Evidence-Based Complementary and Alternative Medicine
Volume 2018 (2018), Article ID 2834650, 14 pages
https://doi.org/10.1155/2018/2834650

Review Article

Efficacy and Safety of the Injection of the Traditional Chinese Medicine Puerarin for the Treatment of Diabetic Peripheral Neuropathy: A Systematic Review and Meta-Analysis of 53 Randomized Controlled Trials

Baocheng Xie,¹ Qinghui Wang,¹ Chenhui Zhou,² Jiahuan Wu,¹ and Daohua Xu1,3

¹Department of Pharmacology, Guangdong Medical University, Dongguan 523808, China
²School of Nursing, Guangdong Medical University, Dongguan 523808, China
³Institute of Traditional Chinese Medicine and New Pharmacy Development, Guangdong Medical University, Dongguan 523808, China

Correspondence should be addressed to Daohua Xu; daohuax108@163.com

Received 7 September 2017; Accepted 17 December 2017; Published 24 January 2018

Academic Editor: Ciara Hughes

Copyright © 2018 Baocheng Xie et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Objective. The injection of the traditional Chinese patent medicine puerarin has been widely used in the treatment of various diseases such as angina pectoris or ischemic stroke. We aim to evaluate the efficacy and safety of puerarin injection for the treatment of diabetic peripheral neuropathy (DPN). Methods. A systematic literature search was performed in seven medical databases from their inception until June 2017. 53 studies with RCTs, totaling 3284 patients, were included in this meta-analysis. The included studies were assessed by the Cochrane risk of bias and analyzed by Review Manager 5.3 software. Results. The meta-analysis showed that puerarin injection for the treatment of DPN was significantly better compared with the control group in terms of the total effective rate. The result showed that puerarin injection for the treatment of DPN can significantly increase the probability of sensory nerve conduction velocity (SNCV) and motor nerve conduction velocity (MNCV) of the median and peroneal nerves. Conclusions. This meta-analysis demonstrated that puerarin injection may be more effective and safe for the treatment of DPN. However, further and higher quality RCTs are required to prove its efficacy and provide meaningful evidence for clinical treatment due to the poor methodological quality.

1. Introduction

Diabetic peripheral neuropathy (DPN) is one of the most common neuropathies of diabetes mellitus (DM) and can lead to foot ulceration and amputation [1]. It affects sensory, autonomic, and motor nerve functions [2]. The annual costs of DPN and its complications are 10.9 billion dollars with a cost-of-illness model in the United States [3]. The enormous therapeutic costs, pain interference with function, and disabilities lead to a significant impact on the quality of life (QOL) and life expectancy of DPN [4]. Available treatments can only ease symptoms and there is currently no effective treatment reversing the progression of DPN [5]. Western medicines such as methylcobalamin and neurotrophin are usually used in the treatment of DPN. But the therapeutic effect of the western medicine was poor in patients with DPN. The traditional Chinese patent medicine puerarin is one of the flavonoids extracted from Gegen and pharmacological studies have confirmed that puerarin injection can lower blood sugar, significantly improve the microcirculation, expand the coronary arteries, and reduce platelet aggregation. Puerarin injection has shown certain advantages in the treatment of DPN and has been widely used for more than 20 years in China. Dysfunction and damage of myelinated and unmyelinated fibers can lead to the symptoms of painful neuropathy, ulceration, and demyelination and axonal degeneration has been considered to be the sign of the pathology of human diabetic neuropathy [6]. Puerarin injection for the treatment of DPN could significantly increase the probability of sensory nerve conduction velocity and motor nerve conduction velocity [7]. However, the use of puerarin injection in the treatment of DPN in other countries is not high and the clinical efficacy of puerarin injection combined with some western medicine was not certain. Therefore, our study included 53 RCTs with a total of 3284 patients who were included in order to acquire high-quality evidence for the clinical efficacy and safety of puerarin injection in DPN, and we also performed subgroup analyses in order to timely find out the clinical efficacy of puerarin injection combined with western medicine in the treatment of DPN.

2. Methods

2.1. Literature Search

We searched clinical studies databases, including CBM, CNKI, PubMed, Embase, ClinicalTrials.gov, and Cochrane Central Register of Controlled Trials, from their inception until June 2017. We used the following search terms: (1) “Puerarin”, “Puerarin injection”, “Kakkonein injection” connected with “OR”; (2) “Diabetic peripheral neuropathy”, “peripheral neuropathy”, “Diabetic”, “diabetic complication” connected with “OR”; (3) “randomized controlled” or “Clinical Trials”. Then, the above search terms of (1), (2), and (3) were connected with “AND”. We manually searched the references of the original and review articles for possible related studies.

2.2. Study Selection

For the systematic review, we searched 53 clinical studies that met the following criteria: (1) studies including patients with DPN, (2) studies including patients who received puerarin injection therapy, (3) studies reported as RCTs, (4) studies where the control group received standard therapy or recovery treatment, and (5) studies that reported efficacy and safety issues.

2.3. Data Extraction and Quality Assessment

Two of the authors independently extracted the data of the literature and carried out a quality assessment process according to the predefined inclusion criteria. Differences between the two authors were resolved by discussion with the third author. We used the Cochrane risk of bias tool for the quality evaluation of the RCTs. This quality evaluating strategy included criteria concerning aspects of random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessors, incomplete outcome data, selective reporting, and other bias.

2.4. Statistical Analyses

In this meta-analysis, all statistical analyses were performed using RevMan software version 5.3 and we used RR with 95% CI for the analyses of dichotomous data, whereas the continuous data were presented as MD or SWD with 95% CI. Heterogeneity between the studies was determined using the chi-square test, with the statistic, where < 25% represents mild inconsistency, values between 25% and 50% represent moderate inconsistency, and values > 50% suggest severe heterogeneity between the studies. We defined > 50% as an indicator of significant heterogeneity among the trials. We used random-effects models to estimate the pooled results to minimize the influence of potential clinical heterogeneity among the studies and the statistical significance was assumed at . Subgroup analyses were assessed using the test. Sensitivity analyses were performed to evaluate the robustness of merged results, by removing individual studies. Publication bias was assessed by means of funnel plots.

