Risk of lower limb amputation in diabetic patients using SGLT2 inhibitors versus DPP4 inhibitors or GLP-1 agonists: a meta-analysis of 2 million patients

BACKGROUND: The objective of this review was to assess the risk of lower limb amputation (LLA) in type 2 diabetic patients based on the use of sodium-glucose cotransporter 2 inhibitors (SGLT2i) versus dipeptidyl peptidase 4 inhibitors (DPP4i) or glucagon-like peptide-1 receptor agonists (GLP1a). METHODS: PubMed, CENTRAL, Scopus, Web of Science, and Embase were referenced for articles published up to 5 February 2023. All types of studies comparing the drugs for LLA risk and reporting hazard ratios (HR) were included. RESULTS: Thirteen studies with 2,095,033 patients were included. Meta-analysis of eight studies comparing SGLT2i with Dipeptidyl peptidase inhibitors (DPPi) showed that there was no difference in the risk of LLA between the two drug groups (HR: 0.98 95% CI: 0.73, 1.31 I(2) = 89%). The outcomes were unchanged on sensitivity analysis. Another pooled analysis of six studies found no significant difference in the risk of LLA between SGLT2i and GLP1a users (HR: 1.26; 95% CI: 0.99, 1.60; I(2) = 69%). The exclusion of a single study showed an increased risk of LLA with SGLT2i (HR: 1.35; 95% CI: 1.14, 1.60; I(2) = 14%). CONCLUSION: The current updated meta-analysis found no significant difference in the risk of LLA between SGLT2i and DPP4i users. A tendency of increased risk of LLA was noted with SGLT2i as compared to GLP1a. Further studies shall increase the robustness of current findings.