Empagliflozin Shown to Reduce Endothelial Dysfunction in Women With INOCA

The sodium-glucose cotransporter 2 inhibitor (SGLT2i) empagliflozin demonstrated significant reductions in inflammatory and oxidative stress markers in women with ischemia and no obstructive coronary arteries (INOCA) complicated by coronary microvascular dysfunction (CMD), according to a pair of phase 2 pilot trials.^1,2

Although up to 70% of patients with angina undergoing coronary angiography have INOCA, treatment options remain limited, particularly for those with CMD and endothelial dysfunction (EnD).¹ These patients often experience impaired myocardial blood flow and ischemia despite no evidence of obstructive coronary artery disease.

Researchers at The Christ Hospital in Cincinnati, Ohio, investigated whether empagliflozin, a therapy known for its cardiovascular benefits in diabetes and heart failure, could provide similar benefit in this high-risk group. Findings were presented at the European Society of Cardiology (ESC) Congress 2025.

Circulating Biomarkers

Patients received empagliflozin 10 mg daily for 90 days. | Image credit: luchschenF – stock.adobe.com

Both abstracts focused on the same cohort: 7 women with a mean age of 63 years.

Patients with INOCA and CMD received empagliflozin 10 mg daily for 90 days. Compared with baseline and a no-CMD control group (n = 4), patients with CMD had significantly elevated levels of 9 proinflammatory cytokines, including C-reactive protein, TNF-α, interleukin (IL)-1β, and IL-6, as well as adhesion molecules such as ICAM-1 and VCAM-1. After 45 days of treatment, these markers decreased substantially, while anti-inflammatory IL-10 levels rose.

Oxidative stress measures followed a similar trend; plasma 8-isoprostane and myeloperoxidase activity were elevated at baseline but reduced after treatment, while antioxidant capacity improved. Circulating endothelial extracellular vesicles (eEVs) also shifted favorably, with reductions in inflammatory VCAM-positive eEVs and increases in repair-associated CD34-positive eEVs. At 45 days, 2 urinary tract infections, 1 vaginal yeast infection, and 1 nonsignificant decrease in glomerular filtration rate were reported.

“This pilot study indicates that SGLT2i treatment is well tolerated and has the potential to reduce inflammation, ROS, and eEVs in INOCA patients with CMD,” the researchers said.

Endothelial Cell Dysfunction

Other results presented at the ESC Congress by the same group used patient sera to test endothelial cell responses in vitro. Human coronary artery endothelial cells (HCAECs) exposed to sera from patients with INOCA and CMD demonstrated higher apoptosis, reduced viability, and increased release of eEVs compared with no-CMD controls.² After empagliflozin treatment, these effects were significantly attenuated.

Notably, sera collected post treatment reduced both the concentration and size of eEVs, lowered VCAM-1 expression in supernatant and cell lysates, and decreased mitochondrial reactive oxygen species staining.

“Sera from INOCA patients with CMD has an increased capacity to induce EnD compared to no-CMD controls and this capacity is reduced following SGLTi treatment,” the researchers concluded. “These results suggest SGLT2is may target the underlying mechanisms of disease (EnD and CMD) in INOCA patients.”

Together, the pilot trials highlight empagliflozin’s potential to directly influence mechanisms of EnD in patients with INOCA and CMD. Although limited by small sample size and short follow-up, the results provide early evidence that SGLT2 inhibition may improve vascular health beyond its established benefits in diabetes and heart failure.

References

1. Tapp DN, Tipler P, Ashokprabhu N, et al. Empagliflozin significantly reduces circulating markers of endothelial dysfunction in ischemia with non-obstructive coronary arteries (INOCA) and coronary microvascular dysfunction: a pilot trial. Presented at: ESC Congress 2025; August 30, 2025; Madrid, Spain. https://esc365.escardio.org/presentation/305790
2. QuesadaO, TappDN, Tipler P, et al. Empagliflozin significantly reduces the capacity of sera to induce endothelial dysfunction in ischemia non-obstructive coronary arteries (INOCA): EMbArk phase II pilot trial. Presented at: ESC Congress 2025; August 29, 2025; Madrid, Spain. https://esc365.escardio.org/presentation/305756