Clinical Application of Traditional Chinese Medicine Therapy for Type 2 Diabetes Mellitus: An Evidence Map

Type 2 diabetes mellitus (T2DM), a common disease with a complex etiology in the world, is an important risk factor for severe cardiovascular and cerebrovascular diseases. However, treatments of T2DM are mainly based on Western medicine, whose severe side effects make traditional Chinese medicine (TCM) therapy more appealing to patients and clinicians. The overall clinical evidence for different TCM therapies in the treatment of T2DM is still unclear. This study aimed to adopt the evidence-mapping method and integrate the evidence from various researches on this topic, to depict the whole picture of TCM therapies for T2DM. This review included searches of PubMed, Embase, Web of Science, and three major Chinese literature databases (CNKI, VIP, and Wanfang) from inception to November 18, 2021. Two independent reviewers screened the literature, extracted information, and evaluated the quality of all included studies. A systematic review was subsequently performed. In total, 47 studies were reviewed, of which 46 studies (97.9%) were from China and 1 (2.1%) was from Canada. The evidence map was conducted according to different TCM therapies, including herbs or herbal extracts, compounds, powders, decoctions, pills, external treatment, basic theories and treatment principles of TCM, proprietary Chinese medicines, and unspecified TCM integrated therapies. According to the AMSTAR-2 scoring results, 4 papers were rated as high quality, 11 were low quality, and 32 were very low quality. Outcome indicators mainly focused on FBG, HbA1c, 2-h PBG, TC, TG, LDL-C, etc. The results showed that different types of TCM treatment had different improvement effects on the outcome indicators of T2DM. More consistent benefits were observed in the improvement of FBG, HbA1c, and 2-h PBG with treatment regimens based on basic theories and treatment principles of TCM, decoctions and pills, and unspecified TCM integrated therapies. Among herbs, ginger and Coptis root showed more improvement in all outcomes. Compounds, powders, and external treatment showed relatively consistent beneficial effects on the improvement of FBG. No serious adverse events were reported. Overall, the current evidence map provided an intuitive overview of the beneficial effects of TCM therapies in the treatment of type 2 diabetes. This study can be used as a reference for the clinical application of traditional Chinese medicine in T2DM, but due to the low-quality level of the included studies, it should be treated with caution in clinical practices.


Introduction
Type 2 diabetes mellitus (T2DM) is a common disease with a complex etiology around the world. e current development of diabetes has far exceeded expectations. e World Health Organization (WHO) reported that approximately 300 million people will suffer from diabetes in 2025 [1][2][3].
e trend of diabetes prevalence in China is the same as in the rest of the world. e prevalence of diabetes in Chinese adults as defined by WHO criteria increased from 9.7% in 2007 to 11.2% in 2017. In the April of 2020, a study showed that the prevalence of diabetes in Chinese adults was 12.8% and the total number of diabetic patients was about 129.8 million [4].
Diabetes is also an important risk factor for severe cardiovascular and cerebrovascular diseases, and T2DM can cause a variety of complications if blood glucose levels were not controlled, resulting in a serious decline in quality of life and high outpatient and inpatient costs. Real-time monitoring and effective control are required to reduce its burden.
Treatments for T2DM are mainly via Western medicine (antidiabetic drugs such as insulin and metformin) and lifestyle modification. However, severe side effects from medications make TCM complementary and alternative therapies more attractive to patients and clinicians [1,5].
A large number of systematic reviews and meta-analyses have been published on the TCM treatment for T2DM, and researchers often conducted clinical trials on a certain type of Chinese herbal medicine, proprietary Chinese medicine, and Chinese medicine compounds to verify its clinical effectiveness. However, the overall clinical evidence for different TCM classifications in the treatment of T2DM remains unclear. erefore, this study aims to reevaluate systematic reviews and meta-analyses, adopt the evidence mapping method, integrate the evidence from various research, and comprehensively sort out the problems in the research topic, thus depicting the whole picture of the research field [6]. No evidence map of T2DM has been published in the field of TCM. erefore, this study used an evidence map to systematically retrieve the relevant literature (SRs) on the clinical treatment of T2DM, in order to better understand the distribution of evidence in this field and provide readers with more valuable and integrative evidence.

Search Strategy. Publication search was conducted in
PubMed, Embase, Web of Science, and 3 major Chinese literature databases, including CNKI, VIP, and Wanfang Data (Supplementary Table 1 to Supplementary Table 6). A manual search of the unpublished literature (including conference proceedings, theses and dissertations, and gray literature) was also performed. e search time frame was from the inception to November 18, 2021, and the language was restricted to Chinese and English.

