Abstract: SA-PO0269
Discovery of Off-Target Effects of SGLT2 Inhibitors
Session Information
- Pharmacology
November 08, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
- 2000 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
Authors
- Billing, Anja M., Aarhus Universitet, Aarhus, Central Denmark Region , Denmark
- Kovalenko, Elina, Aarhus Universitet, Aarhus, Central Denmark Region , Denmark
- Kim, Young Chul, University of San Diego, San Diego, California, United States
- Wulfmeyer, Vera Christine, Aarhus Universitet, Aarhus, Central Denmark Region , Denmark
- Vallon, Volker, University of San Diego, San Diego, California, United States
- Rinschen, Markus M., Aarhus Universitet, Aarhus, Central Denmark Region , Denmark
Background
SGLT2 inhibitors (SGLT2i), initially developed for hyperglycemia management, have shown protective effects against renal and cardiovascular complications, regardless of diabetes status. However, the molecular mechanisms behind these effects remain largely unknown and cannot be fully explained by their primary role in inhibiting renal glucose reabsorption.
Methods
To explore potential off-targets of SGLT2i, we used LC-MS/MS to assess drug-induced proteomic and metabolomic changes in SGLT2 knockout (SGLT2KO) and wildtype (SGLT2WT) mice, both diabetic (Akita) and non-diabetic. Protein-drug interactions were also examined ex vivo in kidney tissue via thermal proteome profiling (TPP). Proteomic analysis was conducted label-free or with TMT-16-plex labeling using an Exploris 480 mass spectrometer and UltiMate3000 RSLC. Targeted metabolomics was performed using a 6495C triple-quadrupole coupled to an Agilent 1290 Infinity HPLC.
Results
Proteomic profiling of the kidney cortex after 12 weeks of dapagliflozin treatment in SGLT2KO and SGLT2WT diabetic and non-diabetic mice revealed clear off-target effects. Functional enrichment analyses point to modulation of solute carrier transmembrane transporters, which were induced by dapagliflozin independently of SGLT2. Two of them, SLC17A1 and SLC31A1, were validated by Westernblotting. Similarly, TPP data suggested the involvement of other solute carriers (SLCs) beyond the primary target, SLC5A2 (SGLT2). To confirm these findings, we measured uremic toxins and SLC-transported metabolites in corresponding serum and urine samples using targeted metabolomics.
Conclusion
Our study identified potential off-targets of SGLT2i in the kidney, which may indirectly contribute to cardiovascular protection. These findings provide new insights into the broader molecular actions of SGLT2 inhibitors.