The efficacy and safety of Chinese herbal medicine combined withACEI/ARB for treatment of incipient diabetic nephropathy:Ameta-analysis

Qi-Yan Zheng,Wei-Jing Liu,2,3,Wei-Wei,Sun,2,Yao-Xian Wang,2,Hong-Fang Liu,2,Lu-Ying Sun,2

Co-first authors:Qi-Yan Zheng and Wei-Jing Liu contributed equally to this work.

1Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine,Beijing,100700,China;2Renal Research Institution,Beijing University of Chinese Medicine;Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing,Beijing,100700,China;3Zhanjiang Key Laboratory of Prevention and Management of Chronic Kidney Disease,Guangdong Medical University,Zhanjiang,Guangdong 524001,China

Abstract Objective:This meta-analysis evaluated the efficacy and safety of Chinese herbal medicine(CHM)combined with angiotensin-converting enzyme inhibitors(ACEIs)and/or angiotensin-receptor blockers(ARBs)for treatment of incipient diabetic nephropathy(IDN).Methods:Nine data bases were searched for randomized controlled trials of Chinese herbal medicine(CHM)and ACEI/ARB for treatment of IDN.Included articles were published between January2006 and December 2016.All studies were divided into prescriptions containing both Astragali Radix and Rehmanniae Radix(i subgroup),Astragali Radix(Huangqi)or Rehmanniae Radix(Dihuang)(ii subgroup),neither Astragali Radix nor Rehmanniae Radix(iii subgroup).Review Manager 5.3 was used for subgroup analysis.Results:In total,28 RCTs with 2017 patients were included.The results showed 1)the urinary albumin excretion rate(UAER)can be reduced significantly using CHM with ACEI or ARB for treatment of IDN compared to ACEI or ARB alone,and reduction of the UAER of the i subgroup was superior to that of the other two subgroups;2)serum creatinine(Scr)levels can be reduced significantly using CHM combined with ACEI or ARB,and reduction of Scr in the ii subgroup was superior to that in the iii subgroup;3)reduction of BUN in group A was not better than that in group B.Conclusion:In summary,CHMs combined with ACEI/ARB can decrease UAER and Scr significantly compared to the use of ACEI/ARB during IDN treatment.The effect was more significant in the CHM group containing Astragali Radix or Rehmanniae Radix.The application of Astragali Radix and Rehmanniae Radix should be emphasized in third stage diabetic nephropathy.

Keywords:Chinese herbal medicine;ACEI/ARB;Incipient diabetic nephropathy;Meta-analysis

Introduction

Diabetic nephropathy(DN)is a common complication of diabetes and has become an important clinical and public health challenge with the global epidemic of diabetes.According to the International Diabetes Federation,there were366 million people with diabetes in 2011,which is expected to increase to 552 million by 2030[1].It is the leading cause of end-stage renal disease requiring dialysis or transplantation in developed countries[2],as well as in some rapidly developing countries in Asia[3].In addition,diabetic nephropathy is associated with increased mortality due to cardiovascular disease.

The costs of diabetic nephropathy to individuals and society are considerable[4].Annual medical costs were 37% higher following progression from normoalbuminuria to microalbuminuria($7,424 vs.$10,188,respectively)and 41% higher following progression from microalbuminuria to macroalbuminuria($8,753 vs.$12,371,respectively)[5-7].Early treatment of diabetic nephropathy is important to improve health outcomes and reduce the societal burden of chronic kidney disease.

Incipient diabetic nephropathy(IDN),the third stage of diabetic nephropathy according to Mogensen,is known as microalbuminuria.In this phase,there is an increase of both systolic blood pressure(SBP)and diastolic blood pressure(DBP),and a loss of the nocturnal dip in blood pressure before progressing to microalbuminuria.Renal function may be increased,normal,or decreased.Effective intervention in this phase may prevent further decline in renal function.Other studies also show that intervention during IDN helps preserve renal function more effectively than intervention during overt diabetic nephropathy(ODN)[8].Without intervention,patients in the third stage of IDN have a much poorer prognosis and a much higher risk of progression to overt renal disease during the following decade than patients in other stages.Current therapy,including treatment for hyperglycemia,hypertension,and dyslipidemia,can slow the progression of DN.Control of blood pressure is particularly important,and the Western medicines that reduce blood pressure, including angiotensin-converting enzyme inhibitors(ACEIs)and angiotensin-receptor blockers(ARBs),have been shown to reduce albuminuria and delay the progression of diabetic kidney disease(DKD).It has become the standard treatment for albuminuric patients[9,10].However,in spite of the renoprotective effects of ACEI and ARB,DKD still progresses to end-stage renal disease(ESRD)in a large proportion of patients[11].Moreover,ACEIs and ARBs are unable to prevent the development of albuminuria in normotensive individuals with diabetes mellitus[12,13].Thus,there is an urgent need to find new effective agents to reduce or delay the progress of microalbuminuria in individuals with diabetes mellitus.The effects of currently used treatments must be maximized,and identification of new strategies and additional complementary and alternative therapies for treating IDN is imperative[14].

According to records,traditional Chinese medicine(TCM)has a history of more than 2000 years of treatment of diabetes mellitus[15,16]and DN[17].Today,Chinese herbal medicine is still widely used in DN treatment.Its effectiveness and safety encourage people to explore and promote it continually.In China,it is well known that CHM can produce remarkable results,and some CHMs have acquired expert consensus[18]and recommendations for reducing microalbuminuria[19,20].Apartfrom decoctions,administration of granules and capsules of Chinese herbal medicine are also increasingly popular.Moreover,there has been a considerable increase in the number of randomized controlled clinical trials(RCTs)examining the treatment of IDN using a combination of Chinese medicine,including herbal extracted products,Chinese patent medicine (CPM),and self-modified herbal formulation combination with ACEI/ARB.Therefore,a sensible systematic review of these trials is of great significance.More importantly,because the phenomenon of the same disease with different symptoms and the same disease with different symptoms are common in clinical，TCM diagnosis and treatment are complexity and diversity.Moreover,there are significant differences in ingredients,formulation,and categories of single herb and compound TCM treatment,and in the doses administered.All of these parameters may have different therapeutic effects.This review classified all cases in the literature into groups for subgroup analysis according to prescriptions of CHM containing either Astragali Radix or Rehmanniae Radix,both,or neither.Our present literature search indicated that the number of such publications has increased substantially since the previous meta-analyses.In light of this significant development,we conducted a new meta-analysis to provide new evidence-based proof for the treatment of IDN.

