HUO Jian,DUAN Junguo,LIU Lisha,ZHANG Fuwen,ZHU Keyu,SUI Jiaqing,JIAN Wenyuan

HUO Jian,Department of Ophthalmology,Chengdu Women′s and Children′s Central Hospital,School of Medicine,University of Electronic Science and Technology of China,Chengdu 611731,China

DUAN Junguo,HUO Jian,LIU Lisha,ZHANG Fuwen,ZHU Keyu,SUI Jiaqing,JIAN Wenyuan,College of Ophthalmology,Chengdu University of Traditional Chinese Medicine,Chengdu 610075,China

Abstract OBJECTIVE: To evaluate the differences in the efficacy of stationary treatment and individualized treatment for patients with nonproliferative diabetic retinopathy (NPDR).METHODS: This study was a randomized,controlled,multicenter clinical trial.Participants with NPDR were randomized into the stationary treatment group or the individualized treatment group.The stationary treatment group was given the basic treatment and Qiming granules,and the individualized treatment group was given the basic treatment,Qiming granules,and individualized Chinese herbal medicines over a 12-week period.The individualized therapeutic formula was also changed over time to adjust to the changes in the clinical presentation of the patient.We conducted observations of fundus retinal exudation and hemorrhage,visual acuity,Traditional Chinese Medicine symptom scores and other indicators.RESULTS: A total of 140 participants with NPDR were randomized into the stationary treatment group or the individualized treatment group,and 132 participants completed this study.Following the 12-week treatment,significant improvements in both primary and secondary outcomes were observed in the stationary and individualized treatment groups.No remarkable difference in the primary outcomes between the two groups was observed.However,there was a significant difference in the Traditional Chinese Medicine symptom scores (18 ± 7 vs 15 ± 6;P ＜ 0.05).There were no severe adverse effects.CONCLUSION: Compared with stationary treatment,individualized treatment is more effective at relieving the Traditional Chinese Medicine symptoms and improving vision and fundus lesions at 12 weeks post treatment.

Keywords: diabetic retinopathy;individualized treatment;randomized controlled trial;Qiming granules

1.INTRODUCTION

Diabetic retinopathy (DR) is a common microvascular complication of diabetes.1At present,the limitations of laser photocoagulation,anti-vascular endothelial growth factor agents and vitreous surgery have led to a growing awareness of the role of Traditional Chinese Medicine(TCM) in the treatment of DR.TCM is an alternative therapeutic that has been used for thousands of years in China and regards DR asQi-Yindeficiency with blood stasis.2,3

Qiming granules were the first nationally approved Chinese herbal medicine formula for the treatment of nonproliferative diabetic retinopathy (NPDR).In addition,based on syndrome differentiation in TCM,Qiming granules are suitable for treatment ofQi-Yindeficiency syndrome.4,5Qiming granules consist of eight Chinese herbal medicines,including Huangqi (Radix Astragali Mongolici),Gegen (Radix Puerariae Lobatae),Dihuang (Radix Rehmanniae),Gouqi (Fructus Lycii),Juemingzi (Semen Cassiae Obtusifoliae),Chongweizi(Fructus Leonuri Japonici),Puhuang (Pollen Typhae),and Shuizhi (Hirudo).6The functions of Qiming granules are the replenishment ofQiand production ofYin,nourishment of the liver and kidney,and activation of channels in the eyes to improve eyesight.7A large number of clinical studies have confirmed that Qiming granules are effective in treating NPDR.In the 2017 Guidelines for Type 2 Diabetes Prevention and Treatment in China,Qiming granules were listed as TCM preparations for the treatment of DR.8In a 3-month,randomized,controlled,double-blinded,multicenter clinical trial of 212 eyes from 212 patients with NPDR(Qiming group,107 patients;Doxium® control group,105 patients),Qiming granules were more effective than Doxium®with respect to the efficacy and total effective rate of TCM.The adverse effect rate in the Qiming group was 0.935%,while that in the Doxium®control group was 7.619%,indicating that Qiming granules are safe.Therefore,Qiming granules might be superior to Doxium®tablets in treating NPDR.4A favorable effect of Qiming granules in the treatment of DR that was observed by analyzing fluorescence fundus angiography after 3 months of medication in a multicenter,randomized,parallel controlled clinical trial (360 DR patients) was improved retinal blood circulation.5

