Meta-Analysis of the Clinical Effectof Ligustrazine on Diabetic Nephropathy
Bin Wang,* Qing Ni,* Xun Wang† and Lan Lin*
*Department of Endocrinology, Guang’anmen Hospital
China Academy of Chinese Medical Sciences, Beijing, China
†School of Pharmaceutical Sciences, Peking University, Beijing, China
Abstract: Ligustrazine, a bioactive component contained in Chuanxiong (Ligusticumchuanxiong Hort), is widely applied in the treatment of vascular diseases in China, e.g.myocardial and cerebral infarction. The aim of this study was to perform a meta-analysis ofrandomized controlled trials (RCTs) to evaluate the clinical effect of Ligustrazine on diabeticnephropathy (DN). PUBMED, EMBASE, the Cochrane Central Register of Controlled Trials(CENTRAL), Chinese Biological Medicine Database (CBM), China National KnowledgeInfrastructure (CNKI) Database, etc. were searched by computer and manual methods toidentify RCTs that were used to evaluate the clinical effect of Ligustrazine on DN patients.Twenty five studies comprising 25 RCTs were involved including 1645 patients (858 in thetreatment group and 787 in the control group). The meta-analysis suggests that comparedwith the control group, Ligustrazine injection has a significant therapeutic effect onimproving renal function (blood urea nitrogen [BUN] and serum creatinine [SCr]) andreducing in urine protein (24 h urine protein, urine micro albumin and urinary albuminexcretion rate [UAER]) in DN patients.
Diabetic nephropathy (DN) is typically defined by albuminuria and abnormal renal func-tion as represented by abnormality in blood urea nitrogen (BUN) and serum creatinine(SCr). Clinically, DN is characterized as high risk of cardiovascular morbidity and mor-tality. In the United States, approximately 20.8 million people (7.0% of the population) areestimated to have diabetes, with a growing incidence. Approximately 20–30% of all
Correspondence to: Dr. Lan Lin, Endocrinology Department, Guang’anmen Hospital, China Academy ofChinese Medical Sciences, Beijing 100053, China. Tel: (þ86) 10-8800-1396, Fax: (þ86) 10-8800-1396, E-mail:
diabetic patients will develop nephropathy, although a higher percentage of type I patientsprogress to end-stage kidney disease (Nordquist and Wahren, 2009).
Ligustrazine (Tetramethylpyrazine), a bioactive component contained in Chuanxiong(Ligusticum chuanxiong Hort), is widely applied in the treatment of vascular diseases inChina, e.g. myocardial and cerebral infarction (Fu et al., 2007; Li et al., 2006). It has beenreported that Ligustrazine causes an increase in myocardial and cerebral blood flow andreduces myocardial and cerebral ischemia in animal models (Dai and Bache, 1985; Yanet al., 2011). In addition, Ligustrazine has been demonstrated to play a protective role inischemia-reperfusion kidney injury in rats (Feng et al., 2004).
The mechanisms of these effects are reducing platelet aggregation, inhibiting freeradicals (Zou et al., 2001), activating the expression of endothelial cell nitric oxidesynthase (ecNOS) protein (Sheu et al., 2000), and down-regulating the expression ofintercellular adhesion molecule-1 (ICAM-1) (Feng et al., 2004).
In recent years, a number of clinical trials have been done to test the efficacy ofLigustrazine for the treatment of DN. However, these studies were published in Chineseand could not be accessed by non-Chinese speaking scientists. The aim of this study is toassess the evidence from these randomized clinical trials (RCTs) for the efficacy ofLigustrazine in the treatment of DN.
Treatment of diabetic nephropathy with traditional Chinese medicine is one of ourresearch directions (Lin et al., 2002, 2010). We did this meta-analysis of clinical studies tofind the potential uses of Ligustrazine in treatment of diabetic nephropathy. The result ofthe meta-analysis is useful for us to understand the benefit effects of Ligustrazinein treatment of diabetic nephropathy. For the next step, we will study the effect ofLigustrazine in treating diabetic nephropathy.
Materials and Methods
Eligible Standard
Study Design
All the randomized control trials (RCTs) were searched. No language or year of publicationwas imposed.
