3.1 Research basic information and quality evaluation
In the literature search, 2,938 potentially related articles were found (PubMed: 621, Embase: 436, Cochrane: 1275, China Knowledge Network: 355, Wanfang Database: 143, Chinese Medical Database: 108). (Figure 1)
At last, 18 studies met the inclusion criteria for this review (16-33), including 1522 patients (763 in the TCM+WM group and 759 in the WM group). Commonly used WM are CD and Yinxingdamo Injection, and commonly used TCM include Qiming Granule, and Compound Xueshuantong Capsule (Table 1). A total of 16 studies reported total efficacy (16-25, 27, 29-33), 7 studies reported vision (17, 19, 20, 23, 26, 29, 31), 4 studies reported fundus efficacy (17, 26, 28, 29), 5 studies reported fasting blood glucose (FBG) (17, 26, 28, 29, 33), 3 studies reported 2 hours-blood glucose (2hPG) (26, 29, 33), 5 studies reported HbAlc (17, 26, 28, 29, 33), 4 studies reported triglycerides (TG) (17, 26, 28, 29), 5 studies reported total cholesterol (TC) (17, 26, 28, 29, 31), 3 studies reported high density lipoprotein (HDL) (17, 28, 31), 5 studies reported low-density lipoprotein (LDL) (17, 26, 28, 29, 31). Randomization was mentioned in all studies, but only 7 studies showed how to generate random distribution sequences (16, 18, 19, 22, 23, 30, 33). All the studies did not mention the information related to allocation hiding and blind method. (Figure 2, Figure 3)
Table 1 Basic characteristics of studies
Study
|
Intervention duration
|
Main Indicators
|
Combined
treatment
|
group
|
Number
(Number of eyes)
|
Gender
M/F
|
Age
|
DR staging(I/II/III)
|
Drug (dose)
|
Case exfoliation
|
JJ,2018(26)
|
12w
|
Visual acuity, fundus, blood sugar, blood lipid, inflammatory index
|
Hypoglycemia, hypotension, lipid regulation
|
WM+TCM
|
30
|
14/16
|
58.97
|
-
|
CD(500mg,tid)+ Yangyin Xiaoyu Mingmu Prescription(100ml,bid)
|
-
|
WM
|
30
|
15/15
|
59.2
|
-
|
CD(500mg,tid)
|
-
|
LWJ,2015(23)
|
9m
|
Visual acuity, symptom score
|
-
|
WM+TCM
|
38
|
32/44
|
57.4±2.8
|
-
|
CD (2 pills,tid)+ Qihuang Mingmu Capsule(4 pills,tid)
|
-
|
WM
|
38
|
|
|
CD(2 pills,tid)
|
-
|
SHL,2014(17)
|
3m
|
Visual acuity, fundus, blood sugar, blood pressure, blood lipids
|
Control of blood sugar
|
WM+TCM
|
43(86)
|
22/21
|
50.22±14.82
|
-
|
CD(2 pills,tid)+ Qiming Granule(4.5g,tid)
|
-
|
WM
|
43(86)
|
23/20
|
50.53±11.28
|
-
|
CD(2 pills,tid)
|
-
|
WQ,2018(22)
|
3m
|
Clinical efficacy
|
-
|
WM+TCM
|
44
|
18/26
|
58.4±7.5
|
-
|
CD(0.5g,tid)+ Qiming Granule(4.5g,tid)
|
-
|
WM
|
44
|
22/22
|
57.8±6.2
|
-
|
CD(0.5g,tid)
|
-
|
YXD,2018(31)
|
3m
|
Visual acuity, mydriasis fundus, anterior segment examination, blood sugar, blood lipid
|
Exercise diet therapy, hypoglycemia
|
WM+TCM
|
50
|
24/26
|
54.63±5.28
|
19/16/15
|
CD(0.5g,tid)+ Qiming Granule(1 bag,tid)
|
-
|
WM
|
46
|
25/21
|
55.27±5.42
|
18/13/15
|
CD(0.5g,tid)
|
-
|
HCL,2018(29)
|
12w
|
fundus score, blood sugar, blood lipid
|
