Phosphodiesterase type 5 inhibitors combined with traditional Chinese medicine for diabetes mellitus-induced erectile dysfunction: A systematic review and meta-analysis

The Abstract
Diabetes mellitus-induced erectile dysfunction (DMED) presents a multifaceted and challenging pathophysiological landscape, frequently leading to suboptimal therapeutic responses when conventional phosphodiesterase type 5 inhibitors (PDE5I) are employed as monotherapy. A promising strategy to potentially augment treatment efficacy involves the synergistic combination of PDE5I with traditional Chinese medicine (TCM) interventions. However, a comprehensive synthesis of the existing evidence supporting this combined therapeutic approach has been conspicuously absent. Therefore, the primary objective of this systematic review and meta-analysis was to rigorously compare the efficacy and safety profiles of PDE5I combined with TCM against PDE5I monotherapy in the comprehensive management of individuals afflicted with DMED.

Background
Diabetes mellitus is a chronic metabolic disorder that can lead to a wide array of complications, including significant microvascular and macrovascular damage. Among the many debilitating consequences, erectile dysfunction (ED) is a particularly prevalent and distressing complication for men with diabetes, often referred to as diabetes mellitus-induced erectile dysfunction (DMED). The pathophysiology of DMED is complex and multifactorial, involving endothelial dysfunction, impaired nitric oxide (NO) signaling, peripheral neuropathy, autonomic neuropathy, smooth muscle dysfunction, and psychological factors. This intricate etiology often renders conventional pharmacological interventions, such as phosphodiesterase type 5 inhibitors (PDE5I), less effective in DMED patients compared to their non-diabetic counterparts. While PDE5Is like sildenafil and tadalafil are the first-line pharmacotherapy for ED by enhancing NO-mediated relaxation of penile smooth muscle, their efficacy in DMED patients is frequently suboptimal, leading to a significant unmet clinical need. Traditional Chinese medicine (TCM) has been utilized for centuries in the management of various chronic diseases, including male sexual dysfunction. TCM principles emphasize a holistic approach, often involving herbal formulations tailored to specific patient syndromes, aiming to restore balance and harmony within the body. Given the complex nature of DMED, which involves multiple pathophysiological pathways, the integration of TCM with its diverse pharmacological actions, alongside conventional PDE5I therapy, has emerged as a potentially synergistic strategy. This combined approach aims to address the multifaceted causes of DMED more comprehensively than either therapy alone. However, despite the growing interest in integrative medicine, a robust and systematic synthesis of the evidence regarding the efficacy and safety of combining PDE5I with TCM for DMED management has been lacking. Therefore, a critical evaluation through a systematic review and meta-analysis is essential to provide high-level evidence for clinical decision-making. Such an analysis would consolidate existing randomized controlled trials (RCTs), assess their quality, and quantitatively determine the comparative benefits and risks of this combination therapy versus PDE5I monotherapy in DMED patients.

Methods
To achieve the stated objectives, a rigorous systematic review and meta-analysis was meticulously conducted, adhering strictly to the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement. The protocol for this review was prospectively registered in the International Prospective Register of Systematic Reviews (PROSPERO) database under registration number CRD42021240608, ensuring transparency and reproducibility. A comprehensive and systematic search strategy was developed and executed across six prominent electronic databases: PubMed, the Cochrane Library, Web of Science, China National Knowledge Infrastructure Database (CNKI), Wanfang Data, and the VIP Science Technology Periodical Database. This extensive search encompassed all relevant studies published up to May 10, 2024, utilizing appropriate keywords and MeSH terms related to diabetes mellitus, erectile dysfunction, phosphodiesterase type 5 inhibitors, and traditional Chinese medicine. The inclusion criteria for studies were strictly defined to encompass only randomized controlled trials (RCTs) that directly compared the efficacy and safety of a combination therapy involving a phosphodiesterase type 5 inhibitor plus traditional Chinese medicine against phosphodiesterase type 5 inhibitor monotherapy in patients diagnosed with diabetes mellitus-induced erectile dysfunction. A critical criterion for patient inclusion was an International Index of Erectile Function-5 (IIEF-5) score of 21 or less, ensuring that only individuals with clinically significant erectile dysfunction were included. Two independent reviewers meticulously screened titles and abstracts, followed by full-text review, to identify eligible studies, resolving any discrepancies through consensus or consultation with a third reviewer. Data extraction from the included RCTs was performed independently by two reviewers using a standardized form to capture essential information, including study characteristics, patient demographics, interventions, outcome measures, and adverse events. The risk of bias for each included study was thoroughly assessed using the Cochrane Collaboration’s tool for assessing risk of bias in randomized trials, which evaluates selection bias, performance bias, detection bias, attrition bias, reporting bias, and other biases. Statistical analyses were performed using RevMan 5.3 software. For dichotomous outcomes, such as clinical efficacy, relative risks (RR) with 95% confidence intervals (CI) were calculated. For continuous outcomes, including IIEF-5 scores and TCM syndrome scores, standardized mean differences (SMD) with 95% CI were employed, particularly when different scales or measurement units were used across studies. Statistical heterogeneity across studies was evaluated using the Chi-squared test and I-squared statistic; an I-squared value greater than 50% or a P-value less than 0.1 was considered indicative of significant heterogeneity. In cases of low heterogeneity, a fixed-effects model was utilized, while a random-effects model was adopted when significant heterogeneity was detected, to provide a more conservative estimate of the effect size. Publication bias was assessed using funnel plots where appropriate, particularly for outcomes with a sufficient number of included studies. The primary outcomes of interest included overall clinical efficacy (typically defined by an improvement in erectile function, often based on IIEF-5 scores or patient global assessment), changes in IIEF-5 scores, changes in TCM syndrome scores (which reflect the severity of specific symptoms according to TCM diagnostic principles), and the incidence of adverse events.

