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Evidence-Based Complementary and Alternative Medicine


Volume 2021, Article ID 2562590, 14 pages
https://doi.org/10.1155/2021/2562590

Review Article
Efficacy and Safety of the Chinese Patent Medicine Yuquan Pill on
Type 2 Diabetes Mellitus Patients: A Systematic Review
and Meta-Analysis

Sihan Peng ,1,2 Ziyan Xie,1,2 Xiyu Zhang,1,2 Chunguang Xie,1 Jian Kang,1 Haipo Yuan,1
Gang Xu,1,2 Xiangeng Zhang,3 and Ya Liu 1
1
Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
2
Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
3
Sichuan Nursing Vocational College, Chengdu, Sichuan, China

Correspondence should be addressed to Ya Liu; liuyaya918@163.com

Received 7 October 2021; Revised 6 November 2021; Accepted 8 November 2021; Published 2 December 2021

Academic Editor: Youhua Wang

Copyright © 2021 Sihan Peng et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background. Yuquan Pill (YQP), a Chinese patent medicine for the treatment of diabetes, is widely used in the treatment of
diabetes and its complications in China. However, the efficacy of YQP on type 2 diabetes mellitus (T2DM) has not been completely
assessed. The aim of this study is to evaluate the efficacy and safety of YQP in the treatment of T2DM. Materials and Methods. We
systematically searched 9 databases for specific keywords from inception to Oct 2021. We included randomized controlled trials
(RCTs) involving YQP in the treatment of T2DM without language limitation. The study conformed to the Cochrane Handbook
and Review Manager software was used for data analysis. The weighted mean differences (WMDs) and 95% confidence intervals
(CIs) were used to measure treatment effects. Results. The final analysis included 10 publications. Analysis showed that the
combination of YQP and conventional treatment was more effective than conventional treatment alone with regard to the levels of
fasting blood glucose (WMD � −0.83; 95% CI [−1.01,−0.66]; p < 0.00001), two-hour postprandial glucose (WMD � −1.40; 95% CI
[−1.49,−1.31]; p < 0.00001), glycosylated hemoglobin (WMD � −0.87; 95% CI [−1.26, −0.49]; p < 0.00001), total cholesterol
(WMD � −0.50; 95% CI [−0.61, −0.39]; p < 0.00001), c-reactive protein (WMD � −0.58; 95%CI [−0.88, −0.28]; p � 0.0002), and
overall effective rate (RR � 1.21; 95% CI [1.12, 1.31]; p < 0.00001). Conclusion. Evidence suggested that YQP might improve glucose
and lipid metabolism and inflammation in patients with T2DM. Serious adverse events were not reported. The quality of the
evidence analyzed was low and therefore our results should be interpreted with caution. More high-quality RCTs are now needed
to verify these findings.

1. Introduction countries [5]. The global prevalence of diabetes is estimated


to be 9.3% (approximately 463 million people), with T2DM
Type 2 diabetes mellitus (T2DM) is a chronic metabolic accounting for more than 90% of all diabetics [6, 7]. Insulin
disease that is characterized by elevated levels of blood resistance and long-term hyperglycemia will inevitably lead
glucose. The pathophysiology of T2DM is characterized by to changes in various metabolic and cellular functions, such
insulin resistance accompanied by reduced insulin secretion as dyslipidemia, increased blood pressure, endothelial dys-
due to the dysfunction of pancreatic β cells [1]. Over the past function, and increased platelet reactivity and oxidative
three decades, the number of people living with diabetes has stress. These factors can cause chronic inflammation,
increased more than double globally. Diabetes has now thereby damaging blood vessels and accelerating the oc-
become a major public health issue across the entire world currence and development of diabetic microvascular and
[2–4]. Moreover, diabetes and its complications have a macrovascular complications [8–12]. Although routine
significant economic impact on individuals, families, and hypoglycemic drugs are widely used, these still fail to
2 Evidence-Based Complementary and Alternative Medicine