Materials and methods

Literature search

All studies published between 2006 and 2016 were identified using PubMed,EMBASE,the Cochrane Library,the Web of Science,the Chinese Biological Medicine Database (CBM),the China National Knowledge Infrastructure (CNKI) Database,the WanFang Digital Periodicals Database(WFDP),and the VIP Chinese journal database.In addition,relevant research articles in our school library were manually searched.The terms “early diabetic nephropathy,”“microalbuminuria diabetic nephropathy,”or“incipient diabetic nephropathy”were used as the subject;“Chinese herbal medicine,” “traditional Chinese medical practice,”“Chinese patent drug,”“Chinese herbs,”and “traditional Chinese medicine”were used as keywords. Studies included in previous meta-analyses were also considered.The reference lists from all identified studies were also scrutinized for additional reports.

Selection of studies for inclusion

The literature inclusion criteria were as follows:①All included patients met the definition of diabetic mellitus(WHO Diabetes Diagnostic Criteria 1999 or ADA Criteria of 1999),and the subjects were diagnosed with stage III IDN according to Mogensen staging(urinary albumin excretion rate of20-200μg/min or 30-300mg/24h) [21,22]; ② the experimental design was RCT;③intervention measures such as basic treatment,including diabetes education,diet,exercise,and control of blood glucose with hypoglycemic drugs or insulin were matched in the treatment and control groups;④there were available data for the prescribed outcomes of this study without language limitation;⑤the experimental group received orally administered CHM including decoctions,pills,granules,tablets,and capsules,plusACEI/ARB treatment,while the control group received ACEI/ARB treatment alone;⑥there was a clear course of treatment in both the experimental and control groups;⑦the basic conditions of the subjects,such as age,gender,duration of DN,basic treatment including diet,exercise,control of blood glucose with hypoglycemic drugs or insulin,and serum lipid level were matched in the treatment and control groups.

The literature exclusion criteria were as follows:①no clear diagnostic criteria or usage standards for the research subjects except the WHO and Mogensen21;②randomization was not mentioned or the study was not RCT;③lack of a clear course of treatment;studies with unavailable data or duplicate publications;⑤clinical trials of CHMs;⑥studies translated from foreign literature or duplicate publications;⑦use of Chinese medicine formulations that were not orally administered,such as milkvetch injections;⑧use of antihypertensive drugs other than ACEI/ARB or improved blood rheology during treatment;⑨patients with chronic diseases(chronic heart disease,liver disease,respiratory disease,tumor,autoimmunity disease,infectious disease)were excluded.

Data extraction and quality appraisal

Two assessors independently reviewed all studies.Eligible data were extracted,cross-checked,and entered into Review Manager software(RevMan 5.3,The Cochrane Collaboration,2014;The Nordic Cochrane Centre,Copenhagen,Denmark).Missing data were obtained from the principal investigators if possible.Any discrepancies were resolved by consensus after consultation and discussion with a third researcher.All authors were blinded to the identity of the study groups.Trials were assessed for methodological quality according to the Cochrane Collaboration as random sequence generation,concealment of allocation,blinding of participants and personnel,blinding of outcome assessment,incomplete outcome data,selective outcome reporting,and“other bias”[23].The following information was extracted from the selected studies:names of first and corresponding authors,publication year,published journal,gender of study population,IDN duration,number of enrolled subjects in the experimental and control groups,participant dropout and loss during follow-up,basic treatment including diet control,exercise,control of blood glucose with hypoglycemic drugs or insulin,intervention measures,control measures,and outcome indicators.

Statistical analyses

We conducted the meta-analyses using Review Manager(Rev Man)version 5.3.We combined risk ratios for dichotomous outcomes using the Mantel-Haenszel random effects model, which weighted studies according to the inverse of their variances,giving more weight to precise studies.Continuous outcomes were combined using inverse-variance random effects meta-analysis,calculating mean differences with 95%confidence intervals(CIs).Heterogeneity within studies was estimated using I2,the percentage of the total variation across studies due to heterogeneity rather than chance.I2 values of 25%,50%,or 75%were considered low,moderate,or high,respectively[24].All cases in the literature were divided into prescriptions containing both Astragali Radix and Rehmanniae Radix (i subgroup),Astragali Radix or Rehmanniae Radix(ii subgroup),or neither Astragali Radix nor Rehmanniae Radix(iii subgroup).Funnel plots were used to determine publication bias.It should be noted that funnel plot asymmetry could have causes other than publication bias[25].

Results

Results of literature retrieval

The initial search algorithm retrieved 674 studies(Figure 1).After excluding 413 irrelevant or duplicate articles by screening the title and then the title and abstract,the remaining 116 full-text articles were reviewed.Of them,88 additional studies were excluded due to lack of a clear course of treatment(n=22),unavailable data or duplicate publications(n=44),use of Chinese medicine formulations that were not orally administered,such as milk vetch injection,or articles without sufficient data(n=20).Our meta-analysis included 28 studies with a total of 2017 patients.

Computer randomization was reported in 5 articles[33,39,46,49,52].A random number table was reported in 10 articles

Figure 1.The initial search algorithm retrieved 674 studies

General characteristics of included literature

A total of 28 studies,comprising 1030 cases and 987 controls,fulfilled the inclusion criteria(Table 1).All of the included studies were conducted in the People’s Republic of China.The composition and efficacy of prescription of CHM literature included is detailed in Table 2.

Quality assessment

Although all 28 studies were RCTs,few provided detailed information on the randomization procedure,allocation concealment,or blinding of assessors,which made it difficult to assess all potential sources of bias.[27,28,32,35,38,43,47,49,51,53]and the rest did not report how to generate random grouping.Protocol blinding was described in 2 article[36,52].Blind evaluation of outcomes was not reported in any article.Research funding and conflicts of interest were mentioned in 5 articles[26,35,37,38,45].