3. Results

3.1. Search Results

A systematic search of studies published until June 2017 was performed through CBM, CNKI, PubMed, Embase, ClinicalTrials.gov, and Cochrane Central Register of Controlled Trials databases since their inception. A total of 361 literatures were searched and 53 studies were included in the inclusion criteria; the literature search procedure is shown in Figure 1.

Figure 1: Flow chart and strategy of the meta-analysis.

3.2. Study Characteristics

The general characteristics of the included studies are listed in Table 1. The included studies were 53 RCTs with a total of 3284 patients: the treatment group of puerarin injection combined with mecobalamin and the control group with mecobalamin (13 studies); the treatment group of puerarin injection combined with epalrestat and the control group with epalrestat (3 studies); the treatment group of puerarin injection combined with danshen injection and the control group with danshen injection (5 studies); the treatment group of puerarin injection combined with vitamins B₁ and B₁₂ and the control group with vitamins B₁ and B₁₂ (4 studies).

Table 1: Characteristics of included articles.

Study
Sample (T/C)
Mean (T/C)
Intervention
Course of disease
Follow-up
Evaluation

T
C
T
C

Zheng and Guo 2006 [8]
61.7/63.2
97/102
Pue (Ivgtt) + scopolamine (IV)
Vit B₁₂ (IM)
T2DM (6.7 y)
4 w
①④⑤

Wang et al. 2005 [9]
48
62/40
Pue (Ivgtt) + Mec (Ivgtt)
Mec (Ivgtt)
T2DM + DPN (1–4 m)
2 w
①⑤

Huang and Xu 2005 [10]
53/50
37/34
Pue (Ivgtt)
Anisodamine (Ivgtt)
T2DM (7.6 y) + DPN (2.3 y)
T2DM (8.3 y) + DPN (2.1 y)
20 d
①

Yu 2002 [11]
56.2/57.2
40/28
Pue (Ivgtt) + anisodamine (Ivgtt)
Danshen (Ivgtt)
T2DM (11.4 y) + DPN (7.6 y)
T2DM (12 y) + DPN (7.3 y)
30 d
①②③④⑤

Tan and Feng 2004 [12]
58.2/56.3
32/32
Pue (Ivgtt) + Vit B₁, B₆ (Ivgtt)
Vit B₁, B₆ (Ivgtt)
DM (10.3 y) + DPN (4.3 y)
DM (11.3 y) + DPN (3.5 y)
4 w
①②③④⑤

Yang 2003 [13]
Unclear
43/40
Pue (Ivgtt) + Mec (IM)
Vit B₁₂ (IM)
Unclear
Unclear
12 d
①

Li 2009 [14]
55/55
64/62
Pue (Ivgtt) + nimodipine (Ivgtt)
Nimodipine (Ivgtt)
DM (3–21 y) + DPN (4 m–6 y)
DM (3–25 y) + DPN (3 m–5 y)
4 w
①

Wang 2008 [15]
55/55.5
32/31
Pue (Ivgtt) + nimodipine (Ivgtt)
Nimodipine (Ivgtt)
DM (5–24 y) + DPN (4 m–6 y)
DM (2–25 y) + DPN (3 m–6 y)
4 w
①

Zhao 2011 [16]
70.5/38–79
40/40
Pue (Ivgtt) + Mec (Po)
Mec (Po)
DM (6.5 y) + DPN (4.2 y)
DM (2–24 y) + DPN (1–17 y)
8 w
①

Zhao and Du 2003 [17]
58.8/No
36/28
Pue (Ivgtt) + Mec (Ivgtt)
Mec (Ivgtt)
DM (6–20 y) + DPN (1–11 y)
Unclear
6 w
①②③④⑤

Yang et al. 2014 [18]
56/56
29/55
Pue (Ivgtt) + Mec (Ivgtt)
Mec (Ivgtt)
DM + DPN (9.6 y)
DM + DPN (9.5 y)
4 w
①②③④⑤

Chen 2008 [19]
55/53.5
40/38
Pue (Ivgtt) + alprostadil (Ivgtt)
Alprostadil (Ivgtt)
Unclear
Unclear
6 w
①

Zhang et al. 2005 [20]
57.3
80/77
Pue (Ivgtt) + prostaglandin E₁ (Ivgtt)
Prostaglandin E1 (Ivgtt)
Unclear
Unclear
14 d
①

Wang and Wu 2016 [21]
62.9/63.2
41/40
Pue (Ivgtt) + Epa (Po)
Epa (Po)
T2DM + DPN (12.7 y)
T2DM + DPN (13.0 y)
2 w
①②③④⑤

Yu and Tan 2003 [22]
58.2/58.8
32/32
Pue (Ivgtt) + Mec (IM)
Mec (Ivgtt)
DM (2–10 y) + DPN (5–56 m)
DM (2.5–11.5 y) + DPN (4–50 m)
20 d
①②③④⑤

Li and Xu 2003 [23]
57.2/58.3
47/32
Pue (Ivgtt) + Mec (Ivgtt)
Mec (Po)
DM (10.7 y) + DPN (3.5 y)
DM (8.8 y) + DPN (3.1 y)
4 w
①②③④⑤

Li and Wang 2011 [24]
47/47
48/46
Pue (Ivgtt) + Mec (Ivgtt)
Mec (Ivgtt)
DM (6 m–15 y) + DPN (6 m–5 y)
DM (8–15 y) + DPN (7–5 y)
6 w
①③⑤

Lan 2005 [25]
65.5/64.8
36/36
Pue (Ivgtt) + Mec (Ivgtt)
Danshen (Ivgtt)
DM + DPN (3 y)
DM + DPN (3.1 y)
6 w
①

Gong 2004 [26]
53.2/52.7
36/32
Pue (Ivgtt) + Mec (IM)
Mec (IM)
T2DM (10.2 y) + DPN (2.6 y)
T2DM (9.7 y) + DPN (2.7 y)
8 w
③⑤

Dou and Wu 2006 [27]
58.5/57.2
28/30
Pue (Ivgtt) + Epa (Po)
Epa (Po)
DM (6.4 y) + DPN (3.2 y)
DM (5.2 y) + DPN (3.0 y)
4 w
①②③④⑤

