Sodium glucose co-transporter inhibition as a strategy to stabilize the microvasculature in sickle cell disease

This editorial refers to ‘Beneficial effects of SGLT1/2 and SGLT2 inhibitors on vaso-occlusive events and organ damage in sickle cell disease mice’, by B.-R. Jin et al., https://doi.org/10.1093/cvr/cvag003. Sickle cell disease (SCD) affects more than 13 million individuals worldwide and remains associated with substantial morbidity, premature mortality, and healthcare utilization.1 SCD is increasingly recognized as a systemic vascular disorder characterized by chronic inflammation, endothelial dysfunction, and microvascular injury. Recurrent vaso-occlusive crises (VOCs), driven by intravascular cell-cell adhesion and inflammatory activation, constitute the hallmark clinical manifestation of SCD and represent a major determinant of impaired quality of life and progressive organ damage.2 Despite advances in disease-modifying and gene-based therapies, safe, accessible, and broadly applicable strategies to mitigate vaso-occlusion among patients with SCD remain limited. A recurring feature of VOC biology is inflammatory endothelial activation and leukocyte recruitment triggered by acute inflammatory stressors, including infection, hypoxia, and systemic physiological stress.2 Emerging mechanistic data indicate that sodium glucose co-transporter (SGLT) inhibition preserves low-density lipoprotein receptor-related protein 2 (LRP2), thereby maintaining circulating apolipoprotein M (ApoM) levels and supporting endothelial barrier integrity during acute inflammatory stress.3 A recent translational study reported that empagliflozin improved anaemic indices in a murine model of SCD and was associated with higher haemoglobin and haematocrit in adults with SCD treated with SGLT2 inhibitors in electronic health record analyses; notably, empagliflozin also reduced infarct size in a murine stroke model, providing an early signal for potential neurovascular and microvascular protection in a disease characterized by inflammation-driven vascular occlusion.4 However, direct mechanistic evidence linking SGLT inhibition to the proximal biology of VOC, endothelial activation, and leukocyte recruitment remains sparse (Figure 1). Sodium glucose co-transporter inhibition as a strategy to stabilize the microvasculature in SCD. In this context, Jin et al.5 should be congratulated on their experimental study, published in this issue of Cardiovascular Research, examining the effects of SGLT inhibition on vaso-occlusive events and organ injury in murine models of SCD.5 Using intravital microscopy and complementary inflammatory analyses, the authors demonstrate that both dapagliflozin, a selective SGLT2 inhibitor, and sotagliflozin, a dual SGLT1/2 inhibitor, attenuate neutrophil recruitment, downregulate endothelial adhesion molecule expression, and improve microvascular perfusion under conditions of inflammatory and hypoxic stress. Notably, only sotagliflozin consistently conferred a survival benefit, highlighting potentially important biological differences between selective and dual SGLT inhibition. The short-term administration of either agent significantly reduced neutrophil adhesion and transmigration within post-capillary venules, accompanied by downregulation of key endothelial adhesion molecules, including ICAM-1 and E-selectin. These effects were reproduced in complementary inflammatory paradigms, including TNF-α challenge and hypoxia-reoxygenation, which strengthen the internal validity of these findings. Moreover, prolonged SGLT inhibition was associated with reduced leukocyte infiltration in pulmonary and hepatic tissue, suggesting that its anti-inflammatory effects extend beyond the microvasculature to limit downstream organ injury. Notably, the absence of direct effects on neutrophil or platelet activation indicates that these organ-level effects are unlikely to be driven by cell-autonomous mechanisms, but rather by upstream modulation of systemic inflammatory signaling. These observations are concordant with extensive cardiovascular evidence indicating that the systemic effects of SGLT inhibition are largely independent of glycemic modulation.6,7 Across multiple disease states, including heart failure (HF), chronic kidney disease (CKD), and atherosclerotic cardiovascular disease (ASCVD), SGLT inhibition has been shown to improve clinical outcomes in both T2DM and non-T2DM populations, implicating mechanisms related to vascular inflammation, endothelial stability, and immunometabolism regulation rather than glucose lowering.8,9 Experimental and translational evidence have shown that SGLT inhibition attenuates endothelial activation, modulates inflammatory cytokine signaling, and preserves microvascular integrity in settings of haemodynamic and inflammatory stress.10,11 Viewed against this background, the findings reported by Jin et al.5 indicate that SGLT inhibition modulates vascular-inflammatory pathways that are fundamental to SCD pathophysiology, which is characterized by microcirculatory instability and inflammation-driven vascular occlusion. A particularly noteworthy observation is the differential survival signal associated with sotagliflozin as compared to dapagliflozin. While both agents reduced neutrophil recruitment and inflammatory markers, only the dual SGLT1/2 inhibitor translated these effects into improved acute survival. Given that SGLT1 is expressed in extra-renal tissues, including the myocardium and gastrointestinal tract, dual inhibition may confer broader metabolic or inflammatory effects that are particularly relevant under conditions of systemic stress. The extent to which this distinction reflects differences in inflammatory signaling, tissue energetics, and vascular integrity remains to be investigated. Several limitations of this study should be acknowledged. Although the murine models employed reproduce key inflammatory and microvascular features of SCD, they cannot fully capture the clinical heterogeneity, chronicity, and comorbidity burden seen in human populations. While TNF-α induced inflammatory stress is an established and informative experimental approach, it represents an acute amplification of inflammation rather than the multifactorial evolving processes that characterize spontaneous VOCs, and therefore may not fully reflect their biological complexity in clinical settings.12 Moreover, the lack of additive benefit with hydroxyurea underscores the challenges of integrating novel anti-inflammatory approaches into established disease-modifying treatment therapies and highlights the need to clarify their complementary or context-specific roles. These considerations emphasize the importance of cautious translational interpretation while reinforcing the value of the current study in addressing proximal mechanisms that have not been investigated in prior studies. Further studies are needed to determine whether these experimental observations translate to meaningful clinical benefit for patients with SCD. Key questions include whether SGLT inhibition can meaningfully reduce VOC burden, mitigate organ-specific injury, or favourably influence cardiovascular phenotypes such as impaired cardiac reserve and HF. Comparative evaluation of selective vs. dual SGLT inhibition, alongside integration with existing disease-modifying therapies, will be essential. Moreover, elucidating the inflammatory pathways that are most responsive to SGLT modulation may help identify patient subgroups most likely to benefit. From a translational perspective, these findings invite closer collaboration between cardiovascular and haematology disciplines. Integrating insights from HF in hemoglobinopathies and vascular biology may help define which SCD phenotypes are most likely to benefit from anti-inflammatory cardiovascular therapies such as SGLT inhibition. As gene-editing and curative therapies for SCD advance, their high cost—often approaching US $1–2 million per patient—along with limited availability, and long-term safety considerations, may constrain global implementation. In contrast, orally administered agents with established cardiovascular safety profiles offer a complementary approach and scalable approach. In summary, Jin et al.5 provide compelling experimental evidence that SGLT inhibition attenuates vascular inflammation and vaso-occlusive pathology in SCD, with dual SGLT1/2 inhibition offering a potentially survival benefit. By reframing SCD as a vascular-inflammatory disorder amenable to therapies developed within cardiovascular medicine, this study broadens the therapeutic horizon and invites further exploration of anti-inflammatory strategies to mitigate one of the most clinically consequential manifestations of SCD. None to declare. There are no new data associated with this article.