Study Object
Patients met the diagnostic criteria for diabetic mellitus (WHO-1999, ADA-1997). Patientsin the clinic stage III-IV of DN were included according to the Mogensen DN diagnosticcriteria (Mogensen et al., 1983). Patients with other chronic diseases (schizophrenia,chronic pulmonary disease, liver disease such as autoimmune hepatitis, alcoholic liverinjury and drug-induced hepatitis, heart failure, myocardial infarction, fatal arrhythmia,autoimmune disease, infectious disease, malignant tumors, serious hypertension, organtransplants, etc.) were excluded.
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Methodological Quality Appraisal
Intravenous drip infusion of Ligustrazine injection was used in the treatment group. Theinjection containing Ligustrazine (20mg/ml) was made from Ligustrazine and compliedwith the quality standard of China State Food and Drug Administration. The dosage was40–400mg/day, and the treatment duration was 10 days–12 weeks.
Search Strategy
Databases were searched by computer and manual methods, including PUBMED,EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Web ofScience, Chinese Biological Medicine Database (CBM), China National KnowledgeInfrastructure (CNKI) Database, Chinese Evidence-Based Medicine Database (CEBM),WanFang Digital Periodicals Database (WFDP), China Science Citation Database, ChineseScience and Technology Document Database (CSTD), etc.
Data Extraction and Criteria of Therapeutic Effects
The following data were extracted: the number of patients in Ligustrazine group and thecontrol group, age, gender, history of DM, intervention, treatment duration, the use of ACEinhibitor or ARB, etc. The data in the Ligustrazine treatment group matched with the datain the control group.
Criteria of therapeutic effects: renal function such as BUN, SCr, and urine protein suchas 24 h urine protein, urine micro albumin and urinary albumin excretion rate (UAER).
Assessment Methodology
Two assessors (Wang Bin and Ni Qin) independently assessed all studies, extracted andcross-checked eligible data, and entered them into the Review Manager software (Rev Man5.0). Missing data of the trials were obtained from the principal investigators if possible.Disagreements were resolved by discussion with the third author (Wang Xun). All authorswere blinded to the identity of the groups of the studies.
The following information was extracted: randomization process, allocation conceal-ment, blinding, participant dropout and loss to follow up, intention-to-treat analysis, andexplicit diagnostic and outcome criteria. The trials were coded as A — adequate, B —
unclear, or C — inadequate, according to the Cochrane Handbook for Systematic Reviewsof Interventions.
Statistical Methods
For both continuous and dichotomous data, meta-analysis was developed using the stat-istical software provided by the Cochrane Collaboration (Rev Man 5.0). Estimated effect ofdata was calculated by standardized mean difference (SMD) and 95% confidence interval(CI). Chi-square test was used for heterogeneity.
META-ANALYSIS OF LIGUSTRAZINE ON DIABETIC NEPHROPATHY 27
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Results
Description of Studies
25 studies comprising 25 RCTs were eligible. The included studies are summarized inTable 1. A total of 1645 patients were enrolled for analysis of effectiveness (858 in thetreatment group and 787 in the control group). All these studies were carried out in patientsof People’s Republic of China.
Blood Urea Nitrogen (BUN)
A total of 10 RCT clinical trials (390 patients in Ligustrazine treatment group and 319 inthe control group) were conducted to analyze the BUN.
Figure 1 shows the forest plot for the BUN comparison. The results show that Ligus-trazine could significantly reduce the level of BUN compared to the control group in DNpatients (SMD: �1:24, 95% CI: �2:02, �0:46, p ¼ 0:002).
Serum Creatinine (SCr)
Ten RCT clinical trials (390 patients in the Ligustrazine treatment group and 319 in thecontrol group) were conducted to analyze the SCr.
Figure 2 showed the forest plot for the SCr comparison. The results show that Ligus-trazine could significantly reduce the level of SCr compared to the control group in DNpatients (SMD: �18:31, 95% CI: �30:94, �5:68, p ¼ 0:004).
24 h Urine Protein
Ten RCT clinical trials (384 patients in the Ligustrazine treatment group and 332 in thecontrol group) were conducted to analyze the 24 h urine protein.
