The Potential Impact of SGLT2-I in Diabetic Foot Prevention: Promising Pathophysiologic Implications, State of the Art, and Future Perspectives-A Narrative Review

Abstract

The impact of diabetic foot (DF) on the healthcare system represents a major public health problem, leading to a considerable clinical and economic burden. The factors contributing to DF's development and progression are strongly interconnected, including metabolic causes, neuropathy, arteriopathy, and inflammatory changes. Sodium-glucose cotransporter 2 inhibitors (SGLT2-i), novel oral hypoglycemic drugs used as an adjunct to standard treatment, have recently changed the pharmacological management of diabetes. Nevertheless, data about the risk of limb amputation, discordant and limited to canagliflozin, which is currently avoided in the case of peripheral artery disease, have potentially discouraged the design of specific studies targeting DF. There is good evidence for the single immunomodulatory, neuroprotective, and beneficial vascular effects of SGLT2-i. Still, there is no clinical evidence about the early use of SGLT2-i in diabetic foot due to the lack of longitudinal and prospective studies proving the effect of these drugs without confounders. This narrative review aims to discuss the main evidence about the impact of SGLT2-i on the three complications of diabetes implicated in the development of DF, the state of the art, and the potential future implications.

Keywords: PAD; SGLT2-i; atherosclerosis; diabetic foot; neuropathy.

Figure 1

Molecular mechanisms of the anti-atherosclerotic effect of SGLT2-i. SGLT2-i reduce the expression of adhesion molecules, such as vascular cell adhesion molecule (VCAM)-1 and intracellular adhesion molecule (ICAM)-1, which promote the recruitment of circulating monocytes into the vascular layer, suppress NLPR3 inflammasome with consequent reduction in IL-1beta levels, and upregulate autophagy, restoring the phosphorylated AMP-activated protein kinase (AMPK) activity. (Created with BioRender.com).

Figure 2

Molecular effect of SGLT2-i on neuropathy. SGLT2-i inhibit the signaling pathways involving p-p38 MAPK, p-ERK1/2, p-NF-κB p65, IL-1β, and TNF-α, reduce miR-21, and increase RECK expression, alleviating neuropathic damage. (Created with BioRender.com).

Figure 3

Main molecular mechanisms and effects of empagliflozin, canagliflozin, and dapagliflozin on immunomodulation, neuropathy, and angiopathy in diabetic patients. (Created with BioRender.com).