Dietary Exercise, Hypotension, Lipid Regulation
|
WM+TCM
|
40(79)
|
-
|
58.95±11.13
|
18/15/7
|
CD(0.5g,tid)+ Tangzhiping Prescription(0.5 agents,bid)
|
3
|
WM
|
40(78)
|
-
|
58.40±9.21
|
17/17/6
|
CD(0.5g,tid)
|
2
|
JHZ,2014(19)
|
6m
|
Clinical symptoms, visual acuity, fundus, optical coherence tomography, Hemorheology
|
Standard diet to control blood sugar
|
WM+TCM
|
51
|
31/20
|
57.8±5.7
|
-
|
CD(0.5g,tid)+ Ziyin Yiqi Tongluo Recipe(100ml,bid)
|
-
|
WM
|
51
|
29/22
|
58.4±6.3
|
-
|
CD(0.5g,tid)
|
-
|
HXD,2017(20)
|
3m
|
Clinical efficacy, depression of lesion improvement score, visual acuity, TCM symptom score
|
-
|
WM+TCM
|
40
|
23/17
|
52.35±3.11
|
10/20/10
|
CD(0.5g,tid)+ Mimeng Flower decoction(0.5 agents,bid)
|
-
|
WM
|
40
|
24/16
|
52.31±3.07
|
8/22/10
|
CD(0.5g,tid)
|
-
|
LD,2018(30)
|
3m
|
Ophthalmic artery,Central retinal artery,Hypoxia-inducible factor-1α、Stromal cell-derived factor 1
|
Hypoglycemic drugs, diet and exercise
|
WM+TCM
|
45
|
27/16
|
48.34±6.49
|
21/13/11
|
CD(250-500mg,tid)+ Compound Xueshuantong Capsule(3 pills,tid)
|
-
|
WM
|
45
|
25/20
|
48.56±7.64
|
20/15/10
|
CD(250-500mg,tid)
|
-
|
XLP,2016(21)
|
6m
|
Visual acuity, slit lamp, intraocular pressure, fundus fluorescein angiography
|
Hypoglycemia, hypotension, lipid regulation
|
WM+TCM
|
110(216)
|
69/41
|
49.5±5.9
|
-
|
CD(250-500mg,tid)+ Compound Xueshuantong Capsule(3 pills,tid)
|
-
|
WM
|
110(214)
|
68/42
|
50.2±6.4
|
-
|
CD(250-500mg,tid)
|
-
|
PCS,2013(25)
|
3m
|
fluorescein fundus angiography, hemorheology, visual field agent flash electroretinogram, overall efficacy
|
Basic treatment of diabetes mellitus
|
WM+TCM
|
28(56)
|
12/16
|
51.7±10.9
|
14/22/20
|
CD(500mg,bid)+ Liangxue Sanyu Decoction(0.5 agents,bid)
|
7
|
WM
|
28(56)
|
13/15
|
49.3±8.9
|
13/26/17
|
CD(500mg,bid)
|
LHY,2019(16)
|
3m
|
Clinical efficacy, visual acuity
|
-
|
WM+TCM
|
60(60)
|
34/26
|
49.4±7.8
|
34/18/8
|
CD(1 pill,tid)+ Compound Xueshuantong Capsule(3 pills, tid)
|
-
|
WM
|
60(60)
|
32/28
|
50.3±7.4
|
34/16/10
|
CD(1pill,tid)
|
-
|
CR,2011(18)
|
3m
|
Clinical efficacy
|
Diabetic diet, hypoglycemic drugs
|
WM+TCM
|
30
|
23/7
|
50.13±6.74
|
11/7/12
|
CD(500mg,tid)+ Yiqi Yangyin Huoxue Prescription(100ml,tid)
|
-
|
WM
|
30
|
21/9
|
51.57±5.62
|
13/12/5
|
CD(500mg,tid)
|
-
|
JCX,2009(27)
|
5m-1y
|
Fundus examination, visual acuity
|
Hypoglycemia, hypotension and lipid regulation
|
WM+TCM
|
20
|
8/12
|
41-82
|
6/10/4
|
yinxingdamo injection(20ml,Intravenous drip)+ Liuwei Dihuang Decoction
|
-
|
WM
|
20
|
7/13
|
45-79
|
5/12/3
|
yinxingdamo injection(20ml,Intravenous drip)
|
-
|
ZSZ,2011(24)
|
4m
|
Clinical efficacy
|
Hypoglycemia, lipid regulation, hypotension
|
WM+TCM
|
20(38)
|
18/22
|
49.35
|
-
|
CD(500mg,tid)+TangWangLing(0.5 agents,bid)
|
-
|
WM
|
20(40)
|
|
|
|
CD500mg,tid
|
-
|
YYK,2016(28)
|
3m
|
Blood sugar, vision, fundus hemorrhage, exudation, microangioma
|
Hypoglycemia, lipid regulation, hypotension
|
WM+TCM
|
40
|
22/18
|
