Combination of traditional Chinese medicine and PDE5i for diabetic erectile dysfunction: a systematic review and meta-analysis of randomized controlled trials

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Combination of traditional Chinese medicine and PDE5i for diabetic erectile dysfunction: a systematic review and meta-analysis of randomized controlled trials

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Although phosphodiesterase type 5 inhibitors (PDE5i) have a therapeutic effect on diabetic erectile dysfunction, its therapeutic effect is not as good as that of non-diabetic population. In recent years, several randomized controlled trials(RCTs) found that the therapeutic effect of traditional Chinese medicine(TCM) combined with PDE5i on diabetic erectile dysfunction may be better than that of PDE5i alone, and we now conduct a systematic review and meta-analysis of these studies. We searched China national knowledge internet (CNKI), Wanfang database, Pubmed, and Embase database. Mean difference (MD) or pooled odds ratio (OR), as well as their 95% confidence intervals (CIs) were calculated. Risk bias tool was used to evaluate the quality of RCTs included in the meta-analysis. Publication bias was estimated by Begg’s funnel plots and Egger’s test. Results of this systematic review and meta-analysis revealed that the change in the IIEF-5 score of TCM + PDE5i group was significantly higher than that of PDE5i group(MD = 3.6, 95% CI [2.34, 4.86]). The clinical efficacy of TCM + PDE5i group was significantly higher than that of PDE5i group(OR = 2.86, 95% CI [1.83, 4.48]). Furthermore, the sexual satisfaction of TCM + PDE5i group was significantly higher than that of PDE5i group (OR = 3.07, 95% CI[1.63, 5.80]). There was no significant difference of the number of adverse events between TCM + PDE5i group and PDE5i group(OR = 0.93, 95% CI [0.49,1.78]). According to the meta-analysis, compared with using PDE5i alone, the regimen combined TCM plus PDE5i has more advantages in terms of IIEF-5, efficiency, and sexual satisfaction, with no increase in adverse effects for erectile dysfunction in patients with type 2 diabetes mellitus. More strict and larger sample size RCTs are needed to verify the findings of this meta-analysis.

Health sciences/Health care/Therapeutics/Drug therapy/Combination drug therapy

Health sciences/Diseases/Metabolic disorders

Traditional Chinese medicine

PDE5 inhibitor

erectile dysfunction

diabetes mellitus

Men's normal sexual function is an important part of good quality of life and the cornerstone for maintaining a harmonious relationship between husband and wife. The male sexual dysfunction mainly includes premature ejaculation and erectile dysfunction. Erectile dysfunction is a disease that males can not have an erection or maintain enough time for sexual intercourse¹. Penile erection is a very delicate and complex process, which requires the joint action of nerves, psychology, blood vessels, endocrine hormones, smooth muscle, etc. When the human body appears sexual impulse under sexual stimulation, the cavernous nerve terminals will release neurotransmitters, which will lead to the release of relaxing factors by endothelial cells, and then the vascular smooth muscle in the cavernous body will relax, and the blood flow to the sponge body will increase rapidly, resulting in penile erection. Any link error in the process will lead to erectile dysfunction². Generally, erectile dysfunction can be divided into organic erectile dysfunction and psychological erectile dysfunction³. At present, the most common drug for the treatment of erectile dysfunction is this as phosphodiesterase 5 inhibitors (PDE5i)^4–6.

In recent years, with the improvement of economy and living standards, as well as the change of diet structure, the number of type 2 diabetic patients increased year by year⁷. In 2019, the number of type 2 diabetic patients in China is about 116.4 million, and the number of type 2 diabetic patients over 65 years old reaches 35.5 million, ranking first in the world. Epidemiological statistics showed that the proportion of erectile dysfunction in type 2 diabetic men was significantly higher than that in non diabetic men⁸. The mechanism of erectile dysfunction caused by diabetes involves many aspects, such as endothelial cell dysfunction, vascular and nerve injury, hypogonadism and inflammatory factors^9,10. Although PDE5i has therapeutic effect on diabetic erectile dysfunction, its therapeutic effect is not as good as that of non-diabetic population^11–13. In recent years, researchers find that the therapeutic effect of traditional Chinese medicine(TCM)combined with PDE5i on diabetic erectile dysfunction may be better than that of PDE5i alone, however, their research results are not completely consistent, and the number of patients included in these studies is small. Therefore, we now conduct a systematic review and meta-analysis of these studies.