Result of the systematic review and meta-analysis

A total of 19 studies[26-28,30,31,34-36,39,40,43-46,49-53]were conducted to compare the effects of CHM combined with ACEI or ARB(group A)with the effects of ACEI or ARB alone(group B)on UAER.Subgroup analysis was conducted according to CHM therapies containing Astragali Radix or Rehmanniae Radix.The heterogeneity among the three subgroups was I2=0%(χ2=0.21;P=0.55),indicating that there may be no heterogeneity.Meta-analysis of groups A and B included 19 studies and indicated high heterogeneity(I2=80%;χ2=88.21;P ＜ 0.001),so a random effects model was selected.The 19 studies(MD=-20.39;95%CI=-24.82--15.96)showed that the difference in groups A and B was significant(Z=9.03;P＜0.00001),which indicated that UAER can be reduced significantly by treatment with CHM combined with ACEIor ARB (group A)when compared with the control(group B).The combined MD values and 95%CIs of the three subgroups(i subgroup,ii subgroup and iii subgroup)were-22.58[-25.87--19.28],-21.25 [-25.90--16.61],and -17.41[-26.26--8.56],respectively(P＜0.001,P＜0.001,P=0.0001),suggesting that reduction of UAER of the subgroup receiving both Astragali Radix and Rehmanniae Radix was superior to the other two subgroups(Figure 3).

A total of 15 studies[28-30,32,35-38,43,46,49-53]compared the effects of group A with group B on Scr.Subgroup analysis was conducted according to the CHM ingredients; prescriptions contained Astragali Radix or Rehmanniae Radix,both,or neither.The heterogeneity between the subgroups was I2=0%(χ2=0.70;P=0.40),indicating that there may be no heterogeneity between the subgroups.The comparison between groups A and B included 15 studies,and showed that the included studies had no heterogeneity(I2=0%;χ2=7.56;P=0.91).A fixed effects model(MD=-1.88;95%CI=-3.45--0.31)showed that the difference between the two groups was significant(Z=2.25;P=0.02),indicating that Scr can be reduced significantly using CHM combined with ACEI or ARB compared with ACEI or ARB alone.The combined MD value and 95%CI of the two groups were-2.32[-4.19--0.45]and-0.85[-3.74--2.34],respectively(P=0.002;P=0.5),suggesting that reduction of Scr in the subgroup receiving Astragali Radix or Rehmanniae Radix was greater than reduction in the subgroup that did not receive CHM(Figure 4).

A total of 15 studies[28-30,32,33,37,38,45,46,48-53]were conducted to compare the effects of group A with group B treatments on BUN.Subgroup analysis was then conducted according to the CHM ingredients.The heterogeneity between the subgroups was I2=7.1%(χ2=2.15;P=0.34),indicating that there may be no heterogeneity among the three subgroups.Meta-analysis showed that the 15 studies had moderate heterogeneity(I2=50%;χ2=28.19.47;P=0.01).A random effects model was used for analysis.The results of 15 studies(MD=-0.18,95%CI=-0.39-0.03)showed that the difference in the two groups was not significant(Z=1.64;P=0.10),which indicated that treatment including CHM was not more effective for BUN reduction than treatment without CHM(Figure 5).

Adverse effects rate

A total of 6 studies[29,31,33,39,45,49]reported the adverse events that occurred in 17 treatment subjects and 12 control subjects.In the treatment group,3 cases of mild diarrhea[29,45],1 case of insomnia[33],5 cases of mild cough[39],2 cases of hacking cough caused by lotensin[45],and 6 cases of nausea occurred[31,49].In the control group,1 case of diarrhea[33],2 cases of dizziness[33],5 case of hacking cough caused by lotensin[39,45],and 3 cases of mild epigastric distention occurred[49];in 1 case,blood potassium levels increased[39].Meta-analysis of the treatment and control groups included 6 studies and showed that the included studies had no heterogeneity(I2=9%;χ2=5.45;P=36).A fixed effects model was selected for analysis.The results of the 6 studies(RR=1.37;95%CI=0.69-2.73)showed that the difference between the two groups was not significant(Z=0.90;P=0.37),indicating that the of the adverse effects rate in the treatment group was similar to that of the control group(Figure 6).

Publication bias

Funnel plot analysis for biases including publication bias showed some asymmetry(Figure 7).The source of this asymmetry maybe due to true heterogeneity related to differences in the methods of intervention and control.

Discussion

Diabetic nephropathy(DN)is a type of glomerular sclerosis caused by abnormal metabolism of diabetes.It is a widely recognized microvascular complication of diabetes and a leading cause of end-stage kidney failure worldwide,responsible for morbidity and mortality[54].Incipient Diabetic Nephropathy(IDN),the third stage according to Mogensen,often occurs 5-15 years after the initial diagnosis;symptoms include increased urinary albumin excretion(UAER)and a microalbuminuria range of 20-200 μg/min or 30-300 mg/24 h[55].Once UAER increases,it may be impossible to stop the progression of nephropathy completely;however,progression may be delayed.In addition to the use of approved medications for the treatment of diabetes mellitus,including intensive glycemic control and lifestyle modifications such as exercise,dietary restrictions,and blood pressure management[56-58],the reduction of urine protein and protection of kidney function become the great challenge for nephrologists.

Meta-analysis is an important research method in evidence-based medicine.High-quality meta-analysis part of evidence-based medicine.In this study,systematic review of the efficacy and safety of CHM combined with ACEI/ARB for treatment of IDN was performed.The results of the meta-analysis showed:1)UAER can be reduced significantly using CHM combined with ACEI or ARB when compared with ACEI or ARB alone;treatment with both Astragali Radix and Rehmanniae Radix was superior for reduction of UAER compared to other treatments;2)Scr can be reduced significantly using CHM combined with ACEI or ARB compared with ACEI or ARB alone;treatment with Astragali Radix or Rehmanniae Radix was superior to prescriptions without Astragali Radix or Rehmanniae Radix;3)the group A treatment was not more effective than the group B treatment for reduction of BUN.The evidence suggests that CHM combined with ACEI or ARB may better improve IDN control thanACEI orARB alone.