Figure 3 shows the forest plot for the 24 h urine protein comparison. The results showthat Ligustrazine could significantly reduce 24 h urine protein compared to the controlgroup in DN patients (SMD: �0:36, 95% CI: �0:56, �0:17, p ¼ 0:0003).
Urine Micro Albumin
Ten RCT clinical trials (363 patients in the Ligustrazine treatment group and 326 in thecontrol group) were conducted to analyze the urine micro albumin.
Figure 4 shows the forest plot for the urine micro albumin comparison. Theresults show that Ligustrazine could significantly reduce urine micro albumin comparedto the control group in DN patients (SMD: �50:78, 95% CI: �72:20, �29:36,p < 0:00001).
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Tab
le1.
The
Brief
Summaryof
theStud
ies
Stud
yBlood
Urea
Nitrogen(m
mol/L)
Serum
Creatinine(¹
mol/L)
24hUrine
Protein
(g)
Urine
Microalbu
min
(mg/24
h)
UAER
(¹g/min)
Baseline
After
Intervention
Baseline
After
Intervention
Baseline
After
Intervention
Baseline
After
Intervention
Baseline
After
Intervention
Chen(2005)
NN
NN
NN
200.50
�21.3
40.60�
6.9
NN
NN
NN
NN
199.00
�19.50
89.00�
6.30
NN
Cui
etal.
(2006)
11.02�
4.8
5.23
�3.6
277.40
�185.2
106.60
�113.5
NN
NN
NN
9.08
�4.4
7.98
�4.3
243.70
�202.3
196.40
�132.2
NN
NN
NN
HeandMa
(2008)
13.70�
3.3
8.80
�2.1
186.10
�26.7
118.50
�34.8
NN
310.50
�105.3
137.80
�48.7
NN
12.60�
3.4
11.00�
3.1
168.90
�31.5
157.70
�22.5
NN
319.40
�98.80
247.10
�66.9
NN
Huang
(2010)
15.70�
3.7
11.30�
2.9
332.10
�92.7
311.50
�83.2
1.89
�0.37
1.15
�0.28
NN
NN
15.10�
3.9
10.20�
3.1
351.5�
73.2
276.50
�81.2
1.75
�0.33
0.89
�0.31
NN
NN
KeandLi
(2007)
NN
NN
NN
218.
00�
16.20
81.00
�13.10
NN
NN
NN
NN
199.
00�
19.50
163.
00�
9.05
NN
Liu
(2007)
8.97
�2.15
4.69
�1.09
172.76
�26.24
81.98�
21.04
2.16
�1.77
0.58
�0.13
NN
NN
9.76
�2.05
6.83
�1.28
176.14
�31.57
117.34
�22.64
2.26
�1.56
1.37
�0.81
NN
NN
Ma(2009)
NN
NN
0.43
�0.13
0.33
�0.07
NN
58.20�
43.00
20.35�
13.80
NN
NN
0.45
�0.14
0.42
�0.13
NN
58.17�
43.40
54.30�
38.20
Niu
andYang
(2007)
NN
NN
NN
198.26
�26.94
123.42
�22.36
NN
NN
NN
NN
197.93
�28.65
197.31
�22.74
NN
Pei
(2005)
NN
NN
1.00
�0.40
0.40
�0.30
NN
NN
NN
NN
0.90
�0.40
0.81
�0.40
NN
NN
META-ANALYSIS OF LIGUSTRAZINE ON DIABETIC NEPHROPATHY 29
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Tab
le1.
(Con
tinued)
Stud
yBlood
Urea
Nitrogen(m
mol/L)
Serum
Creatinine(¹
mol/L)
24hUrine
Protein
(g)
Urine
Microalbu
min
(mg/24
h)
UAER
(¹g/min)
Baseline
After
Intervention
Baseline
After
Intervention
Baseline
After
Intervention
Baseline
After
Intervention
Baseline
After
Intervention
Ren
etal.
