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Sodium-Glucose Cotransporter Inhibition Preserves Apolipoprotein M During Acute Inflammation in Mice and Humans

Carla Valenzuela Ripoll1, Aynaz Lotfinaghsh1, Zhen Guo2

  • 1Washington University School of Medicine, St. Louis, Missouri, USA.

JACC. Advances
|June 27, 2025
PubMed
Abstract

Insights

Sodium-glucose cotransporter inhibitors (SGLT2is) preserve apolipoprotein M (ApoM) levels, crucial for vascular integrity. This study shows SGLT2is protect against inflammation by maintaining ApoM, a novel protective mechanism.

Area of Science:

  • Cardiovascular Research
  • Endocrinology
  • Pharmacology

Background:

  • Sodium-glucose cotransporter inhibitors (SGLT2is) are known to reduce inflammation and maintain vascular integrity.
  • Apolipoprotein M (ApoM) plays a critical role in vascular integrity through sphingosine-1-phosphate (S1P) signaling and is associated with mortality in sepsis and COVID-19.

Purpose of the Study:

  • To investigate whether SGLT2 inhibitors, specifically dapagliflozin (Dapa), increase ApoM levels.
  • To evaluate the effect of Dapa on ApoM in mouse models of inflammation and in human patients with COVID-19.

Main Methods:

  • Studies involved diet-induced obese mice, Lrp2 knockout mice, and ApoM knockout/transgenic mice treated with Dapa or vehicle before lipopolysaccharide (LPS) challenge.
  • ApoM protein levels were measured using Western blot and ELISA.
  • Human plasma samples from the ACTIV-4a trial (standard of care vs. standard of care + SGLT2i) were analyzed for circulating ApoM.

Main Results:

  • Dapagliflozin (Dapa) restored circulating ApoM levels in LPS-treated mice and increased ApoM in COVID-19 patients receiving SGLT2 inhibitors.
  • LRP2 knockout negated Dapa's effect on ApoM, and in vitro studies showed Dapa enhances Lrp2-dependent ApoM uptake.
  • Dapa attenuated LPS-induced vascular leak in an ApoM-dependent manner.

Conclusions:

  • SGLT2 inhibitors maintain Lrp2 levels, which preserves ApoM and enhances endothelial barrier integrity during acute inflammation.
  • This highlights a novel protective mechanism of SGLT2 inhibitors mediated by ApoM preservation.
Keywords:
LRP2SGLT2apolipoprotein Mendothelial vascular integrity

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