title: Effects of Canagliflozin on Fracture Risk in Patients With Type 2 Diabetes Mellitus.
abstract: BACKGROUND
  Canagliflozin is a sodium glucose cotransporter 2 inhibitor developed to treat type 2 diabetes mellitus (T2DM).
  
  
  OBJECTIVE
  The purpose of this study was to describe the effects of canagliflozin on bone fracture risk.
  
  
  METHODS
  This was a randomized phase 3 study in patients with T2DM.
  
  
  METHODS
  Canagliflozin doses of 100 and 300 mg were evaluated in the overall population of patients from 9 placebo- and active-controlled studies (N = 10 194), as well as in separate analyses of a single trial enriched with patients with a prior history/risk of cardiovascular disease (ie, the CANagliflozin cardioVascular Assessment Study [CANVAS]; N = 4327) and a pooled population of 8 non-CANVAS studies (N = 5867).
  
  
  METHODS
  The incidence of adjudicated fracture adverse events (AEs), fall-related AEs, and volume depletion-related AEs was assessed.
  
  
  RESULTS
  The incidence of fractures was similar with canagliflozin (1.7%) and noncanagliflozin (1.5%) in the pooled non-CANVAS studies. In CANVAS, a significant increase in fractures was seen with canagliflozin (4.0%) vs placebo (2.6%) that was balanced between the upper and lower limbs. The incidence of fractures was higher with canagliflozin (2.7%) vs noncanagliflozin (1.9%) in the overall population, which was driven by the increase of fractures in CANVAS. The incidence of reported fall-related AEs was low, but significantly higher with canagliflozin in CANVAS, potentially related to volume depletion-related AEs, but not significantly different in the pooled non-CANVAS studies and the overall population.
  
  
  CONCLUSIONS
  Fracture risk was increased with canagliflozin treatment, driven by CANVAS patients, who were older, with a prior history/risk of cardiovascular disease, and with lower baseline estimated glomerular filtration rate and higher baseline diuretic use. The increase in fractures may be mediated by falls; however, the cause of increased fracture risk with canagliflozin is unknown.
authors.affiliation: Mercy Health Osteoporosis and Bone Health Services Clinical Trial Center (N.B.W.), Cincinnati, Ohio 45236; Division of Endocrinology (J.P.B.), College of Physicians and Surgeons, Columbia University, New York, New York 10032; and Janssen Research & Development, LLC (K.U., R.E., M.D., G.L., G.M.), Raritan, New Jersey 08869.
authors.forename: Nelson B
authors.initials: NB
authors.lastname: Watts
authors.affiliation: Mercy Health Osteoporosis and Bone Health Services Clinical Trial Center (N.B.W.), Cincinnati, Ohio 45236; Division of Endocrinology (J.P.B.), College of Physicians and Surgeons, Columbia University, New York, New York 10032; and Janssen Research & Development, LLC (K.U., R.E., M.D., G.L., G.M.), Raritan, New Jersey 08869.
authors.forename: John P
authors.initials: JP
authors.lastname: Bilezikian
authors.affiliation: Mercy Health Osteoporosis and Bone Health Services Clinical Trial Center (N.B.W.), Cincinnati, Ohio 45236; Division of Endocrinology (J.P.B.), College of Physicians and Surgeons, Columbia University, New York, New York 10032; and Janssen Research & Development, LLC (K.U., R.E., M.D., G.L., G.M.), Raritan, New Jersey 08869.
authors.forename: Keith
authors.initials: K
authors.lastname: Usiskin
authors.affiliation: Mercy Health Osteoporosis and Bone Health Services Clinical Trial Center (N.B.W.), Cincinnati, Ohio 45236; Division of Endocrinology (J.P.B.), College of Physicians and Surgeons, Columbia University, New York, New York 10032; and Janssen Research & Development, LLC (K.U., R.E., M.D., G.L., G.M.), Raritan, New Jersey 08869.
authors.forename: Robert
authors.initials: R
authors.lastname: Edwards
authors.affiliation: Mercy Health Osteoporosis and Bone Health Services Clinical Trial Center (N.B.W.), Cincinnati, Ohio 45236; Division of Endocrinology (J.P.B.), College of Physicians and Surgeons, Columbia University, New York, New York 10032; and Janssen Research & Development, LLC (K.U., R.E., M.D., G.L., G.M.), Raritan, New Jersey 08869.
authors.forename: Mehul
authors.initials: M
authors.lastname: Desai
authors.affiliation: Mercy Health Osteoporosis and Bone Health Services Clinical Trial Center (N.B.W.), Cincinnati, Ohio 45236; Division of Endocrinology (J.P.B.), College of Physicians and Surgeons, Columbia University, New York, New York 10032; and Janssen Research & Development, LLC (K.U., R.E., M.D., G.L., G.M.), Raritan, New Jersey 08869.
authors.forename: Gordon
authors.initials: G
authors.lastname: Law
authors.affiliation: Mercy Health Osteoporosis and Bone Health Services Clinical Trial Center (N.B.W.), Cincinnati, Ohio 45236; Division of Endocrinology (J.P.B.), College of Physicians and Surgeons, Columbia University, New York, New York 10032; and Janssen Research & Development, LLC (K.U., R.E., M.D., G.L., G.M.), Raritan, New Jersey 08869.
authors.forename: Gary
authors.initials: G
authors.lastname: Meininger
mesh_terms: D000058:Accidental Falls; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000068896:Canagliflozin / Q000009:adverse effects* / Q000627:therapeutic use; D002318:Cardiovascular Diseases / Q000150:complications; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy*; D004232:Diuretics / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D050723:Fractures, Bone / Q000453:epidemiology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D015994:Incidence; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D012306:Risk
chemical_list: D004232:Diuretics; D007004:Hypoglycemic Agents; D000068896:Canagliflozin