Shuai Chen,Shuqin ZhengLiaoning University of Traditional Chinese Medicine,Shenyang,Liaoning 003,China.Affiliated Hospital of Liaoning University of Traditional Chinese Medicine,Shenyang,Liaoning 003,China.

Abstract Objective To evaluate the clinical efficacy and safety of Wendan decoction in the treatment of diabetic gastroparesis(DGP).Methods PubMed,MEDLINE,The Cochrane Library,Embase,China Biology Medicine(CBM),Chinese National Knowledge Infrastructure(CNKI),China Science and Technology Journal Database(VIP)and Wanfang databases were searched and eligible randomized controlled clinical trials(RCTs)were included.The quality of the RCTs was evaluated by the Cochrane risk of bias assessment tool,and data analysis were performed with Review Manager 5.3.Results A total of 7 studies were included,including 533 patients.Meta analysis results showed that the effective rate of Wendan decoction in the treatment of diabetic gastroparesis was better than that of the control group[RR=1.30,95%CI(1.20,1.40),P＜0.001],and the improvement of fasting blood glucose(FBG)was better than that of western medicine[MD=-0.43,95%CI(-0.91,-0.01),P=0.05].The recurrence rate in the TCM treatment group was lower than that in the western medicine group[RR=0.29,95%CI(0.13,0.62),P=0.002].Conclusion Compared with western medicine,Wendan decoction has better curative effect on DGPand can reduce its recurrence rate.However,due to the low quality of the included literatures and the possibility of bias,large-scale and high-quality RCTs are still needed for further confirmation.

Keywords:Wendan decoction;Diabetic gastroparesis;Effectiverate;Symptoms;Meta-anaysis

Introduction

According to foreign literatures,about 30%～60%of patients with type I diabetes have gastrointestinal motility disorders[1],and about 10%～20%of patients with type 2 diabetes have gastroparesis[2].Severe cases may increase the risk of hypoglycemia,which is related to death.Diabetic gastroparesis(DGP)is characterized by low gastric motility and delayed emptying.Clinical common symptoms contain postprandial fullness,anorexia,nausea,vomiting,epigastric discomfort,diarrhea or constipation,and so on[3].The pathogenesis of DGPis relatively complex,which has much to do with many factors,such as immune associated anomalies, neuropathy,gastrointestinal hormone disorder,smooth muscle lesion,the ICC damage,microvascular damage and sex hormones[4].The specific mechanism is not fully clear presently.The western medicine treatment of DGPmainly include prokinetics,anti-nausea drugs and surgical treatment,which is on the basis of controlling blood sugar.But the side effects of western medicine and drug resistance are obvious,and the disease can't bewell controlled.

According to the TCM,the location of DGP is mainly in the stomach and closely related to the spleen.The deficiency of spleen Qi and loss of function of transportation and transformation are the root causes of the disease[5].If the function of governing rising and falling of Qi in spleen and stomach is disorder,Qi will be stagnant and dampness get accumulated,resulting to form phlegm.Then after a long time,the phlegm will generate endogenous heat,leading to the complex mechanism of the disease,which characterized by the co-existence of cold and heat.Therefore,DGP has symptoms of Qi stagnation,dyspepsia and turbid sputum.Treatment methods should contain tonifying spleen and moistening dryness,removing heat-phlegm,and regulating qi-flowing for harmonizing stomach.Chen yan of Song dynasty,on the work of S anyin Ji Yi Bingzheng Fang Lun,improved Wendan decoction and acquire the effects of regulating qi-flowing for harmonizing stomach,tonifying spleen and moistening dryness, and removing heat-phlegm, which is consistent with the pathogenesis of DGP.Zabing Yuan Liu Xi Zhuo·Zhongzhang Yuan Liu recorded:Distention and fullness is caused by spleen disease;the asthenia of spleen Qi causes Qi depression and Qi can not move down,resulting in the fullness of stomach;the main reasons of the above results are insufficiency of splenogastric Qi(leading to the losing function of transportation and transformation),dyspepsia,phlegm and dampness-heat."The above theory also provides a theoretical basis for the treatment of DGPwith Wendan decoction.But it is still controversial on the efficacy of Wendan decoction in DGP due to the poor quality of current clinical trials.Therefore,we performed the present meta-analysis to assess the effectiveness of Wendan decoction for DGP so as to provide guidance for clinical application.