Inclusion
Criteria. Inclusion criteria were as follows: (1) All meta-analyses and/or systematic reviews (SRs) on TCM treatments for T2DM were included. (2) Types of studies included in the SRs and meta-analyses should be RCTs.  (7) animal studies were excluded.

Study Selection and Data
Extraction. e authors (WY and DZL) screened the titles and abstracts of all retrieved references after removing duplicates, and the full text was obtained for further screening. WY checked all the eligible studies, and any disagreements were solved by a discussion with DZL, ZYG, and LN. e data extraction was conducted by WY and DZL and then validated by ZYG. e extracted information recorded was the title, authors, publication year, name of TCM, types of research included, the number of research included, interventions, controls, outcomes, effect value, etc. Disagreements were resolved by discussion, and a consensus was reached through a third party.

Quality Assessment.
Two independent reviewers evaluated the quality of included studies. A measurement tool to assess SRs (AMSTAR-2) [7], which consists of 16 items, was used to evaluate the methodological quality of all the included SRs. For each item, when the evaluation criteria were completely satisfied, the result was "yes." When the criteria were partially met, the evaluation result was "partially yes." When no relevant information was reported in the SRs, the result was "no." e key entries were 2, 4, 7, 9, 11, 13, and 15 [8]. If no or only one noncritical item failed, the quality level was high. If more than one noncritical item was not met, the quality level was medium. If one key item was not met, the quality rating was low. If more than one key item was not met, the quality level was very low.

Data Synthesis and Presentation.
e quantitative description was conducted in Microsoft Excel 365. Data summary and analysis were shown as text and charts, distribution of the development trend was depicted as a line chart [9], and the distribution of evidence as bubble plots was conducted in python3 (matplotlib, pandas) [10].

Literature Screening Process and
Results. An initial review of 865 relevant sources was conducted. After removing duplicates, 566 studies were identified. After screening the titles and abstracts, 93 studies were retained. After screening the articles in full text, we further excluded 46 records, so a total of 47 studies  were reviewed ( Figure 1).

e Basic Information of the Included Literature.
e basic information of the included literature is listed in Table 1; 46 studies (97.9%) were from China , and 1 (2.1%) was from Canada [34]. According to different TCM therapies, they were divided into herbs or herbal extracts, compounds, powders, decoctions, pills, external treatment, basic theories and treatment principles of TCM, proprietary Chinese medicines, and unspecified TCM integrated therapies ( Table 2). According to the AMSTAR-2 scoring results, 4 papers were assessed as high quality, 11 were low quality, and 32 were very low quality (Supplementary Table 7). Figure 2, the increasing overall trend in the number of studies was demonstrated. Before 2010, reviews were conducted sporadically. e number increased rapidly after 2010, with up to 144 systematic reviews published in one year. Table 3 shows the outcome indicators of TCM treatments of T2DM, the number of systematic reviews corresponding to the different indicators, and the number of comparative analyses with other control measures.

Effects of the TCM erapies on T2DM.
e metrics of clinical outcomes and intervention are shown in Figures 3-8 according to different TCM classifications. e consistent beneficial effect according to the systematic reviews and meta-analysis are shown in dark green. Nonmeaningful outcomes are shown in dark red, and the numbers of intervention-control comparisons for each outcome are shown as the bubble area.

Proprietary Chinese Medicines.
Of the 47 included systematic reviews, a total of 6 papers [21,22,37,42,51,57] compared the effects of TCMs such as Tianqi Jiangtang capsules, Jinqi Jiangtang tablets, Jinqi Jiangtang tablets and Qihuang capsules, and chromium-containing Chinese herbal medicine Tianmai Xiaoke tablets on the treatment of T2DM by meta-analysis. Improvements in various outcome indicators did not show a more consistent beneficial effect than conventional or placebo therapy alone. Improvements in glycosylated hemoglobin (5/10), 2-hour postprandial glucose (4/7), and FBG (3/7) showed beneficial effects in only half of the studies, with consistent beneficial effects only on TG (6/6).

