Embark: empagliflozin treatment of ischemic with non-obstructive coronary arteries (inoca)

The National Heart, Lung, and Blood Institute awarded $734,266 to the University of Cincinnati's Sponsored Research Services Division on August 1, 2026, under the Cardiovascular Diseases Research program (CFDA 93.837) to investigate the effects of empagliflozin, a sodium-glucose co-transporter 2 inhibitor (SGLT2i), on coronary microvascular dysfunction and endothelial dysfunction in patients with ischemia and non-obstructive coronary arteries (INOCA).

The research addresses INOCA, a cardiovascular condition characterized by angina absent obstructive coronary artery disease, where up to 70-90 percent of patients have coronary microvascular dysfunction associated with 3 to 4-fold increased risk of death. Prior studies demonstrated SGLT2i improvement in microvascular dysfunction measures and reversal of endothelial dysfunction in animal models and patients; a pilot study in INOCA patients treated with empagliflozin showed clinically significant improvement in angina and implicated the tumor necrosis factor alpha, nuclear factor kappa-B, and endothelin-1 pathway in endothelial dysfunction reversal. This project will investigate how SGLT2i modulates this pathway to improve microvascular and endothelial dysfunction in INOCA patients and examine the specific cellular mechanisms underlying SGLT2i cardiovascular benefits beyond glycemic control.

Performance is located in Cincinnati, Ohio, with a period of performance from August 1, 2026, through July 31, 2031. The award is classified as a Project Grant.

Abstract

Ischemia with non-obstructive coronary arteries (inoca) is a cardiovascular condition characterized by angina in the absence of obstructive coronary artery disease (CAD). The majority of inoca patients (up to 70-90%) have coronary microvascular dysfunction (CMD), which is associated with 3 to 4-fold increased risk of death. Endothelial dysfunction (end) contributes to the pathogenesis and progression of CMD and results in impaired myocardial blood flow, leading to ischemia and angina in the absence of obstructive CAD. There is an urgent need to identify effective treatments in inoca targeting CMD and end. Sodium glucose CO-transporter 2 inhibitors (SGLT2I) are a novel class of drugs that show remarkable cardiovascular benefits beyond glycemic control. Although multifactorial, IT is hypothesized that SGLT2I exert their cardiovascular effects at least in part by reversing end; however, the specific cellular pathways remain unknown and the effect of CMD has not been sufficiently tested. Prior studies on SGLT2I treatment have demonstrated (1) improvement in CMD measures in animal models and T2DM patients without CMD, (2) reversal of end in vivo and in vitro and clinical measures, (3) improvement in angina in patients with obstructive CAD. Additionally, our pilot study in inoca patients with CMD treated with SGLT2I empagliflozin (empa) showed (1) clinically significant improvement in angina (2) reversal of end and implicated the tumor necrosis factor α, nuclear factor KB, endothelin-1 (tnfα - NF-ΚB - ET- 1) pathway in our in vitro model. The goal of this is study is to investigate the effects of SGLT2I on CMD and end in inoca patients with CMD and to investigate the tumor necrosis factor α, nuclear factor KB, endothelin-1 (tnfα - NF-ΚB - ET-1) pathway on end and examine how IT is modulated by SGLT2I. We hypothesize that SGLT2I will improve CMD and that there is increased activation of the tnfα - NF-ΚB - ET-1 pathway resulting in end that is disrupted by SGLT2I leading to reversal of end. To test our hypothesis we propose a randomized, double-blinded, placebo controlled, mechanistic clinical trial of inoca patients with CMD (n=120) treated with SGLT2I empagliflozin (empa) 10MG/day for 90-days matched 1:1 with placebo and no- CMD controls (n=30) from our inoca prospective registry. Aim 1 will demonstrate the effect of SGLT2I treatment on CMD (magnetic resonance imaging measured myocardial perfusion reserve index) and end (endopat measured reactive hyperemia index). Aim 2 will study the tnfα - NF-ΚB - ET-1 pathway on end in inoca participants with CMD VS. No-CMD controls and examine how IT is modulated by SGLT2I in inoca participants with CMD in vitro and EX vivo. The results of this study have clinical translation that greatly impacts this understudied patient population. First, improvements in clinical CMD measures would support a multicenter, phase 3 trial testing SGLT2I for patient reported outcomes, mace and mortality in inoca patients. Second, demonstrating that end in CMD patients is mediated by the tnfα - NF-ΚB - ET-1 pathway could lead to future targeted therapies.