However,in clinical practice,Qi-Yindeficiency is the basic syndrome underlying DR and is often accompanied by other TCM syndromes.The three diabetic microvascular complications of DR,diabetic kidney disease (DKD) and diabetic peripheral neuropathy (DPN)often show comorbidity and increase the risk of developing a related comorbidity.It is difficult for Qiming granules to treat all symptoms.In this study,we aimed to evaluate the difference between the individual efficacy of NPDR and Qiming granule fixed prescription treatmentviaa multicenter,randomized,parallel controlled trial.

2.METHODS

2.1.Study design

This was a multicenter,randomized,parallel controlled study conducted in 8 centers in China.It was carried out according to the trial protocol,which had been previously reported.9The eight centers were as follows:The Affiliated Hospital of Chengdu University of Traditional Chinese Medicine,the Dongzhimen Hospital Affiliated with Beijing University of Chinese Medicine,China-Japan Friendship Hospital,the Wangjing Hospital Affiliated with the China Academy of Chinese Medical Sciences,The First Affiliated Hospital of Xiamen University,Guangdong Province Traditional Chinese Medical Hospital,Ningxia People′s Hospital and The People′s Hospital of the Guangxi Zhuang Autonomous Region.The participants were outpatients or inpatients seen by the Department of Ophthalmology or Endocrinology.

2.2.Diagnostic criteria

The diagnosis of NPDR was based on the international clinical DR severity scale;10DKD was defined according to the Kidney Disease: Improving Global Outcomes(KDIGO) guidelines,11and DPN was defined by the American Diabetes Association criteria.12The differentiation of the type of TCMQi-Yindeficiency syndrome and blood stasis was based on TCM guidelines.13

2.3.Inclusion and exclusion criteria

The inclusion criteria were as follows: (a) age between 18-75 years;(b) diagnosis of DR,or combined with DKD,or combined with DPN,or combined with DKD and DPN;(c) met the TCM diagnostic criteria ofQi-Yindeficiency syndrome;(d) best corrected visual acuity(BCVA) in the studied eye of at least 34 ETDRS letters(Snellen 20/200,decimals 0.1);(e) hemoglobin A1c(HbA1c) ≤ 9.5%;and (f) provision of written informed consent.

The exclusion criteria were as follows: (a) refractive media turbidity that made it difficult to conduct an eye fundus image evaluation;(b) high-risk proliferative diabetic retinopathy necessitating immediate retinal photocoagulation;(c) other eye complications,such as glaucoma,uveitis,age-related macular degeneration and optic neuropathy;(d) liver or kidney dysfunction;(e)allergy to the studied treatments;(f) pregnancy;(g)severe mental disorders;and (h) participation in other clinical trials in the past 3 months.

2.4.Randomization

A central randomization system was applied in this study.After baseline assessment,participants were allocated randomly into the stationary treatment group or the individualized treatment group,and the randomization ratio was 1∶1.Random numbers were generated by an independent third party [the Brightech Clinical Information Management System (Brightech CIMS),Chengdu BM Clinical Research Ltd.,www.bmclinsys.com].Then,the group allocation of the participants was made by the third party,and the randomization codes were stored by the principal investigator and the third party.

2.5.Treatments

All patients in both groups were treated with Qiming granules and conventional drug therapy,including antidiabetic,antihypertensive,and lipid-lowering agents.The Qiming granules were taken 4.5 g,3 times a day(Zhejiang Wansheng Pharmaceutical Co.,Ltd.,Zhejiang,China,NMPN: Z20090036).The patients in the individualized treatment group were also treated with individualized Chinese herbal medicines,which were administered 3 times a day (and supplied by Sichuan New Green Pharmaceutical Technology Development Co.,Ltd.,Sichuan,China).The individualized therapeutic formula changed over time to adjust to the changing clinical presentation of the patient.Both groups received treatment for 12 weeks.

