Vericiguat improves MRI-assessed coronary endothelial function in patients with metabolic syndrome or type 2 diabetes mellitus

Background/Introduction Patients with diabetes or the metabolic syndrome are at increased risk for coronary artery disease, in part due to impaired endothelial-derived nitric oxide (NO) bioavailability. NO stimulates soluble guanylate cyclase (sGC), which through downstream signaling leads to phosphorylation of proteins with anti-atherosclerotic properties and alters smooth muscle calcium handling, resulting in vascular relaxation. We have previously shown that coronary endothelial function (CEF) can be assessed noninvasively by MRI as the change in coronary artery cross-sectional area (CSA) during isometric handgrip exercise (IHE), an endothelial NO–dependent stress. A CSA increase of ≥ 5% is indicative of normal CEF, whereas reduced vasodilation or vasoconstriction reflects abnormal CEF. We hypothesized that vericiguat, a direct sGC sensitizer and stimulator, would enhance downstream sGC signaling in settings of reduced NO bioavailability and thereby improve CEF in patients with diabetes or the metabolic syndrome (Figure). Purpose To learn whether vericiguat improves MRI-assessed CEF in patients with diabetes or the metabolic syndrome and baseline coronary endothelial dysfunction. Methods We conducted a randomized, double-blind, placebo-controlled study in 32 patients randomized 2:1 to vericiguat or placebo and assessed CEF by measuring the %-change in CSA from rest to that during IHE. The MRI studies were performed at baseline prior to randomization and six weeks following study drug titration to 10 mg/day, or a lower, maximally tolerated dose. Results Mean(SD) age was 60.6 (8.6) years, 40.6% were women, 13% were Black individuals, 40% had diabetes and 91% had the metabolic syndrome. There were no group differences in baseline clinical characteristics or CEF. In the placebo group, there was a non-significant change in CSA accompanying IHE from that measured at baseline to that at follow-up (-7.4 ± 8.5% to +1.4 ± 12.6%; p = 0.0512). In contrast, CSA during IHE in the vericiguat group increased from -6.8 ± 6.7% to +3.1 ± 8.5%; p = 0.0002. Because PCSK9 inhibitors and GLP-1 receptor agonists may impact CEF and confound the results a sequential sensitivity analysis was performed. After excluding participants who initiated or increased a GLP-1R agonist (n=6) or initiated a PCSK9 inhibitor (n=3) there was no significant change in the placebo group (-5.4 ± 9.4% to -5.1 ± 8.8%; p = 0.862, n=7) and a significant increase in the vericiguat group (-6.3 ± 6.5% to +1.7 ± 8.6%; p = 0.0048, n=16). In a multivariable regression model achieved vericiguat dose was independently associated with greater improvement of CEF (β = 6.34; 95% CI 0.01-12.67; n=32, p = 0.0497). There were no significant group differences in adverse events. Conclusion(s) Vericiguat improved MRI-assessed CEF in patients with diabetes or the metabolic syndrome providing the first in vivo human evidence that direct stimulation of sGC enhances CEF.