Basic eories and Treatment Principles of TCM.
A total of 10 [14,17,19,20,24,28,40,48,55,56] of the 47 included systematic reviews compared the effectiveness of basic theories and treatment principles of TCM, including external treatment of TCM, nourishing Qi, replenishing yin, activating blood flow, replenishing Qi and nourishing yin diet therapy + conventional treatment, replenishing Qi nourishing yin method, heat-clearing method, tonifying spleen, and Qi herbs, strengthening the spleen, and reducing phlegm Chinese medicine, nonreplenishing Qi, and nourishing yin diet therapy + conventional treatment, treating proprietary Chinese medicines and prescriptions from the perspective of the liver, kidney-tonifying and blood-activating TCM compound treatment, and TTSD on the treatment of T2DM by meta-analysis. Improvements in all outcome indicators relative to conventional therapy or placebo therapy alone showed consistent beneficial effects. Improvements in glycated hemoglobin (9/10), 2-hour postprandial glucose (7/7), FBG ( Figure 1: Literature screening process and results.  6 Evidence-Based Complementary and Alternative Medicine Evidence-Based Complementary and Alternative Medicine 7  Evidence-Based Complementary and Alternative Medicine 9 outcomes (6/6) were all highly beneficial. ere were also beneficial effects on the improvements of BMI, LDL-C, TC, INS, ISI, and TCM syndrome.

Herbal Medicine.
A total of 6 [13,26,34,35,43,49] of the 47 included systematic reviews compared the effects of ginger, cassia bark, green tea or green tea extract, Coptis root, and Coptis-cassia bark by meta-analysis for the treatment of T2DM. Coptis root showed beneficial effects on glycated hemoglobin, 2-hour postprandial glucose, FBG, HDL-C, TC, and TG in 10 of 13 meta-analyses. Ginger showed beneficial effects on glycated hemoglobin, FBG, HDL-C, LDL-C, TC, TG, INS, and ISI in 9 of 11 metaanalyses.         Relative to conventional therapies alone, the integrated TCM therapies showed a more consistent beneficial effect on the improvement of glycosylated hemoglobin (7/10), with only 3 unspecified TCMs being insignificant in the 10 comparative studies. ey showed a completely consistent beneficial effect on the improvement of 2-hour postprandial glucose (7/7) and showed a more consistent beneficial effect on the improvement of fasting glucose (18/23), with 2 insignificant multitherapeutic combinations and 3 insignificant TCM methods. e improvement in TC showed a more consistent beneficial effect (9/13); 2 TCM methods were not significant, 1 TCM were unspecified, and 1 multitherapeutic combination was not significant. For the improvement in TG, only half of the studies showed a beneficial effect (8/16), and for improvement in 2 hours' postprandial insulin, the integrated TCM therapies did not show a beneficial effect. e effects of TCM compound, Chinese patent medicine, and TCM unspecified on improving BMI, HDL-C, HOMA-IR, LDL-C, INS, blood glucose target time, average insulin dose, ISI, HOMA-β, number/rate of hypoglycemia, and clinical efficacy, TCM syndrome, follow-up, sleep quality, plasma viscosity, fibrinogen, and quality of life all had beneficial effects.

Adverse Events.
In the intervention group using TCM therapies, there were few reports of adverse reactions, most of which were incidental cases, and no serious adverse reactions were reported. Zhipeng Hu [11] remarked that one RCT reported one case of headache, three cases of nausea and vomiting, one case of dizziness, and one case of dry cough in the TCM treatment group and one RCT reported one case of hypoglycemia and four cases of mild nausea and loss of appetite, which then gradually disappeared. Jiarong Lan [13] mentioned that no serious adverse reactions affecting vital organs occurred during the experiment. e incidence of adverse reactions was dose-dependent. Chi Xiao [18] noted that one RCT reported one case of the hypoglycemic reaction occurred in the TCM treatment group after 2 weeks of treatment, while 2 cases occurred in the control group. Some RCT studies reported possible GI adverse reactions in both the TCM treatment and control groups [21]. One RCT reported a total of 3 cases of gastrointestinal (GI) adverse reactions, but none of them required special treatment [22]. It has been summarized [24] that some RCTs reported the occurrence of adverse reactions, such as mild nausea and vomiting, mild gastrointestinal discomfort, mild hypoglycemia, skin pruritus, and mild tingling in the ear in a few patients. Jiahui Hu [39,40], Huijuan Gao [42], Aiping Deng [50], and Jiaxing Tian [52] noted that there was no statistically significant difference in the incidence of adverse reactions between the TCM treatment group and the control group. Ying Fu [41] mentioned that the studies involved all GI reactions.   Another review concluded [47] that hypoglycemic events were reported in the RCT studies, but there was no significant difference between the control group (6 cases) and the TCM treatment group (5 cases). Jiang Li [48] alluded that one RCT reported 6 cases of hyperthermia in the control group and 4 cases of vomiting in the TCM group, and another RCT reported one case of hypoglycemia in both groups. One literature reported the incidence of GI adverse reactions in the TCM group was 2.5% while that in the control group was 7.5% [48]. It has been indicated [53] that the combination of Liu Wei Di Huang Wan (soup) with metformin for T2DM has the potential to reduce the adverse effects of metformin. Yuming Gu [57] mentioned that the common adverse events in the TCM group were gastrointestinal symptoms (nausea/vomiting, bloating, and diarrhea), neurological symptoms, and hypoglycemia. However, no significant abnormalities in blood, liver, or kidney functions were seen in all studies.