ACE inhibitors are already widely used in IDN clinical management,and increasing evidence suggests that microalbuminuric patients should be offered antihypertensive treatment(unless blood pressure is low)starting with an ACEI or ARB.A reduction in UAER (and blood pressure)is the primary test parameter of the treatment[59].The addition of an ACEI to the treatment program in advanced nephropathy can positively affect advanced renal disease and doubling of creatinine[60].Renal function,albuminuria,and blood pressure(including serum potassium)should be carefully monitored during ACEI therapy.

In China,CHM has been widely used in the treatment of diabetes and its complications for a long time[61];Chen J and Sun SL[62,63]concluded that diabetes and nephropathy are caused by Qi and Yin deficiency.Yin deficiency causes blood flow difficulty,and Qi deficiency leads to weak circulation.Deficiency of both causes extreme heat and blood stasis.Without treatment,these diseases gradually form a tiny lump of abdominal mass and settle on kidney collaterals,eventually progressing to DN.If dialectic treatment can be administered early,disease progression can be delayed.Many RCTs showed that the treatment of DN using CHM has an obvious curative effect on reduction of proteinuria,renal function maintenance,and delay of disease progression[64,65].The results of this study showed that UAER can be reduced significantly using CHM combined with ACEI or ARB compared to the control treatment.As UAER is a good clinical predictor of renal lesions in DN[66,67]and studies show that approximately 80%-90%of patients with albuminuria progress to more advanced stages[68],CHM combined with ACEI/ARB can more effectively delay the development of IDN.In addition,levels of Scr,generally considered a marker of renal function,were significantly decreased after treatment with CHM and ACEI/ARB compared to the control group.The decrease suggested nephroprotective action.In short,CHM in combination with ACEI/ARB had a positive effect on UAER and SCR levels,but did not have significant impact on BUN levels.Moreover,the subgroup analysis showed that CHM containing both Astragali Radix and Rehmanniae Radix(i subgroup)could reduce UAER more significantly than groups receiving CHM containing Astragali Radix or Rehmanniae Radix(ii subgroup)and CHM without Astragali Radix or Rehmanniae Radix(iii subgroup).Meanwhile,the ii subgroup had a better effectthan the iiisubgroup.Subgroup analysis revealed that Scr can be significantly decreased by CHM containing Astragali Radix or Rehmanniae Radix,but there was no significant difference between the CHM group withoutAstragali Radix or Rehmanniae Radix and the control.It should be emphasized that Astragali Radix,a widely used Qi tonifying and immunomodulating herb in CHM,has gradually been recognized as a possible complementary medication for the treatment of IDN.In modern research,various studies on DKD animals have demonstrated that Astragali Radix is capable of reducing albuminuria,improving renal function,and ameliorating pathological changes [69, 70].Additionally,Astragali Radix has an antifibrotic effect in a rat model[71]and enhancesrenal responses to atrial natriuretic peptides(ANP)in human adults[72].Rehmanniae Radix is also a common CHM used in DN that provides nourishing Yin and engendering fluid.A decoction made from Rehmanniae Radix was found to suppress advanced glycation end products induced by inflammation in vitro [73].According to the statistics included in the literature,IDN patients mostly exhibit Qi and Yin deficiency with blood stasis.The CHM treatment of IDN mainly focuses on replenishing the Qi and nourishing the Yin while promoting blood circulation;resolving stasis can be used to tone the entire body.Thus,the early use of Astragali Radix invigorated the Qi and Rehmanniae Radix nourished the Yin to improve the weak state of the early stages of diabetic nephropathy.Results reflected thatthey reduced proteinuria,protected renal function,and delayed the progression of disease.These findings suggest that CHM treatment in the early stages of DN can have a positive therapeutic effect,and the proper application of Astragali Radix and Astragali Radix may have a better effect in the early stages of diabetic nephropathy.

However,Li Ping et al.52 showed that the Tang Shen formula (ingredients: Astragali Radix,Rehmanniae Radix, Rhei Radix et Rhizoma,Notoginseng Radix etRhizoma,etc.) had no significant difference compared to the control group for treatment of IDN and decrease of UAER,but the clinical stage of the patient’s 24-hour urinary protein significantly decreased.This may illustrate that the mechanism of DN in early stages and clinical stages are not the same,so there are some treatment differences.Notoginseng Radix et Rhizoma and Rhei Radix et Rhizoma are primarily based on reducing excessiveness,and significantly affect the tonic effect of Astragali Radix and Rehmanniae Radix.Thus,early DN treatment should focus on reinforcing deficiency,particularly the therapeutic effect of invigorating the Qi and nourishing the Yin.This thought of the different treatments using in different stages provides guidance and a basis for clinical application.Of course,the method of tonifying deficiency supplementation and attack in IDN should also be investigated further.In addition,the early application of Astragali Radix and Rehmanniae Radix in CHM requires numerous RCTs for verification.A meta-analysis[74]suggested that patients with DKD stages III-IV who received Astragali Radix injections(derived from Astragali Radix.)experienced improved renal function and decreased proteinuria compared with controls.However,the advantages of Astragali Radix and Rehmanniae Radix in compound preparations are not available.Due to the complexity and variety of CHM prescriptions,the confirmation of the treatment effects requires strong evidence.

Our analysis has limitations.Publication bias is a concern in all meta-analyses.This study used only journal-published data.Negative studies are less likely to be published,potentially leading to overestimation of effects.Most of the trials were not of very high quality.All clinical trials involved included small samples without blinding methods,so their results may include uncertainties.In these cases,additional studies are necessary to establish true effect sizes.Moreover,this study did not recruit a sufficient number of participants that met the inclusion criteria.In addition,the short-term intervention of this study did not allow for the formation of definite conclusions of long-term effects of different treatments on DN progression.Moreover,the mechanisms underlying the efficacy of CHM have not been clarified.Finally,in different periods of diabetic nephropathy,patients’ clinical manifestations are not identical,and the methods that should be used must be further explored.More importantly,clinical trials of CHM in the treatment of IDN still lack large samples and multi-center,RCTs,and there is no clear objective diagnostic criteria of TCM syndromes and evaluation criteria of the curative effect of CHM.These have caused a number of inconveniences for follow-up clinical work.Thus,more studies of CHM combined with ACEI/ARB for IDN that are large-scale,high quality,and have a long follow-up are warranted to confirm the current findings.In addition,confirmation of the advantages of CHM in the treatment of IDN requires additional studies.