Study search

The present study was conducted in accordance with the PRISMA guidelines. We searched China national knowledge internet (CNKI), Wanfang database, Pubmed, and Embase database. The searching words included: “erectile dysfunction”, or “sexual dysfunction”, or “impotence”, or “sexual impotence”; and “diabetes”, or “diabetes mellitus”, or “glycuresis”, and “Chinese traditional medicine”, or “Chinese medicine”, or “Chinese herbal medicine”, or “Chinese patent medicine”; and “sildenafil”, or “vardenafil”, or “tadalafil”, or “phosphatase 5 inhibitors”, or “PDE5i”, “PDE5 inhibitor”. There are no language and race restrictions in all literature searches.

Study Selection

The two researchers independently screened the literatures that met the inclusion criteria. The criteria of inclusion is: i, patients included in the clinical study should be diagnosed with erectile dysfunction and type II diabetes mellitus; ii, research type should be randomized controlled trial(RCT); iii, the experimental group was given traditional Chinese medicine plus PDE5i, while the control group was only given PDE5i; iv, the comparison results of the two groups should at least include 5-item version of the international index of erectile function (IIEF-5)¹⁴, or clinical effective rate. The exclusion criteria: i, the included patients were diagnosed with erectile dysfunction, but without type 2 diabetes mellitus; ii, the control group was given PDE5i and other drugs; iii, there was no appropriate research data available.

Quality Assessment And Data Extraction

Two researchers collected the following data: study design, publishing date, name of the first author, research area, number of experimental group, number of control group, PDE5i name, treatment strategy of experimental group, treatment strategy of control group, treatment duration, outcome measure, and adverse effects of drugs. Risk bias tool was used to evaluate the quality of RCTs included in the meta-analysis. Blinding method, allocation concealment, selective reporting, generation of sequence, and incomplete data were evaluated; each item was graded as “yes”, “no”, and “unclear”.

Meta-analysis Methods

Mean difference (MD), or pooled odds ratio (OR), as well as 95% CIs were calculated. The heterogeneity of all included studies was analyzed by using Q-test. The Mantel-Haenszel random model was performed when I² > 50% (considered as heterogeneous), otherwise, the Mantel Haenszel fixed model was performed. Publication bias was estimated by Begg’s funnel plots and Egger’s test. A value of “Pr>|z|” lower than 0.05 for Begg’s funnel plots or a value of “P>|t|” lower than 0.05 for Egger’s test was considered positive publication bias. The meta-analysis was conducted using the RevMan (V5.4) and Stata(V16).

The detailed characteristics of the 13 included studies in the present meta-analysis

198 literatures were retrieved by searching CNKI, Wanfang database, Pubmed, and Embase database. We then identified 17 studies by reading the title and abstract of these literatures. On the basis of reading the full text, 4 studies were excluded for the lack of available data. At last, 13 studies were included in the meta-analysis^15–27, including 464 patients in the TCM + PDE5i group and 464 patients in PDE5i monotherapy group. The flow diagram of study research, identification and inclusion was shown in Fig. 1. All 13 studies were randomized controlled trials and were conducted in China. Baseline data are shown in Table 1. The quality evaluation of the included studies was shown in Fig. 2 and Fig. 3.

Table 1

Baseline data of included studies.
First author	Publication year	Study design	Research area	Number of experimental group	Number of control group	PDE5 inhibitor	Treatment duration	Outcome measure	Side effects of drugs
Xianrui Li	2022	RCT	China	41	41	Tadalafil	4 weeks	IIEF-5,Clinical efficacy	NR
Song Sun	2021	RCT	China	33	33	Tadalafil	4 weeks	IIEF-5,Clinical efficacy	NR
Xiaoyue Jia	2021	RCT	China	41	41	Sildenafil	8 weeks	IIEF-5,Clinical efficacy	NR
Mingjian Peng	2020	RCT	China	20	20	Tadalafil	4 weeks	Clinical efficacy	Diarrhea, and headache
Enshi Luo	2019	RCT	China	32	32	Tadalafil	12 weeks	IIEF-5, Success rate of vaginal insertion, success rate of sexual intercourse	NR
Jianzhong Wang	2019	RCT	China	31	31	Tadalafil	4 weeks	IIEF-5,Sexual satisfaction, Frequency of sexual intercourse per week	Dyspepsia, headache, mild nausea
Zhigang Yang	2019	RCT	China	30	30	Sildenafil	8 weeks	IIEF-5,Sexual satisfaction,Clinical efficacy	None
Xiawei Fei	2017	RCT	China	35	35	Sildenafil	4 weeks	IIEF-5,Sexual satisfaction	Nausea, stomach discomfort, flushed face
Hao Yang	2017	RCT	China	60	60	Sildenafil	4 weeks	IIEF-5,Sexual satisfaction,Clinical efficacy	NR
Zhijun Jiang	2017	RCT	China	36	36	Sildenafil	1 months	Clinical efficacy	NR
Chao Jiang	2016	RCT	China	40	40	Tadalafil	4 weeks	IIEF-5, Clinical efficacy	Mild nausea, dyspepsia, mild skin allergy
Youjie Zhang	2016	RCT	China	30	30	Sildenafil	4 weeks	IIEF-5, Clinical efficacy	Mild diarrhea, transient mild headache
Hua Zhou	2015	RCT	China	35	35	Tadalafil	8 weeks	IIEF-5, Erectile time and hardness of penis at night	Flushed face,stuffy nose
NR = not reported, RCT = Randomized controlled trial, TCM = traditional Chinese medicine