Peng 2013 [28]
56.2/57.9
40/40
Pue (Ivgtt) + Epa (Po)
Epa (Po)
T2DM (2–17 y) + DPN (4.1 y)
T2DM (2–18 y) + DPN (4.9 y)
4 w
①②③④⑤

Zhou and Wei 2003 [29]
35–75
53/42
Pue (Ivgtt)
Vit B₁, B₁₂ (IM)
Unclear
Unclear
30 d
①②④⑤

Chen et al. 2003 [30]
57.1/57
40/40
Pue (Ivgtt)
Vit B₁, B₁₂ (IM)
Unclear
Unclear
4 w
①②③④⑤

Liao and Chen 2008 [31]
64
21/21
Pue (Ivgtt)
Vit B₁, B₁₂ (IM)
Unclear
Unclear
2 w
①

Ma et al. 2001 [32]
58/55
21/20
Pue (Ivgtt)
Vit B₁ (Po) + Vit B₁₂ (IM)
DM + DPN (13 y)
DM + DPN (15 y)
15 d
①

Zhu 2013 [33]
61.3
31/31
Pue (Ivgtt)
Vit B
Unclear
Unclear
4 w
①

Chen and Tang 2001 [34]
56/54
32/20
Pue (Ivgtt) + Vit B₁, B₆ (IM)
Vit B₁, B₁₂ (IM)
DM (8.6 y) + DPN (7.2 y)
DM (9 y) + DPN (8 y)
20 d
①

Yang 2010 [35]
58.6/58.4
21/21
Pue (Ivgtt) + Mec (Po)
Mec (Po)
Unclear
Unclear
1 m
①②④⑤

Zhu 2009 [36]
59.6/60.3
25/24
Pue (Ivgtt) + α-lipoic acid (Ivgtt)
Pue (Ivgtt)
T2DM (11.9 y)
T2DM (11.6 y)
2 w
①②③④⑤

Zhu et al. 2001 [37]
54/56
50/42
Pue (Ivgtt)
Vit B₁₂ (I.M.)
DM (144 m) + DPN (28.3 m)
DM (132 m) + DPN (30.4 m)
20 d
①②③④

Zhong 2011 [38]
55/54
65/54
Sodium ozagrel (Ivgtt) + Pue (Ivgtt)
Vit B₁, B₁₂ (IM)
DM (4 y)
DM (3.9)
14 d
②④

Mo and Wang 2012 [39]
65.4/66.2
30/30
Pue (Ivgtt) + Mec (Po)
Pue (Ivgtt)
Unclear
Unclear
2 w
①

Zhang 2007 [40]
62/60
30/30
Pue (Ivgtt) + Mec (IM)
Mec (I.M.)
T2DM (12.3 y) + DPN (4.3 y)
T2DM (11.6 y) + DPN (3.9 y)
4 W
①②③④⑤

Yang and Zhang 2008 [41]
58.6/59.6
45/45
Pue (Ivgtt) + Mec (Po)
Mec (Po)
T2DM (9.7 y)
T2DM (10.0 y)
4 w
①

Yang and Li 2012 [42]
57.2
23/23
Pue (Ivgtt)
Conventional therapy
Unclear
Unclear
2 w
①

Dong and Ge 2015 [43]
46.4/45.6
43/43
Pue (Ivgtt) + Vit B₁, B₁₂
Vit B₁, B₁₂
Unclear
Unclear
4 w
②③④⑤

Zhang 2017 [44]
61/59.4
32/30
Pue (Ivgtt) + Vit B₁, B₁₂ (IM)
Vit B₁, B₁₂ (IM)
Unclear
Unclear
14 d
①②③④⑤

Lin et al. 2000 [45]
58.4/56.9
66/22
Pue (Ivgtt) + Vit B₁, B₁₂ (IM)
Mec (Po) + Vit B₁, B₁₂ (IM)
DM (12.8 y) + DPN (4.2 y)
DM (11.6 y) + DPN (3.9 y)
60 d
①②③④⑤

Tan 2001 [46]
55.6/56.2
47/38
Pue (Ivgtt) + Vit B
Vit B
DM (1–21 y) + DPN (1 m–10 y)
DM (1–20 y) + DPN (1 m–8 y)
60 d
①

Zhu and Quan 2000 [47]
Unclear
33/32
Pue (Ivgtt)
Danshen (Ivgtt)
Unclear
Unclear
3 w
①

T. He and Y. L. He 2002 [48]
56
36/40
Pue (Ivgtt)
Danshen (Ivgtt)
Unclear
Unclear
6 w
①

Zhang 2011 [49]
53.3/54.5
28/29
Pue (Ivgtt) + Vit B₁, B₁₂
Vit B₁, B₁₂
T2DM (6.5 y)
T2DM (6.8 y)
3 w
①

Song and Xu 2000 [50]
17–82
33/29
Pue (Ivgtt) + Mec (IM)
Vit B₁, B₁₂
Unclear
Unclear
4–8 w
①

Wang 2007 [51]
58.9/59.4
48/46
Pue (Ivgtt) + Mec (Po)
Mec (Po)
T2DM (15.6 y) + DPN (8.9 y)
T2DM (16.2 y) + DPN (8.7 y)
3 m
①②③④⑤

Feng et al. 2004 [52]
58.2/56.3
32/32
Pue (Ivgtt) + Mec (Ivgtt) + Vit B₁, B₆ (Ivgtt)
Mec (Ivgtt) + Vit B₁, B₆ (Ivgtt)
T2DM (10.3 y) + DPN (4.3 y)
T2DM (11.3 y) + DPN (3.8 y)
4 w
①②③④⑤

Hu and Li 2006 [53]
48
60/40
Pue (Ivgtt)
Vit B₁, B₁₂ (IM)
Unclear
Unclear
2 w
①

Zuo 2004 [54]
56.5
21/22
Pue (Ivgtt)
Danshen (Ivgtt)
Unclear
Unclear
3 m
①③⑤

Bai 2005 [55]
55.3/57.4
50/30
Pue (Ivgtt)
Conventional therapy
DM (11.8 y) + DPN (6.6 y)
DM (12.5 y) + DPN (7.1 y)
4 w
①②③④⑤

Li 2005 [56]
42.9/43.2
60/30
Pue (Ivgtt) + anisodamine (Ivgtt)
Anisodamine (Ivgtt)
DM + DPN (6.7 y)
DM + DPN (7.1 y)
3 w
②③④⑤