Conclusions

CHM combined with ACEI/ARB can decrease UAER and Scrsignificantly compared to the use of ACEI/ARB for IDN treatment.The effect was more significant in the Chinese herbal medicine group containing Astragali Radix or Rehmanniae Radix.The application of Astragali Radixand and Rehmanniae Radix in third-stage diabetic nephropathy should be emphasized.

Figure 2 Risk of bias graph:review authors'judgments concerning the risk of bias of each item,presented as percentages across all included studies

Figure 3 Forest plot and risk of bias summary of UAER in groups A and B

Figure 4 Forest plot and risk of bias summary of Scr in groups A and B

Figure 5 Forest plot and risk of bias summary of BUN in groups A and B

Figure 6 Forest plot and risk of bias summary of the adverse effects rate

Figure 7 Funnel plot to assess publication bias in the review,outcome:serum

Table 1.The detailed information of literature included

8.2 8±2.5 2-7.1 2±1.2 4-9 3.6±1 5.6-9 4.4±1 5.4.3 1 6 2.6±4 6-1 6 4.8±4 5.6-8 8 m L o s a r t a n B+p o t a s s i u B+B e n a z e p r i l e H y d r o c h l o r i d a d e f o r g s t a s i s i n c a p s u l e S e l f-m t i o n o t i n g b l o o d d l v i n B+p r e s c r i p p r o m c i r c u l a t i o n a n r e s o B+K e L u o X 4 3 2 5 4 3 2 5 N q i-y i n c y,b d e f i c i e n l o o d s t a s i s-7.8±2.5-7.5±3.0 5 6.4 5 2.6±6.2 5 6.7±516.2.4 a n g 2 0 1 5 3 1]2 0 1 3 3 2]5.4 6±1.8 6----1 0 1.8 7±1 2.8 1--8 9 9.5±1 3.4 6-9 0 1 1.1.0 7±7 8±3 9 4 4 0.2.8-8 8.9 8±.5 1 0 3 9 5.3±3 9.5 2 1 2 1 2 8 B t a b l e t s E I/A R B i s a r t a n B+A R B+A C B+T e l m o f Q i d a n a n g g r a i n a d e o f p a c k a g e s c t i o n o f S e l f-m t i o n e n l i n g D i h u B+i n e s e m e d i c i n e d e c o B+p r e s c r i p C h B+T a n g s h 4 4 4 0 4 0 4 7 4 2 4 1 N q i-b l o o d y i n-a n d-y a n g d e f i c i e n c y N-6.2±2.6 1 3.8±7.2-5.7±2.6 1 2.7.5 7±0 5 6.0±3.5 5 1 1 7.2±.2 1 8-8 5 5±3.6.2 5 0.3±1 6.7 X 2 0 1 6 3 3]2 0 0 7 3 4]P 2 0 0 6 3 5]9 3.0 8±1 0.6 8 8 9 2.2±1 2.2 2 9±1 9 5 3 6.8.5 9 5.7 6±.4 3 5 5 6 B e n a z e p r i l B+e s e a n g e l i c a c t i o n f o r d e n r i c h i n g b l o o i n B+C h d e c o 6 0 6 0 N 1 3.8±6.8 1 2.6±7.6 4 9 1 2.2±.5 4 8.5±1 1.6 C F 2 0 0 9 3 0]

-5.7 8±1.7 3 6.5±1.1 9 9.5 4±1 5.6 7 6.7 8±1 2.1 2 1 0 2±1 9 0.3.1 5 5 8 2 1 0 2±7 8.1 3.1±1 1 0 4±1 5 1 6 5.4 5±1 6.9 2--1 6 6.7 1±1 7.1 7--8 2 4 1 2 B+I r b e s a r t a n B+I r b e s a r t a n B+I r b e s a r t a n g k u i c a p s u l e y a n K a n g f u t a b l e t B a i l i n g c a p s u l e B+H u a n B+S h e n B+3 0 3 0 3 2 3 0 3 0 3 2 N N N--5～2 0--5～2-2 5 5 4 6.8.9±4-5 2±1 4 4 7.4 5.2±2 3-5 4±1 7 2 0 1 1 3 6]2 0 1 3 3 7]P 2 0 1 1 3 8]---------6.7±.9 1 9 3 8 1 1 0.5 5±7 5.9 2-2 0 4.3±4 1.5 1 1 3.1 1±6 3.7 8-1 2 8 1 2 a l a p r i l B+E n M a l e a t e B+B e n a z e p r i l B+B e n a z e p r i l b a o d e n T a n g s h e n u l e s u r i s h y i n a n r a t e q i u a n g Y i s h B+g r a n C a p s u l e B+N o v i g o i n B+S a n h 4 0 4 0 4 0 4 0 4 0 4 0 N N q i-y i n c y d e f i c i e n w i t h b l o o d s t a s i s 5.3±4.1 5 4～1 7 1 0.4±5.7 4 8～7 3～1 5 5 3 1 0.6±.8 3 3 0～7 3 5 2.4±1 1.6 4 8～7 3 1～7 1 B 2 0 1 4 3 9]J S 2 0 0 4 4 0]H 2 0 1 1 4 1]

