Effects of Sodium-Glucose Co-Transporter 2 Inhibitors on Vascular Cell Function and Arterial Remodeling

Abstract

Cardiovascular disease is the leading cause of morbidity and mortality in diabetes. Recent clinical studies indicate that sodium-glucose co-transporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in patients with diabetes. The mechanism underlying the beneficial effect of SGLT2 inhibitors is not completely clear but may involve direct actions on vascular cells. SGLT2 inhibitors increase the bioavailability of endothelium-derived nitric oxide and thereby restore endothelium-dependent vasodilation in diabetes. In addition, SGLT2 inhibitors favorably regulate the proliferation, migration, differentiation, survival, and senescence of endothelial cells (ECs). Moreover, they exert potent antioxidant and anti-inflammatory effects in ECs. SGLT2 inhibitors also inhibit the contraction of vascular smooth muscle cells and block the proliferation and migration of these cells. Furthermore, studies demonstrate that SGLT2 inhibitors prevent postangioplasty restenosis, maladaptive remodeling of the vasculature in pulmonary arterial hypertension, the formation of abdominal aortic aneurysms, and the acceleration of arterial stiffness in diabetes. However, the role of SGLT2 in mediating the vascular actions of these drugs remains to be established as important off-target effects of SGLT2 inhibitors have been identified. Future studies distinguishing drug- versus class-specific effects may optimize the selection of specific SGLT2 inhibitors in patients with distinct cardiovascular pathologies.

Comprehensive Analysis of Adverse Events Associated With SGLT2is: A Meta-Analysis Involving Nine Large Randomized Trials

“…Third, this meta-analysis revealed significant association of SGLT2is with lower risks of three kinds of vascular diseases (i.e., hypertension, hypertensive emergency, and varicose vein) and three kinds of infectious diseases (i.e., pneumonia, bronchitis, and respiratory tract infection). SGLT2is were observed with lower risks of hypertension and hypertensive emergency, which is probably because SGLT2is improve the bioavailability of endothelium-derived nitric oxide, favourably regulate the activity of endothelial cells, suppress the contraction of vascular smooth muscle cells ( 19 ), and reduce the activity of sympathetic nervous system ( 20 ). Meanwhile, their glucose-lowering efficacy may be associated with their lower risks of respiratory infections.…”

“…According to this criterion, among all the serious AE reported in the Clinical Trials website 1,009 kinds of serious AE were identified for further meta-analyses. These 1,009 safety outcomes involved various disorders in 24 body systems (listed in Tables SPI: S1-S24), including 1) blood and lymphatic system disorders, 2) cardiac disorders, 3) congenital, familial, and genetic disorders, 4) ear and labyrinth disorders, 5) endocrine disorders, 6) eye disorders, 7) gastrointestinal disorders, 8) general disorders, 9) hepatobiliary disorders, 10) immune system disorders, 11) infections and infestations, 12) injury, poisoning, and procedural complications, 13) investigations, 14) musculoskeletal and connective tissue disorders, 15) neoplasms benign, malignant, and unspecified, 16) nervous system disorders, 17) product issues, 18) psychiatric disorders, 19) renal and urinary disorders, 20) reproductive system and breast disorders, 21) respiratory, thoracic, and mediastinal disorders, 22) skin and subcutaneous tissue disorders, 23) surgical and medical procedures, and 24) vascular disorders. We did not assess those disorders regarding the metabolism and nutrition system because they had already been well investigated.…”

The Role of Sodium Glucose Cotransporter-2 Inhibitors in Atherosclerotic Cardiovascular Disease: A Narrative Review of Potential Mechanisms

“…The endothelium is the major regulator of arterial homeostasis, including regulation of smooth muscle cell proliferation, cell migration, vascular reactivity, inflammation, and thrombosis through a number of mediators of which nitric oxide (NO) has a significant role [22]. Endothelial dysfunction is considered an early process in atherosclerosis, evident before clinical atherosclerotic plaque in arteries [23].…”

“…The major factors contributing to endothelial dysfunction in T2D are hyperglycaemia, insulin resistance and the metabolic syndrome. These factors lead to increased vascular reactive oxygen species (ROS), impaired NO synthesis and degradation [22] and a prothrombotic tendency as well as changes to chemokines and direct mitochondrial oxidative stress [25].…”

Amelioration of endothelial dysfunction by sodium glucose co-transporter 2 inhibitors: pieces of the puzzle explaining their cardiovascular protection

“…Previous studies have shown that SGLT-2i's directly ameliorate endothelial dysfunction in both euglycaemic and hyperglycaemic conditions (Alshnbari et al , 2020;Durante et al , 2021;Salvatore et al , 2021) and that EMPA mitigates endothelial and cardiac dysfunction in patients with HFpEF via reducing inflammatoryoxidative pathways (Kolijn et al , 2020). Our current manuscript focuses on the potential role of improved endothelial function as an indispensable contributor to the enhanced cardiac function in patients receiving SGLT-2i's.…”