Mao 2006 [57]
54
32/20
Pue (Ivgtt) + Mec (IM)
Mec (IM)
Unclear
Unclear
4 w
①②③④⑤

Yang 2016 [58]
54.36/54.1
40/40
Pue (Ivgtt) + Vit B₁, B₆ (IM)
Vit B₁, B₆ (IM)
DM + DPN (8.24 y)
DM + DPN (8.10 y)
2 m
①

Peng and Ren 2005 [59]
Unclear
60/60
Pue (Ivgtt)
Conventional therapy
DM + DPN (4–16 y)
DM + DPN (4–22 y)
1 m
①④⑤

Dong 2015 [60]
54.18/55.3
40/41
Pue (Ivgtt)
Conventional therapy
Unclear
Unclear
2 m
①②③④⑤

Note. T: treatment group; C: control group; y: years; m: months; w: weeks; d: days; DM: diabetes mellitus; T2DM: type 2 diabetes mellitus; DPN: diabetic peripheral neuropathy; Pue: puerarin; Epa: epalrestat; Mec: mecobalamin; Vit B₁, B₆, B₁₂: vitamins B₁, B₆, and B₁₂; IV: intravenous infusion; IM: intramuscular injection; Ivgtt: intravenous guttae; Po: per os; ①: the total effective rate; ②: SNCV of median nerve; ③: SNCV of peroneal nerve; ④: MNCV of median nerve; ⑤: MNCV of peroneal nerve.

3.3. Quality Assessment

The risks of bias in the included studies were evaluated by the Cochrane assessment tool and these results are summarized in Figure 2. One study was at low risk of bias for random sequence and reported the details of allocation concealment. Forty-six studies were at an unclear risk of bias for blinding of participants and personnel according to the Cochrane collaboration tool. Thirty-one studies reported methods with a low risk of attrition bias and thirty studies reported a low risk of reporting bias.

(a)

(b)

Figure 2: Quality of RCTs according to the Cochrane Collaboration Manual. (a) Summary of RCTs quality showing the percentage of RCTs satisfying each risk of bias graph. (b) Detailed item-by-item analysis of the risk of bias summary.

3.4. Major Outcomes

3.4.1. The Total Effective Rate

The total effective rate was reported in 48 studies with a total of 3798 patients treated with puerarin injection and 2840 patients in the control group. The meta-analysis showed that puerarin injection for the treatment of DPN was significantly better compared with the control group in terms of the total effective rate (RR = 1.48, 95% CI = 1.39–1.59, ) (Figure 3).

Figure 3: Forest plot of the meta-analysis with the total effective rate.

3.4.2. Sensory Nerve Conduction Velocity

In 21 studies, the median nerve was included in the analysis and the results indicated that puerarin injection significantly increased the sensory nerve conduction velocity of the median nerve (MD = 3.55, 95% CI = 2.94–4.17, ) compared with the control group (Figure 4). The peroneal nerve was reported in 25 studies with a total of 900 patients treated with puerarin injection and 815 patients in the control group. The results showed that puerarin injection for the treatment of DPN can significantly increase the sensory nerve conduction velocity of the peroneal nerve (MD = 3.89, 95% CI = 3.18–4.59, ) (Figure 5).

Figure 4: Forest plot of the meta-analysis with SNCV of the median nerve.

Figure 5: Forest plot of the meta-analysis with SNCV of the peroneal nerve.

3.4.3. Motor Nerve Conduction Velocity

There were 27 studies with a total of 2106 patients in regard to peroneal nerve and 29 studies with a total of 2233 patients in regard to median nerve. Results of analysis indicated that puerarin injection for the treatment of DPN can significantly increase motor nerve conduction velocity of the median nerve (MD = 4.51, 95% CI = 3.69–5.43, ) and peroneal nerve (MD = 5.14, 95% CI = 4.87–5.41, ) compared with the control group (Figures 6 and 7).

Figure 6: Forest plot of the meta-analysis with MNCV of the median nerve.

Figure 7: Forest plot of the meta-analysis with MNCV of the peroneal nerve.

3.5. Subgroup Analysis

3.5.1. Puerarin Injection + Mecobalamin versus Mecobalamin

Patients with DPN were treated with puerarin injection and mecobalamin in the treatment group and with mecobalamin in the control group. The results of subgroup analysis showed that puerarin injection combined with mecobalamin therapy was more effective than mecobalamin in the total effective rate (RR = 1.31, 95% CI = 1.22–1.41, ), SNCV of the median nerve (MD = 3.64, 95% CI = 2.78–4.5, ), SNCV of the peroneal nerve (MD = 4.26, 95% CI = 2.98–5.55, ), MNCV of the median nerve (MD = 5.18, 95% CI = 3.51–6.85, ), and MNCV of the peroneal nerve (MD = 4.54, 95% CI = 3.23–5.85, ) (Table 2).

Table 2: Subgroup analysis.

