3.1 Basic information and quality evaluation
In the literature search, 3208 articles were found (PubMed: 648, EMBASE: 480, Cochrane: 1346, CNKI: 461, Wanang: 155, CBM: 118) (Fig 1). According to the inclusion criteria, 36 articles were selected. The basic information of the studies is summarized in Table 1, including the diagnostic criteria for DM and NPDR, clinical efficacy evaluation criteria, outcome indicators, basic interventions, number of patients, gender, age, intervention measures and duration of the treatment group and the control group. In Table 2, the TCM included in the study include Qiming granules, Compound Xueshuantong capsules, Qizhen Jiangtang granules, Mimenghua Fang, Tangwangkang capsules, Quyidi capsules, Tincture of Ginkgo biloba leaves, Zhenwu Decoction, Compound Danshen dropping pills, Tangluotong capsules, Danshen injection, Yougui pills, Jinlida granules & Tongxinluo capsules, Qizhi Tongluo capsules & Qiju Dihuang pills, Danggui Buxue Decoction. According to the results of subgroup analysis of different TCM, the results were summarized. In Fig 2, the quality of the included studies was evaluated. Three of the included studies were of high quality (16-18), a total of 13 studies described random (16-28), and three studies adopted blind method (16-18).
Table 1 Basic characteristics of included studies
Reference
|
diagnostic criteria
|
Efficacy criteria
|
Outcome
|
Basic treatment
|
Number
|
Sex(M/F)
|
Age (years)
|
Intervention measures
|
Duration
|
SONG JT
2004(25)
|
1997 WHO
|
2002 GNCM
|
Vision,Fundus photography,FFA
|
CBS
|
T:231
|
160/71
|
59.85±10.52
|
Qiming granule(4.5g,tid)
|
3/6mo
|
1985 SFC
|
C:111
|
40/51
|
59.29±7.62
|
CH(0.5g,bid)
|
LI R
2006(21)
|
1997 WHO
|
2002 GNCM
|
Vision,FFA
|
CBS
|
T:30
|
NA
|
61.37±9.19
|
Tangwangkang capsule(1.5g,tid)
|
3mo
|
1985 SFC
|
C:24
|
59.33±10.91
|
CH(0.5g,tid)
|
DUAN JG
2005(18)
|
1999 WHO
|
2002 GNCM
|
Vision、FFA、Fundus photography
|
CBS
|
T:107
|
42/65
|
59.617±8.463
|
Qiming granule(4.5g,tid) +CH placebo(0.5g,bid)
|
3mo
|
1984 FCDC
|
C:105
|
45/60
|
58.733±9.411
|
CH(0.5g,bid)+ Qiming granule placebo(4.5g,tid)
|
WU L
2009(17)
|
NA
|
NA
|
curative effect
|
NA
|
T:20
|
11/9
|
55.04±7.05
|
Qihuangmingmu capsule (4 grains,tid)+ CH (2 grains,tid)
|
12w
|
PPP
|
C:24
|
8/16
|
56.07±6.82
|
Qihuangmingmu capsule placebo(4 grains,tid) + CH(2 grains,tid)
|
LIN WX
2011(29)
|
NA
|
2002年GNCM
|
Vision,EOF
|
NA
|
T:60(120v
|
16/14
|
52.6;56
|
Compound Xueshuantong capsule(2 grains,tid)
|
3mo
|
1984 FCDC
|
C:30(60 eyes
|
14/16
|
54
|
Pancreatic kininogenase(120U,tid)
|
ZANG LH
2011(30)
|
NA
|
2002 GNCM
|
Vision,EOF,FFA
|
NA
|
T:41(82 eyes
|
48/34
|
36-63
