title: Carcinogenicity in rats of the SGLT2 inhibitor canagliflozin.
abstract: The carcinogenicity potential of canagliflozin, an inhibitor of SGLT2, was evaluated in a 2-year rat study (10, 30, and 100 mg/kg). Rats showed an increase in pheochromocytomas, renal tubular tumors, and testicular Leydig cell tumors. Systemic exposure multiples at the highest dose relative to the maximum clinical dose were 12- to 21-fold. Pheochromocytomas and renal tubular tumors were noted in both sexes at 100 mg/kg. Leydig cell tumors were observed in males in all dose groups and were associated with increased luteinizing hormone levels. Hyperplasia was increased in the adrenal medulla at 100 mg/kg, but only a limited increase in simple tubular hyperplasia was observed in the kidney of males at 100 mg/kg. Hyperostosis occurred and was accompanied by substantial effects on calcium metabolism, including increased urinary calcium excretion and decreased levels of calcium regulating hormones (1,25-dihydroxyvitamin D and parathyroid hormone). A separate study with radiolabeled calcium confirmed that increased urinary calcium excretion was mediated via increased calcium absorption from the gastrointestinal tract. It was hypothesized that, at high doses, canagliflozin might have inhibited glucose absorption in the intestine via SGLT1 inhibition that resulted in glucose malabsorption, which increased calcium absorption by stimulating colonic glucose fermentation and reducing intestinal pH. Pheochromocytomas and adrenal medullary hyperplasia were attributed to altered calcium homeostasis, which have a known relationship in the rat. In conclusion, Leydig cell tumors were associated with increased luteinizing hormone levels and pheochromocytomas were most likely related to glucose malabsorption and altered calcium homeostasis. Renal tubular tumors may also have been linked to glucose malabsorption.
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, 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: Petra
authors.initials: P
authors.lastname: Vinken
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: Inneke
authors.initials: I
authors.lastname: Wynant
authors.affiliation: Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Dirk
authors.initials: D
authors.lastname: Marien
authors.affiliation: Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Helena
authors.initials: H
authors.lastname: Geys
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. Electronic address: MJohnson@its.jnj.com.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Johnson
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000139:chemically induced* / Q000473:pathology; D000818:Animals; D000068896:Canagliflozin; D063646:Carcinogenesis / Q000139:chemically induced*; D015197:Carcinogenicity Tests; D004305:Dose-Response Relationship, Drug; D005960:Glucosides / Q000737:chemistry / Q000633:toxicity*; D007680:Kidney Neoplasms / Q000139:chemically induced* / Q000473:pathology; D007684:Kidney Tubules / Q000187:drug effects / Q000473:pathology; D007984:Leydig Cell Tumor / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D010673:Pheochromocytoma / Q000139:chemically induced* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013329:Structure-Activity Relationship; D013736:Testicular Neoplasms / Q000139:chemically induced* / Q000473:pathology; D013876:Thiophenes / Q000737:chemistry / Q000633:toxicity*
chemical_list: D005960:Glucosides; C490300:Slc5a2 protein, rat; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013876:Thiophenes; D000068896:Canagliflozin
keywords: Canagliflozin; Kidney tumors; Leydig cell tumors; Pheochromocytomas; Rat carcinogenicity; SGLT2 inhibitor