Metformin is the first line oral antidiabetic in diabetics with LLPAD and while data on this application are scarce, studies do demonstrate a positive effect on CV survival, but not on prevention of amputation.42,43 In the cardiovascular assessment study of canagliflozin (Canvas), this drug was associated with an increased risk of amputation among patients with diabetes, which was not observed with other SGLT-2 inhibitors such as empagliflozin and dapagliflozin. This evidence concerns the gene SLC5A2 and diabetes mellitus.