|
Qiming granule(4.5g,tid)
|
3mo
|
1984 FCDC
|
C:41(82 eyes
|
CH(0.5g,tid)
|
YAN J
2013(31)
|
NA
|
2002 GNCM
|
Vision,EOF,FFA
|
NA
|
T:124
|
NA
|
NA
|
Mi Meng Hua Fang(0.5 agents,bid)
|
3mo
|
1984 FCDC
|
C:121
|
CH(0.5g,bid)
|
YANG L
2013(32)
|
1999 WHO
|
NA
|
Vision,EOF
|
CBS
|
T:35
|
17/18
|
50.23±7.15
|
Qiming granule(4.5g,tid)
|
6mo
|
1984 FCDC
|
C:36
|
18/18
|
50.94±8.01
|
—
|
SUI HL
2014(33)
|
NA
|
NA
|
Vision,EOF,FFA
|
CBS
|
T:43
|
22/21
|
50.22±14.82
|
Qiming granule(4.5g,tid)
|
3mo
|
NA
|
C:43
|
23/20
|
50.53±11.28
|
CH(0.5g,tid)
|
LIAN FM
2015(16)
|
NA
|
NA
|
FFA,EOF
|
CBS
|
T:56
|
27/29
|
58.9±8.1
|
Compound Danshen dropping pills( 20 pills,tid)
|
12w
|
AAO
|
C:56
|
25/31
|
58.9±7.6
|
Placebo( 20 pills,tid)
|
LIU SL
2015(34)
|
NA
|
NA
|
curative effect
|
CBS
|
T:40
|
23/17
|
55.63±12.28
|
Qiming Jiangtang granules(10g,tid)
|
6mo
|
2002
|
C:40
|
21/19
|
57.15±13.62
|
VitC,vitb12,Rutin Tablets
|
KONG WJ
2015(35)
|
NA
|
DCOC
|
Vision,EOF,Retinal circulation time
|
NA
|
T:36
|
24/12
|
45.15±3.26
|
Qiming granule(4.5g,tid)
|
180d
|
Practical Ophthalmology (3rd Edition)
|
C:36
|
22/14
|
46.77±4.06
|
CH (0.5g, tid)
|
|
LI WJ
2015(24)
|
NA
|
GPTDF
|
Vision,EOF
|
NA
|
T:38
|
32/44
|
57.4±2.8
|
CH( 2 grains,tid) + Qihuangmingmu capsule(4 grains,tid)
|
3mo
|
PPP
|
C:38
|
|
|
CH( 2 grains,tid)
|
SHI JC
2015(36)
|
NA
|
SDCTC
|
Vision,EOF
|
CBS
|
T:28
|
14/14
|
56.3±5.8
|
Quyidi capsule
|
24w
|
NA
|
C:28
|
15/13
|
54.3±4.6
|
—
|
CHEN XL
2016(19)
|
NA
|
NA
|
Vision,FFA,EOF
|
NA
|
T:60(114 eyes
|
46/74
|
52
|
Whole retinal photocoagulation + Huo Xue Ming Mu Pian(1.5g,tid)
|
3mo
|
2001 International Conference on ophthalmology (Sydney)
|
C:60(112 eyes
|
|
|
Whole retinal photocoagulation
|
ZHU CY
2016(37)
|
1999 WHO
|
NA
|
Vision,FFA
|
CBS
|
T:41(78 eyes
|
21/20
|
62.64±3.80
|
Aspirin enteric coated tablets( 100mg,qd)+ Tincture of Ginkgo biloba leaves(2ml,tid)
|
6mo
|
2014 FOCMA
|
C:39(72 eyes
|
20/19
|
61.37±5.63
|
Aspirin enteric coated tablets( 100mg,qd)
|
LIU X
2016
|
NA
|
NA
|
Vision,EOF
|
CBS
|
T:49
|
55/43
|
65.6±2.9
|
CH(1g,bid) or Pancreatic kininogenase(120IU,tid)+ Zhenwu Decoction(0.5 agents,bid)
|
3mo
|
DCDR
|
C:49
|
|
|
CH(1g,bid) or Pancreatic kininogenase(120IU,tid)
|
YAO YK
2016
|
NA
|
NA
|
Vision,EOF
|
CBS, BP, blood lipid
|
T:40
|
22/18
|
51
|
CH(0.5g,tid) + Sanqi powder(2g,tid)
|
3mo
|
1985 SFC
|
C:40
|
19/21
|
50
|
CH(0.5g,tid)
|
SUN GX
2016
|
1999 WHO
|
2002 GNCM
|
Vision,EOF,FFA,OCT
|
NA
|
T:64(128 eyes
|
32/32
|
48.98±9.34
|
Compound Xueshuantong capsule(1.5g,tid)
|
6mo
|
Global diabetic retinopathy project 2002
|
C:64(120 eyes
|
36/28
|
49.81±8.55
|
CH( 600mg,tid)
|
ZHANG Y
2016
|
NA
|
NA
|