---8 0.2±1 5.6-8 1.3±1 6.4-2.4±.5 1 3 3 2-1 3 3.8±3 3.7 8 1 2 B+L o s a r t a n B+V a l s a r t a n e s e a n g e l i c a C h i n e s e r o o t s i x-5.3 3±1.8 1 6.8±1.5-1 0 3±1 7 9 3.3±2 8.7-1 0 6±1 9 9 4.7±3 0.4 1 1 8.8 9 0.4 1.6.6±4 9.7±1 3 3 8 0.5±1 8 5 0 1 1 4.4 5±4 4.4 3 1 4 2.6±3 7.5 1 7 8.2±5 7.9 1 2 8 1 2 i s a r t a n T e l m B e n a z e p r i l e L o s a r t a n B+B+H y d r o c h l o r i d B+g t h e n i n g c t i o n f o r c a p s u l e a d e i n c t i o n f o r e n r i c h i n g d+d e c o c t i o n o f B a i l i n g g n o u r i s h i n g i n b a o e y,s t r e n,r e s o l v i n g B a o s h e n l e e n d o p e n s t a s i s c h a n a n X i a o d e c o C h x g l o v e i n g r e d i e n t s S e l f-m B+d e c o b l o o f o B+B+2 4 3 0 2 4 3 0 N N n e l s n k e j i n s h u i c a p s u l e k i d n t h e s p D e c o c t i o B+B+3 0 2 6 2 0 3 0 2 6 2 0 q i-y i n c y 4～1 8-7～2 0 2～1 6 4 5～7 5.4 4 3～7 6 5 7.3±9 X M 2 0 0 9 4 2]L 2 0 1 4 4 3]d e f i c i e n w i t h b l o o d s t a s i s N N 7.8 8±1.3 6 9.3±2.0 1 0.7±5.5 7.7 7±1.3 9 1 0.1.9 1±1 1.5.3 2±5 4 9.1 2.2±4 9 1 2.1±.7 4 9.1±7.9 5 2.2±8.2 7 4 8.8±1 0.9 5 0.8.3±7 X 2 0 1 0 4 4]B 2 0 0 7 4 5]C H 2 0 1 3 4 6]

-8.5 5±0.7 8 8.0 9±1.2 5 6.1 2±1.5 4 6.1 3±1.5 6--1 0 3.5 4±1 8.8 6 7 8.1±1 2.6 7 9.1±1 2.7--9 1 0 9.4.2±2 0 7 1 8 0 1 1.1.1±8 0.0±1 1.1--.1 2 2 3.8 6±7 0.3 5 1 1 4.9±2 1 1 1 5.9 9±2 1.1--2 1 9.6 7±6 8.5 4 1 1 4.5±2 0.3 1 1 4.4 9±2 0.3 1 2 8 1 2 1 6 1 6 r i l a l a p r i l v a l s a r t a n v a l s a r t a n B+C a p t o p B+I r b e s a r t a n B+E n M a l e a t e O r a l O r a l d,a d e e n i n e f o r e q i,n c t i o n f o r e y e g k i d n g t h e d g e l i c a S e l f-m a d g b l o o n e l s i n s t r e n g t h e n d o p P r e s c r i p t i o n t h t h A n g s t a s i s o t i n n o u r i s h i n g c a p s u l e u i c a p s u l e d e c o a n u i B+S e l f-m l v i n d i f i e d a n g k a n g k s p l e e n c h a n B+r e p l e n i s h i n g n o u r i s h i n g y i n,p r o m c i r c u l a t i o n a n r e s o B+M o P e o n y D e c o c t i o H u H u 5 6 2 3 4 8 3 2 3 2 5 6 2 3 4 8 3 3 3 2 N N N N N 1 0.2±5.1-5.8 5±1.3 2--1 0.4.6 8±-5.2 1±1.4 6--.8±4.6 4 5±.1 3 1 3 6 6 6 1 6 5 4.5.2±4 5 8.5±1 6.2 4 5 9.4±1 5.3 1 6 7.5.2±4 4 3±1 7.6 5 3.2 5.2±2 0 5 7 8±.9 1 6.0 7 5 8 9±.8 1 5.9 8 R 2 0 1 0 4 7]2 0 1 2 4 8]X Y 2 0 1 6 4 9]Z Z 2 0 1 0 5 0]X C 2 0 1 0 5 1]

Note:n=patient number enrolled;T=treatment group;C=control group;y,=year;w=week;B=basic treatment(including diabetes education,diet control,exercise,control of blood glucose);N,=not mentioned

