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

Abstract

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.

Figure 1A.

Kaplan-Meier plot for the propensity-score matched primary outcome of pelvic fracture, hip fracture requiring intervention (surgery, casting, splinting), humerus fracture requiring intervention, or radius/ulna fracture requiring intervention. Legend: GLP1 = Glucagon-like peptide-1. SGLT2 = sodium glucose co-transporter 2 and included canagliflozin alone.

Figure 1B.

Kaplan-Meier plot for the propensity-score matched outcome of pelvic, hip, humerus, radius, ulna, or other sites of fracture reported in CANVAS (carpal, metacarpal, metatarsal, ankle). Legend: CANVAS = CANagliflozin cardioVascular Assessment Study (CANVAS), GLP1 = Glucagon-like peptide-1, SGLT2 = sodium glucose co-transporter 2 and included canagliflozin alone.

Figure 2A.

Forest-plot of sensitivity analyses and secondary analyses for propensity score matched outcomes in Optum.

Figure 2B.

Forest-plot of sensitivity analyses and secondary analyses for propensity score matched outcomes in Truven.