(1998)
13.11�
6.20
7.00
�2.04
205.97
�84.86
116.64
�32.71
2.23
�1.18
1.08
�0.96
NN
NN
13.07�
5.89
10.23�
3.41
203.60
�82.60
177.23
�84.27
2.32
�1.21
1.70
�0.86
NN
NN
Shang
andXu
(2009)
NN
NN
1.86
�0.81
1.26
�0.77
NN
NN
NN
NN
1.84
�0.56
1.67
�0.39
NN
NN
Sun
(2008)
7.92
�1.65
6.02
�1.27
95.81�
11.09
82.65�
14.31
1.42
�0.58
0.66
�0.55
NN
NN
7.65
�2.02
7.05
�1.40
92.16�
11.26
85.49�
11.60
1.44
�0.56
1.09
�0.48
NN
NN
Tan
andWang
(2003)
NN
NN
NN
NN
132.00
�60.0
48.00�
6.00
NN
NN
NN
NN
126.00
�60.0
84.00�
6.00
Tanget
al.
(2001)
5.68
�1.20
5.44
�1.52
80.64�
12.50
76.02�
11.20
NN
203.52
�63.84
111.68
�53.82
NN
5.72
�1.16
5.77
�1.12
78.80�
12.40
77.22�
10.90
NN
216.45
�68.36
193.44
�62.72
NN
Tianet
al.
(2004)
NN
NN
NN
130.40
�85.70
99.30�
63.10
NN
NN
NN
NN
138.50
�91.30
57.70�
48.80
NN
WangandHui
(2010)
NN
NN
NN
NN
152.00
�73.30
42.60�
3.90
NN
NN
NN
NN
151.40
�62.10
58.10�
4.20
Wangand
wang
(2005)
NN
NN
NN
169.11
�42.71
123.78
�37.11
NN
NN
NN
NN
168.28
�43.51
152.89
�39.19
NN
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Tab
le1.
(Con
tinued)
Stud
yBlood
Urea
Nitrogen(m
mol/L)
Serum
Creatinine(¹
mol/L)
24hUrine
Protein
(g)
Urine
Microalbu
min
(mg/24
h)
UAER
(¹g/min)
Baseline
After
Intervention
Baseline
After
Intervention
Baseline
After
Intervention
Baseline
After
Intervention
Baseline
After
Intervention
Wen
etal.
(1995)
4.82
�1.66
4.65
�1.53
68.53�
21.97
64.68�
13.83
NN
NN
88.13�
30.48
30.16�
16.58
4.58
�1.39
4.46
�1.58
63.94�
24.86
61.24�
16.36
NN
NN
83.46�
32.37
56.29�
17.64
Yangand
Xiong
(2008)
NN
NN
1.97
�1.13
0.96
�0.40
NN
NN
NN
NN
1.92
�1.10
1.50
�1.00
NN
NN
Yanget
al.
(2007)
NN
NN
NN
43.40�
14.80
21.60�
7.60
NN
NN
NN
NN
42.60�
13.20
22.60�
9.90
NN
Yu(1998)
NN
NN
NN
255.35
�90.20
106.55
�79.38
NN
NN
NN
NN
237.50
�105.19
200.00
�90.26
NN
Zenget
al.
(2005)
11.89�
4.24
8.97
�3.72
221.13
�114.28
154.43
�89.21
2.75
�0.87
1.85
�0.68
NN
NN
10.76�
3.97
8.56
�4.14
218.37
�108.18
192.13
�104.28
2.69
�0.74
2.23
�0.67
NN
NN
Zhang
(2010)
NN
NN
NN
NN
N58.06�
8.21
29.23�
6.16
NN
NN
NN
N57.68�
7.45
38.97�
7.26
Zhao(2004)
NN
NN
NN
139.80
�19.90
88.40�
14.00
NN
NN
NN
NN
133.40
�28.10
130.6�
30.40
NN
Zhouet
al.
(2009)
12.31�
3.98
9.24
�3.16
179.18
�69.30
142.32
�61.79
2.51
�1.41
1.49
�0.33
NN
NN
12.33�
3.86
11.87�
4.03
178.83
�70.13
162.12
�68.68
2.48
�0.41
1.99
�0.39
NN
NN
META-ANALYSIS OF LIGUSTRAZINE ON DIABETIC NEPHROPATHY 31
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Figure 1. Effect of Ligustrazine on BUN in DN patients.
Figure 2. Effect of Ligustrazine on SCr in DN patients.