The individualized Chinese herbal medicines were as follows: DR,none;DR and DKD,addition of 10 g Taizishen (Radix Pseudostellariae) and 5 g Dahuang(Radix Et Rhizoma Rhei Palmati);DR and DPN,addition of 10 g Sumu (Lignum sappan) and 15 g Yanhusuo(Rhizoma Corydalis Yanhusuo);DR,DKD and DPN,addition of 10 g Taizishen (Radix Pseudostellariae),5 g Dahuang (Radix Et Rhizoma Rhei Palmati),10 g Sumu(Lignum sappan) and 15 g Yanhusuo (Rhizoma Corydalis Yanhusuo);Qideficiency,addition of 10 g Renshen (Radix Ginseng);blood deficiency,addition of 15 g Danggui (Radix Angelicae Sinensis);Yindeficiency,addition of 15 g Tiandong (Radix Asparagi Cochinchinensis);Yangdeficiency,addition of 15 g Yanhusuo (Rhizoma Corydalis Yanhusuo);blood stasis,addition of 15 g Danshen (Radix Salviae Miltiorrhizae)and 3 g Sanqi (Radix Notoginseng);turbid phlegm,addition of 15 g Banxia (Rhizoma Pinelliae) and 15 g Zhebeimu (Bulbus Fritillariae Thunbergii);Qistagnation,addition of 10 g Chaihu (Radix Bupleuri Chinensis) and 10 g Zhiqiao (Fructus Aurantii Submaturus);water-dampness,addition of 15 g Zhuling(Polyporus) and 15 g Cheqianzi (Semen Plantaginis).

2.6.Outcomes

The primary outcomes were the change in the area of retinal hemorrhage and exudation (hard and soft exudation) as assessed for 12 weeks from the time of randomization.The secondary outcomes were the BCVA(ETDRS visual acuity chart,4 m distance),the improvement of TCM symptoms (evaluated according to the TCM syndrome score),the HbA1c and safety assessment (results of routine blood tests,including fasting blood glucose (FPG),alanine transaminase(ALT),aspartate aminotransferase (AST),etc.),which were assessed at the scheduled time-points.

2.7.Statistical analysis

Patients were analyzed according to their randomization group after the inclusion of all patients with complete observation.Continuous variables are expressed as the mean ± standard deviation.Comparisons between two groups were assessed using a two-samplettest (for normally distributed data),and the Mann-WhitneyUtest(for nonnormally distributed data),pairedttest (for normally distributed data) and Wilcoxon test (for nonnormally distributed data) were used to perform comparisons before and after treatment within the groups.Categorical variables were expressed as percentage and analyzed by the χ2test.Date were analyzed using SPSS 21.0 (IBM Corp.,Released 2012,IBM SPSS Statistics for Windows,Version 21.0,Armonk,NY,USA).We consideredP＜ 0.05 to indicate a significant difference.

She could see him smiling as he did when they were at home under the rose trees! He would be so pleased to see her, and to hear how they all were at home

3.RESULTS

3.1.Baseline characteristics

A total of 140 participants with NPDR were enrolled and randomized into the stationary treatment group or the individualized treatment group from October 2016 to March 2018.Eight participants dropped out the study.Therefore,a total of 132 participants completed this study.In the stationary treatment group,64 of the 70 participants (91.4%) fulfilled the protocol,four dropouts were lost to follow-up,and two dropouts occurred due to family-related factors.In the individualized treatment group,68 of the 70 participants (97.1%) completed the study,and two dropouts were lost to follow-up (Figure 1).The baseline clinical characteristics were similar between the study groups and are presented in Table 1.

Figure 1 Flow diagram of the trial

3.2.Primary outcomes

Regarding the two components of the primary outcome,a significant reduction in the area of retinal hemorrhage and exudation was observed in both the stationary treatment group and the individualized treatment group(P＜ 0.05).Upon comparison of the two groups,there was no obvious difference in the fundus hemorrhage and exudation area after 12 weeks of treatment (P＞ 0.05);however,the reduction in the retinal hemorrhage and exudation area difference in the individualized treatment group was slightly higher than that in the stationary treatment group,but no remarkable difference was observed (P＞ 0.05,Table 2).