Subgroups
Trials
Effects models
Pooled effect
95% Cl
value

The total effective rate

Pue + Mec versus Mec
11
Fixed
RR 1.31
1.22–1.41
0.00001

Pue + Vit B₁, B₁₂ versus Vit B₁, B₁₂
3
Fixed
RR 1.61
1.24–2.10
0.0004

Pue + Epa versus Epa
2
Fixed
RR 1.38
1.12–1.69
0.002

Pue versus Danshen
5
Fixed
RR 1.44
1.24–1.68
0.00001

SNCV of median nerve

Pue + Mec versus Mec
7
Random
MD 3.64
2.78–4.5
0.0001

Pue + Vit B₁, B₁₂ versus Vit B₁, B₁₂
2
Random
MD 5.43
4.16–6.7
0.00001

Pue + Epa versus Epa
3
Random
MD 3.43
1.28–5.58
0.002

SNCV of peroneal nerve

Pue + Mec versus Mec
8
Random
MD 4.26
2.98–5.55
0.00001

Pue + Vit B₁, B₁₂ versus Vit B₁, B₁₂
3
Random
MD 3.96
2.94–4.97
0.00001

Pue + Epa versus Epa
3
Random
MD 2.57
0.08–5.06
0.04

Pue versus Danshen
2
Random
MD 3.10
1.91–4.29
0.00001

MNCV of median nerve

Pue + Mec versus Mec
7
Random
MD 5.18
3.51–6.85
0.00001

Pue + Vit B₁, B₁₂ versus Vit B₁, B₁₂
3
Random
MD 5.14
2.31–7.97
0.0004

Pue + Epa versus Epa
3
Random
MD 2.32
−0.7–5.34
0.13

MNCV of peroneal nerve

Pue + Mec versus Mec
10
Random
MD 4.54
3.23–5.85
0.00001

Pue + Vit B₁, B₁₂ versus Vit B₁, B₁₂
3
Random
MD 5.01
4.06–5.95
0.00001

Pue + Epa versus Epa
3
Random
MD 2.80
−0.40–6.00
0.09

Pue versus Danshen
2
Random
MD 9.35
−2.13–20.82
0.11

Note. Pue: puerarin; Epa: epalrestat; Mec: mecobalamin; Vit B₁, B₁₂: vitamins B₁ and B₁₂; Danshen: danshen injection; MD: weighted mean difference; RR: relative risk.

3.5.2. Puerarin Injection + Vitamins B₁ and B₁₂ versus Vitamins B₁ and B₁₂

Patients with DPN were treated with puerarin injection and vitamins B₁ and B₁₂ in the treatment group and with vitamins B₁ and B₁₂ in the control group. The results of subgroup analysis showed that puerarin injection combined with vitamins B₁ and B₁₂ therapy was better than vitamins B₁ and B₁₂ in the total effective rate (RR = 1.61, 95% CI = 1.24–2.10, ), SNCV of the median nerve (MD = 5.43, 95% CI = 4.16–6.7, ), SNCV of the peroneal nerve (MD = 3.96, 95% CI = 2.94–4.97, ), MNCV of the median nerve (MD = 5.14, 95% CI = 2.31–7.97, ), and MNCV of the peroneal nerve (MD = 5.01, 95% CI = 4.06–5.95, ) (Table 2).

3.5.3. Puerarin Injection + Epalrestat versus Epalrestat

Patients with DPN were treated with puerarin injection and epalrestat in the treatment group and with epalrestat in the control group. The results of subgroup analysis showed that puerarin injection combined with epalrestat therapy could significantly improve the total effective rate (RR = 1.38, 95% CI = 1.12–1.69, ) and increase the SNCV of the median nerve (MD = 3.43, 95% CI = 1.28–5.58, ) and peroneal nerve (MD = 2.57, 95% CI = 0.08–5.06, ) (Table 2).

3.5.4. Puerarin Injection versus Danshen Injection

Patients with DPN were treated with puerarin injection in the treatment group and with danshen injection in the control group. The results of subgroup analysis showed that puerarin injection therapy was more effective than danshen injection in the total effective rate (RR = 1.44, 95% CI = 1.24–1.68, ) and the SNCV of the peroneal nerve (MD = 3.10, 95% CI = 1.91–4.29, ) (Table 2).

3.6. Heterogeneity and Publication Bias

According to this meta-analysis, sensitivity analysis was performed using Galbraith plot for the total effective rate and SNCV of the peroneal nerve. The results showed that there was no substantial change in the total effective rate, indicating that the results of the meta-analysis were credible. But a significant heterogeneity was noted for SNCV of the peroneal nerve using the random-effects model ( > 50%) (Figure 8). A significant symmetry was noted for distribution in funnel plots of the total effective rate. The quantitation of Egger’s test with SNCV of the peroneal nerve (, 95% CI = −1.86–12.6) indicated that publication bias was not obvious in the included studies (Figure 9).

(a)

(b)

Figure 8: Meta-analysis of sensitivity. (a) Galbraith plot of the total effective rate. (b) Galbraith plot of SNCV of the peroneal nerve.

(a)

(b)

Figure 9: Meta-analysis of publication bias. (a) Funnel plot of the total effective rate. (b) Funnel plot of SNCV of the peroneal nerve.

3.7. Safety

In the 53 included studies, two studies reported that 8 patients had dizziness after injection in the puerarin group and the dizziness began to ease up after slowing down the intravenous infusion. One study reported that 2 patients felt facial fever and the other patients did not experience any other adverse drug reactions. There were 1 patient with nausea and 1 patient with diarrhea in the treatment group and 2 patients with nausea in the control group. No severe adverse drug reaction occurred in the treatment group and control group.

4. Discussion

4.1. Main Outcome

Puerarin is an isoflavone compound and it is the main active ingredient of Pueraria lobata. The pharmacological effects of puerarin can expand blood vessels, relieve vasospasm, and improve circulation. Puerarin injection as a traditional Chinese patent medicine has been widely used in the treatment of various diseases such as diabetic peripheral neuropathy (DPN), cardiovascular diseases, sudden deafness, angina pectoris, or ischemic stroke [18, 43, 44]. Our study included 53 RCTs with a total of 3284 patients who were included in order to acquire high-quality evidence for the clinical efficacy and safety of puerarin injection therapy in DPN. The result showed that puerarin injection for the treatment of DPN significantly improved the probability effect of total effective rate by 48% compared with control groups. Analyses of SNCV showed that puerarin injection for the treatment of DPN can significantly increase the conduction velocity of the median nerve and peroneal nerve by 3 m/s (). Analyses of MNCV demonstrated a significant improvement in the median nerve and peroneal nerve by 4 m/s (). The EMG showed that nerve conduction velocity increased by 1–5 m/s after treatment with puerarin injection.

4.2. Subgroup Analysis

Mecobalamin is one of the coenzyme forms of vitamin B₁₂, which can promote the synthesis of lecithin and the formation of neuronal myelin in the body. Moreover, mecobalamin can promote neuronal differentiation and replication [61, 62]. It was reported that mecobalamin could improve neuropathic symptoms. In our meta-analysis of subgroup analysis, the results showed that puerarin injection combined with mecobalamin therapy was more effective than mecobalamin in the total effective rate, SNCV of the median nerve and peroneal nerve, and MNCV of the median nerve and peroneal nerve. We analyzed the effect of puerarin injection and vitamins B₁ and B₁₂ in the treatment group and vitamins B₁ and B₁₂ in the control group. The results of subgroup analysis showed that puerarin injection combined with vitamins B₁ and B₁₂ therapy was better than vitamins B₁ and B₁₂ in the total effective rate, SNCV of the median nerve and peroneal nerve, and MNCV of the median nerve and peroneal nerve.

