Sodium-glucose cotransporter 2 inhibitors and fracture risk in patients with type 2 diabetes mellitus: A systematic literature review and Bayesian network meta-analysis of randomized controlled trials

Aim: To perform a systematic literature review and network meta-analysis (NMA) of randomized controlled trials (RCTs) to estimate effect of SGLT2 inhibitors on fracture risk in patients with T2DM.

Methods: A systematic search was performed on PubMed/Medline and ClinicalTrials.gov from inception to May 2018 to identify RCTs reporting fracture events with the use of SGLT2 inhibitors compared to control group in patients with T2DM. NMA within a Bayesian framework was performed to calculate the odds ratio (OR) and 95% credible intervals (CrI) using random effect model. Node splitting method was applied to evaluate the presence of inconsistency for NMA.

Results: A total of 40 RCTs including 32,343 T2DM patients with 466 fracture cases. Pairwise meta-analysis showed no association between risk of fracture and SGLT2 inhibitors use (OR = 1.01, 95%CI 0.83-1.23; p = 0.91; I² = 27%) compared with the control group. The NMA has shown a non-significant association with fracture risk and canagliflozin (OR = 0.57, 95%CrI 0.12-1.90), dapagliflozin (OR = 0.58, 95%CrI 0.13-2.00), and empagliflozin (OR = 0.78, 95%CrI 0.23-2.80) use when compared to placebo. No association was also found among SGLT-2 inhibitors (canagliflozin OR = 2.6, 95%CrI 0.69-16.00; dapagliflozin OR = 2.6, 95%CrI 0.52-22.00; and empagliflozin OR = 3.7, 95% CrI 1.0-27.00), when compared to active treatment. Node-splitting analysis shows non-significant inconsistency between direct and indirect comparisons.

Conclusion: The current NMA result suggests no detrimental effect of SGLT2 inhibitors on fracture risk in patients with T2DM. Further RCTs and real-world studies with long-term follow up are required to confirm the present findings.