After concerns about the cardiovascular safety of some anti-diabetic drugs, the US Food and Drug Administration (FDA) implemented a guidance statement in 2008 recommending cardiovascular safety trial of each new anti-diabetic agent. Thus, several RCTs were conducted worldwide and demonstrated the non-inferiority of some new inhibitors of dipeptidyl peptidase 4 (DPP-4) or glucagon-like peptide-1 (GLP-1) receptor agonists, compared with placebo in patients with type 2 diabetes [
68‐
71]. Interestingly, other trials have shown cardiovascular benefit of some GLP-1 receptor agonists (liraglutide, semaglutide, and albiglutide) or sodium glucose co-transporter 2 (SGLT2) inhibitors (empagliflozin and canagliflozin) [
72‐
76]. In contrast to cardiovascular and cerebrovascular endpoints, LEAD was not fully investigated in these studies. Although, Marso et al. reported in the SUSTAIN-6 trial, that participants treated by semaglutide, a prolonged action GLP-1 receptor agonist, had a significant 35% lower risk of coronary and peripheral revascularization, but with no specific data dedicated to lower-limb procedures [
73]. A recent post hoc analysis of the liraglutide effect and action in diabetes: evaluation of cardiovascular outcome results (LEADER) trial displayed a fewer LLA rate among patients with diabetic foot assigned to liraglutide, compared with those assigned to placebo [
77]. This difference seemed to be driven mainly by major amputation rather than minor amputation, but there was no difference between study arms in diabetic foot requiring peripheral revascularization. The incidence of LEAD was similar among study arms (exenatide versus placebo) in the Exenatide Study of Cardiovascular Event Lowering (EXCEL) trial [
78]. Notably, the Canagliflozin Cardiovascular Assessment Study (CANVAS) trial has shown a twofold higher risk of LLA in participants assigned to canagliflozin, compared with those assigned to placebo [
75]. This increased risk of amputation has been mainly driven by vascular disease, while the rate of diabetic neuropathy seemed to be lower in the canagliflozin group than in the placebo arm (CANVAS Program Collaborative Group, the 53rd Annual Meeting of the European Association for the Study of Diabetes, Lisbon, 15 September 2017;
https://www.easd.org/programme-glance.html). The pathophysiological mechanisms likely to explain the high risk of LLA associated with canagliflozin in the CANVAS trial have not yet been established. It remains unclear if the risk of amputation is a class effect for all SGLT-2 inhibitors. While some studies suggested association with different SGLT-2 inhibitors and increased risk of LLA [
79‐
81], the secondary analyses of the EMPA-REG OUTCOME trial have shown a similar incidence of LLA in empagliflozin versus placebo group [
82]. Furthermore, a recent large real-life study conducted in the USA did not show association between SGLT2 inhibitors and the risk of LLA [
83].