Effects of Phosphodiesterase-5 Inhibitors on Mortality and Clinical Outcomes in Advanced Interstitial Lung Disease with Severe Impairment in Gas Exchange: A Systematic Review and Meta-Analysis

Why clinicians should know about it

• Picked for Pulmonary and Respiratory Medicine (paper of the day, 16 September 2026): Systematic review, PDE5I efficacy in advanced ILD
• Picked for Pharmacology (medical) (top studies of the week, 13 September 2026): Meta-analysis of PDE5I efficacy, no PK/PD focus

Abstract

PURPOSE: Given limited treatments for advanced interstitial lung disease (ILD), this updated study focuses strictly on phosphodiesterase 5 inhibitors (PDE5Is) efficacy exclusively in a clinically high-risk ILD subgroup, unlike prior meta-analyses that pooled diverse lung diseases or mixed vasodilator classes. METHODS: We systematically searched PubMed, Embase, and the Cochrane Library from inception to February 2026 to identify randomized controlled trials (RCTs) and observational cohort studies evaluating PDE5Is in advanced ILD. The primary outcome was all-cause mortality. The secondary outcomes were the St. George's Respiratory Questionnaire (SGRQ) score, forced vital capacity (FVC), B-type natriuretic peptide (BNP) levels, and serious adverse events. Effect sizes were pooled using random-effects models, and between-study heterogeneity was assessed using the I² and τ² statistics. FINDINGS: Six studies (including 3 RCTs) with a total of 1,800 patients were analyzed (759 patients in the PDE5Is group and 1,041 patients in the control group; 4 IPF and 2 generalized ILD studies). Overall, PDE5I therapy was not associated with a significant reduction in all-cause mortality, and substantial between-study heterogeneity was observed (HR 0.76, 95% CI 0.31-1.90; p = 0.56; I² = 96%). However, a subgroup analyses suggested a lower mortality point estimate in the clinically suspected or hemodynamically confirmed PH-targeted population (HR 0.51, 95% CI 0.37-0.71; p < 0.01; I² = 23%), whereas no significant mortality benefit was observed in the untargeted advanced ILD population (HR 1.11, 95% CI 0.33-3.72; p = 0.86; I² = 91%), though the subgroup interaction was statistically insignificant (p(interaction) = 0.23). Additionally, PDE5I therapy significantly improved SGRQ scores (-3.48; 95% CI -5.41 to -1.55; p < 0.001; I² = 0%) without significantly affecting FVC, BNP or serious adverse events (RR= 0.84; 95% CI 0.62-1.14; p = 0.27). IMPLICATIONS: Our findings show that PDE5I therapy was not associated with a statistically significant overall survival benefit in advanced ILD, although a favorable survival trend is observed within the clinically suspected or hemodynamically confirmed PH-targeted population. (HR 0.51, 95% CI 0.37-0.71). However, the absence of a statistically significant subgroup interaction indicates that this finding should be interpreted with caution.

Abstract as published, via PubMed.