title: Carbohydrate malabsorption mechanism for tumor formation in rats treated with the SGLT2 inhibitor canagliflozin.
abstract: Canagliflozin is an SGLT2 inhibitor used for the treatment of type 2 diabetes mellitus. Studies were conducted to investigate the mechanism responsible for renal tubular tumors and pheochromocytomas observed at the high dose in a 2-year carcinogenicity study in rats. At the high dose (100mg/kg) in rats, canagliflozin caused carbohydrate malabsorption evidenced by inhibition of intestinal glucose uptake, decreased intestinal pH and increased urinary calcium excretion. In a 6-month mechanistic study utilization of a glucose-free diet prevented carbohydrate malabsorption and its sequelae, including increased calcium absorption and urinary calcium excretion, and hyperostosis. Cell proliferation in the kidney and adrenal medulla was increased in rats maintained on standard diet and administered canagliflozin (100mg/kg), and in addition an increase in the renal injury biomarker KIM-1 was observed. Increased cell proliferation is considered as a proximal event in carcinogenesis. Effects on cell proliferation, KIM-1 and calcium excretion were inhibited in rats maintained on the glucose-free diet, indicating they are secondary to carbohydrate malabsorption and are not direct effects of canagliflozin.
authors.affiliation: Janssen Research & Development, LLC, 1000 Route 202 South, Raritan, NJ 08869, United States.
authors.forename: Rao N V S
authors.initials: RN
authors.lastname: Mamidi
authors.affiliation: Janssen Research & Development, LLC, 1000 Route 202 South, Raritan, NJ 08869, United States.
authors.forename: Jim
authors.initials: J
authors.lastname: Proctor
authors.affiliation: Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Sandra
authors.initials: S
authors.lastname: De Jonghe
authors.affiliation: Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Bianca
authors.initials: B
authors.lastname: Feyen
authors.affiliation: Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Esther
authors.initials: E
authors.lastname: Moesen
authors.affiliation: Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Petra
authors.initials: P
authors.lastname: Vinken
authors.affiliation: Janssen Research & Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, United States.
authors.forename: Jing Ying
authors.initials: JY
authors.lastname: Ma
authors.affiliation: Janssen Research & Development, LLC, 1400 McKean Road, Spring House, PA 19477, United States.
authors.forename: Stewart
authors.initials: S
authors.lastname: Bryant
authors.affiliation: Janssen Research & Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, United States.
authors.forename: Sandra
authors.initials: S
authors.lastname: Snook
authors.affiliation: Janssen Research & Development, LLC, 1400 McKean Road, Spring House, PA 19477, United States.
authors.forename: Calvert
authors.initials: C
authors.lastname: Louden
authors.affiliation: Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Godelieve
authors.initials: G
authors.lastname: Lammens
authors.affiliation: Janssen Research & Development, LLC, 920 Route 202 South, Raritan, NJ 08869, United States.
authors.forename: Kirk
authors.initials: K
authors.lastname: Ways
authors.affiliation: Janssen Research & Development, LLC, 1400 McKean Road, Spring House, PA 19477, United States.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Kelley
authors.affiliation: Janssen Research & Development, LLC, 1000 Route 202 South, Raritan, NJ 08869, United States. Electronic address: MJohnson@its.jnj.com.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Johnson
mesh_terms: D000818:Animals; D000068896:Canagliflozin; D002239:Carbohydrate Metabolism, Inborn Errors; D063646:Carcinogenesis; D015815:Cell Adhesion Molecules / Q000378:metabolism; D049109:Cell Proliferation; D005960:Glucosides / Q000494:pharmacology*; D007150:Immunohistochemistry; D007668:Kidney / Q000473:pathology; D008286:Malabsorption Syndromes; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: D000068896:Canagliflozin; D015815:Cell Adhesion Molecules; D005960:Glucosides; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013876:Thiophenes; C110936:Havcr1 protein, rat
keywords: Canagliflozin; Carbohydrate malabsorption; Hypercalciuria; Kidney tumors; Pheochromocytomas; SGLT2 inhibitor