Effects of Canagliflozin on Fracture Risk in Patients With Type 2 Diabetes Mellitus

J Clin Endocrinol Metab. 2016 Jan;101(1):157-66. doi: 10.1210/jc.2015-3167. Epub 2015 Nov 18.


Context: 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.

Design and setting: This was a randomized phase 3 study in patients with T2DM.

Patients and interventions: 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).

Outcome measures: 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.

Trial registration: ClinicalTrials.gov NCT00968812 NCT01032629 NCT01064414 NCT01081834 NCT01106625 NCT01106651 NCT01106677 NCT01106690 NCT01137812.

Publication types

  • Clinical Trial, Phase III
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Accidental Falls
  • Adult
  • Age Factors
  • Aged
  • Aged, 80 and over
  • Canagliflozin / adverse effects*
  • Canagliflozin / therapeutic use
  • Cardiovascular Diseases / complications
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diuretics / adverse effects
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Female
  • Fractures, Bone / epidemiology*
  • Humans
  • Hypoglycemic Agents / adverse effects*
  • Hypoglycemic Agents / therapeutic use
  • Incidence
  • Kaplan-Meier Estimate
  • Male
  • Middle Aged
  • Risk


  • Diuretics
  • Hypoglycemic Agents
  • Canagliflozin

Associated data

  • ClinicalTrials.gov/NCT00968812
  • ClinicalTrials.gov/NCT01032629
  • ClinicalTrials.gov/NCT01064414
  • ClinicalTrials.gov/NCT01081834
  • ClinicalTrials.gov/NCT01106625
  • ClinicalTrials.gov/NCT01106651
  • ClinicalTrials.gov/NCT01106677
  • ClinicalTrials.gov/NCT01106690
  • ClinicalTrials.gov/NCT01137812