Vision,EOF,FFA
|
CBS
|
T:45
|
44/47
|
45-70
|
Qiming granule(4.5g,tid)
|
6mo
|
NA
|
C:46
|
|
|
—
|
LUO D
2016
|
1999 WHO
|
NA
|
Vision,Fundus examination
|
Diet and sports education
|
T:30(60 eyes
|
13/17
|
58.5
|
Tangluotong granules, (0.5 agents,tid)
|
12w
|
1985 SFC
|
C:30(60 eyes
|
16/14
|
57.8
|
CH(0.5g,tid)
|
XIAO LP
2016
|
NA
|
NA
|
Vision,Slit lamp,Intraocular pressure,EOF
|
CBS, Blood pressure, blood lipid
|
T:110(216 eyes
|
69/41
|
49.5±5.9
|
CH(0.5g/0.25g,tid) + Compound Xueshuantong capsule( 3 capsules,tid)
|
6mo
|
1985
|
C:110(214 eyes
|
68/42
|
50.2±6.4
|
CH(0.5g/0.25g,tid)
|
ZHENG Q
2016
|
NA
|
NA
|
EOF,macular edema
|
NA
|
T:47
|
29/18
|
44.94±5.36
|
Qiming granule(4.5g,tid)
|
180d
|
NA
|
C:41
|
25/16
|
46.72±5.43
|
CH(0.5g,tid)
|
WANG ZZ
2017
|
NA
|
NA
|
curative effect,Vision,Fundus photography,Visual field sensitivity
|
Diet and sports education
|
T:47(47 eyes
|
29/18
|
54.5±4.8
|
CH(0.5g,tid) + Qiming granule(4.5g,tid)
|
3mo
|
GDTDR
|
C:47(47 eyes
|
26/21
|
54.3±4.9
|
CH(0.5g,tid)
|
ZHANG Y
2017
|
1999 WHO
|
2002 GNCM
|
Vision,EOF
|
CBS
|
T:40
|
24/16
|
48.55±11.17
|
Qizhen Jiangtang granules( 1 bag,tid)
|
3mo
|
2014 FOCMA
|
C:40
|
27/13
|
48.61±11.26
|
—
|
DAI GL
2017
|
NA
|
NA
|
Vision,EOF
|
CBS
|
T:40
|
45/35
|
52.24±4.75
|
CH(0.5g,tid) + Danhong injection(40ml,qd)
|
3mo
|
NA
|
C:40
|
|
|
CH(0.5g,tid)
|
LI C
2017
|
1999 WHO
|
NA
|
Vision,Macular thickness
|
CBS
|
T:58
|
32/26
|
62.23±7.54
|
Photocoagulation + Compound Xueshuantong capsule( 3 capsules,tid)
|
3mo
|
NA
|
C:58
|
28/30
|
61.57±6.89
|
Photocoagulation
|
HU XD
2017
|
NA
|
SDCTC
|
Vision,EOF
|
NA
|
T:40
|
23/17
|
52.35±3.11
|
CH( 2 tablets,bid) + Mi Meng Hua Fang(0.5 agents,bid)
|
3mo
|
Practical Ophthalmology
|
C:40
|
24/16
|
52.31±3.07
|
CH( 2 tablets,bid)
|
YIN XD
2018
|
NA
|
NA
|
Vision,EOF
|
CBS
|
T:50
|
24/26
|
54.63±5.28
|
CH( 2 tablets,tid) + Qiming granule(4.5g,tid)
|
3mo
|
NA
|
C:46
|
25/21
|
55.27±5.42
|
CH( 2 tablets,tid)
|
WEI G
2018
|
1999 WHO
|
2002 GNCM
|
Vision,Fundus photography,FFA
|
CBS
|
T:30
|
12/18
|
58.13±8.42
|
CH(0.5g,tid)+ Jinlida granules(0.5g,tid) + Tongxinluo capsule(1.04g,tid)
|
12w
|
1985 SFC
|
C:32
|
14/18
|
58.29±7.56
|
CH(0.5g,tid)
|
LIU D
2018
|
NA
|
NA
|
curative effect
|
CBS
|
T:45
|
27/16
|
48.34±6.49
|
CH (500mg /250mg,tid)+ Compound Xueshuantong capsule( 3 capsules,tid)
|
3mo
|
NA
|
C:45
|
25/20
|
48.56±7.64
|
CH (500mg /250mg, tid)
|
YANG M
2018
|
NA
|
NA
|
Vision,EOF
|
CBS
|
T:32
|
42/22
|
65.8±3.4
|
CH (1 tablets,tid)or Pancreatic kininogenase(120IU,tid) + YouguiWan(0.5 agents,bid)
|
3mo
|
2014 FOCMA
|
C:32
|
|
|
CH (1 tablets,tid)or Pancreatic kininogenase(120IU,tid)
|
WANG Q
2018
|
NA
|
NA
|
