Fracture Risk After Initiation of Use of Canagliflozin A Cohort Study

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 A_1c 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.

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