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The effect of SGLT2 inhibition on immune cells and transplant rejection/failure: A drug-targeted mendelian

Hanyu Xiao1, Xiang Zeng1, Qidan Pang2

  • 1Department of General Surgery/Gastrointestinal Surgery, Bishan Hospital of Chongqing Medical University, Bishan Hospital of Chongqing, Chongqing, China.

Transplant Immunology
|April 6, 2026
PubMed
Abstract

Insights

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) show a protective effect against transplant rejection and failure (TRF). This study provides genetic evidence that SGLT2 inhibition may reduce TRF risk by influencing immune cell profiles.

Area of Science:

  • Pharmacogenomics
  • Transplantation Immunology
  • Cardiorenal Medicine

Background:

  • Sodium-glucose cotransporter-2 inhibitors (SGLT2i) offer cardiorenal benefits beyond glycemic control.
  • Emerging evidence suggests SGLT2i may benefit organ transplantation, but causal links are unclear.
  • Investigating the causal effect of SGLT2 inhibition on transplant rejection and failure (TRF) is crucial.

Purpose of the Study:

  • To investigate the causal effect of SGLT2 inhibition on transplant rejection and failure (TRF).
  • To explore the mediating role of immune cell profiles in the SGLT2i-TRF relationship.

Main Methods:

  • A drug-targeted and mediation Mendelian randomization (MR) study was performed.
  • Genetic instruments for SGLT2 inhibition were derived from SLC5A2 expression and HbA1c reduction variants.
  • TRF data from FinnGen and immune cell traits from a Sardinian cohort were utilized.

Main Results:

  • Genetically proxied SGLT2 inhibition was associated with a reduced risk of TRF (OR=0.81).
  • SGLT2i significantly impacted 66 immune cell traits, including alterations in B cells, T cells, and NK cells.
  • Mediation analysis did not reach statistical significance for immune cell mediation of TRF risk.

Conclusions:

  • This MR study provides genetic evidence supporting a protective effect of SGLT2 inhibition against TRF.
  • SGLT2 inhibition may influence immune cell profiles, potentially contributing to reduced transplant rejection.
  • Further research is warranted to elucidate the precise mechanisms of SGLT2i in transplantation.
Keywords:
Allograft failureImmune cellMendelian randomizationSGLT2 inhibitorTransplant rejectionTransplantation

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