Canagliflozin and fracture risk in type 2 diabetes

Takeaway

• This study found no definitive explanation for either the fracture risk observed in the overall CANagliflozin cardioVascular Assessment Study (CANVAS) Program or for the difference observed in fracture risk in the CANVAS and CANVAS-renal (CANVAS-R).

Why this matters

• The recently reported Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial suggested that the observed association in CANVAS was a chance observation.
• Canagliflozin can be used with greater confidence because fracture risk appears unlikely to be an adverse effect, particularly in patients with nephropathy.

Study design

• Analysis of 2 similar trials, the CANVAS, and the CANVAS-R, performed in 10,142 patients with type 2 diabetes and history or at higher risk of cardiovascular disease who received (1:1:1) canagliflozin (100/300 mg once daily) or placebo.
• Effects of canagliflozin on adjudicated fractures overall and by type, location, association with a fall, dose and follow-up time was assessed.
• Funding: Janssen Research & Development, LLC.

Key results

• During follow-up, canagliflozin was associated with a higher risk for all fracture compared with placebo (n=496, recorded ≥1 fracture event:15.40 vs 11.93 per 1000 patient-years; HR, 1.26; 95% CI, 1.04-1.52).
• Significant heterogeneity was observed in the effects on fracture (P=.005) between the CANVAS (HR, 1.55; 95% CI, 1.21-1.97) and the CANVAS-R (HR, 0.86; 95% CI, 0.62-1.19).
• Differences in baseline characteristics, interactions of randomised treatment with patient characteristics, dose effects, follow-up time, metabolic effects, adverse events related to falls or possibly causing falls did not clearly explained the between-study heterogeneity in fracture risk.

Limitations

• Under-representation of women reduced the power to assess the effects of sex on fracture risk.