Materialsand methods

Inclusion criteria

Types of participants:(1)All the involved participants were diagnosed as diabetes according to the diagnostic criteria established by American Diabetes Association(ADA)and World Health Organization(WHO).(2)All the participants meet the diagnostic criteria of gastroparesis according to Guidelines for clinical management of gastroparesis issued by American journal of gastroenterology in 2013:①Delayed gastric emptying;②symptoms of gastroparesis,including anorexia, nausea, early fullness,vomiting,abdominal distension,and so on;③excluding the organic lesion of the pylorus[2].The age,sex,course of disease and source of cases of patientsarenot limited.

Types of interventions: Patients in the experimental group were given Wendan decoction alone or Wendan decoction combined with prokinetic drugs;patients in the controlled group were given prokinetic drugs alone.The interventions of the two group were both on the routine treatment of diabetes.There is no limitation in the drug dosage and frequency.

Outcomes: Primary outcomes: (1) Total effective rate.The efficacy criteria was as follows:①Obvious effect:symptoms were significantly improved or disappeared,or the gastric peristalsis was normal,or the gastric emptying time returned to normal or significantly shortened than before treatment;no significant gastric dilatation was found in the gastroduodenal barium meal examination; gastroscope or barium meal examination showed gastric peristalsis and the gastric emptying was normal②Effective:symptoms improved,or normal gastric peristalsis,or gastric emptying time returned to normal or shorter than before treatment;gastroscopy or barium meal examination showed increased gastric peristalsis and shorter gastric emptying time than before.③Inefficacy:no improvement or even worsening of clinical symptoms,no changes in gastric peristalsis and emptying revealed by gastroscope or upper gastrointestinal barium meal examination.(2)Gastric emptying rate(3)Fasting blood-glucose(FBG).Secondaryoutcomes including recurrence rate and incidence of adversereactions.

Types of studies:RCTs,whether adopting blind methods or allocation concealment,with the language of Chineseand English.

Exclusion criteria

(1)Non-RCTs(2)RCTs with pre-and post-control study(3)Case reports or summary of experience without statistic analysis(4)The experimental group include a variety of treatment methods,such as Wendan decoction combined with acupuncture or acupoint application,emotion and psychological intervention,and so on(5)Repeated published data.

Searching strategies

The retrieval was performed in the following databases from January,2000 to December,2018:Cochrane Library,Pubmed,MEDLINE,The Cochrane Library,Embase,CBM,CNKI,VIPand the Wanfang Database.Retrieval terms include“diabetes”,“gastroparesis”,“Wendan decoction”.References of important articles retrieved weremanually searched.

Literature Selection and Data Extraction

Relevant literatures from all databases were collected according to the above searching strategies.Endnote software was utilized to filter the duplication.The title and abstract of the articles were carefully examined to make the preliminary screening to exclude the studies that do not meet criteria.Then the full text was continued to be reviewed for further confirmation.The following information was collected in this meta-analysis:the first author's name,publication year,baseline data of patients,intervention,course of treatment,and the data of outcomes.

The assessment of methodological bias risk

The methodological bias risk of all studies was evaluated by using the Cochrane evaluation handbook of RCTs(5.1.0).The bias risk indices were the random sequence generation,the allocation concealment,the blinding of participants,data integrity,the selective reporting and the other bias.Each item was judged on three levels such as low risk of bias,high risk of bias and unclear risk of bias.

Statistical analysis

The meta-analysis was performed using Review Manager(RevMan)5.3.P＜0.05 was considered to be statistically significant.The chi-square test was applied to evaluate heterogeneity among studies,and I2was used to show the magnitude of this heterogeneity.Results of P≥0.1 and I2≤50%suggested a lack of significant heterogeneity;the fixed-effect model was used accordingly.For cases with P＜0.1 and I2＞50%,we adopted a random-effect model,and subgroup analysis was presented to explore the sources of heterogeneity.Funnel plots were used to reveal the potential publication bias.

Results

Search results

Initially,70 potentially relevant articles were retrieved, which were all Chinese articles,including 50 from CNKI,7 from VIP,4 from Wanfang databases and 9 from CBM.34 articles were included after cancel the repeated ones.Then the titles and abstracts were read to reject the 20 irrelevant studies.Finally,7 articles,including 533 patients,were included for this meta-analysis after reviewing full texts.The flow diagram in Figure 1 illustrates the selection process.The characteristics of the included trials are shown in Table 1.

