Key result
Combined SGLT2i and GLP-1Ra cut monocyte reactive oxygen species by ~84% ex vivo.
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In vitro treatment with SGLT2 inhibitors and GLP-1 receptor agonists synergistically reduces the pro-inflammatory M1 phenotype of monocytes from CAD patients and protects against endothelial dysfunction, providing mechanistic insight into their cardiovascular benefits.
Background Coronary artery disease (CAD) is the most prevalent cardiovascular disease and is associated with inflammatory induction of microvascular endothelial dysfunction. Although SGLT2 inhibitors (SGLT2i) and GLP-1R agonists (GLP-1Ra) demonstrated cardiovascular benefits in clinic, their effect on inflammatory resolution is poorly studied. Aim This work studied the phenotype of monocytes in CAD patients, the effects of their released mediators on endothelial function and the impact of SGLT2i + GLP-1Ra. Methods Blood from 100 CAD patients and 50 healthy subjects were collected and monocytes were isolated. The activity, secretion profile and phenotype of monocytes were studied and compared to the patients’ plasma profile. The effects of plasma and monocytes-conditioned medium was evaluated on human microvascular endothelial cells (HMEC-1). Results Plasma and monocytes-conditioned medium of CAD patients showed higher levels of pro-inflammatory cytokines, chemokines and soluble adhesion molecules compared to those of healthy donors. The levels of pro-inflammatory cytokines in CAD plasma positively correlated to the levels of their release from monocytes, which were significantly reduced, in synergy, by a combination of 10 nM SGLT2i + GLP-1Ra. Similarly, the level of reactive oxygen species (ROS) generated by CAD monocytes was 2.5-fold higher than that by healthy ones and was reduced synergically by 84% using SGLT2i + GLP-1Ra. In addition, CAD monocytes demonstrated higher activity evident by their elevated adhesion to healthy endothelial cells and higher levels of thrombin generation as compared to healthy monocytes. Such activity was linked to increased expression of NADPH oxidase subunits, adhesion molecules, prothrombotic tissue factor (TF) and M1 macrophage phenotype markers, along with SGLT2 and GLP-1R. These effects were significantly inhibited by SGLT2i + GLP-1Ra and associated with elevated expression of M2 phenotype markers. On the other hand, stimulation of HMEC-1 with 10% patient plasma or CAD monocytes-conditioned medium elevated ROS generation and blunted nitric oxide formation by endothelial cells, both of which were synergically prevented by SGLT2i + GLP-1Ra. Further, stimulated HMEC-1 exhibited higher adhesion of healthy human monocytes and platelets in addition to elevated TF-mediated thrombin generation which were all significantly reduced by SGLT2i + GLP-1Ra. The protective effects of the SGLT2i + GLP-1Ra on both monocytes and endothelial cells were associated with reduced glucose uptake and enhanced cAMP signaling respectively, indicating on-target effects of the compounds. Conclusion Our results demonstrated that the combination of low-dose SGLT2i + GLP-1Ra induced the resolution of M1 macrophage into M2 and prevented endothelial dysfunction, suggesting a promising strategy to reduce CAD burden in patients.
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Mroueh et al. (2025) studied Coronary artery disease (n=150). SGLT2i + GLP-1Ra vs. Untreated cells / Healthy monocytes was evaluated on Reactive oxygen species (ROS) generation and inflammatory mediator release. Ex vivo treatment with 10 nM SGLT2i and GLP-1Ra synergistically reduced reactive oxygen species generation by CAD monocytes by 84% and prevented endothelial dysfunction.
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