Shuangdan Mingmu Capsule for Diabetic Retinopathy: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Objective To systematically evaluate the efficacy and safety of the Shuangdan Mingmu capsule in the treatment of diabetic retinopathy (DR). Methods Common Chinese and English databases, including PubMed, Medline, Embase, VIP, Wanfang, and the Chinese National Knowledge Infrastructure (CNKI), were searched from their inception to May 31, 2022. According to the Cochrane Handbook, two reviewers independently evaluated and collected data on the included studies. Meta-analysis was performed by RevMan software 5.4. Results Seven trials with a total of 835 patients were included. The clinical effectiveness rate was defined as the primary outcome, and the TCM symptom score, Chinese-Version Low Vision Quality of Life Questionnaire (CLVQOL) scores, macular thickness, hemorrhagic spot area, vascular endothelial growth factor levels, platelet-derived growth factor levels, and the incidence of adverse effects were the secondary outcome. The results of the meta-analysis showed that, compared with conventional medical treatment alone, the Shuangdan Mingmu capsule combined with conventional treatment could significantly improve the clinical effectiveness rate of treating DR (OR = 4.07, 95% CI (2.10, 7.89), p < 0.0001), and reduce the incidence of adverse reactions in DR patients (OR = 0.47, 95% CI (0.26, 0.86), p=0.01). In addition, other results showed that TCM symptom score(OR = −3.47, 95% CI (−3.84, −3.10), p < 0.00001); CLVQOL scores (OR = 23.93, 95% CI (21.37, 26.49), p < 0.00001); macular thickness (OR = −47.34, 95% CI (−50.67, 44.00), p < 0.00001); hemorrhagic spot area (OR = −0.91, 95% CI (−1.01, −0.81), p < 0.00001); vascular endothelial growth factor levels (OR = −45.76, 95% CI (−49.74, 41.79), p < 0.00001); platelet-derived growth factor levels (OR = −1.73, 95% CI (−2.15, −1.31), p < 0.00001). Conclusion Compared with conventional treatment alone, the Shuangdan Mingmu capsule combined with conventional treatment is more effective and safer in the treatment of diabetic retinopathy. However, due to the limitations of the included studies, more high-quality studies are still needed to further assess the efficacy and safety of the Shuangdan Mingmu capsule in the treatment of diabetic retinopathy.


Introduction
Diabetes mellitus is a disease characterized by chronic hyperglycemia caused by metabolism disorders of sugar, fat, and protein due to insufcient insulin secretion or defective function. Diabetic retinopathy (DR) is a microangiopathy that mainly involves small blood vessels, causing microvascular occlusion, bleeding, and hemorrhage and eventually leading to retinal detachment, which seriously afects the quality of life of patients [1]. In 2019, diabetes and its complications became one of the major causes of death worldwide, and its prevalence in the world reached 10.2% [2,3]. In 2020, the number of patients with DR in China reached 6 million, and 1.34 million were at risk of visual impairments.
At present, the conventional treatment for DR is mainly Western medicine. Calcium dobesilate, which inhibits vasoactive substances and improves microvascular circulation, is a common drug for treating DR. However, the efcacy of calcium dobesilate alone in the treatment of DR is not ideal. In China, a combination of traditional Chinese medicine (TCM) and conventional treatment has often been prescribed for DR patients with the aim of improving efcacy [4].
Shuangdan Mingmu capsule (SDMMC) is a Chinese patent medicine prepared from traditional Chinese medicines such as Nvzhenzi (Frustus Ligustri Lucidi) and Mohanlian (Yerbadetajo Herb), which have the activities of invigorating the blood and brightening the eyes, benefting the kidney, and nourishing the liver. An increasing number of clinical trials have assessed the efcacy and safety of SDMMC combined with conventional treatment for the treatment of DR; most studies suggest that SDMMC can improve the clinical efectiveness rate (CER), TCM symptom score, and quality of life (QOL), and can also reduce adverse events [5]. However, the efects of SDMMC combined with conventional treatment for patients with DR have never been systematically evaluated.
In SDMMC, Ligustrum lucidum and Moxanthus are rich in favonoids, which are rich in phenolic hydroxyl groups and have strong antioxidant capacity. Several studies have found that Ligustrum lucidum and Moxanthus have hepatoprotective efects on acute liver injury, and both of them can reduce the serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in a dose-dependent manner in a liver injury model. It can reduce the content of malondialdehyde (MDA) in liver tissue homogenate and enhance the activity of superoxide dismutase (SOD). Te combination of the two drugs can efectively improve the pathological changes in liver tissue [6].
In this study, the efcacy and safety of SDMMC combined with conventional treatment for DR patients were systematically evaluated, aiming to provide evidence for clinical practice.

Protocol and Registration.
Te present systematic review and meta-analysis of RCTs were performed following the PRISMA guidelines [7]. Te protocol of this study was registered in PROSPERO with the registration number CRD42022361851 (https://crd.york.ac.uk/PROSPERO/ display_record.php?RecordID=361851).

