Direct and Indirect Therapeutic Effect of Traditional Chinese Medicine as an Additional Drug on Non-proliferative Diabetic Retinopathy: A systematic review and meta-analysis of high-quality studies

Background Diabetic retinopathy (DR) is the leading cause of blindness in many countries. The current treatment of non-proliferative DR (NPDR) with Western medicine (WM) alone are still insucient. At present, the treatment of NPDR with the combination of traditional Chinese medicine (TCM) and WM is universally applied, and we would evaluate the effectiveness and safety of TCM as an additional drug for NPDR with systematic reviews and meta-analysis. Method Data before July 6, 2019 were searched as randomized controlled trials (RCTs) of TCM for the treatment of NPDR with WM, which were collected from China National Knowledge Infrastructure , Wanfang Database , China Biomedical Database , Pubmed , Embase and Cochrane Library . Relevant data was extracted by two reviewers respectively. I 2 statistics was adopted to appraise the heterogeneity, if I 2 <50% then the xed-effects model would be employed, otherwise the random-effect model would be employed. (PROSPERO: Result 18 RCTs (1522 patients) were included according to the inclusion criteria. The results showed that compared with WM, TCM (including Compound Xueshuantong Capsule, Qiming Granule, and others)+ WM for NPDR could improve overall eciency [n=1686,RR1.24(1.18,1.30), P <0.00001, I 2 =0%], and reduce the level of risk factors related to NPDR, such as glycated hemoglobin level [n=360, MD -0.85(-1.28, -0.41), P =0.0001, I 2 =72%], triglyceride and total cholesterol, but not Qiming Granule. Moreover, no serious adverse events were reported. Conclusion Compared with WM alone, TCM+WM could signicantly improve NPDR, and also reduced the correlation levels of risk factors, considering the sample size and the number of patients included in the study, there might be publication bias, so the corresponding results should be treated with caution.


Background
According to International Diabetes Federation, the number of diabetes mellitus (DM) patients in the world has reached 415 million, and by 2040, the total patients will exceed 600 million. In China, the prevalence rate of DM has risen from 0.67% in 1980 to 10.4% in 2013 (1), and DM complications will bring greater economic and social burden. Complications of DM include macrovascular complications (i.e. cardiovascular disease, stroke), microvascular complications (i.e. diabetic nephropathy, diabetic retinopathy (DR), and diabetic peripheral neuropathy). Among them, DR is a continuous process of microcirculation and continuous lesions. According to the Ophthalmology Clinical Guidelines edited by the American Academy of Ophthalmology in 2006, DR is mainly divided into no obvious DR, non-proliferative DR (NPDR), proliferative DR (PDR), and often accompanied by diabetic macular edema (DME). The quality of life, psychology, and social behavior are affected in patients with PDR, and more medical expenses are needed (2). Vision loss occurs in the late stage of DME or PDR, and DR is one of the major causes of blindness in many countries (3).
For the pathogen of DR, there are mainly disease course, family inheritance, hyperglycemia, hyperlipemia, hypertension (4,5). For the treatment of DR, the most important is to low blood sugar. Studies have shown that glycosylated hemoglobin (HbAlc) is reduced by 10% on the original basis (such as 10% to 9%), and the progression of DR is reduced by 43% (6). As demonstrated by the United Kingdom Prospective Diabetes Study, patients with tightly controlled blood pressure have a signi cant protective effect on the progression of DR (7). Hyperlipidemia are associated with an increased risk of DR in Chinese patients with T2DM, suggesting that controlling blood lipids may reduce the risk of DR (8). In the non-proliferative phase, the main treatments are oral medications, including Calcium Dobesilate (CD), Intestinal Kininogenase, and large doses of Compound Danshen Dripping Pills; In the proliferative phase, laser surgery, and anti-vascular endothelial growth factor (VEGF) when patients with DME are needed. But real clinical research shows that the current treatment still has certain drawbacks, such as oral WM, not suitable for all patients, and the effect is not so good. For laser surgery, it is a destructive treatment, only blocking the occurrence of blindness but does not improve the patient's vision and fundus lesions. Although recent trials have shown that laser treatment can actually improve the vision of some patients (9). After injected VEGF, a relatively high proportion of patients (46%) may still require local or grid laser treatment (10).
Traditional Chinese medicine (TCM) has been in the prevention and treatment of chronic diseases for nearly 2,000 years and has an indelible contribution.
Signi cant progress has been made in the treatment of DM and its complications. Many studies have shown that Jiangtang Tiaozhi Fang can effectively reduce the levels of blood sugar and lipids (11). Compound Danshen Dripping Pills is used to treat NPDR (12). Nowadays, the combination of TCM and WM is more common in clinical practice, the same to NPDR. There are randomized clinical trials (RCTs) showing that this measure is feasible and has good curative effect (12). However, there is currently no systematic review to prove its effectiveness and safety, and there is still a lack of high-level evidence. Therefore, we systematically evaluate the e cacy and safety of TCM as an additional drug in the treatment of NPDR, in order to provide high-level, referenceable evidence for the selection of clinical drugs.

