The prevalence of diabetes mellitus is increasing and is linked to several complications, including diabetic foot. Novel glucose-lowering agents are sought that also have beneficial effects in reducing diabetic complications. Among the novel glucose-lowering agents demonstrating clinical promise, three classes stand out: dipeptidyl peptidase-4 inhibitors (DPP-4is), glucagon-like peptide-1 receptor agonists (GLP-1RAs), and sodium-glucose cotransporter-2 inhibitors (SGLT2is). Some of these agents provide cardiovascular and kidney benefits, and there is evidence suggesting they also offer protective effects against diabetic foot complications. In this review, we summarize the preclinical and clinical evidence proof these three glucose-lowering agents for diabetic foot, highlighting their potential in enhancing diabetic wound healing and limb preservation. In conclusion, existing available trials have shown that certain DPP-4is and GLP-1RAs possess protective effects against diabetic foot conditions. However, SGLT2is have not demonstrated a significant protective effect. We encourage larger-scale studies on the protective effects of these three types of drugs for diabetic foot to guide physicians in providing personalized treatment strategies, achieving blood glucose targets, and promoting the healing of chronic wounds in patients.
Type 2 diabetes mellitus (T2DM) constitutes a significant global health challenge, affecting an estimated 451 million people around the world. As a chronic complication of diabetes, diabetic foot is characterized by structural and functional disturbances in the foot. These problems arise from changes in the peripheral blood vessels and nerves of the lower extremities. It involves numerous risk factors and presents complicated mechanisms alongside minor clinical manifestations. Between 19% and 34% of diabetic individuals are prone to developing diabetic foot. The substantial burden, economic costs, and mortality rates linked to diabetic foot are comparable to those of cancer. Diabetic foot-related problems result in prolonged hospitalization, significant economic burdens on healthcare, and a diminished quality of life. Furthermore, diabetic foot is recognized as the predominant cause of non-traumatic lower extremity amputations globally. Standard and fundamental management strategies for diabetic foot encompass debridement, revascularization, systemic antibiotic therapy, and stringent glycemic control. These interventions, while essential, are costly and require frequent hospitalizations. While existing treatments featuring tissue repair or the use of anti-inflammatory agents can be beneficial in closing or managing the progression of diabetic foot, most of these interventions are not well supported by clinical evidence. Furthermore, reports indicate that ulcer recovery with these therapies is inefficient and takes a long time. The high occurrence of lower limb ulcers and amputations in people with diabetes highlights an urgent need for improved treatments.
The standard strategy for preventing diabetes-related complications, as recommended by international guidelines, involves the application of glucose-lowering treatments to attain optimal glycemic levels and the reduction of modifiable risk factors. From a historical perspective, the glucose-lowering agents most frequently prescribed are metformin, insulin, and sulfonylureas (SU). Despite the proven efficacy of these drugs in reducing the risk of diabetic complications, their use is not without significant side effects, including hypoglycemia, particularly with insulin, and weight gain with SU.
In recent years, the therapeutic landscape for T2DM and its associated complications has undergone a dramatic transformation due to the influx of novel oral glucose-lowering agents. These medications, include dipeptidyl peptidase-4 inhibitors (DPP-4is), glucagon-like peptide-1 receptor agonists (GLP-1RAs), sodium-glucose cotransporter-2 inhibitors (SGLT2is), with some of these drugs showing not only antidiabetic properties but also potential benefits for end organs.
An increasing body of evidence supports the potential cardioprotective and renoprotective properties of novel glucose-lowering agents beyond glycemic control. Nonetheless, research into their protective effects against diabetic foot complications is scant, and there is a lack of systematic summary. In this paper, we present a comprehensive narrative review of the existing evidence on the protective effects of novel hypoglycemic agents—DPP-4is, GLP-1RAs, and SGLT2is—on diabetic foot, summarizing proposed mechanisms and clinical findings.
DPP-4is, known as conventional anti-hyperglycemic drugs, are globally utilized and recommended as the first-line therapy for T2DM patients by the American Association of Clinical Endocrinologists. DPP-4is are progressively gaining prominence in the management of T2DM, progressively supplanting sulfonylureas in many countries. This trend is attributable to the characteristics of DPP-4is, which include no weight gain or hypoglycemia, a favorable safety profile, and ease of use.
