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-IRAs) 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, I-2 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-IRAs 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-IRAs may reduce such a risk. (C) 2022 Elsevier Masson SAS. All rights reserved.

Automated summary

The relationship between sodium-glucose cotransporter type 2 inhibitors (SGLT2is) and the risk of lower limb amputations (LLA) remains controversial. Some studies have found that SGLT2i users have more than twofold increased risk of LLA compared to patients treated with glucagon-like peptide-1 receptor agonists (GLP-IRAs), while others have found no such increased risk. Overall, the use of SGLT2is may not increase the risk of LLA, and GLP-IRAs may help reduce such risk.