Table 2.Composition and efficacy of prescription literature included

g y i n,p r o m g s t a s i s p r o m g y i n,g s t a s i s p r o m g y i n,g s t a s i s b l o o d o u r i s h i n d r e s o l v i n i n d r e s o l v i n i n d r e s o l v i n t i n g g s t a s i s l v i n q i,n o u r i s h o u r i s h r o m o r e p l e n i s h i n g d c i r c u l a t i o n a n q i,n q i,n q i,p n a n d r e s o b l o o r e p l e n i s h i n g d c i r c u l a t i o n a n b l o o r e p l e n i s h i n g d c i r c u l a t i o n a n b l o o r e p l e n i s h i n g c i r c u l a t i o-e n z i),a(Y i m u c a o),g),g),o i n k g a(F u l i n L o b a t a e R a d i x(G e g e n),G s(N v z h g h u a)i z o m o r i a F r u c t u R h d i x(D i h u a n H e r b,P(H o n c i d i r i R a d i x e t i g u s t r i L u e o n u i F l o s a r t h a m R h e i i z h i),m a n n i a e R a e h R a d i x(D a n g g u i)r i a e a n g),L h u)u e r a g),C(S a(D a n s h e n),L d i h u u l i n S i n e n s i s g q i),P i z o m o r i a(F H i r u d o a(D a n s h e n),R a(G a n c a o e l i c a e d i x(H u a n h u e R a d i x e t R h a n z h u y u),P z i),F r u c t u s(G o u q i z i)R h i z o m d i x p r a e p a r a t a(S i z o m F r u c t u s(N v z h e n n g d i x e t R h i),A a n g q R a l i e R a F r u c t u s(S h e R a d i x e t y c i i g a R a d i x(H u d i x(D a n g g u i),A s t r a m a n n i a e R a M i l t i o r r h i z a M i l t i o r r h i z a l y c y r r h i z a e h a n y a o),C i g R a u s t r i L u c i d i d i x(T a i z i s h e n),L s t r a g a l i a l v i a e h a n l i a n),S a l v i a e o r n i g q i),R a(S h g q i),L r i a e a n y a o),G a n g),A R a g q i),S e S i n e n s i s x i n g y e)d i x(H u a n i z o m i z o m a(S h d i x(D i h u i n R h d i x(H u a n d i x(H u a n R h R a g e l i c a(Y a l i R a H e r b a(M o a l i R a u a n g),P s e u d o s t e l l a a l i R a a n n i a e A n F o l i u m A s t r a g E c l i p t a e D i o s c o r e a e A s t r a g a h(D A s t r a g D i o s c o r e a e R e h m e t c.g C F 2 0 0 9[3 0]g Z M 2 0 1 5[3 1]F 2 0 1 3[3 2]i X 2 0 1 6[3 3]i J 2 0 0 7[3 4]l e n i s h i n g h e a t n i f y t o d e x p e l e y,p r o m a n n e,r e p d c l e a r i n g a n d d a m p n e s s,d e t o x i f y g y i n,a n g y i n,l e e n i n o u r i s h a n d k i d n o u r i s h i n d o p e n i n g c h g t h e s p e l l i n g e l u n g i n q i,n t h e u m a q i,n s t r e n g t h e n y i n a n u r i s h i n g h e a t x i c i t y t t o r a t i n g p n d c i r c u l a t i o n a n n o C l e a r i n g a n d r e l i e v i n g s w r e p l e n i s h i n g k i d n e y,i n v i g o r a t i n g s p l e e n r e m n a n v i g o I n b e n e f i t i n g r e p l e n i s h i n g b l o o t i g m a t a d i x e t u c o m m i a e r r h i z a e R a g),E a(S h a n y a o),S M i l t i o a n s c o r e a e R h i z o m c a o),S a l v i a e d i x e t n i a e R a d i x(D i h u i o a n H e r b a(Y i m u a n g z i)),R e h m n u r i e o s(N i u b r r h i z a e R a e R a d i x(T a i z i s h e n),D a o g e n),L r c t i i F r u c t u k u i h u a)M i l t i o a i h u a s h e s h e c a o e(B a i m i z o m y a o),S a l v i a e a n g s h u(B g q i),A s e u d o s t e l l a r i a a n d i x(H u a n C o r o l l a(H u a(S h l d e n l a n d i a g x i a c a o)e r a t a e i z o m c h o n n g a l i R a R h u z h o n g)d i x(H u a n g q i),P r h i x u),I m p A s t r a g s c h i e l m o a(D a n s h e n),O a l i R a A b D i o s c o r e a e i z o m R h C o r t e x(D A s t r a g m a y d i s(Y u m J P 2 0 0 6[3 5]n M 2 0 1 1[3 6]n M 2 0 1 3[3 7]2 0 1 1[3 8]C o r d y c e p s(D o C P X B 2 0 1 4[3 9]

q i a n d p r o m g s t a s i s i s h i n g d c i r c u l a t i o n g k i d n e y i n g y i n,y i n,r e p l e n d r e s o l v i n o u r i s h d t o n i f y i n q i,n u r i s h i n g g b l o o y i n a n o t i n d c i r c u l a t i o n a n n o p r o m r e p l e n i s h i n g b l o o N o u r i s h i n g o r n i y a o),i z o m a d i h u a n g),o u t a n a n a t i O d o r a t i R h a(H u a n g j i n g)；C h u g),M a(S h r i(S g n u e o r a t a u l i n o r i a(F R h i z o m a n x i o n h u R h i z o m g z i)；L d i x p r a e p a e n),D i o s c o r e a e g),P o l y g o n n s h e n),C n a t i a(Z e x i e),P i d o n a(D a F r u c t u s(J i n y i n R h i z o m m a n n i a e R a s h p o g o n i s R a d i x(M a R h i z o m s h e n),P o l y g o L a e v i g a t a e e h n g a t i s d i x(X i y a r r h i z a e R a d i x e t s(F o s h o u)n g i),R d i x(X i y a l i s m n g g u o),A R a R a o s a e i),R R a d i x(D a a(S h a n y a q u e f o l i i i o p h q u e f o l i i s h i z o m Q u i n M i l t i o a c t y l i s F r u c t u Q u i n R a d i x(D a n g g u i)a n a c i s a n a c i s i z i),S a l v i a e e n s i s F r u c t u s(W u w e i z i),O s c o r e a e R h u r y a l e s S e m e n(Q i a n i o d i x(H u a n g q i),P u q e l i c a e S i n e n s i s A n g e l i c a e S i n e n s i s u y u),D a(D a n s h e n)s(G o z h i n n x i o n g),C i t r i S a r c o d u y u),E F r u c t u n g a n a l i R a y c i i(Y u z u),L a(C h d i x(H u a n g q i),P u a z h o),A d i x(H u a n g q i)u d a n p i)i z o m a l i R a a n c a n d r a e C h a l i R a(M R h A s t r a g S c h i s a R h i z o m A s t r a g F r u c t u s(S h H e r b a(Y i m u A s t r a g C o r n i F r u c t u s(S h C o r t e x g J S 2 0 0 4[4 0]2 0 0 9[4 2]X H 2 0 1 1[4 1]g X M e y,t h e g w a r m a n d k i d n t r e n g t h e n i n g i n d e t o x i f y e y,a n d o p e n i n g y i n,e l u n g o u r i s h a n n e l s e l u n g a n d k i d n r a t i n g p n t h e u m a r a t i n g s p l e e n,S q i,n l v i n g s t a s i s o v i n g b l o o d s t a s i s g c h t h e u m a v i g o b e n e f i t i n g v i g o r e s o e n i n r a t i n g p n I n i n k i d n e y n e l s c h a n r e p l e n i s h i n g Y a n g,r e m a n d o p I n v i g o b e n e f i t i n g a n g)o r n i L a e v i g a t a e a(D a h u a n g),C d i x e t o s a e a n g),R e R a d i x(D i h u r r h i z a e R a R h i z o m a(D a h u n n i a e d i x e t i a e h m a h e i R a e h m a n n M i l t i o d i x e t R h i z o m g),R g q i),R g),S a l v i a e e i R a(S h u d i h u a n a(D a n s h e n),R d i x(H u a n t a u l i n i z o m o r i a(F n g e o),R h r i n u R h R a l i d i x e t y a o),L g a a(Z e x i e),P a(D i l o n g)s t r a a(C h u a n x i o a n e R a d i x p r a e p a r a e R a n n R h i z o m u a n x i e),P h e r e t i m i a g x i a c a o)e h m a l v i a e M i l t i o r r h i z a d i x(T a i z i s h e n),A a t i s i z o m c h o n l i s m h u a n x i o n g R h i z o m a(S h i o s c o r e a e R h g x i a c a o)n g R a n g),S a c h o n C o r d y c e p s(D o r i a e u y u),A u a n g P s e u d o s t e l l a a n z h g z i),D o),S c o r p i o(Q d i x(H u a n g q i),R F r u c t u s(S h a(D a n s h e n),C c a a l i R a e n g d i h R h i z o m F r u c t u s(J i n y i n H e r b a(Y i m u A s t r a g R a d i x(S h C o r d y c e p s(D o u L 2 0 1 4[4 3]W X 2 0 1 0[4 4]2 0 1 3[4 6]H B 2 0 0 7[4 5]g C H

