Sodium-Glucose Cotransporter-2 Inhibitors and Lower-Extremity Amputation

Type-2 diabetes mellitus (T2DM) is a risk factor for cardiovascular and renal disease, and the use of sodium-glucose cotransporter-2 (SGLT2) inhibitors was shown to have favorable effects on relevant biomarkers and to reduce the risk of serious cardiovascular and renal complications.1–4 SGLT2 inhibitors are nearly established as a novel class of glucose-lowering agents, and their use is now recommended as a second-line or third-line treatment in the management of T2DM.5 Despite the cardiovascular benefits of SGLT2 inhibitor therapy, safety concerns were raised in the CANVAS (Canagliflozin Cardiovascular Assessment Study) trial for canagliflozin.2 In this trial, Neal et al2 observed an increased risk of lower-extremity amputation (LEA) in patients with T2DM when treated with canagliflozin treatment versus placebo, which led to the issuing of a bulletin regarding amputation risk from the US Food and Drug Administration. [...]observational studies were undertaken but resulted in conflicting findings. [...]far, the rate of LEA associated with medicinal treatments has been compared between SGLT2 inhibitors and new antidiabetic agents, such as Dipeptidil peptidase inhibitor 4 and glucagon-like peptide-1 (GLP-1) receptor antagonists, or with old ones, such as sulfonylurea, metformin, thiazolidinediones, or even placebo. The use of SGLT-2 inhibitors compared with GLP-1 receptor agonists was not associated with an increased rate of any amputation (adjusted HR 1.02, 95% confidence interval 0.82 to 1.27) or below-knee amputation (adjusted HR 1.05, 95% confidence interval 0.84 to 1.32).