The soluble guanylate cyclase stimulator riociguat: Evidence in pulmonary hypertension and beyond

Abstract

The soluble guanylate cyclase (sGC) stimulators riociguat and vericiguat elevate intracellular cyclic guanosine monophosphate (cGMP) levels via stimulation of the nitric oxide-sGC-cGMP pathway resulting in vasodilatory, anti-inflammatory, anti-proliferative, and anti-fibrotic effects. Riociguat is approved for the treatment of pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH). Placebo-controlled phase 3 trials in both indications demonstrated significant improvements in exercise capacity, functional class, and pulmonary hemodynamics, with sustained efficacy and good tolerability in long-term open-label extension studies. Pilot or phase 2 studies of riociguat in pulmonary hypertension associated with heart failure (HF) or chronic obstructive pulmonary disease showed improvements in some hemodynamic parameters, although riociguat is contraindicated in pulmonary hypertension associated with idiopathic interstitial pneumonias. Riociguat is undergoing trials in other conditions including diffuse cutaneous systemic sclerosis. Vericiguat, a novel once-daily sGC stimulator, is well tolerated in patients with HF and is undergoing a phase 3 trial in HF with reduced ejection fraction. These ongoing studies will clarify the roles of sGC stimulators in indications beyond PAH and CTEPH.