SGLT2 inhibitors, the observed male mouse renal tumors are not considered relevant to humans.<\/jats:p>","DOI":"10.1002\/jat.4329","type":"journal-article","created":{"date-parts":[[2022,4,8]],"date-time":"2022-04-08T01:18:46Z","timestamp":1649380726000},"page":"1570-1584","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Mode of action and human relevance assessment of male CD\u20101 mouse renal adenocarcinoma associated with lifetime exposure to empagliflozin"],"prefix":"10.1002","volume":"42","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7290-754X","authenticated-orcid":false,"given":"Jonathan A.","family":"Phillips","sequence":"first","affiliation":[{"name":"Nonclinical Drug Safety Boehringer Ingelheim Pharmaceuticals, Inc  Ridgefield Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mitchell E.","family":"Taub","sequence":"additional","affiliation":[{"name":"Drug Metabolism and Pharmacokinetics Boehringer Ingelheim Pharmaceuticals, Inc  Ridgefield Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew S.","family":"Bogdanffy","sequence":"additional","affiliation":[{"name":"Nonclinical Drug Safety Boehringer Ingelheim Pharmaceuticals, Inc  Ridgefield Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Yuan","sequence":"additional","affiliation":[{"name":"Pfizer Inc  Cambridge Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2019-3201","authenticated-orcid":false,"given":"Brian","family":"Knight","sequence":"additional","affiliation":[{"name":"Nonclinical Drug Safety Boehringer Ingelheim Pharmaceuticals, Inc  Ridgefield Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James D.","family":"Smith","sequence":"additional","affiliation":[{"name":"Nonclinical Drug Safety Boehringer Ingelheim Pharmaceuticals, Inc  Ridgefield Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Warren W.","family":"Ku","sequence":"additional","affiliation":[{"name":"Nonclinical Drug Safety Boehringer Ingelheim Pharmaceuticals, Inc  Ridgefield Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,4,18]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/ki.1993.151"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/0024-3205(86)90664-8"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1177\/1091581814551648"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1080\/10408440600977677"},{"key":"e_1_2_12_6_1","unstructured":"Brown P.(2013 5\/27\/2013).Invokana (canagliflozin) Pharmacology Review (FDA) NDA# 204042.application number: 204042Orig1s000. 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