Vericiguat, a Soluble Guanylate Cyclase Stimulator Approved for Heart Failure Treatment

Heart failure (HF) is an emerging, global epidemic associated with substantial morbidity and mortality. In recent years, significant advancements have been made in the development of pharmacotherapies that provide mortality benefits in HF. Research into the pathophysiology of HF with reduced ejection fraction (HFrEF) has identified significant abnormalities in the critical nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) cascade. In HFrEF, there is reduced NO bioavailability, impaired sGC activity, and upregulation of phosphodiesterase activity, all causing a significant decrease in cGMP, impairing vasodilation and increasing cardiac fibrosis and hypertrophy. Vericiguat, an sGC stimulator, was developed to potentially harness the therapeutic efficacy of this pathway. In a major clinical trial, vericiguat use in patients with HFrEF on guideline-directed medical therapy and recent worsening of HF resulted in a significant decrease in the composite of death from cardiovascular causes or first hospitalization for HF compared with placebo. Current American Heart Association guidelines recommend that in selected high-risk patients with HFrEF and recent worsening of HF already on guideline-directed medical therapy, initiation of the oral sGC stimulator vericiguat may be considered to reduce HF hospitalization and cardiovascular death. However, while vericiguat represents a major accomplishment in capitalizing on the therapeutic potential of the NO-sGC-cGMP pathway, there remain significant challenges regarding the personalization of therapy and identification of the phenotype of the HFrEF population that most benefits from vericiguat therapy. Further research is currently underway to identify vericiguat's potential role in the treatment of chronic stable HFrEF without recent worsening of HF.