{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T20:30:02Z","timestamp":1793046602613,"version":"4.5.0"},"reference-count":40,"publisher":"American Society for Clinical Investigation","issue":"8","funder":[{"name":"Division of Intramural Research, National Institute of Diabetes and Digestive and Kidney Disease","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,4,19]]},"abstract":"<jats:p>\n                    <jats:bold>BACKGROUND.<\/jats:bold>\n                    Sodium glucose cotransporter-2 (SGLT2) inhibitors are the most recently approved class of drugs for type 2 diabetes and provide both glycemic efficacy and cardiovascular risk reduction. A number of safety issues have been identified, including treatment-emergent bone fractures. To understand the overall clinical profile, these safety issues must be balanced against an attractive efficacy profile. Our study was designed to investigate pathophysiological mechanisms mediating treatment-emergent adverse effects on bone health.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>METHODS.<\/jats:bold>\n                    We conducted a single-blind randomized crossover study in hospitalized healthy adults (\n                    <jats:italic>n<\/jats:italic>\n                    = 25) receiving either canagliflozin (300 mg\/d) or placebo for 5 days. The primary end-point was the drug-induced change in AUC for plasma intact fibroblast growth factor 23 (FGF23) immunoactivity between 24 and 72 hours.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>RESULTS.<\/jats:bold>\n                    Canagliflozin administration increased placebo-subtracted mean levels of serum phosphorus (+16%), plasma FGF23 (+20%), and plasma parathyroid hormone (PTH) (+25%), while decreasing the level of 1,25-dihydroxyvitamin D (\u201310%). There was substantial interindividual variation in the magnitude of each of these pharmacodynamic responses. The increase in plasma FGF23 was correlated with the increase in serum phosphorus, and the decrease in plasma 1,25-dihydroxyvitamin D was correlated with the increase in plasma FGF23.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>CONCLUSIONS.<\/jats:bold>\n                    Canagliflozin induced a prompt increase in serum phosphorus, which triggers downstream changes in FGF23, 1,25-dihydroxyvitamin D, and PTH, with potential to exert adverse effects on bone health. These pharmacodynamic data provide a foundation for future research to elucidate pathophysiological mechanisms of adverse effects on bone health, with the objective of devising therapeutic strategies to mitigate the drug-associated fracture risk.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>TRIAL REGISTRATION.<\/jats:bold>\n                    ClinicalTrial.gov (NCT02404870).\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>FUNDING.<\/jats:bold>\n                    Supported by the Intramural Program of NIDDK.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.99123","type":"journal-article","created":{"date-parts":[[2018,4,18]],"date-time":"2018-04-18T11:02:49Z","timestamp":1524049369000},"source":"Crossref","is-referenced-by-count":154,"title":["Canagliflozin triggers the FGF23\/1,25-dihydroxyvitamin D\/PTH axis in healthy volunteers in a randomized crossover study"],"prefix":"10.1172","volume":"3","author":[{"given":"Jenny E.","family":"Blau","sequence":"first","affiliation":[{"name":"Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and"},{"name":"Office of the Clinical Director, National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viviana","family":"Bauman","sequence":"additional","affiliation":[{"name":"Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen M.","family":"Conway","sequence":"additional","affiliation":[{"name":"Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2774-9161","authenticated-orcid":true,"given":"Paolo","family":"Piaggi","sequence":"additional","affiliation":[{"name":"Obesity and Diabetes Clinical Research Section, NIDDK, NIH, Phoenix, Arizona, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary F.","family":"Walter","sequence":"additional","affiliation":[{"name":"Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth C.","family":"Wright","sequence":"additional","affiliation":[{"name":"Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanna","family":"Bernstein","sequence":"additional","affiliation":[{"name":"Nutrition Department, Hatfield Clinical Research Center, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amber B.","family":"Courville","sequence":"additional","affiliation":[{"name":"Nutrition Department, Hatfield Clinical Research Center, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael T.","family":"Collins","sequence":"additional","affiliation":[{"name":"Skeletal Clinical Studies Unit, Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research (NIDCR), NIH, Bethesda, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina I.","family":"Rother","sequence":"additional","affiliation":[{"name":"Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7500-7854","authenticated-orcid":true,"given":"Simeon I.","family":"Taylor","sequence":"additional","affiliation":[{"name":"Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and"},{"name":"Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2018,4,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2017.04.011"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1504720"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1611925"},{"key":"B4","unstructured":"FDA Drug Safety Communication: FDA revises label of diabetes drug canagliflozin (Invokana, Invokamet) to include updates on bone fracture risk and new information on decreased bone mineral density. Food and Drug Administration. http:\/\/www.fda.gov\/Drugs\/DrugSafety\/ucm461449.htm Published September 10, 2015. Updated January 15, 2016. Accessed March 30, 2018"},{"key":"B5","unstructured":"FDA Drug Safety Communication: Interim clinical trial results find increased risk of leg and foot amputations, mostly affecting the toes, with the diabetes medicine canagliflozin (Invokana, Invokamet); FDA to investigate. Food and Drug Administration. https:\/\/www.fda.gov\/Drugs\/DrugSafety\/ucm500965.htm Published May 18, 2016. Updated May 17, 2017. Accessed March 30, 2018"},{"key":"B6","unstructured":"FDA Drug Safety Communication: FDA revises labels of SGLT2 inhibitors for diabetes to include warnings about too much acid in the blood and serious urinary tract infections. Food and Drug Administration. Published December 4, 2015. Updated January 19, 2018. 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