Repurposing SGLT2 and DPP‐4 inhibitors for mild cognitive impairment in type 2 diabetes mellitus: Insights from proteomics, target prediction and molecular docking

Background and purpose: The rising prevalence of type 2 diabetes mellitus (T2D) has led to an increase in complications, including mild cognitive impairment. Accordingly, there is a growing interest in the potential neuroprotective benefits of newer anti-diabetic drugs, such as dipeptidyl peptidase 4 inhibitors (DPP-4is) and sodium-glucose cotransporter-2 inhibitors (SGLT2is). Although clinical studies suggest that these drugs mitigate cognitive decline, the underlying mechanisms remain unclear. This study aimed to elucidate the potential mechanisms through which DPP-4is or SGLT2is, in combination with metformin, confer neuroprotection. Experimental approach: We conducted a cross-sectional study involving T2D patients on either metformin alone or in combination with a DPP-4i or SGLT2i, alongside healthy controls. Cognitive and metabolic phenotypes were assessed, followed by serum proteomic profiling, computational drug target prediction, network analyses and molecular docking to identify signalling pathways linked to cognitive impairment. Key results: T2D patients on combination therapy demonstrated better cognitive function, independent of other phenotypic, metabolic and biochemical factors. Proteomic profiling revealed 36 differentially expressed proteins that were preserved or restored to control levels in the combination therapy group. Gene set enrichment analysis highlighted the modulation of the complement pathway, particularly the involvement of ficolin-3 (FCN3). Molecular docking suggested that the sugar-like or glycyl moieties in anti-diabetic drug molecules interacted with FCN3, potentially inhibiting complement system activation. Such interaction was confirmed by binding studies using surface plasmon resonance. Conclusion and implications: These findings are significant in tailoring T2D treatment to reduce cognitive complications and exploring drug design to target neuroinflammatory disorders.