Canagliflozin and fracture risk in individuals with type 2 diabetes: results from the CANVAS Program

Abstract

Aims/hypothesis: An increased risk of fracture with canagliflozin vs placebo was reported from the CANagliflozin cardioVascular Assessment Study (CANVAS) Program, with heterogeneity of findings identified between the two trials that comprise the CANVAS Program, CANVAS and CANVAS-R. The objective of these analyses was to identify reasons for the possibly different effects on fracture observed between CANVAS and CANVAS-R.

Methods: This study was an analysis of two highly similar trials, CANVAS and CANVAS-R, conducted in 10,142 individuals with type 2 diabetes and history or high risk of cardiovascular disease who received canagliflozin (pooled 100/300 mg once daily) or placebo. Outcomes assessed in this analysis were effects on adjudicated fractures overall and by type, location, association with a fall, dose and follow-up time.

Results: A total of 496 participants recorded ≥1 fracture event during follow-up (15.40 vs 11.93 per 1000 patient-years with canagliflozin vs placebo; HR 1.26 [95% CI 1.04, 1.52]). There was significant heterogeneity in the effects on fracture (p = 0.005) between CANVAS (n = 4330: HR 1.55 [95% CI 1.21, 1.97]) and CANVAS-R (n = 5812: HR 0.86 [95% CI 0.62, 1.19]). The between-study heterogeneity in fracture risk was not clearly explained by differences in baseline characteristics, interactions of randomised treatment with participant characteristics, dose effects, duration of follow-up, metabolic effects, adverse events related to falls or adverse events possibly causing falls.

Conclusions/interpretation: There was no evidence to explain clearly the fracture risk observed in the CANVAS Program or the heterogeneity in fracture risk between the two studies. The recently reported null result for fracture in the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial suggests that the observed association in CANVAS is likely to be a chance finding, although an unidentified fall-related mechanism remains a possibility.

Trial registration: ClinicalTrials.gov NCT01032629, NCT01989754.

Keywords: CANVAS Program; Canagliflozin; Fracture; Sodium glucose co-transporter 2 inhibitors; Type 2 diabetes mellitus.

Figures

Fig. 1

Time to first fracture in (a) CANVAS Program, (b) CANVAS vs CANVAS-R and (c) canagliflozin 100 mg vs 300 mg vs placebo in CANVAS

Fig. 2

Effects of canagliflozin on fracture in participant subgroups in the CANVAS Program. aAccording to the 2018 World Bank open data (https://data.worldbank.org/): sites with high economic levels include Australia, Belgium, Canada, Czech Republic, Germany, Spain, Estonia, France, UK, Hungary, Israel, Italy, South Korea, Taiwan, Luxembourg, Netherlands, Norway, New Zealand, Poland, Sweden and USA; sites with low or middle economic levels include Argentina, Brazil, China, Colombia, India, Mexico, Malaysia, Russia and Ukraine. PVD, peripheral vascular disease; ROW, rest of the world