Risk of Bias Evaluation.
Te methodological quality of the included literature was evaluated. Te risk of bias assessment tool recommended by the Cochrane Handbook was used to assess the risk of bias, which was classifed into 3 levels: low risk, unclear risk, and high risk. Te assessment was based on the following seven domains: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other biases [8][9][10].
2.6. Statistical Analysis Methods. RevMan software 5.4 (Copenhagen: Te Nordic Cochrane Centre, Te Cochrane Collaboration, 2020) was applied for statistical processing. Te odds ratio (OR) with 95% confdence intervals (CI) was used for count data (the clinical efcacy rate, adverse efects), and the mean diference (MD) with 95% CI was used for continuous outcomes. If I 2 ≤ 50%, homogeneity was suggested, and a fxed-efects model was used; conversely, if I 2 > 50%, substantial heterogeneity was suggested, and a random-efects model was used for synthetic analysis. Evidence-Based Complementary and Alternative Medicine Diferences were considered statistically signifcant if p < 0.05 [11][12][13].

Publication Bias.
Funnel plots were performed to examine the potential bias in the RCTs included in the metaanalysis when the number of the included RCTs was more than 10 [8,12].

Literature Search and Screening Results.
A total of 96 papers were searched; 7 studies [14][15][16][17][18][19][20] met the criteria and were included after eliminating duplicates and intensive reading of the abstract and full text; all the included RCTs were performed in China ( Figure 1).

Basic Characteristics of the Included Literature.
According to the inclusion and exclusion criteria, 7 RCTs with a total of 835 patients were included, including 419 cases in the test group and 416 cases in the control group [14][15][16][17][18][19][20]. Te test group was treated with SDMMC combined with conventional treatment, and the control group was treated with conventional treatment alone (Table 1).

Assessment of the Quality of the Included Studies.
Te baseline indicators of the seven included studies were largely consistent, but the random assignment method was unclear, and some did not mention allocation concealment and blinding. Te primary outcomes of all studies were fully consistent with the expected reporting. Tere was no selective report bias and no other risks of bias in the included literature ( Table 2, Figures 2 and 3).

Te Clinical Efective Rate.
Te clinical efectiveness rate was described in 5 studies included in this study [16][17][18][19][20], including 649 patients. Te results of the meta-analysis showed a statistically signifcant diference in the clinical efectiveness rate of the test group compared with the control group (OR � 4.07, 95% CI (2.10, 7.89), p < 0.0001). Tis result indicated that SDMMC could improve the clinical efectiveness rate of treating DR ( Figure 4). Tere was homogeneity for this outcome (I 2 � 0%), and a fxed-efects model was used.

TCM Symptom Score.
Two studies assessed the efect of diferent interventions on TCM syndromes [16,17]. Metaanalysis showed a statistically signifcant diference in the TCM syndrome score between the test group and the control group (OR � − 3.47, 95% CI (− 3.84, − 3.10), p < 0.00001). Tis result indicated that the SDMMC could improve the TCM symptom score of DR patients ( Figure 5). Tere was homogeneity for this outcome (I 2 � 39%), and a fxed-efects model was used.  Figure 6). Tere was homogeneity for this outcome (I 2 � 0%), and a fxed-efects model was used.

Chinese-Version Low Vision
3.7. Macular Tickness. Macular thickness was described in 2 studies [16,20]. Te results of the meta-analysis showed a statistically signifcant diference in macular thickness between the test group and the control group (OR � − 47.34, 95% CI (− 50.67, 44.00), p < 0.00001). Tis result indicated that the SDMMC could reduce the macular thickness in DR patients ( Figure 7). Tere was homogeneity for this outcome (I 2 � 18%), and a fxed-efects model was used.

Hemorrhagic Spot Area.
Te bleeding spot area was described in 2 included studies [16,20]. Te results of the meta-analysis showed a statistically signifcant diference in bleeding spot area in the test group compared with the control group (OR � − 0.91, 95% CI (− 1.01, − 0.81), p < 0.00001). Tis result indicated that SDMMC could reduce the area of bleeding spots in DR patients ( Figure 8).
Tere was homogeneity for this outcome (I 2 � 0%), and a fxed-efects model was used.

Platelet-Derived Growth Factor Levels (PDGF).
PDGF levels were described in 2 studies [16,20]. Te results of the meta-analysis showed a statistically signifcant difference in PDGF levels in the test group compared with the control group (OR � − 1.73, 95% CI (− 2.15, − 1.31), p < 0.00001). Tis result indicated that SDMMC signifcantly downregulated PDGF levels in DR patients (Figure 10). Tere was substantial heterogeneity for this outcome (I 2 � 51%), and a random-efects model was applied.
3.11. Blood Glucose. Among these studies, only one study described blood glucose [15]. Comparing fasting blood glucose (FBG) and 2 h postprandial blood glucose (2 h PBG) before and after treatment between the two groups, the diferences between the groups were statistically signifcant (p < 0.05). Meta-analysis was not possible for this outcome.

