Type 2 diabetes mellitus is a key public health problem worldwide with current trends predicting that 500 million people will have diabetes in 2035. The escalating prevalence of type 2 diabetes worldwide presents a critical cardiovascular challenge. Patients with type 2 diabetes experience accelerated vascular aging, premature atherosclerotic cardiovascular disease, and increased rates of cardiovascular events. There is considerable interest in the clinical cardiovascular benefits of new agents to treat type 2 diabetes including sodium-glucose cotransporter-2 (SGLT2) inhibitors such as dapagliflozin. However, the mechanisms of cardiovascular activity remains incompletely understood. Metabolic disturbances underlie the systemic vascular dysfunction in type 2 diabetes. Elevated glucose and lipids alter signal transduction thereby changing gene expression resulting disturbing endothelial homeostasis. Alterations in endothelial function including inflammation and reduced nitric oxide production promote atherogenesis in diabetes.

Several studies suggest activity of SGLT2 inhibitors on vascular function in animal models and humans. The robust clinical trial evidence with these classes of diabetes medications has not yet been accompanied by complete mechanistic evidence in the vasculature.
Combining vascular functional assessment with targeted endothelial cell gene expression and nitric oxide characterization will expand critical evidence about the mechanisms of action. Prior clinical studies evaluating the effects of SGLT-2 inhibitors have been limited to evaluation of vascular health without measures of endothelial cell phenotype that will provide additional mechanistic information. Dapagliflozin, a SGLT2 inhibitor, has effects on endothelial cell inflammation in cultured cells and improved vasodilation in animal models; however the effect on endothelial cell health in patients is not well-defined. Emerging experimental evidence in preclinical models also links SGLT2 inhibitors to reduction in mitochondrial oxidative stress.
We aim to investigate treatment with a SGLT2 inhibitor for diabetes will alter endothelial cell phenotype and ncRNA or biomarkers. We plan to test this hypothesis by conducting an interventional crossover study with dapagliflozin. We anticipate that evaluating endothelial cell phenotype will provide key additional information regarding the ability of novel treatments for type 2 diabetes to restore vascular health. Our study will provide novel evidence about endothelial cell effects of dapagliflozin that link to both animal models of diabetes and clinical trial data.