59.85±11.00
|
15/28/11
|
CD(0.5g,tid)+ Panax Notoginseng Powder(2g,tid)
|
-
|
WM
|
40
|
19/21
|
63.83±9.44
|
12/30/8
|
CD(0.5g,tid)
|
-
|
WZZ,2017(32)
|
3m
|
Average visual field sensitivity, related cytokines, efficacy, safety indicators
|
Scientific Dietary Exercise
|
WM+TCM
|
47(47)
|
26/21
|
54.3±4.9
|
14/18/15
|
CD(0.5g,tid)+ Qiming Granule(4.5g,tid)
|
NA
|
WM
|
47(47)
|
29/18
|
54.5±4.8
|
14/18/15
|
CD(0.5g,tid)
|
-
|
MJP,2018(33)
|
5m
|
Clinical efficacy, blood sugar, inflammatory factors
|
Symptomatic treatment
|
WM+TCM
|
27(34)
|
16/11
|
53.02±4.13
|
9/10/8
|
CD(3pills,tid)+ Compound Xueshuantong Capsule(3 pills,tid)
|
-
|
WM
|
27(34)
|
15/12
|
53.08±4.25
|
10/9/8
|
CD(3pills,tid)
|
-
|
Abbreviation: Intervention duration, m: month, w: week; Gender M/F, M: male, F: female.
3.2 Main Outcomes
3.2.1 Overall efficacy
All studies showed that the overall efficacy showed homogeneity (I2 = 0%). Statistical data were obtained by using fixed effect model. The results showed that the overall efficacy of TCM (including Compound Xueshuantong Capsule, Qiming Granule, and others) +WM in the treatment of NPDR was significantly better than that of WM alone [n = 1686, RR 1.24 (1.18, 1.30), P < 0.00001, I2 = 0%]. (Figure 4)
3.2.3 Vision
There is no difference in the vision level between the TCM+WM group and WM group before intervention (P < 0.27). The results showed that the vision after intervention were heterogeneity (I2=95%). The data were analyzed by random effect model. The results showed that compared with WM alone, TCM (including Qiming Granule, and others) +WM treatment of NPDR improved vision significantly [n=640, MD 0.16 (0.06, 0.27), P=0.003, I2=95%]. (Figure 5, Figure 6)
3.2.4 Retinal fundus
The results showed that the retinal fundus effect showed homogeneity (I2=0%). Statistical data were obtained by using fixed effect model. The results showed that compared with WM alone, TCM+WM in the treatment of NPDR fundus improved significantly [n = 553, RR 1.30 (1.19, 1.42), P < 0.00001, I2 = 0%]. (Figure 7)
3.2.5 FBG
There is no difference in FBG level between the WM group and the TCM+WM group before intervention (P = 0.16). The results of FBG showed heterogeneity in the two groups after intervention (I2=67%). Statistical data were obtained by random effect model. The results showed that compared with WM alone, TCM+WM could effectively reduce FBG level in NPDR patients [n=360, MD -0.56 (-0.91, -0.22), P=0.001, I2=67%]. (Figure 8, Figure 9)
3.2.6 2hPG
There is no difference in 2hPG level between the WM group and the TCM+WM group (P=0.71). The results showed that the 2hPG level after intervention showed homogeneity (I2=0%). Statistical data were obtained by using fixed effect model. The results showed that compared with WM alone, TCM+WM could effectively reduce the 2hPG level after intervention in patients with NPDR [n=194, MD-1.12 (-1.62, -0.61), P < 0.0001, I2=0%]. (Figure 10, Figure 11)
3.2.7 HbAlc
