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Updated: Jun 27, 2026

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Published on: February 2, 2024

SGLT2 Inhibitors Attenuate Neutrophil-Mediated Endothelial Injury in Coronary Artery Disease With Type 2 Diabetes

Wenyuan Zheng1, Yixin Zhou2, Bozhi Ye2

  • 1Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, National Clinical Research Center for Interventional Medicine, Key Laboratory of Viral Heart Diseases, National Health Commission, Chinese Academy of Medical Sciences, Shanghai, China.

Journal of Cardiovascular Pharmacology
|June 26, 2026
PubMed

Insights

Sodium-glucose cotransporter 2 (SGLT-2) inhibitors protect against cardiovascular damage in type 2 diabetes by reducing neutrophil-driven inflammation and improving endothelial function. These drugs modulate GREM1 expression and TGF-β/Smad signaling, offering novel therapeutic avenues.

Area of Science:

  • Immunology
  • Cardiology
  • Endocrinology

Background:

  • Type 2 diabetes mellitus (T2DM) significantly increases coronary artery disease (CAD) risk, with neutrophils implicated in its pathogenesis.
  • Sodium-glucose cotransporter 2 (SGLT-2) inhibitors provide cardiovascular benefits beyond glucose control, yet their impact on innate immunity in T2DM-CAD is not fully understood.

Purpose of the Study:

  • To investigate the role of neutrophils and GREM1 in T2DM-CAD and elucidate the immunomodulatory mechanisms of SGLT-2 inhibitors.
  • To assess the effects of SGLT-2 inhibitors on neutrophil function, endothelial injury, and cardiac damage in a T2DM-CAD context.

Main Methods:

  • Neutrophil isolation and analysis using transcriptomics, flow cytometry, ELISA, and Western blotting.
  • In vitro endothelial injury assays using co-cultures of neutrophils and human aortic endothelial cells.
  • In vivo assessment of cardiac injury in a diabetic rat model.

Main Results:

  • T2DM-CAD patients exhibited elevated neutrophils, cell-free dsDNA, elastase 2, and GREM1, which were reversed by SGLT-2 inhibitors.
  • SGLT-2 inhibition ameliorated neutrophil-induced endothelial injury and in vivo cardiac damage by suppressing GREM1 and restoring TGF-β/Smad signaling.
  • Increased GREM1 expression in T2DM-CAD neutrophils correlated with impaired Smad1/5/9 signaling and heightened endothelial injury.

Conclusions:

  • SGLT-2 inhibitors offer vascular protection in T2DM-CAD through GREM1 downregulation and modulation of the TGF-β/Smad pathway.
  • Targeting neutrophil-mediated inflammation via GREM1 presents a novel immunoregulatory strategy for managing diabetic cardiovascular complications.
Keywords:
GREM1TGF-βcoronary artery diseaseneutrophilsodium–glucose cotransporter 2 (SGLT-2) inhibitortype 2 diabetes mellitus

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