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Serum Proteome Profiling of Diabetic Patients Treated With DPP4 and SGLT2 Inhibitors Shows Improved Cognitive and

Md Abdul Hakim1, Akeem Sanni1, Shams T Osman2

  • 1Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas, USA.

Proteomics
|July 18, 2025
PubMed

Insights

Combination therapy with dipeptidyl peptidase 4 (DPP4) and sodium-glucose cotransporter 2 (SGLT2) inhibitors improves cognitive and cardiovascular pathways in type 2 diabetes (T2D) patients. This offers a therapeutic advantage over metformin monotherapy for managing T2D complications.

Area of Science:

  • Metabolomics
  • Proteomics
  • Endocrinology

Background:

  • Type 2 diabetes (T2D) is a growing global health concern, associated with severe complications like cognitive decline and cardiovascular disease.
  • Existing T2D treatments, including metformin, may not fully address these complications, and their protective mechanisms are not fully understood.
  • Newer antidiabetic drugs, such as dipeptidyl peptidase 4 (DPP4) inhibitors and sodium-glucose cotransporter 2 (SGLT2) inhibitors (SGLT2is), show promise, but their impact on cognitive and central nervous system (CNS) pathways requires further investigation.

Purpose of the Study:

  • To investigate the molecular effects of combination therapy (DPP4 and SGLT2 inhibitors with metformin) compared to metformin monotherapy in T2D patients.
  • To explore the impact of these therapies on biological pathways crucial for cognitive function and cardiovascular health.
  • To identify potential therapeutic advantages of newer antidiabetic drug combinations independent of glycemic control.

Main Methods:

  • Comprehensive proteomic analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS) on serum samples from 76 participants.
  • Analysis included healthy controls, T2D patients on metformin monotherapy, and T2D patients on combination therapy (metformin + DPP4/SGLT2is).
  • Statistical analysis and ingenuity pathway analysis (IPA) were performed, with key findings validated by parallel reaction monitoring (PRM).

Main Results:

  • Identified and quantified 505 low-abundance proteins, revealing significant alterations in pathways related to synaptogenesis, insulin-like growth factor transport, and neurovascular coupling.
  • Metformin monotherapy was associated with adverse effects on pathways critical for cognitive and cardiovascular health.
  • Combination therapy demonstrated significant improvements in these pathways, suggesting enhanced neuroprotective and cardioprotective effects.

Conclusions:

  • Combination therapy with DPP4 and SGLT2 inhibitors offers a significant therapeutic advantage in managing T2D complications, particularly cognitive and cardiovascular health.
  • These benefits appear to be mediated through the activation of key CNS and vascular pathways, independent of glycemic control.
  • Findings support the development of personalized treatment strategies for T2D, targeting specific molecular pathways to mitigate disease progression and improve patient outcomes.
Keywords:
Type 2 diabetescognitive declineneurovascular couplingsynaptogenesis

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