effectively prevent the progression of diabetes and may cause We systematically searched 9 databases for specific
side effects such as gastrointestinal reactions (nausea, keywords from inception to Oct 2021, including PubMed,
vomiting, and diarrhea), dizziness [13], and hypoglycemia Web of Science, the Cochrane Library, the China National
[14]. Thus, the treatment of T2DM has become a significant Knowledge Infrastructure (CNKI), China Biology Medicine
hotspot for medical research, particularly with regard to Disc (Sino Med), the Wan Fang Database, and the VIP in-
developing new treatments for T2DM. formation resource integration service platform (CQVIP).
Traditional Chinese medicine (TCM) has a long history in YQP (approval number: Z51021085) is a commonly used
the treatment of diabetes and has been associated with re- Chinese patent medicine for the treatment of diabetes in
markable curative effects. TCM plays an important role in the China. In order to avoid missing unpublished clinical trials for
management of diabetes in China [15] and is believed to relieve patent reasons, we additionally searched the patent database.
diabetes by comprehensively regulating the qi and blood A detailed retrieval of domestic and foreign patent infor-
balance in human body. As a representative Chinese patent mation was carried out in Patent Search and Analysis of
medicine, YQP has been approved by the China Food and National Intellectual Property Administration (http://pss-
Drug Administration (CFDA) (approval number: Z51021085) system.cnipa.gov.cn/sipopublicsearch/portal/uiIndex.shtml).
for the treatment of diabetes and its complications. YQP Google scholar was also carefully searched to find missing
comprises the following herbs: Pueraria montana var. publications. We included all RCTs that were associated with
Thomsonii (Benth.) (gě g�en), Trichosanthes kirilowii Maxim. YQP for T2DM without language limitation. The search terms
(ti�an hu�a fěn), Ophiopogon japonicus (Thunb.) Ker Gawl. (mài were as follows: “Yuquan Pill,” “Yuquan wan,” “Yuquan,”
d�ong), Rehmannia glutinosa (Gaertn.) DC. (dı̀ huáng), Schi- “Yu-Quan Pill,” “yuquan pill,” “Diabetes Mellitus,” “Diabetes
sandra chinensis (Turcz.) Baill. (wǔ wèi zǐ), and Glycyrrhiza Insipidus,” “Diet, Diabetic,” “Prediabetic State,” “Glycation
glabra L. (g�an cǎo). According to the basic theory of TCM, End Products, Advanced,” “Gastroparesis,” and “Glucose
T2DM is triggered by yin deficiency. YQP has the efficacy of Intolerance.” Meanwhile, we also carefully studied the ref-
nourishing yin, moistening dryness, and promoting fluid, erences of the relevant literature for more available studies.
which can treat T2DM in essence. The composition and details
of YQP are generalized in Figure 1 and Table 1.
Since its approval, YQP has become one of the most 2.2. Inclusion and Exclusion Criteria. Only randomized
commonly used Chinese patent medicines to treat diabetes and controlled trials (RCTs) that assessed the effects of YQP for
its complications. The Guidelines for the Prevention and T2DM were selected. Reviews, retrospective study, and animal
Treatment of Diabetes by Traditional Chinese Medicine (2011 experiments were excluded. For participants, we only included
Edition) issued by the Chinese Medical Association recom- adult patients with a definite diagnosis of T2DM, without
mends YQP as the prescription for the treatment of diabetes limitations relating to gender, regions, and ethnicity. According
[16]. Studies have shown that YQP can improve insulin sen- to the American Diabetes Association’s diabetes guidelines
sitivity, regulate glucose and lipid metabolism, and improve [28], the diagnostic criteria for T2DM are as follows: fasting
macrovascular disease and microvascular disease in diabetic blood glucose (FBG) ≥126 mg/dL (7.0 mmol/L) or 2-hour
patients [17–19]. YQP has also been shown to protect endo- postprandial blood glucose (2hPG) ≥200 mg/dL (11.1 mmol/L)
thelial cells, alleviate inflammatory responses, and reduce the during Oral glucose tolerance test (OGTT) or glycosylated
serum levels of vascular endothelial growth factor (VEGF) hemoglobin (HbA1c) ≥6.5% (48 mmol/mol) or in a patient
[20–22]. An increasing number of clinical studies have re- with classic symptoms of hyperglycemia or hyperglycemic
ported that YQP may effectively improve the clinical symptoms crisis, a random plasma glucose ≥200 mg/dL (11.1 mmol/L). In
and indicators of T2DM [23–26]. However, to the best of our terms of types of interventions, the treatment groups were
knowledge, there has been no evaluation that has systematically treated with YQP, including pills, decoction, and granules,
analyzed the efficacy and safety of YQP and whether this drug regardless of frequency and duration. The control group re-
represents an ideal form of alternative therapy. In the present ceived conventional diabetes medicine or placebo treatment. It
study, we used evidence-based methods to evaluate the efficacy was worth mentioning that the studies that adopted multiple
and safety of YQP for the treatment of T2DM. Our aim was to interventions or that YQP was not the primary intervention
provide more robust scientific evidence for clinicians, re- had been excluded. As this research aims to systematically
searchers, and policy makers. evaluate the effects of YQP in the treatment of T2DM, the
primary outcomes of the present study were FBG, 2hPG, and
HbA1c. The secondary outcomes were total cholesterol (TC),
2. Methods c-reactive protein (CRP), and overall effective rate, while the
2.1. Database and Search Strategies. The protocol for this safety was measured by adverse effects.
systematic review was registered in the International Pro-
spective Register of Systematic Reviews (PROSPERO) with a 2.3. Data Collection and Analysis
registration number CRD42021261805.
This review was designed and performed in accordance 2.3.1. Study Selection. Study selection was independently
with the guidelines of Preferred Reporting Items for Sys- done by two investigators (JK and HY), based on the titles
tematic Review and Meta-Analysis Protocols (PRISMA-P) and abstracts to select for appropriate publications. EndNote
2015 [27]. All reviewers received relevant training to grasp V.X9 software was used for literature management. Any
the background, purpose, and process of the review. disagreements were submitted to a senior investigator (GX).
Evidence-Based Complementary and Alternative Medicine 3