curative effect
|
NA
|
T:44
|
22/22
|
57.8±6.2
|
CH(0.5g,tid)+ Qiming granule(4.5g,tid)
|
3mo
|
NA
|
C:44
|
18/26
|
58.4±7.5
|
CH(0.5g,tid)
|
FAN YP
2018
|
NA
|
2002 GNCM
|
Macular thickness,Retinal circulation time,Vision
|
CBS
|
T:47(60 eyes
|
26/21
|
48.6±5.1
|
CH(0.5g,tid) + Qiming granule(4.5g,tid)
|
6mo
|
Practical Ophthalmology
|
C:47(60 eyes
|
27/20
|
47.5±4.9
|
CH(0.5g,tid)
|
LIU LW
2019
|
NA
|
2002 GNCM
|
Vision,EOF,Hemorheology
|
CBS
|
T:30
|
14/16
|
51.2±3.9
|
CH(0.5g,tid) + Qizhi Tongluo Capsule (4 pills, bid)+ Qiju Dihuang pill( 8 pills, tid)
|
3mo
|
2014 FOCMA
|
C:32
|
15/17
|
52.5±5.1
|
CH(0.5g,tid)
|
SUN XH,2019
|
GPTDC
|
2002 GNCM
|
Vision,Fundus examination,macular edema
|
CBS
|
T:48(92 eyes
|
30/18
|
55.9±3.5
|
CH(0.5g,tid) + Danggui Buxue Decoction( 0.5 agents,bid)
|
3mo
|
NA
|
C:48(90 eyes
|
31/17
|
55.3±3.7
|
CH(0.5g,tid)
|
Abbreviation: 1999 WHO (1999 world health organization diagnostic Standard); 2002 GNCM (Guiding principles for clinical research of new Chinese Medicine); DCOC:Diagnostic criteria for clinical efficacy of ophthalmology in China; GPTDF:Guidelines for the prevention and treatment of diabetic fundus diseases; SDCTC :The standard of diagnosis and curative effect of traditional Chinese Medicine; AAO :American Association of Ophthalmology, 2006; GPTDC: Guidelines for the prevention and treatment of type 2 diabetes in China (2017); GDTDR:Guidelines for clinical diagnosis and treatment of diabetic retinopathy in China ; DCDR :Diagnostic criteria of diabetic retinopathy;EOF(examination of ocular fundus); SFC:The standard of fundus diseases group in China; FCDC: The first Chinese Fundus Disease Conference;FOCMA:Fundus lesions group, ophthalmology society, Chinese Medical Association; CH:Calcium hydroxybenzenesulfonate; CBS:Control blood sugar;PPP: Preferred Practice Pattern;BP: blood pressure;BL: blood lipid;T:Test group;C: control group;
Table 2 Composition and function of included TCM
TCM
|
Compose
|
Main functions
|
Reference
|
Results (efficiency)
|
Qiming granule
|
Astragaluspropinquus Schischkin,Puerariamontana var. lobate (Willd.) Sanjappa & Pradeep,Rehmannia glutinosa (Gaetn.) Libosch. ex Fisch. et Mey.,FRUCTUS LYCII,Seed of Cassia toraLinn,Seed of Leonurus japonicus Houtt.,Typha angustifolia L.,Whitmania pigra Whitman
|
Replenishing qi and promoting body fluid, nourishing liver and kidney, clearing collaterals and brightening eyes
|
(18, 20, 25, 27, 30, 32, 33, 35, 38-41)
|
n=1594, RR 1.30 (1.18, 1.43), P<0.00001, I2=67%
|
Compound Xueshuantong capsule
|
Panaxnotoginseng(Burk.)F.H.Chen,Astragaluspropinquus Schischkin,Salvia miltiorrhiza Bge.,Scrophularia ningpoensis Hemsl.
