Beneficial effects of SGLT1/2 and SGLT2 inhibitors on vaso-occlusive events and organ damage in sickle cell disease mice

Abstract

Aims: Sodium-glucose co-transporter 2 inhibitors are widely used to treat patients with type 2 diabetes and exhibit beneficial cardiovascular effects beyond glucose lowering. In this study, we investigated their potential to alleviate vaso-occlusive events and organ damage in sickle cell disease (SCD) mice.

Methods and results: Intravital and immunofluorescence microscopy reveal that 4-day oral administration of dapagliflozin (DAPA) or sotagliflozin (SOTA) significantly reduces neutrophil adhesion and transmigration in cremaster venules, with SOTA showing greater inhibition, and downregulates E-selectin and intercellular adhesion molecule-1 (ICAM-1) expression in cremaster venules of TNF-α-challenged SCD mice. Intriguingly, only SOTA improves mouse survival acutely. Similar inhibitory effects on neutrophil recruitment are observed in SCD mice subjected to hypoxia-reoxygenation. Flow chamber assays indicate that neither drug directly affects neutrophil or endothelial cell adhesive function. In addition, treatment of neutrophils and platelets from SCD mice and patients with DAPA or SOTA does not affect their activation. When administered for 4 months, DAPA or SOTA mitigates neutrophil recruitment and enhances microcirculation in cremaster venules of TNF-α-challenged SCD mice, while only SOTA confers a survival benefit. Both drugs reduce leukocyte infiltration in the liver or lungs, suggesting their ability to protect against organ damage. Co-administration with hydroxyurea for 4 months does not enhance these effects. Multiplex analysis shows that DAPA and SOTA lower plasma levels of soluble P-selectin, ICAM-1, S100A8/A9, and pro-inflammatory cytokines in SCD mice.

Conclusions: Our findings suggest that DAPA and SOTA mitigate vaso-occlusive events in SCD, with SOTA providing superior benefits.

Translational perspective: Sickle cell disease (SCD) is an inherited autosomal recessive disorder characterized by red blood cell hymolysis, oxidative stress, and chronic inflammation. Recurrent vaso-occlusive crises driven by intravascular cell-cell adhesion and aggregation and the hallmark of SCD. In this study, we show that dapagliflozing (DAPA), a sodium-glucose co-transporter 2 inhibitor (SGLT2i), and sotagliflozin (SOTA), an SGLT1/2i, reduce acute vaso-occlusion in SCD mice subjected to severe inflammation or hypoxia-reoxygenation, with SOTA providing greater benefit.These findings suggest that SGLT2 or SGLT1/2 inhibition may help attenuate vaso-occlusive pain crises in SCD patients.

Keywords: SGLT2 inhibitors; anti-inflammatory effects; neutrophil recruitment; organ damage; sickle cell disease.