Epalrestat is a noncompetitive and reversible aldose reductase inhibitor used for the treatment of diabetic neuropathy by relieving oxidative stress and suppressing the polyol pathway [63, 64]. A study [65] reported that 2190 patients were treated with epalrestat, and the result showed that the improvement rate of the subjective symptoms was 75% and that of the nerve function test was 36%. We performed a meta-analysis on patients with DPN treated with puerarin injection combined with epalrestat in the treatment group and with epalrestat in the control group. The results of subgroup analysis showed that puerarin injection combined with epalrestat therapy could significantly improve the total effective rate by 38% and increase the SNCV of the median nerve and peroneal nerve, compared with the control group.

According to the above analysis, the clinical efficacy of puerarin injection combined with western medicine was significantly better than that of western medicine in the treatment of DPN.

4.3. Limitations and Critical Considerations

We must be tapered in view of the limitations of this meta-analysis with low quality, high heterogeneity, and publication bias. The study would lead to publication bias because of low quality trials, such as a lack of reporting about random sequence generation and concealment, especially in early and small trials. The review includes 53 RCTs, with 3284 patients, which were published in Chinese. Most of the studies were just referring to randomized trials, but there were no specific randomized trials of random sequence generation, allocation concealment, and blinding of outcome assessment. The methodological quality was generally low in most of the studies, which perhaps led to a risk of bias. Sensitivity analysis was performed using Galbraith plot and the results showed that there was no substantial change in the total effective rate, indicating that the results of the meta-analysis were credible. But a significant heterogeneity was noted for SNCV of the peroneal nerve and median nerve using the random-effects model ( > 50%). We considered high heterogeneity among studies as studies differed in design, underlying disease, follow-up duration, and the drugs of treatment. Reporting bias is an important issue of meta-analysis. Many results of negative studies may be filtered or hidden in such a way that the studies become positive and some negative studies would be unpublished. Symmetry was noted for distribution in funnel plots of the total effective rate. The quantitation of Egger’s test with SNCV of the peroneal nerve () indicated that publication bias was not obvious in the included studies.

5. Conclusions

In summary, this systematic review and meta-analysis demonstrated that puerarin injection may be effective and safe for the treatment of DPN. Subgroup analyses indicated that the clinical efficacy of puerarin injection combined with western medicines such as mecobalamin and epalrestat was significantly better than that of western medicine in the treatment of DPN. However, further and higher quality RCTs are required to prove its efficacy and provide meaningful evidence for clinical treatment due to the poor methodological quality and lack of adequate safety data.

Conflicts of Interest

The authors declare that there are no conflicts of interest.

Authors’ Contributions

Baocheng Xie and Qinghui Wang equally contributed to this work. Baocheng Xie and Qinghui Wang were responsible for the study concept and design and literature searching. Baocheng Xie, Qinghui Wang, Chenhui Zhou, and Daohua Xu were responsible for formal analysis and interpretation. Chenhui Zhou, Jiahuan Wu, and Daohua Xu performed searches, appraised and selected trials, extracted data, and contributed to data analysis and software.

Acknowledgments

This research was supported by the Natural Science Foundation of Guangdong Province, Social Science and Technology Development Project of Dongguan, and the Administration of Traditional Chinese Medicine of Guangdong Province.

References

S. Tesfaye, D. Selvarajah, R. Gandhi et al., “Diabetic peripheral neuropathy may not be as its name suggests: evidence from magnetic resonance imaging,” PAIN, vol. 157, supplement 1, pp. S72–S80, 2016.

S. Tesfaye, A. J. M. Boulton, and A. H. Dickenson, “Mechanisms and management of diabetic painful distal symmetrical polyneuropathy,” Diabetes Care, vol. 36, no. 9, pp. 2456–2465, 2013.

A. Gordois, P. Scuffham, A. Shearer, A. Oglesby, and J. A. Tobian, “The health care costs of diabetic peripheral neuropathy in the U.S.,” Diabetes Care, vol. 26, no. 6, pp. 1790–1795, 2003.

L. Prompers, M. Huijberts, and J. Apelqvist, “Resource utilisation and costs associated with the treatment of diabetic foot ulcers. Prospective data from the Eurodiale Study,” Diabetologia, vol. 51, no. 10, pp. 1826–1834, 2008.

M. Greig, S. Tesfaye, D. Selvarajah, and I. D. Wilkinson, “Insights into the pathogenesis and treatment of painful diabetic neuropathy,” Handbook of Clinical Neurology, vol. 126, pp. 559–578, 2014.

R. A. Malik, “Pathology of human diabetic neuropathy,” Handbook of Clinical Neurology, vol. 126, pp. 249–259, 2014.

J. Wu, X. Zhang, and B. Zhang, “Efficacy and safety of puerarin injection in treatment of diabetic peripheral neuropathy: a systematic review and Meta-analysis of randomized controlled trials,” Journal of Traditional Chinese Medicine, vol. 34, no. 4, pp. 401–410, 2014.

W. Zheng and B. Q. Guo, “Puerarin injection combined with scopolamine in treatment of diabetic peripheral neuropathy,” Medicine World, no. 11, pp. 22-23, 2006.

Y. H. Wang, Q. P. Yang, and G. P. Yang, “Effect of puerarin and methylcobalamin in injection on diabetic peripheral neuropathy,” Medical Information, vol. 18, no. 11, pp. 128-129, 2005.

Q. Y. Huang and J. H. Xu, “Clinical effect of puerarin injection in the treatment of diabetic peripheral neuropathy,” Chinese Journal of Integrative Medicine on Cardio-/Cerebrovascular Disease, vol. 3, no. 5, pp. 387-388, 2005.

J. Yu, “Effect of puerarin on electromyogram and blood rheology in diabetic peripheral neuropathy,” Journal of Sichuan of Traditional Chinese Medicine, vol. 20, no. 2, pp. 7-8, 2002.