IIEF-5

There were 11 studies investigating IIEF-5. This result was influenced by heterogeneity (I² = 91%), and so a random model was used. Meta-analysis results revealed that the change in the IIEF-5 score of TCM + PDE5i group was significantly higher than that of PDE5i group (MD = 3.60, 95% CI [2.34, 4.86],shown in Fig. 4). This result suggested that combination of TCM and PDE5i can significantly improve IIEF-5 compared with PDE5i monotherapy.

Clinical Efficacy

There were seven studies investigating the incidence of clinical efficacy. There was no heterogeneity (I² = 0%), and so a fixed-effect model was used. Meta-analysis results(shown in Fig. 5) showed that the clinical efficacy of TCM + PDE5i group was significantly higher than that of PDE5i group(OR = 2.86, 95% CI [1.83, 4.48]). This result suggested that combination of TCM and PDE5i has better clinical efficacy compared with PDE5i monotherapy.

Sexual Satisfaction

There were three studies investigating sexual satisfaction. There was no heterogeneity (I² = 0%), and so a fixed-effect model was used. Meta-analysis results (sown in Fig. 6)showed that the sexual satisfaction of TCM + PDE5i group was significantly higher than that of PDE5i group (OR = 3.07, 95% CI[1.63, 5.80]). This result suggested that combination of TCM and PDE5i can significantly improve sexual satisfaction compared with PDE5i monotherapy.

Adverse Events

In the final statistical analysis, five RCTs reported the adverse events(shown in Table 1). There was no heterogeneity (I² = 0%), and so a fixed-effect model was used. There was no significant difference of the number of adverse events between TCM + PDE5i group and PDE5i group(OR = 0.93, 95% CI [0.49,1.78], shown in Fig. 7).

Publication Bias

Begg’s funnel plots and Egger’s test were conducted to assess the publication bias among the included studies. Begg’s test(P = 0.119)as well as Egger’s test༈P = 0.575༉found no publication bias in our meta-analysis for IIEF-5(the funnel plot was shown in Fig. 8). The results of Egger’s and begg’s test on clinical efficacy, sexual satisfaction and adverse events using the same method indicated that the differences were not statistically significant. To sum up, there was no significant bias in the included data.

Sensitivity Analysis

Sensitivity analysis was performed to determine the impact of each study data on the final outcomes. There were no significant differences in overall pooled ORs and MDs, regardless of which study was deleted(shown in Fig. 9).

Erectile dysfunction refers to the inability of the penis to maintain enough rigidity and enough time to complete satisfactory sexual intercourse. Penile erection is a physiological reaction under the joint participation of many factors. With the deep research on penile erection in medicine, it is believed that penile erection is a process of hemodynamic evolution under the combined effect of nerve, blood vessel, endocrine, social psychology and other factors. With the change of living environment, the increase of work pressure, absence of physical exercise, insufficient sleep, sub-healthy status, and the change of dietary structure, the incidence of erectile dysfunction is increasing year by year, and more and more young men also suffer from erectile dysfunction^28,29. Erectile dysfunction has seriously affected men's marital relationship, quality of life, mental health, as well as all-cause mortality, and formed a vicious circle.

