The Effect of SGLT2 Inhibition on Adipose Tissue Inflammation and Endothelial Function

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Project Summary/Abstract The prevalence of obesity is increasing globally, and chronic systemic and adipose tissue (AT) inflammation in obesity contribute to increased risk of cardiovascular disease (CVD). While several anti-inflammatory agents have shown benefit in reducing adverse cardiovascular (CV) outcomes, none are standard of care in obesity. Thus, there remains a residual risk of CV events and a significant need for new therapeutics to target the inflammation in obesity and prevent or reverse these outcomes. Furthermore, our understanding of AT inflammation in humans is limited due to difficulty obtaining samples in clinical trials, and discoveries in animals do not consistently translate. SLGT2 inhibitors reduce major adverse CV events through unknown mechanism(s) and beyond what is expected from their anti-hyperglycemic or weight loss benefits. An anti- inflammatory effect of SGLT2 inhibition has been demonstrated in animals, and if present in humans could point to a potential mechanism for the CV benefit. Our central hypothesis is that SGLT2 inhibitors decrease systemic and AT inflammation and result in improvements in endothelial function as a surrogate of CVD. With a mentoring team combining expertise in clinical study design, AT immunology and endothelial measures, we can address this scientific gap and advance our understanding of the CV benefits of SGLT2 inhibition. Our team will enroll obese individuals with pre-diabetes and treat them with 12 weeks of an SGLT2 inhibitor or placebo in a randomized double-blind trial. In Aim 1, we will test that SGLT2 inhibition reduces AT and systemic inflammation by quantifying immune cell populations and transcripts. In Aim 2, we will test that SGLT2 inhibition reduces endothelial inflammation and improves endothelial vasodilatory function. We will assess whether changes in endothelial function are associated with changes in AT and systemic inflammation. In Aim 3, we will interrogate the molecular effects of SGLT2 inhibition on immune and endothelial cell interactions in vitro. Through the activities in this proposal, the candidate will (Objective 1) design and implement a mechanistic human trial from inception to completion; (Objective 2) establish and lead a multidisciplinary program at the intersection of immunology, AT biology and CVD; (Objective 3) develop expertise in analyzing immune and endothelial cell interactions in vitro; and (Objective 4) gain investigative skills in surrogate measures of CVD. These objectives will assist the candidate in achieving her long-term career goal to lead a translational research program at the interface of immune function and vascular disease in obesity and define new pathways for targeted interventions to prevent and treat cardiometabolic diseases. She will accomplish these goals within an institution with a tremendous track record of supporting early career physician-scientists. She also has the support of an exceptional mentoring team that has jointly mentored many physician-scientists to autonomy, and that has a diverse and multidisciplinary set of interests that are distinct from, yet mirror and enhance those of the candidate.