J. F. Tan and K. Feng, “Puerarin in the treatment of diabetic peripheral neuropathy in 32 cases,” Chinese Journal of Integrated Traditional and Western Medicin, vol. 24, no. 7, p. 653, 2004.

X. F. Yang, “Observation of puerarin injection combined with mecobalamin in treating diabetic peripheral neuropathy,” China Journal of Modern Medicine, vol. 13, no. 11, p. 161, 2003.

H. M. Li, “To observe the effect of puerarin and nimodipine in treatment of diabetic peripheral neuropathy,” Chinese Journal of Practical Nervous Diseases, vol. 12, no. 17, pp. 59-60, 2009.

X. K. Wang, “To observe the effect of puerarin and nimodipine in treatment of diabetic peripheral neuropathy,” Journal of Clinical and Experimental Medicine, vol. 7, no. 09, p. 100, 2008.

P. Zhao, “To observe the curative effect of puerarin injection combined with methylcobalamin in treatment of diabetic peripheral neuropathy,” Chinese Journal of Modern Drug Application, vol. 5, no. 13, pp. 59-60, 2011.

J. Zhao and Q. P. Du, “Puerarin combined with mecobalamin on diabetic peripheral neuropathy clinical observation of 36 cases,” Shandong Medical Journal, vol. 43, no. 19, p. 8, 2003.

M. H. Yang, C. X. Yu, and L. Liu, “Efficacy and safety of puerarin injection combined with mecobalamin injection in treating diabetic peripheral neuropathy,” Journal Medical Forum, vol. 35, no. 10, pp. 64–66, 2014.

C. X. Chen, “Clinical analysis of puerarin injection combined with alprostadil in the treatment of diabetic peripheral neuropathy,” Medical of Journal Communications, vol. 22, no. 03, pp. 275-276, 2008.

C. Y. Zhang, M. X. Li, and Y. C. Han, “Clinical observation of puerarin combined with prostaglandin E1 in treatment of diabetic peripheral neuropathy,” Journal of Emergency in Traditional Chinese Medicine, vol. 14, no. 08, pp. 733–763, 2005.

J. X. Wang and W. P. Wu, “Curative effect observation of puerarin and epalrestat in the treatment of diabetic peripheral neuropathy,” Chinese Community Doctors, vol. 32, no. 21, pp. 44-45, 2016.

Q. Y. Yu and W. L. Tan, “Puerarin combined with methylcobalamin in treatment of diabetic peripheral neuropathy in 32 cases,” Hainan Medical Journal, vol. 14, no. 5, pp. 14-15, 2003.

X. M. Li and N. Xu, “Observation on effects of karonein combined with mecobalamin treating diabetic peripheral neuropathies,” Modern Diagnosis & Treatment, vol. 14, no. 2, pp. 65–67, 2003.

H. Y. Li and M. Z. Wang, “Clinical observation of puerarin injection combined with Mecobalamin in treatment of diabetic peripheral neuropathy,” Practical Clinical Journal of Integrated Traditional Chinese and Western Medicine, vol. 11, no. 5, pp. 6-7, 2011.

L. S. Lan, “Puerarin combined with methylcobalamin in treatment of diabetic peripheral neuropathy: report of 36 cases,” Acta Academiae Medicinae Jiangxi, vol. 45, no. 5, p. 163, 2005.

X. H. Gong, “Puerarin and mecobalamin in treating diabetic peripheral neuropathy,” Clinical Medicine, vol. 24, no. 4, pp. 60-61, 2004.

L. J. Dou and Q. Q. Wu, “Therapeutic effect of puerarin combined with epalrestat on diabetic peripheral neuropathy,” Qinghai Medical Journal, vol. 36, no. 12, pp. 9–11, 2006.

R. Peng, “Clinical effect of combination of puerarin and epalrestat in treatment with diabetic peripheral neuropathy patients,” Chinese Journal of Medicine Guide, vol. 15, no. 06, pp. 984–985,987, 2013.

L. P. Zhou and X. Q. Wei, “Efficacy of puerarin in the treatment of peripheral neuropathy in type 2 diabetes mellitus: a report of 53 cases,” Journal of Beijing University of Traditional Chinese Medicine, vol. 10, no. 1, pp. 7-8, 2003.

G. Z. Chen, M. Fang, J. R. Wang, and X. Chen, “Treatment of diabetic peripheral neuropathy with Puerarin,” Herald of Medicine, vol. 22, no. 3, pp. 171-172, 2003.

X. Liao and H. J. Chen, “Clinical observation of puerarin injection in the treatment of diabetic peripheral neuropathy in 42 cases,” Journal of Henan Medical College for Staff and Worker, vol. 20, no. 2, pp. 157-158, 2008.

H. C. Ma, S. F. Chen, and L. Tian, “Treatment of diabetic peripheral neuropathy with puerarin: a clinical observation of 21 cases,” Journal of Luoyang Medical College, vol. 19, no. 2, pp. 136-137, 2001.

J. G. Zhu, “Treatment of diabetic peripheral neuropathy with Puerarin: a clinical observation of 31 cases,” Drugs and Clinical, no. S1, pp. 232-233, 2013.

X. Chen and K. Tang, “Puerarin in the treatment of diabetic peripheral neuropathy in 32 cases,” Shaanxi Journal of Traditional Chinese Medicine, vol. 22, no. 3, pp. 132-133, 2001.

M. G. Yang, “Therapeutic effect of puerarin injection on diabetic peripheral neuropathy,” Modern Journal of Integrated Traditional Chinese and Western Medicine, vol. 19, no. 14, pp. 1753-1754, 2010.

S. L. Zhu, “Clinical observation of α-lipoic acid combined with puerarin injection in the treatment of diabetic peripheral neuropathy,” Chinese Journal of Practical Nervous Diseases, vol. 12, no. 19, pp. 59-60, 2009.

H. P. Zhu, R. C. Pu, and J. Xiong, “Therapeutic effect of Puerarin on diabetic peripheral neuropathy,” Journal of Chinese Physician, vol. 3, no. 4, pp. 310-311, 2001.

X. Y. Zhong, “Effects of puerarin combining with ozagrel injection on diabetic per ipheral neuropathy,” Journal of Hainan Medical University, vol. 17, no. 9, pp. 1182–1183+1186, 2011.