3.3.Key secondary outcomes

Based on the BCVA analysis,the BCVA was significantly improved after treatment in both the stationary treatment group and the individualized treatment group (P＜ 0.05).There was no remarkable difference in the BCVA between the two groups before and after treatment (P＞ 0.05).A comparison of the difference in the visual acuity score after treatment showed that the improvement of the BCVA in the individualized treatment group was greater than that in the stationary treatment group,but the difference was not statistically significant (P＞ 0.05).

The TCM syndrome scores were notably decreased in each group after treatment (P＜ 0.05).There was a significant difference between the TCM syndrome scores of the individualized treatment group and the stationary treatment group after 12 weeks of treatment (P＜ 0.05).Compared with the difference in the TCM syndrome scores after treatment,the reduction in the scores of the individualized treatment group was slightly higher than that of the stationary treatment group,but no remarkable difference was observed (P＞ 0.05).

After therapy discontinuation,the HbA1c was significantly decreased in both groups compared with that before treatment (P＜ 0.05),but no remarkable difference was observed between the two groups (P＞ 0.05).Comparison of the differences in the HbA1c before and after treatment showed that the reduction in the HbA1c in the individualized treatment group was slightly greater than that in the stationary treatment group,but no remarkable difference was observed (P＞ 0.05).

All of the secondary efficacy outcomes showed the same trend and are displayed in Table 3.

Table 1 Baseline characteristics and medical history ()

Table 1 Baseline characteristics and medical history ()

Notes: ST group: patients were treated with Qiming granules (4.5 g each time,three times a day) and conventional drug therapy for 12 weeks.IT group: patients were treated with individualized Chinese herbal medicines (three times a day),Qiming granules (4.5 g each time,three times a day) and conventional drug therapy for 12 weeks.ST: stationary treatment;IT: individualized treatment;DR: diabetic retinopathy.

Table 2 Change in the primary outcomes between the groups ()

Table 2 Change in the primary outcomes between the groups ()

Notes: ST group: patients were treated with Qiming granules (4.5 g each time,three times a day) and conventional drug therapy for 12 weeks.IT group: patients were treated with individualized Chinese herbal medicines (three times a day),Qiming granules (4.5 g each time,three times a day) and conventional drug therapy for 12 weeks.ST: stationary treatment;IT: individualized treatment;RHA: retinal hemorrhage area;REA:retinal exudation area.aP ＜ 0.05,compared with itself at baseline;bP ＜ 0.05,comparison between the two groups.

Table 3 Change in the secondary outcomes between the groups ()

Table 3 Change in the secondary outcomes between the groups ()

Notes: ST group: patients were treated with Qiming granules (4.5 g each time,three times a day) and conventional drug therapy for 12 weeks.IT group: patients were treated with individualized Chinese herbal medicines (three times a day),Qiming granules (4.5 g each time,three times a day) and conventional drug therapy for 12 weeks.ST: stationary treatment;IT: individualized treatment;VS: vision score;TCMSS: TCM syndrome scores.aP ＜ 0.05,compared with itself at baseline;bP ＜ 0.05,comparison between the two groups.

3.4.Safety assessments

Throughout the trial,there were no records of major adverse events related to Qiming granules.There were 2 adverse events that were reported during the trial: 1 patient had conjunctivitis,and 1 patient received YAG iris laser prophylactic treatment due to a shallow anterior chamber.The occurrence of adverse events was considered to be irrelevant to the tested herbs,and the trial was continued.

