The Effect of Phosphodiesterase-type 5 Inhibitors on Erectile Function: An Overview of Systematic Reviews

Abstract

Background: Multiple systematic reviews explore the effect of phosphodiesterase type 5 (PDE5) inhibitors on erectile dysfunction (ED), with each study addressing specific outcomes. However, physicians and policymakers require a holistic approach of this topic.Objective: To summarize the current evidence regarding the efficacy and safety of PDE5 inhibitors for the management of ED through an overview of systematic reviews.Methods: Studies were identified by searching PubMed, Web of Science, Cochrane Library and Scopus databases, as well as sources of grey literature until June 12, 2021 (PROSPERO: CRD42020216754). We considered systematic reviews, meta-analyses or network meta-analyses of randomized trials that provided outcomes about the efficacy and safety of any approved PDE5 inhibitor (avanafil, sildenafil, tadalafil and vardenafil). We constructed forest plots for meta-analytic effects regarding the change in erectile function, adverse events and dropouts after administration of PDE5 inhibitors in the general population and in specific patient groups.Results: We included 23 studies with 154,796 participants and a total of 258 meta-analytic effects. Sildenafil 25 mg [Weighted Mean Difference (WMD): 13.08, 95% Confidence Interval (CI): 10.1-16.06] seemed to be statistically superior to all interventions in improving erectile function compared to placebo, but studies with low-dose sildenafil are lacking. Moreover, comparing among different PDE5 inhibitors, sildenafil 50 mg or sildenafil 100 mg were considered the most effective compounds in the general population. The latter derived, however, predominantly from indirect comparisons among different PDE5 inhibitors. Still, sildenafil 100 mg was associated with more treatment-related adverse events and dropouts. Interestingly, low-dose daily tadalafil may be more effective than high-dose on-demand tadalafil (WMD: 1.24, 95% CI: 0.03-2.44). Furthermore, testosterone and PDE5 inhibitors in patients with ED and hypogonadism seem to further improve symptoms, while the addition of a-blockers in patients with urinary symptoms treated with PDE5 inhibitors does not provide additional benefits (WMD: −0.8, 95% CI: −1.65-0.06).Conclusion: Although the efficacy and safety of PDE5 inhibitors, compared to placebo, is well-documented, the existing evidence comparing different PDE5 inhibitors is low. Therefore, high-quality, head-to-head, trials comparing different PDE5 inhibitors are necessary to determine their ideal dosage and formulation based on their safety and efficacy profile.Systematic Review Registration: PROSPERO, identifier [CRD42020216754].

The Effect of Low-Intensity Shock Wave Therapy on Moderate Erectile Dysfunction: A Double-Blind, Randomized, Sham-Controlled Clinical Trial

“…In particular, most patients with moderate ED opt for PDE5 inhibitors and initially respond well to oral treatment. 17 However, in many cases these patients develop severe ED due to progression of the underlying ED pathophysiology. 18 Therefore, patients with moderate ED may be an ideal population for the application of regenerative treatment modalities in an attempt to delay ED progression.…”

Reporting guideline for overviews of reviews of healthcare interventions: The Preferred Reporting Items for Overviews of Reviews (PRIOR) Explanation & Elaboration

“…All analyses were undertaken using Microsoft Excel (Version 16.42) and R statistical software (version 3.6.3)." (75) CERTAINTY ASSESSMENT Item 14. Describe the methods used to collect data on (from the systematic reviews) and/or assess certainty (or confidence) in the body of evidence for an outcome.…”

Phosphodiesterase‐5 Inhibitory Activity of Canthin‐6‐One Alkaloids and the Roots ofEurycoma longifoliaandEurycoma harmandiana

“…Tadalafil, a commercialized β ‐carboline drug well‐known drug for erectile dysfunction treatment, has been reported to inhibit phosphodiesterase‐5 (PDE‐5) by competitively binding with it at the catalytic active site [5] . Tadalafil has a 4‐fold longer half‐life than sildenafil (tadalafil; 17.5 h, sildenafil; 4 h), and affects sexual stimulation 30 min to 36 h after drug administration [6] .…”

“…[4] Tadalafil, a commercialized β-carboline drug wellknown drug for erectile dysfunction treatment, has been reported to inhibit phosphodiesterase-5 (PDE-5) by competitively binding with it at the catalytic active site. [5] Tadalafil has a 4-fold longer half-life than sildenafil (tadalafil; 17.5 h, sildenafil; 4 h), and affects sexual stimulation 30 min to 36 h after drug administration. [6] The modified structure of tadalafil, a piperazine-dione ring formed by the hydantoin ring of sildenafil, is up to 9000 times more selective for PDE-5 compared with the other PDE-5 inhibitor drugs.…”