Treatment Selection in Pulmonary Arterial Hypertension: Phosphodiesterase Type 5 Inhibitors versus Soluble Guanylate Cyclase Stimulator

Abstract

Pulmonary arterial hypertension is a chronic and life-threatening disease that if left untreated is fatal. Current therapies include stimulating the nitric oxide–soluble guanylate cyclase (sGC)–cyclic guanosine monophosphate axis, improving the prostacyclin pathway and inhibiting the endothelin pathway. Phosphodiesterase type 5 inhibitors, such as sildenafil, and the sGC stimulator riociguat are currently used in the treatment of pulmonary arterial hypertension. This article discusses the similarities and differences between phosphodiesterase type 5 inhibitors and sGC stimulator based on pharmacological action and clinical trials, and considers which is better for the treatment of pulmonary arterial hypertension.

Novel Insights Regarding Nitric Oxide and Cardiovascular Diseases

“…In PAH, therapeutic strategies aimed to restore or potentiate the NO/cGMP pathway have received considerable attention. 138,139…”

“…In PAH, therapeutic strategies aimed to restore or potentiate the NO/cGMP pathway have received considerable attention. 138,139 Phosphodiesterase type 5 is highly expressed in the pulmonary vasculature and evidence showed an upregulation of this cGMP hydrolyzing enzyme in PAH. 138 Therefore, PDE5 inhibitors are primarily indicated to treat PAH, and among the 4 approved drugs (avanafil, sildenafil, tadalafil, and vardenafil), tadalafil and tildenafil efficiently lowered pulmonary artery pressure, reduced vascular remodeling, and improved clinical outcome in patients (Table 2).…”

“…138,139 Phosphodiesterase type 5 is highly expressed in the pulmonary vasculature and evidence showed an upregulation of this cGMP hydrolyzing enzyme in PAH. 138 Therefore, PDE5 inhibitors are primarily indicated to treat PAH, and among the 4 approved drugs (avanafil, sildenafil, tadalafil, and vardenafil), tadalafil and tildenafil efficiently lowered pulmonary artery pressure, reduced vascular remodeling, and improved clinical outcome in patients (Table 2). 138 Indeed, in the SUPER-1 (Sildenafil Use in Pulmonary Arterial Hypertension) trial (NCT00644605), 278 naive PAH patients were treated with placebo or sildenafil for 12 weeks.…”

“…138 Therefore, PDE5 inhibitors are primarily indicated to treat PAH, and among the 4 approved drugs (avanafil, sildenafil, tadalafil, and vardenafil), tadalafil and tildenafil efficiently lowered pulmonary artery pressure, reduced vascular remodeling, and improved clinical outcome in patients (Table 2). 138 Indeed, in the SUPER-1 (Sildenafil Use in Pulmonary Arterial Hypertension) trial (NCT00644605), 278 naive PAH patients were treated with placebo or sildenafil for 12 weeks. 140 Sildenafil provided significant improvements in the 6-minute walk distance (6MWD) and pulmonary artery pressure versus placebo but with no difference in clinical worsening incidence.…”

Effectiveness and safety of endothelin receptor antagonists, alone and in combination therapy, in the pulmonary arterial hypertension‐connective tissue disease subtype: A systematic review and meta‐analysis

“…PDE5 is predominantly found in the pulmonary arteries and degrades cyclic guanylate monophosphate(cGMP). By preventing the breakdown of cGMP, PDE5i effectively enhances smooth muscle relaxation and vasodilation of the pulmonary arteries 15 . PDE5i may offer additional benefit through their effects on the right ventricle by improving contractility and cardiac output 16 .…”