With the improvement of living standard and the change of diet and lifestyle, the incidence rate of type 2 diabetes is increasing. Although the use of oral hypoglycemic drugs and insulin keeps blood glucose within normal range, diabetes still causes damage to peripheral vascular endothelium and nerves. Diabetes is one of the factors causing erectile dysfunction, and the severity of erectile dysfunction is positively correlated with the course and severity of diabetes³⁰. The pathogenesis of erectile dysfunction in male diabetic patients is more complex than that in non diabetic men. Endothelial dysfunction, and diabetic neuropathy caused by diabetes mellitus are the factors causing erectile dysfunction, of course, there are many other unknown mechanisms. Endothelial dysfunction makes an important contribution to the pathophysiological process of type 2 diabetes mellitus with erectile dysfunction. It will affect the release of NO, reduce the activity of endothelial nitric oxide synthase (eNOS), lead to the reduction of the bioavailability of endothelial NO and induce oxidative stress. The reduction of the bioavailability of NO and oxidative stress is the key pathogenic process for the development of erectile dysfunction³¹. The process of penis erection is controlled by the nervous system, so neuropathy is also one of the causes of erectile dysfunction caused by diabetes³². Long term hyperglycemia causes hyperglycemia toxicity and the increase of oxygen free radicals, leading to neuropathy in the body, hindering the nerve conduction pathway that controls the penis, and further causing damage to the vascular intestinal peptidergic, cholinergic, adrenergic and other nerve fibers that control the penis cavernous body, resulting in penile vein leakage. The long-term hyperglycemic environment will affect the hormone secretion of the hypothalamus- pituitary- gonad secretory axis of the body, reduce the secretion of gonadotropin and pituitary follicle stimulating hormone, further reduce the number of testicular mesenchymal cells and change their morphology, thus affecting erectile function³³. Type 2 diabetes can affect sexual desire by reducing the level of androgen in the body, leading to erectile dysfunction. A randomized controlled trial proved the view that abnormal hormone levels lead to decreased sexual function. When the total testosterone level (TT) is ≤ 8nmol/L, testosterone undecanoate can produce significant effects and improve the erectile function of diabetic patients with erectile dysfunction³⁴.

PDE5 inhibitors are the most commonly used drugs in the treatment of erectile dysfunction, and its effective rate can reach 70% in patients with non-diabetic erectile dysfunction^35,36. However, to our disappointment, the effective rate of PDE5 inhibitors in patients with diabetic erectile dysfunction is only about 50%^2,37,38. The combination of drugs may provide a new direction for the treatment of diabetic erectile dysfunction³⁹. Chinese medicine is the crystallization of the wisdom of Chinese ancestors. According to Chinese medicine, the human body needs to harmonize Yin and Yang. In fact, the effect of TCM on erectile dysfunction and premature ejaculation is very significant⁴⁰. Through animal experiments and cell biology experiments, we have preliminarily identified the mechanism of TCM. TCM is able to reduce the incidence of vascular endothelial injury and vascular protection^41,42. It also has an effect on improving diabetic peripheral neuropathy, and improving peripheral nerve conduction velocity^43,44. In addition, it is able to promote gonadal development, enhance the activity of NOS, increase the production of NO and its metabolites, and increase the content of serum total testosterone, so as to better promote erection⁴⁵. In recent years, researchers find that the therapeutic effect of TCM combined with PDE5i on diabetic erectile dysfunction may be better than that of PDE5i alone, however, their research results are not completely consistent, and the number of patients included in these studies is small. Therefore, we now conduct a systematic review and meta-analysis of these studies.

In the present study, 13 studies were included in the meta-analysis, including 464 patients in the TCM + PDE5i group and 464 patients in PDE5i monotherapy group. The meta-analysis results suggested that combination of TCM and PDE5i can significantly improve IIEF-5 as well as sexual satisfaction compared with PDE5i monotherapy. Furthermore, combination of TCM and PDE5i has better clinical efficacy compared with PDE5i monotherapy.

There are several limitations of our study. Firstly, the available evidence is limited to a short period of use of the drug, no longer than 12 weeks. The short follow-up did not allow for detection of serious or rare treatment-emergent adverse events. Secondly, most of the included studies have a small sample size. Thirdly, although all included studies are RCTs, some of them have not specially described the methods, such as blinding, randomization, therefore, the quality of these studies are low. We need more high quality RCTs to verify our findings.

In conclusion, according to the meta-analysis, compared with using PDE5i alone, the regimen combined TCM plus PDE5i has more advantages in terms of IIEF-5, efficiency, and sexual satisfaction, with no increase in adverse effects for erectile dysfunction in patients with type 2 diabetes mellitus. More strict and larger sample size RCTs are needed to verify the findings of this meta-analysis.

Acknowledgments

Funding:

This study was supported by Shaoxing Health Science and Technology Project（Grant Number:2022KY012）

Conflict of interest:

None

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There is NO conflict of interest to disclose.

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Combination of traditional Chinese medicine and PDE5i for diabetic erectile dysfunction: a systematic review and meta-analysis of randomized controlled trials

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Abstract

Figures

Introduction

Method

Study search

Study Selection

Quality Assessment And Data Extraction

Meta-analysis Methods

Results

The detailed characteristics of the 13 included studies in the present meta-analysis

IIEF-5

Clinical Efficacy

Sexual Satisfaction

Adverse Events

Publication Bias

Sensitivity Analysis

Discussion

Conclusion

Declarations

References

Additional Declarations

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