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.

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

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.

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).

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.