|
Promoting blood circulation and removing blood stasis, benefiting qi and nourishing yin
|
(17, 22, 24, 26, 29, 42, 43)
|
n=1064, RR 1.20 (1.12, 1.29), P<0.00001, I2=0%
|
Qizhen Jiangtang granules
|
Astragaluspropinquus Schischkin,Ligustrum thibeticum Decne.,Cornus officinalis Sieb. et Zucc.,Coptis chinensis Franch.,Rhus chinensis Mill.
|
Nourishing liver and kidney
|
(34, 44)
|
n=160, RR 1.32 (1.11, 1.58), P=0.002, I2=0%
|
Mi Meng Hua Fang
|
Buddleja officinalis Maxim.,Coptis chinensis Franch.,Cinnamomum cassia Presl,Astragaluspropinquus Schischkin,Ligustrum thibeticum Decne.,Leonurus artemisia (Laur. )S. Y. Hu F
|
Invigorating qi and Yin, promoting blood circulation and eyesight
|
(45)
|
NA
|
Tangwangkang capsule
|
Astragaluspropinquus Schischkin,Ligustrum thibeticum Decne.,Angelica sinensis,Salvia miltiorrhiza Bge.,Carthamus tinctorius L.,FRUCTUS LYCII,Panaxnotoginseng(Burk.)F.H.Chen,Ligusticum chuanxiong hort
|
Invigorating Qi, nourishing Yin, removing blood stasis and brightening eyes
|
(21)
|
NA
|
Quyidi capsule
|
Astragaluspropinquus Schischkin,Panax ginseng C. A. Mey.,Rehmannia glutinosa (Gaetn.) Libosch. ex Fisch. et Mey.,Atractylodes lancea (Thunb.) DC.,Poria cocos (Schw.) Wolf,Scrophularia ningpoensis Hemsl.,Polygonatum sibiricum,Polygonatum odoratum (Mill.)Druce,Pinellia ternata(Broiled),Coptis chinensis Franch.,Whitmania pigra Whitman,Scolopendridae
|
Invigorating Qi, nourishing Yin, promoting blood circulation and eliminating phlegm
|
(36)
|
NA
|
Tincture of Ginkgo biloba leaves
|
Ginkgo biloba L.
|
Promoting blood circulation, removing blood stasis and unblocking collaterals
|
(37)
|
NA
|
Zhenwu Decoction
|
Poria cocos(Schw.)Wolf,Paeonia lactiflora Pall.,Zingiber officinale Roscoe,Aconitum carmichaelii Debx,Atractylodes macrocephala Koidz.
|
Warming Yang, benefiting qi and benefiting water
|
(46)
|
NA
|
Compound Danshen Dropping Pill
|
Panaxnotoginseng(Burk.)F.H.Chen,Salvia miltiorrhiza Bge.,Borneolum Syntheticum
|
Promoting blood circulation and removing blood stasis, regulating qi and relieving pain
|
(16)
|
NA
|
Tangluotong granules
|
Rehmannia glutinosa (Gaetn.) Libosch. ex Fisch. et Mey.,Dioscoreaoppositifolia L.,Panax quinquefolius,Cornus officinalis Sieb. et Zucc.,CORTEX MOUTAN,Cuscuta chinensis Lam.,Cistanche deserticola Ma,Angelica sinensis,Leonurus artemisia (Laur. )S. Y. Hu F,twig of Winged Euonymus,Ligustrum thibeticum Decne.,FRUCTUS LYCII,Panaxnotoginseng (Burk.) F.H.Chen
|
Invigorating Qi, nourishing Yin, promoting blood circulation and removing stasis
|
(47)
|
NA
|
Danhong injection
|
Salvia miltiorrhiza Bge.,Carthamus tinctorius L.
