SGLT‐2 inhibitors and the risk of lower‐limb amputation: Is this a class effect?

Inhibitors of the sodium‐glucose co‐transporter‐2 (SGLT‐2) are a novel class of glucose‐lowering agents that show promising results. However, the use of canagliflozin has been associated with an increased risk of lower‐limb amputation. Whether this risk concerns other SGLT‐2 inhibitors is unclear, and our objective was to address this issue. We performed a disproportionality analysis using the WHO global database of individual case safety reports (VigiBase). Among the 8 293 886 reports available between January 2013 and December 2017, we identified 79 reports of lower‐limb amputation that were associated with SGLT‐2 inhibitors. Among all blood glucose lowering drugs, the proportional reporting ratio (PRR) was increased only for SGLT‐2 inhibitors (5.55 [4.23, 7.29]). While we observed an expected signal for canagliflozin (7.09 [5.25, 9.57]), the PRR was also high for empagliflozin (4.96 [2.89, 8.50]) and, for toe amputations only, for dapagliflozin (2.62 [1.33, 5.14]). In conclusion, our results reveal a positive disproportionality signal for canagliflozin, and also for empagliflozin, and, for toe amputations only, for dapagliflozin. However, our analysis relies on a limited number of cases and is exposed to the biases inherent to pharmacovigilance studies. Further prospective data are therefore needed to better characterize the risk of amputations with different SGLT‐2 inhibitors.