There is no difference in the HbAlc level between the WM group and the TCM+WM group before intervention (P=0.16). The results showed that the results of HbAlc after intervention showed heterogeneity (I2=72%). The data were analyzed by random effect model. The results showed that TCM+WM could effectively reduce the level of HbAlc in patients compared with WM alone [n=360, MD -0.85 (-1.28, -0.41), P=0.0001, I2=72%]. (Figure 12, Figure 13)
3.2.8 TG
There is no difference in TG level between the WM group and the TCM+WM group before intervention (P=0.53). Studies showed that after intervention, the results of TG showed heterogeneity (I2=69%). Random effect model was used to analyze the data. The results showed that compared with WM alone, TCM+WM could effectively reduce TG level in patients with NPDR [n=220, MD -0.65 (-0.79, -0.51), P < 0.00001, I2=0%], but not Qiming Granule (P=0.23). (Figure 14, Figure 15)
3.2.9 TC
There is no difference in the TC level between the WM group and the TCM+WM group before intervention (P = 0.10). All studies showed that TC after intervention showed heterogeneity (I2=91%). Random effect model was used to analyze the data. The results showed that TCM+WM could effectively reduce TC level in patients with NPDR compared with WM alone [n=220, MD-0.66 (-1.05, -0.27), P=0.0008, I2=71%), but not Qiming Granule (P=0.15). (Figure 16, Figure 17)
3.2.10 HDL
There is no difference in the HDL level between the WM group and the TCM+WM group before intervention (P=0.96). The results showed that after intervention, HDL showed heterogeneity (I2=99%). The data were analyzed by random effect model. Fig. 19 shows that there is no difference in the HDL level between the WM group and the TCM+WM group after intervention [n=262, MD 0.48 (-0.46, 1.41), P=0.32, I2=99%]. (Figure 18, Figure 19)
3.2.11 LDL
There is no difference in LDL level between the WM group and the TCM+WM group before intervention (P=0.32). The results showed that after intervention, LDL showed heterogeneity (I2=87%). Statistical data were obtained by random effect model. The results showed that compared with WM alone, TCM+WM could effectively reduce LDL level in patients with NPDR [n=402, MD-0.44 (-0.76, -0.11), P=0.009, I2=87%]. (Figure 20, Figure 21)
3.3 Adverse events
7 studies referred to adverse events (17, 20, 21, 26, 31-33), Only 1 study showed 2 cases of nausea and 2 cases of loss of appetite in the TCM+WM group, 2 cases of stomach discomfort and 3 cases of loss of appetite in the WM group (20). There was no difference between the two groups. No follow-up treatment of adverse reactions was mentioned in all studies.
3.4 Publication bias
Funnel charts are used to investigate publication bias. The funnel charts of the overall efficacy and fundus outcomes are basically symmetrical, indicating potential publication bias. Unpublished research may be considered a factor in publication bias. (Figure 22, Figure 23)