DOI: 10.1161/atvbaha.126.324735 ISSN: 1079-5642

Empagliflozin Improves Angina and Endothelial Dysfunction Indices in Angina and No Obstructive Coronary Arteries (ANOCA)

Danielle N. Tapp, Sukhleen Kaur, Olga Toleva, Paxson Tipler, Namrita Ashokprabhu, Pooja Acharya, Christian W. Schmidt, Leslie Korbee, Michelle Hamstra, Michael Tranter, Andreas Tzoumas, Ayushi Mohan, Shesh N. Rai, Dirk J. Duncker, John Beltrame, Steve Miner, C. Noel Bairey Merz, Timothy D. Henry, A. Phillip Owens, Odayme Quesada
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BACKGROUND:

Treatments targeting endothelial dysfunction in patients with angina and no obstructive coronary arteries (ANOCA) and coronary microvascular and vasomotor dysfunction (CMVD) are lacking. We evaluated the effects of SGLT2i (sodium-glucose cotransporter-2 inhibition) on angina, inflammatory and oxidative stress biomarkers, and endothelial dysfunction indices using a serum-induced in vitro model in ANOCA patients with CMVD. We conducted an open-label pilot trial of 11 ANOCA participants with CMVD diagnosed by invasive coronary function testing receiving empagliflozin (10 mg daily) for 90 days.

METHODS:

Angina (Seattle Angina Questionnaire), circulating inflammatory and oxidative stress biomarkers, and endothelial microvesicles (eEVs) were assessed from baseline to 45 and 90 days, and from 90 days to posttreatment discontinuation in a subset (N=5). A serum-induced in vitro model of human coronary artery endothelial cells was used to evaluate endothelial cell apoptosis, viability, eEV release, VCAM-1 (vascular cell adhesion molecule-1) expression, and mitochondrial reactive oxygen species. Stored serum from ANOCA patients without CMVD (controls, N=6) was compared with baseline samples.

RESULTS:

All trial participants had coronary endothelial dysfunction, with concomitant coronary microvascular dysfunction (55%), coronary spasm (54%), and microvascular spasm (18%). Empagliflozin significantly improved Seattle Angina Questionnaire summary scores by 14.0 (4.2–23.9) points at 90 days ( P <0.001). Compared with baseline, empagliflozin significantly reduced inflammatory cytokines, oxidative stress biomarkers, and inflammatory eEVs while increasing anti-inflammatory cytokines, antioxidants, and repair eEVs at 45 and 90 days; these effects rebounded after treatment discontinuation. Similarly, serum collected during empagliflozin treatment significantly reduced endothelial cell apoptosis, eEV release, VCAM-1 expression, and mitochondrial reactive oxygen species in vitro, with reversal of these effects at posttreatment discontinuation.

CONCLUSIONS:

In ANOCA participants with invasive coronary function testing confirmed CMVD, SGLT2i therapy produced clinically meaningful anti-anginal effects and reversed multiple indices of endothelial dysfunction, with rebound after treatment discontinuation. These findings support further evaluation in larger clinical trials.

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