4.DISCUSSION

The HbA1c mainly reflects the average blood glucose level of patients over the previous 8-12 weeks and is an important basis for the screening and diagnosis of diabetes.Strict control of blood glucose and the HbA1c is still an important measure to delay the development of DR.Animal experiments and clinical trials have shown that Qiming granules have a certain effect on reducing blood glucose and the HbA1c and can downregulate the expression of insulin-like growth factor-1 (IGF-1) in serum.4,14-17IGF-1 promotes the development of DR.The results of this trial are similar to those of previous research,further confirming that Qiming granules are effective in reducing the HbA1c.The results of the study indicate that the individualized treatment group showed the improvement of hypoglycemia.It is speculated that this might be because most patients in the individualized treatment group were given Renshen (Radix Ginseng),Danshen(Salvia Miltiorrhiza),and Sanqi(PanaxNotoginseng),and these Chinese herbal medicines have been proven to have a hypoglycemic effect.18-20Renshen(Radix Ginseng) has a synergistic hypoglycemic effect with Huangqi (Radix Astragali Mongolici) and Dihuang(Radix Rehmanniae) in Qiming granules.At the same time,Cheqianzi(Semen Plantaginis),Tiandong (Radix Asparagi Cochinchinensis) and other Chinese herbal medicines,which were also given to the individualized group,were also confirmed to have a hypoglycemic effect.21,22

Retinal microvascular damage,such as retinal hemorrhage,exudation,and neovascularization,caused by DR can cause different degrees of vision loss.Studies have shown that Qiming granules can improve the blood circulation in the retina and choroid,improve fundus lesions in DR,and improve retinal function.4,5,23In this study,a quantitative analysis of retinal imaging technology was used to evaluate the effect on microvascular damage,such as retinal hemorrhage and exudation.The fundus imaging data obtained from exudation and hemorrhage lesions were selected for analysis,and the data of eyes without fundus exudation and hemorrhage lesions before (or before and after)treatment were excluded.In the stationary treatment group,the areas of exudation and hemorrhage were reduced after 12 weeks of treatment,and the results support previous research showing that Qiming granules can improve DR fundus lesions.Improved vision and decreased TCM syndrome scores were also observed in previous studies.

Although there was no significant difference in visual acuity and fundus lesions between the individualized treatment group and the stationary treatment group after 12 weeks of treatment,the visual acuity improvement was greater in the individualized treatment group,and the reduction in the areas of exudation and hemorrhage in the individualized treatment group was slightly greater than that in the stationary treatment group.This suggests that individualized treatment had a slightly superior effect on improving vision and fundus lesions.The comparison of TCM syndrome scores found that the TCM syndrome scores in the individualized treatment group showed a greater decrease,indicating that the individualized treatment group showed greater improvement of TCM symptoms than the stationary treatment group.It is speculated that the reason for this might be that the blood glucose level is positively correlated with fundus lesions.DR is the result of pathological changes caused by hyperglycemia,and the individualized treatment had a greater hypoglycemic effect;TCM states that blood stasis is related to DR,so Chinese herbal medicines such as Danshen (Radix Salviae Miltiorrhizae),Sanqi (Radix Notoginseng),which have effects on the blood circulation and blood stasis inhibition,were added to the individualized treatment.Studies also confirmed that the Compound Danshen Dripping pills composed of Danshen (Radix Salviae Miltiorrhizae) and Sanqi (Radix Notoginseng)had effects on improving vision,could control fundus hemorrhages and microaneurysms,and had an effect on visual function recovery in DR patients.24

The characteristics of TCM are reflected in the emphasis on overall regulation and individualized treatment.However,due to the fixed nature of Traditional Chinese Medicine compound preparations,it is difficult to fully explore the importance of TCM in individuals.The research results also show that individualized treatment with TCM,based on the effects on fundus lesions,TCM syndrome scores,the HbA1c and other indicators,showed better efficacy than the stationary Qiming granule treatment,especially since the TCM syndrome scores could better reveal the effects on efficacy to achieve the goal of improving clinical efficacy.

The results of study might have some limitations.The duration of DR is long and requires long-term observation and follow-up.The observation period of this study was 12 weeks,and the observation time was relatively short,so the DKD and DPN efficacy parameters were not analyzed.This would have provided us with a strong impetus for further development of an individualized treatment in further studies.

In conclusion,Qiming granules are effective in the treatment of NPDR.In patients with NPDR,the addition of individualized herbals to fixed Qiming granule therapies improved their efficacy in improving the HbA1c,vision,fundus lesions and TCM syndrome scores.It is an effective treatment and superior to the use of Qiming granules alone.However,there are some inevitable limitations in this study.Future investigations of individualized treatment for patients with NPDR are needed.