|
Promoting blood circulation and removing blood stasis
|
(48)
|
NA
|
You Gui pill
|
Rehmannia glutinosa (Gaetn.) Libosch. ex Fisch. et Mey.,Aconitum carmichaeli Debx.,Cinnamomum cassia Presl,Dioscoreaoppositifolia L.,Cornus officinalis Sieb. et Zucc. (processing with wine),Cuscuta chinensis Lam.,Colla Corni Cervi,FRUCTUS LYCII,Angelica sinensis,Eucommia ulmoides Oliver(Salt making)
|
Warming the kidney yang, filling the essence and stopping the remaining
|
(28)
|
NA
|
Jinlida granule, Tongxinluo capsule
|
Panax ginseng C. A. Mey.,Polygonatum sibiricum, Atractylodes lancea (Thunb.) DC.(bran-fry),Radix Sophorae Flavescentis,Ophiopogon japonicus (Linn. f.) Ker-Gawl.,Rehmannia glutinosa (Gaetn.) Libosch. ex Fisch. et Mey.,Cinnamomum cassia Presl,Fallopia multiflora (Thunb.) Harald.,Cornus officinalis Sieb. et Zucc.,Poria cocos(Schw.)Wolf,Eupatorium fortunei Turcz.,Coptis chinensis Franch.,Anemarrhena asphodeloides Bunge.,Epimedium brevicornu Maxim.,Salvia miltiorrhiza Bge.,Pueraria montana var. lobata (Willd.,Seed of Litchi chinensis Sonn.,Lycium chinense Mill.;Panax ginseng C. A. Mey.,Whitmania pigra Whitman,Buthus martensii Karsch,Paeonia lactiflora Pall.,Periostracum Cicadae,Eupolyph,aga sin,ensis Walker,Scolopendridae,Santalum album L.,Dalbergia odorifera T.Chen,Boswellia carterii Birdw.,Seed of Ziziphus jujuba Mill. var. spinosa (Bunge) Hu ex H. F. Chow,Borneolum Syntheticum
|
Invigorating qi and Yin, strengthening the spleen and promoting the circulation of Tianjin;Invigorating qi and promoting blood circulation, unblocking collaterals and relieving pain
|
(49)
|
NA
|
Qizhi Tongluo capsule, Qiju Dihuang Pill
|
Whitmania pigra Whitman,Geosaurus,Buthus martensii Karsch,Eupolyph,aga sin,ensis Walker,Bombyx mori Linnaeus,Borneolum Syntheticum,Astragaluspropinquus Schischkin,Salvia miltiorrhiza Bge.,Carthamus tinctorius L.,Aconitum gymnandrum Maxim.,Curcuma rcenyujin Y,H. Chenet C.Ling,Angelica sinensis,Spatholobus suberectus Dunn,Panax ginseng C. A. Mey.,Rhizoma Arisaematis Cum Bile,Paeonia lactiflora Pall.,Gastrodia elata Bl.,Curcuma longa L.,Ligusticum chuanxiong hort,Ilex pubescens Hook. et Arn.,Ophiopogon japonicus (Linn. f.) Ker-Gawl.,Schisandra chinensis (Turcz. )Baill.,Fructus Gleditsiae Abnormalis,Notopterygium incisum Ting ex H. T. Chang,Cinnamomum cassia Presl,Fallopia multiflora (Thunb.) Harald.;FRUCTUS LYCII,Dendranthema morifolium(Ramat. )Tzvel.,Rehmannia glutinosa (Gaetn.) Libosch. ex Fisch. et Mey.,Cornus officinalis Sieb. et Zucc.,CORTEX MOUTAN,Dioscoreaoppositifolia L.,Poria cocos (Schw.) Wolf,Alisma plantago-aquatica Linn.,
|
Invigorating Qi, promoting blood circulation and unblocking collaterals;Nourishing the kidney and nourishing the liver
|
(23)
|
NA
|
Danggui Buxue Decoction
|
Astragaluspropinquus Schischkin,Angelica sinensis
|
Invigorating qi and generating blood
|
(50)
|
NA
|
Abbreviation: NA:Not applicable.