Discussion
Diabetic retinopathy is a common complication of diabetes mellitus, which mainly manifests as blurred vision, fundus exudation, and retinal edema. According to traditional Chinese medicine, DR is associated with "abrupt blindness (Bao Mang)," "dimness of vision (Shi Zhan Hun Miao)," "internal obstruction (Nei Zhang)," and "blood flling the pupil (Xue Guan Tong Shen)," etc. [21]. In 2011, the Chinese Diabetes Society summarized the etiology and pathogenesis of DR, considering yin defciency of the liver and kidney as the underlying pathogenesis and blood stasis blocking the veins as the surface pathogenesis [22]. According to TCM theory, the functions of the SDMMC include nourishing the qi and yin of the liver and kidney, promoting blood circulation, and brightening the eyes, which work against the pathogenesis of DR. SDMMC is derived from the combination of the Erzhi pill in the medical book "Yibian" of the Ming Dynasty and the Liuwei Dihuang pill in the "Straight Guide to Pediatric Medicine (Xiaoer Yaozheng Zhijue)" written by Qian Yi of the Song Dynasty. Te main herbs of the formula are Nvzhenzi (Frustus Ligustri Lucidi) and Mohanlian (Yerbadetajo Herb), which can nourish the yin of the liver and kidney. In addition, Mohanlian (Yerbadetajo Herb) is also good at cooling the blood to stop bleeding. Shanzhuyu (Fructus Corni) and Shanyao (Rhizoma Dioscoreae) can nourish the kidney and liver and invigorate the spleen. Danshen (Radix Salviae Miltiorrhizae) and Sanqi (Sanchi) can invigorate and promote blood circulation to remove blood stasis. Mudanpi (Cortex Moutan), Zexie (Rhizoma Alismatis), and Fuling (Poria) have the activities of clearing the liver and draining fre, as well as drying dampness. Niuxi (Radix Achyranthis Bidentatae) can invigorate blood circulation, remove blood stasis, and strengthen tendons and bones; it is also good at preventing the rising of qi and blood [23,24]. Te combination of these Chinese medicinal herbs is benefcial to the kidney and liver, blood circulation, and eyesight, and is especially suitable for the treatment of diabetic retinopathy caused by yin defciency of the liver and kidney and blood stasis [25] (Table 3).
Te results of this study showed that the clinical efectiveness rate of patients in the test group was signifcantly          Evidence-Based Complementary and Alternative Medicine higher than that of the control group; the TCM symptom score was signifcantly lower than that of the control group; the CLVQOL score was signifcantly higher than that of the control group; the macular thickness and hemorrhagic spot area were signifcantly smaller than those of the control group; the abovementioned diferences were statistically signifcant (p < 0.05). Tese fndings indicate that SDMMC combined with conventional treatment is efective for DR, which can improve the overall clinical efcacy rate, symptoms of patients, quality of life, and some objective signs of patients with DR.

Evidence-Based Complementary and Alternative Medicine
Tis study also showed that the serum VEGF and PDGF levels of patients in the test group were signifcantly lower than those in the control group, and the diferences were statistically signifcant (p < 0.05). VEGF enhances retinal capillary permeability and afects patients' visual acuity [26]. PDGF is a peptide that can be produced by a variety of cellular stimuli and can induce cell proliferation and promote extracellular matrix accumulation and monocyte-macrophage infltration. Numerous studies have shown that PDGF is involved in the process of glucose metabolism in the diabetic state and can promote its own expression, thus forming a vicious cycle. Te combination of SDMMC with conventional medicine downregulated the VEGF and PDGF levels, which might bring long-term benefts to DR patients [27,28].
In addition, in this study, six of the seven included studies observed adverse reactions, and the meta-analysis showed that the incidence of adverse reactions in the test group was signifcantly lower than that in the control group, indicating that the combination of SDMMC with conventional treatment was safe and could reduce the incidence of adverse reactions in DR patients [29,30].
Tere were some of the following limitations in this study: (a) the number of studies that met the inclusion criteria of this study was relatively small, all of which were written in Chinese; (b) only three of the included studies specifed the randomization method, and the rest did not specify the randomization grouping method, which might have led to selective bias; (c) most of the included studies did not mention blinding, allocation concealment, follow-up, or prognosis; (d) only one study described blood glucose, meta-analysis was not possible for this outcome; (e) for all outcomes, the number of included studies was less than 10; therefore, funnel plots were not performed.

Conclusions
Compared with conventional treatment alone, the Shuangdan Mingmu capsule combined with conventional treatment is more efective and safer in the treatment of diabetic retinopathy. However, due to the limitations of the included studies, more high-quality studies are still needed to further assess the efcacy and safety of the Shuangdan Mingmu capsule in the treatment of diabetic retinopathy.  Favours (experimental) Figure 11: Adverse reactions.