Sodium-glucose co-transporter-2 inhibitors (SGLT2i) use and risk of amputation: an expert panel overview of the evidence.

Sodium-glucose co-transporter-2 inhibitors (SGLT2i) are oral antidiabetic agents that exert their glucose-lowering effect by increasing renal excretion of glucose. These drugs have been reported to beneficially affect cardiovascular (CV) and renal outcomes. However, concerns have recently been raised in relation to increased risk of lower-extremities amputation with canagliflozin and it remains unclear whether and to what extent this side effect could also occur with other SGLT2i. The present expert panel overview focuses on the three SGLT2i available and widely used in the US and Europe, i.e. empagliflozin, canagliflozin and dapagliflozin and only refers briefly to other SGLT2i for which less data are available. The results of large CV outcome trials with these SGLT2i are presented, focusing specifically on the data in relation to amputation risk. The potential pathophysiological mechanisms involved in this side effect are discussed. Furthermore, available data reporting amputation cases in SGLT2i users are critically reviewed. The expert panel concludes that, based on current data, increased amputation risk seems to be related only to canagliflozin, thus representing a drug-effect rather than a SGLT2i class-effect. The exact pathways underlying this drug-induced adverse event, possibly related to off-target drug effects rather than SGLT2 inhibition per se, should be elucidated in future studies. Continuous monitoring and pharmacovigilance is necessary and head to head trials would also be essential to provide definitive conclusions.