p r o m g l i v e r a n d k i d n e y,i n v i g o r a t i s t d i u r e s i p r o m i n g l e n i s h i n g q i,p r o m o t i n g d r e s o l v i n g s t a s i s g s t a s i s v i n g g s t a s i s i n g y i n,g y i n,g y i n,o u r i s h d r e s o l v i n d,r e m o d b l o o h e a t,p r o m o t i n g x i f i c a t i o n i n o u r i s h d r e s o l v i n i n o u r i s h a n d S t r e n g t h e n s p l e e n,r e p r e p l e n i s h i n g q i,n c i r c u l a t i o n a n d c i r c u l a t i o n a n a n q i a y p n e s s,d e t o q i,n q i,n s p l e e n T o n i f y i n a w r a t i n g b l o o R e g u l a t i n g c l e a r i n g d e t o x i f y i n g H e a t,d a m r e p l e n i s h i n g b l o o d c i r c u l a t i o n a n r e p l e n i s h i n g i n v i g o k i d n e y m a n n i a e R a d i x c t y l o d i s s l i R a d i x r e a e h i o p o g o n i s i o s c o r e a e a t i s s e h s t r a g a),A t r a t i i F r u c t u R a d i x e t l i s m F r u c t u s(J i n y i n g z i),R u y u),A a o a(B a i z h u),D i o s c o y c i i a n g),,O p u r a n s e n g a i s h s(S h a n z h u y u),D a n x i o n g(B g),A i n o t o g y a o),A u y u),L a n z h h u a n g),N a(S h z h a n L a e v i g a t a e F r u c t u e R h i z o m e e r s i c a F r u c t u e R a d i x A l b a a n a n g d i h u a n g),C o r n i F r u c t u s(S h h u i z o m s(S h o s a e a t a e n c a o)i),P n n i a e R a d i x(D i h u o r n i a(Z e x i e),C i a a e o n i a e R a d i x(D i h u a(D a n)F r u c t u e v i g n g g u a(G a e h m a o n g h u a)a(Z e l a n n i o s c o r e a e R h o r n i s(f u p e n z i),R L a R a d i x(D a i),P R h i z o m a(D a n s h e n),C d i x(T a i z i s h e n),R t i s R h i z o m F l o s(H H e r b e h m a g q R h i z o m o s a e d i x e t a n b i F r u c t u s h i),R d i x e t i z o m),A l i s m a p i),L y c o p i i j i a n y u),R h e i R a d i x(M a i d o n g),C S e m e n(Q i a n e R a d i x(S h e n t r a c t y l o d i s M a c r o c e p h a l a S i n e n s i s R a e R a R h R a d i x(H u a n a(H u a n g j i n g),D u d a f e n),R u i(G u e R a d i x e t s t r a g a l i z h n g e l i c a e u y u),R i z h i),G l y c y r r h i z a e i z o m s e u d o s t e l l a r i a n i s R a n x i o n g)e S e m e n(T a o r e n),C a r t h a m i)a(B a i z h u),P o r i a(F u l i n g i a a n(M u a d i x(D a n g g u i),A i o C o r t e x p o)u a r y a l e s n n d i x(T i a n h u M i l t i o r r h i z a a n g s h e n),A p i l o s u l a(D e h m a u a n x i o n g),M o u t a n i h i h p h u l i n g),A u l i E u o n y m o l y g o n a t i R h g o g s h u k u(S h u d i h u a n g),R S e m e n(T u s i z i),E u g),O R a h u g s h u k u(F i z o m a m a n a n o r i a(F e r s i c a u l i n R h S e m e n(T a o r e n),H i r u d o(S o s a n t h i s a(C h d i x(M a i d o n g),S a l v i a e e R h i z o m y a o),P o r i a y a o),P R a u a n g q i),C o d o n o p s i s r i c h n g d i x(H u a n g q i),R d i x(H u a n g q i),P a n a n e S i n e n s i s M a c r o c e p h a l a u a a(C h C o r o l l a(H u C o r o l l a(H u s(Z h i s h i),C o r n i F r u c t u s(S h i)n q d i x(H u a n g q i),P C u s c u t a e p r a e p a r a t a a(S h a l i R a a(S h i z o m s c h i s c h i a l i R a t u r u a(S a a l i R a a(Z e x i e),P z i),C h u a n x i o(H R h i z o m A s t r a g R a R h i z o m A n g e l i c a R h e l m o A b e l m o A s t r a g I m R h m a i z o m A s t r a g R h i z o m F r u c t u s(G o u q i z i),T(J i n y i n g 2 0 1 0[4 7]X 2 0 1 2[4 8]2 0 1 6[4 9]2 0 1 0[5 1]2 0 0 9[5 3]n J R g X Y o Z Z 2 0 1 0[5 0]A b g X C i P 2 0 1 5[5 2]g H M