F. H. Mo and H. M. Wang, “To observe the curative effect of puerarin injection combined with methylcobalamin in treatment of diabetic peripheral neuropathy,” Xinjiang Medical Journal, vol. 42, no. 1, pp. 117-118, 2012.

S. H. Zhang, “Clinical observation of 30 cases of puerarin injection combined with mecobalamin on diabetic peripheral neuropathy,” Chinese Journal of Coal Industry Medicine, vol. 10, no. 4, pp. 429-430, 2007.

L. L. Yang and M. Zhang, “Observation of puerarin injection combined with methylcobalamin in treatment of diabetic peripheral neuropathy,” Chinese Community Doctors, vol. 10, no. 21, p. 44, 2008.

Q. L. Yang and J. G. Li, “Clinical application of puerarin injection in diabetic peripheral neuropathy,” Guide of China Medicine, vol. 10, no. 23, pp. 305-306, 2012.

S. D. Dong and A. L. Ge, “The application of puerarin injection into treating diabetic peripheral neuropathy,” Henan Traditional Chinese Medicine, no. 07, pp. 1698-1699, 2015.

L. W. Zhang, “Clinical observation of 62 cases of diabetic peripheral neuropathy treated with gegensu injection,” Journal of Aerospace Medicine, no. 04, pp. 410-411, 2017.

J. Y. Lin, L. Dai, and J. G. Xu, “Effects of puerar in injection on diabetic peripheral neuropathy,” Chinese Journal of Diabetes, vol. 5, no. 05, pp. 14–16, 2000.

S. Z. Tan, “Therapeutic effect of puerarin on diabetic peripheral neuropathy,” Journal of Chenzhou Medical College, vol. 3, no. 1, pp. 13–16, 2001.

S. Zhu and H. Quan, “Therapeutic effect of puerarin injection on diabetic peripheral neuropathy,” Journal of Changchun College of Traditional Chinese Medicine, vol. 16, no. 1, p. 24, 2000.

T. He and Y. L. He, “Therapeutic effect of puerarin injection on diabetic peripheral neuropathy,” Xinjiang Journal of Traditional Chinese Medicine, vol. 20, no. 5, pp. 11-12, 2002.

Y. M. Zhang, “Clinical observation of puerarin injection in the treatment of diabetic peripheral neuropathy,” Chinese Journal of Modern Drug Application, vol. 5, no. 1, p. 147, 2011.

H. L. Song and R. T. Xu, “Mecobalamin combined with puerarin in the treatment of diabetic peripheral neuropathy,” Liaoning Journal of Practical Diabetology, vol. 2, no. 2, pp. 25-26, 2000.

X. S. Wang, “Mecobalamin combined with puerarin in the treatment of diabetic peripheral neuropathy,” Journal of Gansu College of Traditional Chinese Medicine, vol. 24, no. 5, pp. 16–18, 2007.

K. Feng, J. F. Tan, Y. Hou, and Y. Z. Yang, “Clinical observation of puerarin effects on diabetic peripheral neuropathy,” Heilongjiang Medical Journal, vol. 28, no. 6, pp. 412-413, 2004.

X. P. Hu and C. Q. Li, “Clinical analysis of puerarin in the treatment of peripheral neuropathy in type 2 diabetes mellitus: a report of 60 cases,” Journal of Qiqihar Medical College, vol. 27, no. 1, p. 37, 2006.

X. Q. Zuo, “Clinical observation of puerarin in the treatment of diabetic peripheral neuropathy (DPN),” Journal of Sichuan of Traditional Chinese Medicine, vol. 22, no. 8, pp. 47-48, 2004.

X. T. Bai, “Treatment of diabetic peripheral neuropathy with puerarin: a clinical observation of 50 cases,” Journal of Clinical Internal Medicine, vol. 22, no. 4, pp. 270-271, 2005.

Z. S. Li, “Puerarin combined with anisodamine in the treatment of diabetic peripheral neuropathy,” Journal of Shandong University of Traditional Chinese Medicine, vol. 29, no. 3, pp. 204-205, 2005.

J. H. Mao, “Puerarin injection combined with mecobalamin in treatment of diabetic peripheral neuropathy,” Guangdong Medical Journal, vol. 27, no. 7, pp. 1093-1094, 2006.

Y. H. Yang, “Evaluation of the effect of puerarin injection in the treatment of diabetic peripheral neuropathy,” China Practical Medicine, no. 1, pp. 158-159, 2016.

Y. L. Peng and D. Ren, “Clinical observation on the treatment of 60 cases of diabetic peripheral neuropathy through puerarin injection together with common method,” Guiding Journal of Traditional Chinese Medicine, vol. 11, no. 1, pp. 34-35, 2005.

F. H. Dong, “Effect of puerarin injection on diabetic peripheral neuropathy and its influence on hemorheology,” Journal of Clinical Medicine in Practice, vol. 19, no. 17, pp. 114-115, 2015.

A. Miller, M. Korem, R. Almog, and Y. Galboiz, “Vitamin B12, demyelination, remyelination and repair in multiple sclerosis,” Journal of the Neurological Sciences, vol. 233, no. 1-2, pp. 93–97, 2005.

H. Mizukami, S. Ogasawara, S.-I. Yamagishi, K. Takahashi, and S. Yagihashi, “Methylcobalamin effects on diabetic neuropathy and nerve protein kinase C in rats,” European Journal of Clinical Investigation, vol. 41, no. 4, pp. 442–450, 2011.

Q.-R. Li, Z. Wang, W. Zhou et al., “Epalrestat protects against diabetic peripheral neuropathy by alleviating oxidative stress and inhibiting polyol pathway,” Neural Regeneration Research, vol. 11, no. 2, pp. 345–351, 2016.

K. Yama, K. Sato, N. Abe, Y. Murao, R. Tatsunami, and Y. Tampo, “Epalrestat increases glutathione, thioredoxin, and heme oxygenase-1 by stimulating Nrf2 pathway in endothelial cells,” Redox Biology, vol. 4, pp. 87–96, 2015.

S. Sharma and N. Sharma, “Epalrestat, an aldose reductase inhibitor, in diabetic neuropathy: an Indian perspective,” Annals of Indian Academy of Neurology, vol. 11, no. 4, pp. 231–235, 2008.