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. Electronic supplementary material The online version of this article (10.1007/s00125-019-4955-5) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Sodium-glucose cotransporter 2 inhibitors and fracture risk in patients with type 2 diabetes mellitus: a meta-analysis of randomized controlled trials

“…Our results are consistent with those of previous meta-analyses 30,31 in that we find that SGLT2i may have a beneficial effect on fracture in a follow-up of less than 52 weeks, but when this period is extended to more than 52 weeks, this benefit disappears. However, we also found that canagliflozin may increase the incidence of fracture, which is different from the findings of the previous study; this is likely to be because we included the CANVAS study using the newest follow-up data, 17,18 which showed an obvious increase in fracture. Because the CANVAS study introduces heterogeneity to the subgroup analysis of canagliflozin, the heterogeneity drops from 32% to 0 if the CANVAS study is excluded.…”

“…17 A subsequent study attempted to determine the reasons for this increase in fracture risk, but did not succeed. 18 A study with a follow-up period of 104 weeks found that SGLT2i may be related to an elevated incidence of fracture (7.7% versus 0%). 19 Another study indicated that the decrease in BMD in the canagliflozin group appears to be associated with increased fracture risk, 20 while other studies found that SGLT2is could lower the incidence of fracture.…”

The Interplay Between Bone and Glucose Metabolism

“…There was instead no difference in the incidence of fracture in the CANVAS-R study in the canaglifozin vs. placebo group, nor in the most recent CREDENCE trial (104,105). Finally, the analysis of data from the CANVAS and the CANVAS-R trials comprising 10,142 participants concluded that data from the CANVAS trial could be related to chance or presumably to the presence of falls, whose prevalence was not specifically recorded in all studies (106).…”

Therapy of Type 2 Diabetes

“…In the recently published large RCT (CREDENCE study) with canagliflozin, however, no sign of an increased risk for fractures was found [93]. The careful elaboration of the CANVAS and CANVAS-R data showed a significant heterogeneity of the fracture risk in both studies: in the CANVAS study (n = 4330: HR 1.55; 95 % CI 1.21-1.97) the risk was significantly increased, whereas this could not be proven in the CANVAS-R study (n = 5812: HR 0.86; 95 % CI 0.62-1.19) [102].…”