It was previously reported that canagliflozin may be associated with increased fracture risk, but new analysis of data from the CANagliflozin cardioVascular Assessment Study (CANVAS; ClinicalTrials.gov Identifier: NCT01032629) published in Diabetologia found no clear explanation for the association between the use of the sodium-glucose cotransporter 2 inhibitor and incident fracture.

The CANVAS trial reported that treatment with canagliflozin was associated with an increased fracture risk while the CANVAS-Renal trial (ClinicalTrials.gov Identifier: NCT01989754), a second parallel analysis of canagliflozin, found significant heterogeneity in the effects of canagliflozin compared with placebo on fracture risk, with no association between the medication and fracture. Researchers aimed to assess the reasons for the different effects on fracture risk in the two studies.

The primary outcome for this analysis was all adjudicated fractures. Furthermore, the investigators evaluated fractures of different types and locations and whether they were associated with a fall.

In the CANVAS Program, which included both CANVAS (4330 patients) and CANVAS-Renal (5812 patients), a total of 10,142 patients with type 2 diabetes and a history of cardiovascular disease or high cardiovascular risk were included (overall mean age at baseline, 63.3 years; 35.8% women; 21.8% with a history of fracture).

A total of 496 (4.9%) individuals had at least 1 fracture event during follow-up, and canagliflozin was associated with a higher risk for all fractures compared with placebo (15.40 vs 11.93 per 1000 patient-years; overall hazard ratio [HR], 1.26; 95% CI, 1.04-1.52). There was significant heterogeneity in the effects on fracture between CANVAS (HR, 1.55; 95% CI, 1.21-1.97) and CANVAS-Renal (HR, 0.86; 95% CI, 0.62-1.19).

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There was no clear evidence that differences in baseline characteristics, treatment dose, duration of follow-up, metabolic effects, or adverse events were responsible for the difference in fracture risk between the two studies.

In the overall CANVAS Program, 200 fractures were identified as having been and 52 were identified as not having been associated with a fall. In addition, 267 fractures were reported in which the relationship with a fall was uncertain. Considering that most fractures were the result of a fall and data suggested no clear influence on metabolic bone disease, the researchers suggested that a fall was the most plausible mechanism for these findings.

“[W]e could find no clear explanation for either the fracture risk observed in the CANVAS Program or the difference in fracture risk observed in CANVAS compared with [CANVAS-Renal]. In practice, however, most fractures are caused by falls and the observed association is likely a consequence of either an unidentified fall-related mechanism or else a chance finding,” concluded the researchers.

Disclosure: This clinical trial was supported by Janssen Research & Development, LLC. Please see the original reference for a full list of authors’ disclosures.

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Reference

Zhou Z, Jardine M, Perkovic V, et al. Canagliflozin and fracture risk in individuals with type 2 diabetes: results from the CANVAS Program [published online August 10, 2019]. Diabetologia. doi:10.1007/s00125-019-4955-5