Fracture Risk After Initiation of Use of Canagliflozin: A Cohort Study

Ann Intern Med. 2019 Feb 5;170(3):155-163. doi: 10.7326/M18-0567. Epub 2019 Jan 1.


Background: Sodium-glucose cotransporter-2 inhibitors promote glycosuria, resulting in possible effects on calcium, phosphate, and vitamin D homeostasis. Canagliflozin is associated with decreased bone mineral density and a potential increased risk for fracture.

Objective: To estimate risk for nonvertebral fracture among new users of canagliflozin compared with a glucagon-like peptide-1 (GLP-1) agonist.

Design: Population-based new-user cohort study.

Setting: Two U.S. commercial health care databases providing data on more than 70 million patients from March 2013 to October 2015.

Patients: Persons with type 2 diabetes who initiated use of canagliflozin were propensity score-matched in a 1:1 ratio to those initiating use of a GLP-1 agonist.

Measurements: The primary outcome was a composite end point of humerus, forearm, pelvis, or hip fracture requiring intervention. Secondary outcomes included fractures at other sites. A fixed-effects meta-analysis that pooled results from the 2 databases provided an overall hazard ratio (HR).

Results: 79 964 patients initiating use of canagliflozin were identified and matched to 79 964 patients initiating use of a GLP-1 agonist. Mean age was 55 years, 48% were female, average baseline hemoglobin A1c level was 8.7%, and 27% were prescribed insulin. The rate of the primary outcome was similar for canagliflozin (2.2 events per 1000 person-years) and GLP-1 agonists (2.3 events per 1000 person-years), with an overall HR of 0.98 (95% CI, 0.75 to 1.26). Risk for pelvic, hip, humerus, radius, ulna, carpal, metacarpal, metatarsal, or ankle fracture was also similar for canagliflozin (14.5 events per 1000 person-years) and GLP-1 agonists (16.1 events per 1000 person-years) (overall HR, 0.92 [CI, 0.83 to 1.02]).

Limitation: Unmeasured confounding, measurement error, and low fracture rate.

Conclusion: In this study of middle-aged patients with type 2 diabetes and relatively low fracture risk, canagliflozin was not associated with increased risk for fracture compared with GLP-1 agonists.

Primary funding source: Brigham and Women's Hospital, Division of Pharmacoepidemiology and Pharmacoeconomics.

Publication types

  • Meta-Analysis
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Canagliflozin / adverse effects*
  • Diabetes Mellitus, Type 2 / complications*
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Female
  • Follow-Up Studies
  • Fractures, Bone / etiology*
  • Glucagon-Like Peptide 1 / agonists
  • Humans
  • Hypoglycemic Agents / adverse effects*
  • Longitudinal Studies
  • Male
  • Middle Aged
  • Propensity Score
  • Proportional Hazards Models
  • Risk Assessment
  • Sodium-Glucose Transporter 2 Inhibitors / adverse effects*


  • Hypoglycemic Agents
  • Sodium-Glucose Transporter 2 Inhibitors
  • Canagliflozin
  • Glucagon-Like Peptide 1