Summary of Findings.
e evidence map for TCM treatments of T2DM was developed based on 47 SRs and metaanalyses, providing an evidence overview of the impact of different TCM therapies on different outcomes. e included literature was for patients with only T2DM but not comorbidities and complications. ere were many systematic reviews on Coptis root, Jinqi Jiangtang tablets, Liuwei Dihuang pills, Xiaoke pills, and methods of nourishing Qi, replenishing yin, and activating blood flow. e outcome indicators mainly focus on FBG, HbA1c, 2-h PBG, TC, TG, and LDL-C. e results showed that different types of TCM treatments had different improvement effects on the outcome indicators of T2DM. More consistent benefits were observed in the improvement of the primary outcomes with basic theories and treatment principles of TCM, decoctions and pills, and unspecified TCM integrated therapies. Among the herbal medicine, ginger and Coptis root showed benefits in all outcomes. e improvement of FBG was more consistent with compounds, powders, and external treatment. No report of serious adverse reactions has been found, but mild gastrointestinal reactions were common, such as nausea, vomiting, abdominal distension, and diarrhea, and they did not require special treatments.

Differences from Previous Studies.
e method of using the evidence map to provide evidence summary has been used in the treatment of hypertension with TCM [55], and there have been reviews published in English on the treatment of diabetes with TCM [1]. is paper is the first evidence map systematic review on the treatment of T2DM with TCM.

Limitations.
e study has some limitations. First, most systematic reviews of TCM research were published in Chinese, which may have publication bias. Second, in all SRs and meta-analyses included, only a few studies were of high quality, and most were of low or very low quality.

Implications for Future Research.
e study provides enlightenment for the future TCM treatments of diabetes and related academic research. First, the results of FBG showed the most consistent beneficial effect among different TCM treatments, which was beneficial for long-term control and prevention of complications. Second, in most of the included SRs and meta-analyses, TCM therapies were used in combination with conventional Western medicine treatment, but the different combinations of TCM and Western medicine may achieve different results and further clinical studies are needed. ird, a few studies found that TCM may reduce the side-effects of Western medicine, but the evidence was not clear enough. e interaction between TCM and Western medicine needs to be explored.

Implications for Clinical Practice.
In China, emphasizing the application of both TCM and Western medicine has become a national strategy. But in clinical practice, the indications of TCM therapies are currently too broad, and the current evidence cannot convince clinicians to choose a specific treatment method. e evidence map shows that the external treatment of TCM, replenishing Qi and nourishing yin diet therapy + conventional treatment, replenishing Qi nourishing yin method, heat-clearing method, tonifying spleen and Qi herbs, strengthening the spleen and reducing phlegm Chinese medicine, nonreplenishing Qi and nourishing yin diet therapy + conventional treatment, TTSD, Xiaoke recipe, Banxia Xiexin decoction, Xiaoke pills, Liuwei Dihuang Wan (soup), and chromium-containing Chinese herbal medicine Tianmai Xiaoke tablets have a relatively clear application value for hypoglycemia and can be used as a careful reference for making diagnosis and treatment plans in clinical practice. However, the combined usage, administration time, and duration of TCM therapies still need to be further explored. Given the promising findings in the evidence map from this paper, the use of these TCM therapies may become more widespread if supported by further welldesigned trials or real-world studies.

Conclusions
Overall, the evidence map provides an intuitive overview of the beneficial effects of TCM therapies in the treatment of T2DM. is study can be used as a reference for the clinical application of TCM in T2DM, but due to the relatively lowquality level of the included studies, it is recommended to be used with caution in clinical practice. is study also enlightens the future research direction of evidence-based medicine and further study about the clinical application of TCM.

Conflicts of Interest
e authors declare that there are no conflicts of interest regarding the publication of this paper.
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