Soluble Guanylate Cyclase Stimulators and Activators: Novel Therapies for Pulmonary Vascular Disease or a Different Method of Increasing cGMP?

Abstract

Pulmonary arterial hypertension (PAH) is a progressively worsening disorder characterized by increased pulmonary vascular resistance leading to increased afterload, right ventricular hypertrophy, and ultimately right heart failure and death. Current pharmacologic treatments primarily act to reduce pulmonary vascular resistance (PVR) and provide some benefit but do not cure PAH. Canonical vasodilator therapy involving the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cGMP pathway has demonstrated efficacy, but in pathologic states, endothelial dysfunction within the pulmonary vasculature leads to the reduced synthesis and bioavailability of NO. Acting downstream of NO, sGC stimulators and activators restore the endogenous functions of NO and exploit the positive effects of sGC stimulation on various organ systems, including the heart. Riociguat (BAY 63-2521) is the first agent in a class of sGC stimulators to receive FDA approval for the treatment of PAH and chronic thromboembolic hypertension (CTEPH). Riociguat has demonstrated significant benefit as assessed by 6MWD, PVR, N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, time to clinical worsening, World Health Organization (WHO) functional class, and other quality of life measures in clinical trials as a monotherapy and in combination with endothelin receptor antagonists or non-intravenous prostanoids. Riociguat is the first FDA-approved treatment option for inoperable or persistent CTEPH and adds a new effective drug to available treatment options for pulmonary hypertension (PH). The question of whether riociguat is superior to other available treatment options is unanswered at the present time and requires further study.

A focus on riociguat in the treatment of pulmonary arterial hypertension

“…An increase in 6MWD of 50 m after the first year and 47 m after the second year has been found . After 1 and 2 years, the survival on riociguat was 97% and 93%, respectively . In the SUPER‐2 trial, on long‐term sildenafil use, the 2‐year survival was estimated to 88% .…”

“…It is a haem mimetic binding and replacing endogenous haem in sGC. The drug is, like riociguat, lacking specificity for the pulmonary vasculature and is furthermore not approved for the treatment of PAH, 15 but sGC activators might have future potential in the treatment of PAH. In Europe, the incidence and prevalence of PAH have been estimated to 5-10/million/y and 15-60/million.…”

“…42 After 1 and 2 years, the survival on riociguat was 97% and 93%, respectively. 15,42 In the SUPER-2 trial, on long-term sildenafil use, the 2-year survival was estimated to 88%. 42 Comparisons between trials should be made with caution, but survival on riociguat seems slightly better than on sildenafil.…”

Effect of Riociguat and Sildenafil on Right Heart Remodeling and Function in Pressure Overload Induced Model of Pulmonary Arterial Banding

“…The Nitric Oxide- (NO-) cyclic guanosine monophosphate (cGMP) pathway plays a major role in the cardiovascular system [ 7 , 8 ]. NO activates soluble guanylate cyclase (sGC) to generate the second messenger cGMP, which is in turn degraded and thereby deactivated by phosphodiesterases (PDEs), like PDE 5.…”

Nitric oxide–sensitive guanylyl cyclase stimulation improves experimental heart failure with preserved ejection fraction

“…Such stimulators are currently under investigation as a potential treatment for HFpEF (19,24). With riociguat, the first NOsGC stimulator has been approved for the treatment of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) in 2013 (25).…”