Background: The U.S. Food and Drug Administration recently issued a safety communication requiring new warnings of increased leg and foot amputation risk be added to canagliflozin drug labelling. However, the risk associated with other sodium-glucose co-transporter 2 inhibitors (SGLT2i) remains uncertain.

Aim: This meta-analysis aimed to evaluate the potential risks of diabetic foot syndrome (DFS) and amputation associated with SGLT2i.

Methods: Relevant databases were searched from inception to June 14, 2017 to identify randomized controlled trials (RCTs) that evaluated risks of DFS and amputation associated with SGLT2i use. A random effects model was performed to estimate odds ratios (ORs) and 95% confidence intervals (CIs) using STATA 14.

Results: Fourteen RCTs involving 26,167 patients were eligible for this meta-analysis. SGLT2i were not significantly associated with increased risk of DFS compared with placebo (OR 1.05, 95% CI: 0.58-1.89). No significant association was observed in the subgroup and sensitivity analysis on DFS risk either. Although SGLT2i, as a class, were not significantly associated with amputation risk (OR 1.40, 95% CI: 0.81-2.41), subgroup analysis showed an increased incidence of amputation in participants using canagliflozin (OR 1.89, 95% CI: 1.37-2.60), compared with oral anti-diabetic drugs and placebo, but not in those using empagliflozin (OR 1.02, 95% CI: 0.71-1.48).

Conclusion: Current evidence from RCTs suggests that canagliflozin may be positively associated with an increased risk of amputation. Due to limited data, large-scale studies are required to further clarify the association between amputation and individual SGLT2i drugs.