Results
A comprehensive and rigorous search strategy yielded a total of twelve randomized controlled trials (RCTs) that met all pre-defined inclusion criteria, collectively enrolling a substantial cohort of 1070 participants afflicted with diabetes mellitus-induced erectile dysfunction (DMED). A pooled analysis of these studies revealed that the combination therapy of phosphodiesterase type 5 inhibitors (PDE5I) with traditional Chinese medicine (TCM) demonstrated a statistically significant and clinically meaningful improvement in overall clinical efficacy when compared to PDE5I monotherapy. The meta-analysis calculated a relative risk of 2.86, with a 95% confidence interval ranging from 2.13 to 3.84, and a P-value of less than 0.001, unequivocally indicating the superior effectiveness of the combined approach. Further granular insights were obtained through subgroup analyses focusing on the specific type of PDE5I used. For patients receiving tadalafil in combination with TCM, there was a significantly higher improvement in International Index of Erectile Function-5 (IIEF-5) scores, with a standardized mean difference (SMD) of 1.07 (95% CI [0.85, 1.30], P < 0.001). Similarly, when sildenafil was combined with TCM, the improvement in IIEF-5 scores was also profoundly significant, yielding an SMD of 1.38 (95% CI [1.11, 1.65], P < 0.001). These results consistently highlight the benefit of adding TCM to both commonly used PDE5I agents. Beyond the standard erectile function assessment, the combination therapy also demonstrated a substantial positive impact on TCM syndrome scores. These scores, which quantify the severity of specific symptoms based on traditional Chinese medical diagnostic principles, significantly decreased with combination therapy. Specifically, the tadalafil + TCM subgroup showed an SMD of -3.43 (95% CI [-3.93, -2.94]), and the sildenafil + TCM subgroup exhibited an SMD of -1.40 (95% CI [-1.77, -1.03]), indicating a marked reduction in the characteristic TCM-defined symptom profiles associated with DMED. Crucially, the safety profile of the combination therapy was comparable to that of PDE5I monotherapy. A thorough analysis of adverse event rates, including commonly reported side effects such as dizziness, gastrointestinal effects, and facial flushing, revealed no statistically significant differences between the combination therapy group and the PDE5I alone group, with all P-values exceeding 0.05. This finding suggests that the enhanced therapeutic benefits of combining PDE5I with TCM do not come at the cost of increased adverse reactions, which is a vital consideration for clinical applicability.

Conclusion
This comprehensive systematic review and meta-analysis unequivocally demonstrates that the strategic combination of phosphodiesterase type 5 inhibitors (PDE5I) with traditional Chinese medicine (TCM) offers superior efficacy in significantly improving both erectile function, as measured by standardized indices like the IIEF-5, and the specific symptom profiles characterized by TCM diagnostic frameworks in patients suffering from diabetes mellitus-induced erectile dysfunction (DMED). Crucially, this enhanced therapeutic benefit is achieved without concurrently increasing the incidence or severity of adverse events, thereby indicating a favorable risk-benefit profile for the combined approach. However, it is imperative to acknowledge certain inherent limitations that may influence the generalizability and robustness of these findings. These limitations include, but are not limited to, a notable variability in the specific TCM formulations utilized across the included studies, which often encompass diverse herbal compounds and dosages, making direct comparisons challenging. Furthermore, there was considerable variation in the treatment durations across the trials, potentially influencing the long-term effects and sustainability of the observed improvements. Additionally, several trials exhibited unclear or inadequate blinding protocols, particularly regarding the blinding of participants and outcome assessors, which could introduce performance or detection bias and potentially inflate observed effects. The heterogeneity stemming from these factors necessitates a cautious interpretation of the findings. Consequently, to definitively validate the optimal regimens, clarify long-term outcomes, and establish the broader applicability of these promising results, there is a pressing need for future high-quality, meticulously designed randomized controlled trials with standardized TCM formulations, consistent treatment durations, and rigorous blinding methodologies.

Key Concepts
The key concepts explored within this study are centered on the intricate condition of diabetes mellitus-induced erectile dysfunction (DMED), emphasizing its complex pathophysiology and the limitations of conventional monotherapy. Central to the investigation are phosphodiesterase type 5 inhibitors (PDE5I), Enpp-1-IN-1 which represent the standard pharmacological approach for erectile dysfunction. A significant focus is placed on the potential synergistic role of traditional Chinese medicine (TCM) as an adjunctive therapy. The research employs robust meta-analytical techniques to synthesize evidence from randomized controlled trials, comparing clinical efficacy and safety outcomes. Essential outcome measures include the International Index of Erectile Function-5 (IIEF-5) scores and TCM syndrome scores, alongside the monitoring of adverse events.