Objective Whether sodium-glucose cotransporter 2 inhibitors (SGLT2is) increase the risk of amputation or not remains controversial. We aimed to evaluate the relative risk of different SGLT2is and Non-SGLT2i antihyperglycemic drugs (NonSGLT2is) in leading to amputation by network meta-analysis of large sample studies. Methods We searched Embase and PubMed for relevant large sample studies. We conducted Bayesian network meta-analysis using random-effects model. Effect size was presented as hazard ratio (HR) and 95% confidence interval (CI). Results Seventeen large studies involving 1 million SGLT2i users and 3 million NonSGLT2i users were included in network meta-analysis. SGLT2is [HR (95% CI): 1.38 (1.02, 1.91)] versus NonSGLT2is significantly increased the amputation risk, whereas SGLT2is [HR (95% CI): 1.45 (0.94, 2.17)] versus placebo did not. Compared with glucagon-like peptide 1 receptor agonists (GLP1RAs), canagliflozin [HR (95% CI): 1.5 (1.01, 2.33)] along with incorporative SGLT2is [HR (95% CI): 1.64 (1.07, 2.53)] significantly increased the amputation risk, whereas empagliflozin [HR (95% CI): 1.46 (0.83, 2.67)] and dapagliflozin [HR (95% CI): 1.22 (0.7, 2.23)] did not due to the wide 95% CIs of HRs. Conclusion Although SGLT2is versus placebo do not significantly increase the amputation risk, SGLT2is (especially, canagliflozin) versus NonSGLT2is (especially, GLP1RAs) significantly increase that risk.