Method
This study was conducted and reported in accordance with the Preferred Reporting Project (PRISMA) guidelines for systematic reviews and meta-analysis (13). The PROSPERO registration number is CRD42019134947.

Search strategy and data organization
Chinese Knowledge Network, Wanfang Database, China Biomedical Database, Pubmed, Embase, and Cochrane Library were searched for RCTs of TCM for the treatment of NPDR with WM before July 6, 2019. The search mainly considers three aspects: patients (NPDR patients), treatment measures (with TCM based on WM), and research types (RCTs). The search uses a combined text and Mesh heading search strategy, and the search terms include "early or nonproliferative phase" and "diabetic retinopathy" and "randomized controlled trial or randomized". Titles and abstracts of included this work were screened by Xuedong An and Fengmei Lian respectively. Different opinions are resolved through discussion.

Studies inclusion criteria
RCTs; Patients diagnosed as T2DM and NPDR; The TCM+WM group was treated with TCM on the basis of WM, and the WM group was compared with WM; Intervention time is 3 months (or 12 weeks) and above.

Data extraction
Data were collected from Xuedong An and Fengmei Lian, including basic information such as gender, age, duration of disease, basic treatment, major outcome indicators, medication, intervention time, case shedding, and adverse events.

Assessing the risk of bias and the quality of evidence
RCTs included in this review were assessed using the Cochrane Bias Risk Tool (CRBT), which included that random sequence generation, allocation concealment, blinding, incomplete data, selective reporting and other biases, and each of these aspects was assessed as low, high or unclear risk of bias.
Xuedong An and Fengmei Lian independently applied CRBT to assess the risk of bias in each study. Controversy opinions are resolved through discussion.

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 (I 2 =0%). Statistical data were obtained by using xed 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, I 2 =0%]. (Figure 10, Figure 11)

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

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 (I 2 =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, I 2 =71%), but not Qiming Granule (P=0.15). (Figure 16, Figure 17)

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 (I 2 =99%). The data were analyzed by random effect model. Fig. 19 shows that there is no difference in the HDL level  (17,20,21,26,(31)(32)(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.

Publication bias
Funnel charts are used to investigate publication bias. The funnel charts of the overall e cacy and fundus outcomes are basically symmetrical, indicating potential publication bias. Unpublished research may be considered a factor in publication bias. (Figure 22, Figure 23)

