Lower limb amputations: protection with GLP-1 receptor agonists rather than increased risk with SGLT2 inhibitors?

An increased risk of lower limb amputations (LLA) has been suspected with the use of sodium-glucose cotransporter type 2 inhibitors (SGLT2is) after the publication of CANVAS with canagliflozin compared with placebo. A more than twofold increase of the risk of LLA in SGLT2i users compared with patients treated with glucagon-like peptide-1 receptor agonists (GLP-1RAs) has been reported in a Scandinavian cohort observational study, yet other observational studies gave less alarming findings. Our meta-analysis of 12 retrospective cohorts revealed significant increase in LLA with a HR 1.15 (95% CI 1.05-1.24, I² 69%) when comparing SGLT2i users versus GLP-1RA users. However, another meta-analysis of observational studies showed no increased risk when SGLT2is were compared to dipeptidyl peptidase-4 inhibitors (DPP-4is) and some data showed a lower incidence of LLA in patients treated with GLP-1RAs compared to those treated with DPP-4is. When summarizing all available data with direct and indirect comparisons, a conclusion emerges that SGLT2is do not increase the risk of LLA but rather that GLP-1RAs may reduce such a risk.