The risk of methodological bias

None of the trials provided the detailed informations about the allocation concealment and blinding of the participants.No absence of data and no selective reporting existed(Figure 2).

Outcomes

Total effective rate

All the 7 studies had been included in the analysis,and the experimental groups and control groups involved 272 and 261 cases,respectively.We made heterogeneity test and found that there was no statistical heterogeneity among the 7 trials(P=0.91, I2=0%).Therefore, the data was calculated by using a fixed-effects model.The result showed that the experimental group could increase the RR, and the difference was statistically significant[RR=1.30,95%CI(1.20,1.40),P＜0.001],indicating that Wendan decoction could improve the effective rate of DGP(Figure 3).

Then we performed subgroup analysis according to the interventions.In five studies[7-11],the experimental group patients were given Wendan decoction alone and patients in the control group were given western medicine.In the subgroup analysis of the five studies,we found that Wendan decoction can increase the effective rate compared with the control group[RR=1.26,95%CI(1.15,1.38),P＜0.001].The experimental group patients in another two studies[12,13]were given Wendan decoction and western medicine,and the analysis suggested that Wendan decoction plus western medicine were also had higher effective rate than western medicine alone[RR=1.41,95%CI(1.18,1.67),P=0.0001](Figure 4).

Figure 1.Flowchart of literature search

Tables 1 The basic characteristics of the included studies

Figures2 Risk of bias summary

Figures3 Forest plot of the total effective rate

FBG

Two studies[7,11]adopted the FBG as one index of side effects,including 175 cases.There was no statistical heterogeneity(P=0.72,I2=0%)and the fixed effect model was implemented.Meta-analysis revealed that the FBG of Wendan decoction groups was lower than control group and the statistically significant difference was detected between two groups[MD＝-0.43,95%CI(-0.91,-0.01),P=0.05](Figure 5).

Recurrence rate

Two studies[7,8]reported recurrence rate in the two groups,including 174 patients.There was no statistical heterogeneity among the 2 trials(P=0.02,I2=0%)and the fixed-effects model was performed.Meta-analysis revealed that compared with the control group,Wendan decoction can reduce the recurrence rate of diabetic gastroparesis, the statistically significant difference was detected between these two groups[RR=0.29,95%CI(0.13,0.62),P=0.002](Figure 6).

Publication bias

The publication bias analysis was performed and the funnel plots were asymmetrical,indicating that there was publication bias in the included studies(Figure 7).

Discussion

In this study,we evaluated the clinical efficacy and safety of Wendan decoction and western medicine in the treatment of DGP.According to the strict inclusion and exclusion criteria,7 RCTs were eventually included.The meta-analysis results showed that the Wendan decoction or Wendan decoction plus western medicine group was superior to the western medicine group in the aspects of total effective rate,recurrence rate and FBG improvement rate.At present,the commonly used western medicine in the treatment of DGPis domperidone,which is a kind of selective peripheral dopamine D2 receptor antagonist.Domperidone can directly act on the stomach dopamine receptor to enhance gastric motility and inhibit lower esophageal sphincter tension.But long-term ingestion or overdose of domperidone can lead to serum prolactin level increasing,lactation and gynecomastia[15].Mosapride will improve esophageal motility and the lower esophageal sphincter muscle tension to prevent the gastric contents back into the esophagus and enhance the scavenging function of the esophagus.However,mosapride can also cause mild tiredness,dizziness,loose stools,mild abdominal pain,etc.,with the incidence of about 5% [16].Trimebutine has bidirectional regulation effect on gastrointestinal smooth muscle,and are effective on gastrointestinal motility disorder,such as diarrhea and constipation.But trimebutine can lead to thirsty,mouth numbness,borborygmus,constipation,tachycardia,drowsiness,dizziness,headache,rash and other adverse reactions[17].Comparing to the above side effects of western medicine,the traditional Chinese medicine can be adjusted according to the symptoms of patients and reduce adverse reactions.

