Vericiguat Improves MRI-Assessed Coronary Endothelial Function in Patients with the Metabolic Syndrome and Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Study

Aims Impaired coronary endothelial function (CEF) is an early manifestation of coronary atherosclerosis and contributes to the development and progression of the disease. In patients with diabetes or the metabolic syndrome, diminished nitric oxide (NO) signaling may impair CEF. We evaluated whether pharmacologic stimulation of the nitric oxide–soluble guanylate cyclase (NO–sGC)–cyclic guanosine monophosphate (cGMP) pathway with vericiguat, which stimulates sGC and improves the sensitivity of sGC to NO, improves CEF assessed non-invasively by magnetic resonance imaging (MRI). Methods and Results In this prospective, randomized, double-blind, placebo-controlled trial, 34 participants with metabolic syndrome or type 2 diabetes mellitus and impaired CEF were randomized to vericiguat (n = 23) or placebo (n = 11). Thirty-two participants (21 vericiguat and 11 placebo) completed baseline and follow-up MRI assessment of CEF, quantified as the percentage change in coronary artery cross-sectional area (CSA) from the value at rest to the one during isometric handgrip exercise. Baseline demographic, clinical, and imaging characteristics were similar between groups. CEF improved significantly with vericiguat, with the mean ± SD stress-induced change in CSA increasing from −6.8 ± 6.7% at baseline to +3.1 ± 8.5% at follow-up (within-group P = 0.0002). In contrast, CEF in the placebo-treated participants demonstrated a smaller, and non-significant improvement (−7.4 ± 8.5% to +1.4 ± 12.6%; within-group P = 0.051). Findings remained consistent after exclusion of participants initiating or intensifying GLP-1 receptor agonists or PCSK9 inhibitors. In multivariable analysis, achieved vericiguat dose was independently associated with improved coronary endothelial function (β = 6.34; 95% confidence interval 0.01–12.67; P = 0.0497). Adverse events were similar between the two groups. Conclusion Vericiguat significantly improved MRI-assessed coronary endothelial function in patients with metabolic syndrome or type 2 diabetes and baseline coronary endothelial dysfunction. These findings provide direct in vivo evidence that pharmacologic stimulation of the NO–sGC–cGMP pathway improves coronary vasoreactivity and support MRI-derived coronary endothelial function as a promising translational imaging biomarker for evaluating vascular-targeted therapies.