Empagliflozin significantly reduces circulating markers of endothelial dysfunction in Ischemia with Non-Obstructive Coronary Arteries (INOCA) and coronary microvascular dysfunction: a pilot trial

Abstract Introduction Up to 70% of patients with angina undergoing invasive coronary angiography have Ischemia with Non-Obstructive Coronary Arteries (INOCA). Patients with endothelial dysfunction EnD and coronary microvascular dysfunction CMD have impaired myocardial blood flow and ischemia despite the absence of obstructive CAD, which is partially attributed to inflammation. Sodium Glucose Co-Transporter 2 inhibitors (SGLT2i’s) have remarkable cardiovascular benefits and reduce EnD. However, these effects have not been examined in an INOCA population with CMD. Methods Phase II open label pilot trial was conducted in INOCA patients (n = 7) with CMD treated with the SGLT2i Empagliflozin (EMPA, 10mg/daily) for 90 days. CMD was diagnosed with the invasive thermodilution method using adenosine and acetylcholine, excluding patients with diabetes or heart failure. We investigated change in circulating levels of inflammatory cytokines, ROS markers (plasma 8-isoprostane, myeloperoxidase – MPO and total MPO activity), antioxidants (total antioxidant capacity) and circulating levels of CD34+ repair endothelial microvesicles (eEVs) and inflammatory VCAM+ eEVs at baseline and 45-days following treatment. We also compared baseline samples to INOCA with no-CMD controls (n = 4) from stored samples. Results In an all-female cohort, mean age was 60 + 12 years (Table 1). Through the 45-day visit, there were two reported UTI’s, one vaginal yeast infection and one non-clinically significant decrease in GFR. INOCA patients with CMD had significantly upregulated levels of 9 proinflammatory cytokines (CRP, TNFα, IL1β, IL-6, ICAM-1, VCAM-1, E-Selectin, Thrombomodulin, VEGF) compared to no-CMD controls; and these levels were reduced following EMPA treatment (Fig 1A – 1D; 1F – 1J); and anti-inflammatory IL-10 was downregulated compared to non-CMD controls and increased with treatment (Fig. 1E). INOCA patients with CMD had elevated ROS markers and reduced antioxidant capacity compared to no-CMD controls, and these improved with treatment (Fig 1K – 1N). INOCA patients with CMD had significantly elevated total concentration of inflammatory eEVs (VCAM+) and reduced repair eEVs (CD34+) at baseline that improved with EMPA treatment (Fig. 1O – 1P). Conclusions In a cohort of INOCA patients, as compared to patients with no-CMD, patients with CMD had elevated circulating markers associated with EnD. 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. Figure 2