Anti-inflammatory role of SGLT2 inhibitors as part of their anti-atherosclerotic activity: Data from basic science and clinical trials

Abstract

Atherosclerosis is a progressive inflammatory disease leading to mortality and morbidity in the civilized world. Atherosclerosis manifests as an accumulation of plaques in the intimal layer of the arterial wall that, by its subsequent erosion or rupture, triggers cardiovascular diseases. Diabetes mellitus is a well-known risk factor for atherosclerosis. Indeed, Type 2 diabetes mellitus patients have an increased risk of atherosclerosis and its associated-cardiovascular complications than non-diabetic patients. Sodium-glucose co-transport 2 inhibitors (SGLT2i), a novel anti-diabetic drugs, have a surprising advantage in cardiovascular effects, such as reducing cardiovascular death in a patient with or without diabetes. Numerous studies have shown that atherosclerosis is due to a significant inflammatory burden and that SGLT2i may play a role in inflammation. In fact, several experiment results have demonstrated that SGLT2i, with suppression of inflammatory mechanism, slows the progression of atherosclerosis. Therefore, SGLT2i may have a double benefit in terms of glycemic control and control of the atherosclerotic process at a myocardial and vascular level. This review elaborates on the anti-inflammatory effects of sodium-glucose co-transporter 2 inhibitors on atherosclerosis.

Keywords: SGLT2; SGLT2 inhibitors (SGLT2i); atherosclerosis; atherosclerosis cardiovascular diseases; inflammation.

Figure 1

Sodium-glucose co-transport 2 inhibitors' effects on inflammation in atherosclerosis. SGLT2i inhibit endothelial dysfunction reducing the expression of circulating inflammatory molecules and LDL-oxidation. Moreover, SGLT2i attenuate macrophages infiltration, M1 polarization and foam cell formation. M1 macrophages express the main pro-inflammatory molecules playing role in maintaining chronic inflammation, forming foam cells, and plaque initiation and progression Inversely, M2 macrophages are associated with an anti-inflammatory phenotype producing anti-inflammatory factors. The imbalance of these,polarized macrophages may be responsible for plaque development or regression. ox-LDL, oxidized-LDL; ILs, interleukins; TNF-α, tumor necrosis factor-α; CCR2, C-C chemokine receptor type 2; NOS 2, nitric oxidase synthase 2; TGF-β, transforming growth factor beta; M-CSF, macrophage colony-stimulating factor.