Figure 3. Effect of Ligustrazine on 24 h urine protein in DN patients.
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Urinary Albumin Excretion Rate (UAER)
There were five RCT clinical trials (153 patients in the Ligustrazine treatment group and136 in the control group) conducted to analyze the UAER.
Figure 5 shows the forest plot for the UAER comparison. The results show thatLigustrazine could significantly reduce UAER compared to the control group in DNpatients (SMD: �21:42, 95% CI: �29:01, �13:83, p < 0:00001).
Adverse Effects
There was no meta-analysis of adverse effects due to lack of side effect reports in theseclinical trials.
Discussion and Conclusion
DN is currently the most common cause of end-stage kidney failure worldwide and isacknowledged as an independent risk factor for cardiovascular disease (Obineche andAdem, 2005). Once urinary albumin excretion is raised, it may be impossible to stop the
Figure 4. Effect of Ligustrazine on urine micro albumin in DN patients.
Figure 5. Effect of Ligustrazine on urinary albumin excretion rate in DN patients.
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progression of nephropathy completely; however, it is possible to substantially delay it.The roles of glucose control and blood pressure control are certain.
Ligustrazine is a monomer, its chemical name is 2,3,5,6-tetramethylpyrazine, molecularformula is C8H12N2, and molecular weight is 136.20 (Ho et al., 1989). Ligustrazine is anew effective drug to reduce urine protein, protect kidney function, and slow down the DN.In animal studies, Ligustrazine could reduce 24 h urine protein; inhibit glucose concen-tration and BUN elevation. Ligustrazine could also remarkably reduce the degree oflipoperoxidation (Lee et al., 2002). The therapeutic mechanisms of Ligustrazine on DNanimals include following aspects: first, it inhibits the over-expression of vascular endo-thelial growth factor (VEGF) (Huang et al., 2004) and monocyte chemotactic protein-1(MCP-1); second, it decreases the expression of connective tissue growth factor (CTGF),osteopontin (OPN) (Yang et al., 2008), ICAM-1 (Yang and Xie, 2009), and aldosereductase (Wang et al., 2009).
Levels of BUN and SCr, which are generally considered as markers of renal function,were higher before treatment, implying the presence of diabetic kidney disease with renallesion. Proteinuria (macroalbuminuria) is the universal finding in progressive renal disease,and is viewed as a measure of the severity and determinant for diabetic renal diseaseprogression. Albuminuria is a marker for early DN, an independent predictor for mortality,and is associated with renal and cardiovascular risks (Cai et al., 2010; Parving, 2001).
The proteinuria that develops after induction of diabetes is mainly due to an increasedexcretion of an array of low molecular weight proteins where albumin comprises a rela-tively low proportion (5–20%) of total urinary protein (Pennel and Meinking, 1982;Siddiqui et al., 2010). UAER has been demonstrated to be a good clinical predictor of renallesions in DN (Parving et al., 2001; Viberti and Wheeldon, 2002).
Our results showed that levels of BUN and SCr were significantly decreased afterLigustrazine treatment compared to the control group. Administration of Ligustrazine alsosignificantly decreased 24 h urine protein, urine micro albumin and UAER in DN patients,which implicated its nephroprotective action. Current evidence suggested that Ligustrazinewas more efficacious on DN patients compared to the control group, and did not result inany additional safety problems.
It is important to mention that there are limitations in the present meta-analysis. Thequality of the RCTs was not of very high, because the follow-up was not used. Althoughthe main worldwide biomedical databases were searched to identify potential RCTs,publication bias could not be avoided completely.
In conclusion, our meta-analysis initially demonstrated the therapeutic effects ofLigustrazine on DN patients by improving renal function and reducing urine protein.However, follow-up was not used in the included RCTs. In the future, the mechanisms ofLigustrazine need to be carried out.
Acknowledgments
We thank Dr. Tianshen Wang for his effort in the English editing of the manuscript. Thiswork was sponsored by Clinical Advantage Project of the Chinese Academy of Traditional
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Chinese Medicine (CACMS05Y026), “Eleventh Five-Year” National Science and Tech-nology Support Project (2006BAI04A04-2-2), Great Platform of National New traditionalChinese Medicine “(2009ZX09301-005).
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