The pervasive expression of DPP4 suggests additional roles for this enzyme beyond the regulation of endogenous glucose levels. Beyond glucose-lowering properties, multiple studies have pointed out that DPP-4is may exert additional effects on diabetic foot protection. DPP4, expressed on endothelial and epithelial cells, lymphocytes, and fibroblasts, exerts a range of diverse effects. Research on both diabetic humans and mice suggests that DPP-4is may mitigate several risk factors associated with diabetic foot complications. Beyond their favorable impact on glucose regulation, DPP-4is have demonstrated a spectrum of effects on blood pressure, postprandial lipemia, body weight, inflammatory markers, endothelial function, and oxidative stress, ranging from neutral to modestly beneficial in patients with T2DM. Even though each effect might seem modest in isolation, the hypothesis that their cumulative impact could yield positive outcomes for diabetic foot care is plausible. Recent studies conducted recently have shown a different pattern of DPP4 expression in wounds between diabetic and healthy mice. Furthermore, DPP4-knockout mice exhibited expedited wound healing, suggesting that DPP4 impedes wound repair and regeneration. Consequently, DPP-4is may offer therapeutic potential in promoting the healing process of diabetic foot.
The EMT refers to the complete process of phenotypic transformation in quiescent epithelial cells, playing a significant role in the healing of skin wounds. During this process, dormant keratinocytes migrate across the wound bed through EMT, thereby restoring the epidermal barrier integrity. Experimental studies demonstrate that saxagliptin administration in both animal models (diabetic mice with dorsal skin ulcers) and clinical trials (diabetic foot patients) modulates EMT-related protein expression, including a decrease in E-cadherin and an increase in vimentin. Concurrently, saxagliptin enhances stromal cell-derived factor-1α (SDF-1α) production in fibroblasts, which directly or indirectly induces keratinocyte EMT, thereby accelerating wound epithelialization. In obese diabetic mice, the use of the DPP4 inhibitor linagliptin also facilitates wound healing by boosting epithelialization and the development of myofibroblasts.
EPCs constitute a heterogeneous cell population derived from bone marrow, exerting vasculoprotective effects through promoting endothelial repair and neovascularization. EPC mobilization is mediated via the SDF-1α/chemokine receptor type 4 axis, which is modulated by DPP-4 enzymatic activity. Notably, studies reveal that DPP-4is modulate EPC dynamics and SDF-1α levels through mechanisms independent of HbA1c, indicating SDF-1α serves as the predominant regulator of EPC mobilization. This glucose-independent pathway exerts more critical effects on augmenting peripheral blood EPC counts compared to systemic glycemic control. As all DPP-4is (sitagliptin, vildagliptin, saxagliptin, alogliptin, and linagliptin) consistently elevate circulating EPCs and SDF-1α, these findings suggest this mechanism may represent a class-wide glycemic-independent pleiotropic effect, fostering a pro-healing microenvironment in diabetic wounds.
In chronic diabetic skin ulcers, local tissue hypoxia initiates adaptive responses through HIF-1α activation. HIF-1α orchestrates VEGF induction and upregulates iNOS, while critically mediating EPCs recruitment. This transcription factor concurrently mitigates hypoxic injury in wound beds and potentiates angiogenesis. Experimental evidence indicates that vildagliptin therapy attenuates oxidative stress, thereby suppressing 20S proteasome activity. This proteolytic inhibition reduces HIF-1α degradation, amplifying VEGF expression, which drives neovascularization in ulcerated tissues, ultimately accelerating wound closure through enhanced capillary network formation. Experimental studies indicate that the level of HMGB1 in the skin wounds of diabetic mice decreases. Administering HMGB1 locally can increase vascular density and accelerate wound healing in the skin of diabetic mice. DPP-4 inhibits HMGB1-induced endothelial cell migration and angiogenesis. However, after treatment with DPP-4is, serum levels of intact HMGB1 increase, reversing the inhibitory effect of DPP-4 on HMGB1-induced angiogenesis, thereby promoting wound neovascularization.
MMPs and tissue inhibitors of MMPs (TIMPs) are essential enzymes for wound healing, and their levels are inversely related. A disruption in the balance between MMPs and TIMPs can interfere with the cellular scaffolding needed for wound healing, resulting in impaired recovery. Studies have found that alogliptin can promote wound healing by inhibiting lipopolysaccharide-mediated extracellular signal-regulated kinase phosphorylation, suppressing macrophage DNA synthesis, and rebalancing the levels of MMPs and TIMPs.
Summaries of the potential mechanisms of DPP-4is in diabetic foot healing or development are shown in Table 1.