3.2 Outcome
3.2.1 Overall efficacy
3.2.1.1 Subgroup analysis based on different TCM
The data were statistically analyzed by the random effect model. The results showed that the total curative effect of TCM in the treatment of NPDR was significant [n = 4028, RR 1.20 (1.16, 1.25), P < 0.00001, I2 = 35%], among which Qiming granule, Compound Xueshuantong capsule, Qizhen Jiangtang capsule, Mimenghua formula, Zhenwu Decoction, Danggui Buxue Decoction showed obvious therapeutic advantage, Qihuang Mingmu capsule, Tangwangkang capsule, Quyidi capsule, Tincture of Ginkgo biloba leaves, Danhong injection, Yougui Pill, Jinlida granule & Tongxinluo capsule, Qizhi Tongluo Capsule & Qiju Dihuang pill had no significant effect. (Fig 3)
3.2.1.2 Subgroup analysis on the combined use of drugs
The data were statistically analyzed by fixed effect model. The results showed that the total effect of TCM or with other treatment measures (including calcium dobesilate, aspirin, photocoagulation, calcium dobesilate or pancreatic kininogenase) on the treatment of NPDR was significant [n = 4028, RR 1.21 (1.17, 1.25), P < 0.00001, I2 = 35%], TCM alone, or plus calcium hydroxybenzene sulfonate, or photocoagulation, or calcium hydroxybenzene sulfonate or Pancreatic Kallidinogenase showed significant effect, among which Tincture of Ginkgo biloba leaves & aspirin had no significant effect. (Fig 4)
3.2.2 Fundus effect
The results of fundus efficacy showed heterogeneity (I2 = 93%). The data were statistically analyzed by random effect model. The results showed that the efficacy of TCM in the treatment of fundus was significant [n = 1901, RR 1.38 (1.15, 1.67), P = 0.0008, I2 = 93%]. (Fig 5)
3.2.3 Vision
The results of vision showed heterogeneity (I2 = 93%). The data were statistically analyzed by random effect model. The results showed that TCM treatment could significantly improve the vision of NPDR patients [n = 806, MD 0.17 (0.08, 0.25), P = 0.0002, I2 = 93%]. (Fig 6)
3.2.3 Macular thickness
The results of macular thickness showed heterogeneity (I2 = 94%). The data were statistically analyzed by random effect model. The results showed that TCM could significantly reduce macular thickness of the NPDR patients [n = 396, md-19.33 (- 32.24, - 6.41), P = 0.003, I2 = 94%]. (Fig 7)
3.2.4 Microangioma
The results of microangioma showed heterogeneity (I2 = 95%). The data were statistically analyzed by random effect model. The results showed that TCM could significantly reduce the micro angioma of NPDR patients [n = 352, md-1.40 (- 2.15, - 0.65), P = 0.0002, I2 = 95%]. (Fig 8)
3.2.5 Retinal circulation time
The results of retinal circulation time showed heterogeneity (I2 = 77%), and the random effect model was used. The results showed that the effect of TCM on retinal circulation time was not significant [n = 280, md-0.34 (- 0.86, - 0.18), P = 0.20, I2 = 77%]. (Fig 9)
3.2.6 Adverse events
A total of 15 studies mentioned adverse events (16-18, 20, 21, 25, 26, 33, 38, 39, 43-45, 49, 50) and 9 studies reported adverse events (16, 18, 20, 21, 25, 44, 45, 49, 50). The results showed heterogeneity (I2 = 29%), and the data were statistically analyzed with fixed effect model. The results showed that TCM was safer [n = 1243, MD 0.45 (0.29, 0.69), P = 0.0002, I2 = 29%]. (Fig 10)
3.3 Publication bias
The funnel chart shown in Fig 11 and Fig 12 is basically symmetrical, indicating the potential publication bias. Unpublished research may be considered a factor in publication bias.