Figure 4 The subgroup analysis of total effective rate

Figures 5 Forest plot of FBG

Figures6 Forest plot of recurrence rate

Figure 7 The funnel plots of the meta-analysis

Wendan decoction was first recorded in JiYan Fang written by Sengyuan Yao in the South and North Dynasty of China.Wendan decoction mentioned in our study comes from Sanyin Fang·The ninth volume·Xufan Zheng Zhi and Sanyin Fang·The tenth volume·Jingji Zheng Zhi and the components mainly include Pinellia Ternata,Bamboo Shavings,Fructus Aurantii Immaturus,Pericarpium Citri Reticulatae,and Poria Cocos.In the Wendan decoction,Pinellia Ternata has the property of acrid and warm,which can regulate Qi and midsection,just as recorded in Ben Cao Hui Yan;Pericarpium Citri Reticulatae has function of strengthening spleen-stomach and regulating Qi;Poria Cocos has the effect of clearing damp and promoting diuresis;Fructus Aurantii Immaturus can depress Qi and eliminate epigastric fullness;Bamboo Shavings not only has unique functions of depressing Qi and preventing emesis,but also can clear heat,promote Qi circulation and relieve depression;Ginger and Jujube can act commonly to strengthen the spleen and stomach.From the composition of Wendan decoction,the prescription take"regulating Qi and resolving phlegm"as the main therapeutic effect,which is consistent with the basic pathogenesis of DGP.In addition,from the perspective of drug combination,the results of the study on the law of drugs for DGP based on data mining indicate that the usage frequency of combination of Pinellia Ternata and Poria Cocos,Pinellia Ternata and Liquorice,Pericarpium Citri Reticulatae and Poria Cocos,Pinellia Ternata and Pericarpium Citri Reticulatae,Liquorice and Poria Cocos,rank the second,forth,fifth,eighth and ninth respectively,and all combination amount to more than forty.From the perspective of single herbs,the usage frequency of Pinellia Ternata,Pericarpium Citri Reticulatae,Poria Cocos,Liquorice and Fructus Aurantii Immaturus,are 71,57,64,60,32,23 respectively.From the data mining records,among the top five herbs in frequency,four herbs are from Wendan decoction except Atractylodes Macrocephala Koidz.

Meanwhile,Wendan decoction has significant effect on phlegm-heat diabetes.In modern society,people usually increase intake of unhealthy diet,such as fat,sweet,strong food,which gradually lead to the disorder of transportation and the obstruction of phlegm-damp.In addition,with the quickening pace of modern life and the increasing professional competition,people are usually under great pressure and in the condition of different degree depressive mood,usually causing the stagnation of Qiactivity in body.Due to the above reasons,phlegm and Qi both in the state of stagnation,gradually to form phlegm-heat diabetes,which should be treated through the method of regulating Qi,clearing heat and eliminating phlegm.From the composition of Wendan decoction,it conforms to the pathogenesis and therapeutical principle of phlegm-heat diabetes.Pinellia Ternata combines with Bamboo Shavings to act together to eliminate phlegm-heat.According to the theory of“regulating Qi before eliminate phlegm;phlegm will be removed after Qi get unobstructed”,Fructus Aurantii Immaturus,as the powerful qi-regulating drug,is used to disentangle Qi depression and further to dissolve phlegm.Pericarpium Citri Reticulatae has the function of regulating Qi,drying damp and dissipating phlegm,which can assist Pinellia Ternata to eliminate phlegm and strengthen the effect of Fructus Aurantii Immaturus.Poria cocos can regulate the source of phlegm,that is the spleen,so as to treat phlegm fundamentally.Ginger and Jujube was used to reconcile epigastrium and reinforce the spleen,leading to water-dampness run unobstructed.The whole decoction simultaneously has the functions of eliminating phlegm,regulating Qi and clearing heat,ultimately make the symptoms of diabetes relieved.

There were some limitations in this study.Firstly,the quality of the seven RCTs enrolled in this study was not high.Most RCTs did not refer to the specific random grouping method,and the allocation concealment were not clear as well.Secondly,the studies enrolled were all from the Chinese databases,resulting in a source of selection bias.Thirdly,these patients involved were given different drug dosages and courses,which increased the heterogeneity between the groups.The future studies about Wendan decoction treating DGP should focus on the standardized objective outcome indicators and decreasing the methodological bias risk.In addition,it is necessary to combine with the characteristics of TCM,and future studies can be carried out from the aspects of improvement of physiological and biochemical indexes,the modified method,dosage and treatment course of Wendan decoction,so as to provide high-quality RCTs for further verification.