Sodium-glucose co-transporter 2 (SGLT2) inhibitors, known for their ability to reduce plasma glucose levels by impeding renal glucose reabsorption[1], have demonstrated the potential to mitigate the risk of major adverse cardiovascular events (MACE) in patients with diabetes and atherosclerotic cardiovascular disease (ASCVD). These events encompass non-fatal myocardial infarction (MI), non-fatal stroke, cardiovascular mortality, and hospitalization due to heart failure (HHF)[2]. A clinical trial published in 2015 (EMPA-REG OUTCOME) of patients with type 2 diabetes and cardiovascular disease (CVD) showed that empagliflozin decreased the risk of MACE (cardiovascular death, non-fatal stroke, non-fatal MI) more effectively than placebo [3]. Meanwhile, a separate trial (DECLARE-TIMI 58) showed that, compared with placebo, dapagliflozin can reduce the rates of cardiac death and HHF, but not those of MACE. In subgroup analysis, the incidence of MACE was lower in patients with the history of ASCVD than in those with multiple risk factors; but this difference was not statistically significant [4]. Conversely, Furtado et al. reported on the DECLARE-TIMI 58 trial, in which patients with the history of MI and treated with dapagliflozin had a lower incidence of MACE than those treated with placebo [5]. The potential underlying causes encompass the fact that SGLT2 inhibitors not only reduce the progression of myocardial JunD/PPAR-γ pathway activity, myocardial insulin resistance, and lipid accumulation, all of which are associated with diabetic cardiomyopathy[6], but also have a regulatory effect on endothelial function. This regulation involves the mitigation of oxidative stress and inflammation, resulting in a reduction in the development of atherosclerosis[7].

The use of glucagon-like peptide-1 (GLP-1) receptor agonist (RA) may decrease the risk of cardiovascular events in patients with type 2 diabetes and the history of CVD [8]. Even so, evidence on the effects of GLP-1 RA and SGLT2i use on CVD outcomes in patients with diabetic foot ulcer is scarce.

Although SGLT2i use may improve CVD outcomes, it may also increase the risk of low extremity amputation (LEA). A clinical trial (CANVAS) has shown that canagliflozin may increase the rate of LEA compared with placebo[9]. The amputation risk of patients with a history of amputation or peripheral artery disease (PAD) was further increased by the use of canagliflozin [9]. In contrast, the EMPA-REG OUTCOME trial reported leg amputation rates in participants who used empagliflozin and placebo as 1·9% and 1·8%, respectively [10]. Furthermore, findings from the DECLARE-TIMI 58 trial indicated that dapagliflozin did not elevate the risk of amputation when compared to a placebo, irrespective of the patient's PAD history[11].

Nonetheless, an independent trial (CREDENCE) presented contrasting results regarding the use of canagliflozin in patients with type 2 diabetes and confirmed nephropathy. In this trial, canagliflozin did not lead to an increased amputation rate when compared to a placebo. It's worth noting that the study excluded patients with a history of traumatic amputation within the 12 months preceding screening, those with an active skin ulcer, osteomyelitis, gangrene, or critical ischemia of the lower extremity within 6 months of screening[12]. Overall, the evidence on the safety of canagliflozin in patients with PAD or a history of amputation remains unclear.

Zhang et al. published a meta-analysis in 2016, which estimated the global prevalence of diabetic foot ulcer (DFU) as approximately 6·3% [13]. Nevertheless, the prevalence of diabetic foot complications (DFCs), including ulcers, infections, gangrene, and hospitalization for PAD in patients with type 2 diabetes in Taiwan was 1·98% in 2014[14]. Diabetes patients with DFU had higher rates of all-cause mortality (relative risk [RR]=1·89, 95% confidence interval [CI]: 1·60, 2.23), fatal MI (RR=2·22, 95% CI: 1·09, 4·53), and fatal stroke (RR=1·41, 95% CI: 0·61, 3·24) than those without DFU[15]. Armstrong and colleagues calculated the 5-year mortality rates for patients with Charcot foot, DFU, and minor and major amputations as 29.0%, 30.5%, 46.2%, and 56.6%, respectively[16].

Previous research indicates that in patients with diabetes mellitus, DPP4i exhibit neutral effects on cardiovascular and renal outcomes [17, 18]. Therefore, the present study aimed to examine the impact of SGLT2i and GLP-1 RA use on the rates of MACE and amputations compared with DPP4i use in patients with type 2 diabetes and without CVD.