3.3 Mechanism summary
The mechanism included in the treatment of NPDR with TCM mainly involves the intervention of polyol pathway (Qiming granules), oxidative stress (Compound Xueshuantong capsule, Qihuangmingmu capsule, Qiju Dihuang pill), reduction of VEGF (Compound Xueshuantong capsule, Qihuangmingmu capsule, Danhong injection), reduction of neuron damage (Mimenghua formula, Tincture of Ginkgo biloba leaves, Danhong injection), and improvement blood retinal barrier, reduce capillary permeability (Tangwangkang capsule, Tongxinluo capsule, Dangguibuxue Decoction), reduce advanced glycosylation accumulation (Qizhen Jiangtang granules), inflammation (Tongxinluo capsule).( Table 3, Fig 13 )
Table 3 Mechanism of TCM in treating DR
TCM
|
Mechanism
|
Qiming granule
|
Qiming granule can reduce the content of malondialdehyde in serum and retina, increase the activity of superoxide dismutase and glutathione peroxidase(51), inhibit the abnormal activity of polyol pathway in retina of diabetic rats, promote the increase of inositol synthesis, reduce the content of sorbitol, glucose and fructose (52), and reduce the expression of collagen IV in retinal vascular basement membrane(53).
|
Compound xueshuantong capsule
|
Compound xueshuantong capsule can reduce oxidative stress injury, decrease the expression of bioactive factor, VEGF and inducible nitric oxide synthetase, and up regulate the expression of pigment epithelium derived factor (54, 55)。
|
Qihuangmingmu capsule
|
Qihuangmingmu capsule can inhibit the expression of VEGF, recombinant human VEGF receptor-1, fetal liver kinase-1, transforming growth factor - β, insulin-like growth factor-I in diabetic mice, interfere with the signal transduction pathway of VEGF receptor, inhibit the phosphorylation level of p38 mitogen activated protein kinase (56-58), and reduce the visual net of diabetic mice expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin (59).
|
Mimenghua formula
|
Mimenghua formula can reduce the damage of retinal nerve cells in early stage of diabetic rats through the mechanism of glutamate and sigma-1r (60, 61); the serum containing Mimenghua formula can inhibit the apoptosis and damage of retinal ganglion-5 cells under the condition of high glucose, and its mechanism may be related to the regulation of brain-derived neurotrophic factor, the expression of ciliary neurotrophic factor and sigma-1r (62).
|
Tangwangkang capsule
|
Tangwangkang capsule can reduce blood glucose and capillary permeability of rats (63)。
|
Qizhen Jiangtang granule
|
Qizhen Jiangtang granule can reduce blood glucose, increase superoxide dismutase level and reduce the accumulation of advanced glycation end products (64)。
|
Quyidi capsule
|
None
|
Tincture of Ginkgo biloba leaves
|
Ginkgo biloba extract can effectively protect retinal ganglion cells, which may be related to the activation of NF-E2-related factor 2 / extracellular regulatory protein kinase pathway and the expression of Bcl-2 and p53 protein (65); increase the expression level of matrix metalloproteinase 9 and inducible nitric oxide synthetase, and reduce the damage of retinal ganglion cells (66).
|
Zhenwu Decoction
|
None
|
Tangluotong granules
|
None
|
Danhong injection
|
Danhong injection improves retinal ischemia and hypoxia by reducing VEGF, reduces retinal neovascularization, and can reduce retinal nerve cell apoptosis to a certain extent (67).
|
Jinlida granule & Tongxinluo capsule
|
Jinlida granules: None. Tongxinluo capsule can reduce the pathological damage of retina in diabetic mice, and its mechanism may be related to the reduction of p38 mitogen-activated protein kinase protein phosphorylation (68); Expression can improve retinopathy (69); can significantly improve retinopathy in KK / Upj-Ay mice, with inhibition inhibitor of nuclear factor kappa-B kinase / human nuclear factor kappa inhibitory protein α / NF-kB (IKKβ / IKBα / NF-kB pathway (70-72).
|
Qizhi Tongluo Capsule & Qiju Dihuang Pills
|
Qizhi Tongluo Capsule: None; Qiju Dihuang Pills can significantly prove retinopathy in rats by increasing antioxidant enzyme activity and inhibiting aldose reductase activation (73).
|
Danggui Buxue Decoction
|
Danggui Buxue Decoction can reduce blood-retinal barrier leakage in GK rats (74).
|
Abreviation: QM: Qiming granule; QZJT: Qizhen Jiangtang Capsule; CXST: Compound Xueshuantong capsule; QHMM: qihuangmingmu capsule; TXL: Tongxinluo capsule; MMH: mimonghua formula; DHI: Danhong injection; TGBL: gingko leaf tincture; PARP: Poly ADP ribose polysaccharide