Discussion
The Wisconsin Epidemiologic Study of Diabetic Retinopathy reported that about 75% of DM patients developed DR 10 years after diagnosis, while about twothirds of those who developed DR at baseline developed more severe DR stages, and 20% developed PDR or MDE (34). As the incidence of DM increases at an alarming rate, the number of patients with DR is expected to increase from 126.6 million in 2010 to 191 million in 2030. According to current estimates, the number of DR with visual threat is expected to increase from 37.3 million to 56.3 million (35). Also, the cost of DR is more than half that of non-DR. To sum up, DR has brought us tremendous social and economic burdens.
At present, the most effective intervention for DR is early screening (i.e. using fundus photography, and fundus uorescence angiography), and early diagnosis. Studies have shown that standardized, national DR screening can reduce the blindness rate of DM patients up to 30-50% (36). At the same time, DM duration, hyperglycemia and hypertension are the most relevant risk factors for DR. Previous epidemiological and clinical studies have shown that NPDR can reduce the risk and progress of DR by controlling blood sugar and blood pressure levels (37). Strict control of blood pressure can reduce the risk of DR blindness by 47% (38). However, the current understanding of DR risk factors is still insu cient, because the current risk factors are not applicable to all patients (39). For example, HbA1c may account for only 10% of the risk of DR; Blood pressure and serum TC may account for less than 10% of the risk of DR (40); Family inheritance accounts for about 25-50% (41). In fact, studies have shown that DR does not occur in some patients with poor blood sugar and/or blood pressure control (42), other properly controlled patients may have a severe stage of DR (43), this suggests that other unknown risk factors are also playing an important role.
In the non-proliferative phase, CD and pancreatic kallikrein are commonly used orally. CD can improve retinal microneuropathy, retinal hemorrhage, exudates and whole blood viscosity (44), and the mechanism is related to the decrease of serum endothelin-1 and high-sensitivity C-reactive protein levels (45,46). Pancreatic kallikrein mainly reduces the resistance of peripheral blood vessels by degrading kallikrein into kallikrein, expanding capillaries, inhibiting platelet aggregation (47).
For PDR, treatments include laser surgery, vitrectomy, tractive retinal detachment, and injection of antiangiogenic factors or application of steroid hormones with DME (39). Retinal photocoagulation can effectively inhibit and treat retinal neovascularization and reduce the blindness rate by 50-60% (48). Laser surgery is also a destructive treatment, which can only block the occurrence of blindness, but cannot improve the vision and fundus lesions of patients. For injection of anti-VEGF, it can manifest intraocular in ammation, hemorrhage, elevated intraocular pressure and loss of retinal ganglion cells. Corticosteroid hormones prevent vascular leakage by reducing the secretion of VEGF and the release of in ammatory cytokines. However, the incidence of corticosteroid complications is high, most commonly intraocular pressure rise and cataract formation (49). Therefore, the current treatment measures still cannot solve the problem of DR treatment.
With the main characteristics of simplicity, convenience, cheapness and testing, TCM has played an indelible role in the prevention and treatment of diseases.
In the actual clinical process, more cooperation with WM can increase the e cacy of WM, reduce adverse events, and even reduce the dosage of WM. For the treatment of DR, Qiming Granule is commonly used, which can relieve retinal hypoxia and ischemia by increasing retinal blood ow and improving blood circulation (50), and can also lower HbAlc level alone (51); Compound Xueshuantong Capsule can protect DR by regulating Hippo pathway (52), and it can also reduce the expression of VEGF, aldose reductase activity, whole blood viscosity and plasma viscosity (53) and can also lower blood sugar level alone (54).
According to the screening criteria, 18 RCT studies were included to evaluate the quality of studies. The results show that the overall quality of research is low. For publication bias, funnel plots of overall e cacy and visual acuity showed that the gures were basically symmetrical, but there was still some publication bias. In conclusion, TCM as an additional drug for NPDR is effective, safe and worthy of clinical application. However, considering the low quality of current research and possible publication bias, it is necessary to be cautious to refer to the results of this study.

Conclusion
Compared with WM alone, TCM+WM could signi cantly improve NPDR, and also reduced the correlation levels of risk factors, considering the sample size and the number of patients included in the study, there might be publication bias, so the corresponding results should be treated with caution. Availability of data and materials The data included original studies and meta-analysis le with TCM+WM for NPDR. rm5. The data used to support the ndings of this study are available from the corresponding author upon request.
Author contributions FML and XLT designed the review protocol. DJ and LYD carried out the literature search. FML and XDA contributed to data extraction and quality assessment. RRZ, and SHZ provided statistical supports for meta-analysis. All authors approved the nal version of the manuscript.

Competing Interests
Not Applicable  Overall e cacy Vision before intervention Figure 6 Vision after intervention   18 HDL before intervention Figure 19 19 HDL after intervention  Funnel plot of fundus effect