Pueraria montana var. thomsonii (Benth.). Trichosanthes kirilowii Maxim. Ophiopogon japonicus (Thunb.) Ker Gawl.

Yuquan Pill

Rehmannia glutinosa (Gaertn.) DC. Schisandra chinensis (Turcz.) Baill. Glycyrrhiza glabra L.

Figure 1: The composition of Yuquan Pill.

Table 1: Details of Yuquan Pill.


Chinese herbs Latin name Family Part of herbs Function in Chinese medicine
Pueraria montana var. Thomsonii
Ge Gen (gě g�en) Fabaceae Root To promote fluid, relieve thirst, and clear heat
(Benth.).
Tian Hua Fen (ti�an
Trichosanthes kirilowii Maxim. Cucurbitaceae Root To clear heat and promote fluid
hu�a fěn)
Ophiopogon japonicus (Thunb.) To nourish yin, moisten lung, and promote
Mai Dong (mài d�
ong) Asparagaceae Root
Ker Gawl. fluid
Rehmannia glutinosa (Gaertn.)
Di Huang (dı̀ huáng) Plantaginaceae Root To nourish yin, promote fluid, and clear heat
DC.
Wu Wei Zi (wǔ wèi Schisandra chinensis (Turcz.) To promote fluid and nourish lung and
Schisandraceae Fructus
zǐ) Baill. kidney
Root and To replenish qi, tonify spleen, moisten lung,
Gan Cao (g�an cǎo) Glycyrrhiza glabra L. Fabaceae
rhizome and promote fluid

2.3.2. Data Extraction and Management. The following [29]. The grades were rated as “low,” “high,” or “unclear”
information was independently extracted by two reviewers risk of bias, based on the following items: random se-
(JK and GX): general information, including the first author, quence generation, allocation concealment, incomplete
journal, publication time, and country; participant charac- data, blinding, selective reporting, and other sources of
teristics, such as sample size, gender, mean age, and duration bias. Any differences were discussed and resolved with a
of disease; interventions of treatment and control groups; third researcher (HY).
outcomes including FBG, 2hPG, HbA1c, TC, CRP, and
overall effective rate. The information was cross-checked by
two investigators, and any disagreements were resolved by a 2.3.4. Data Analysis. We used Review Manager (version 5.3)
third reviewer (SP). software to analyze all data to evaluate the effect of YQP on
T2DM patients from the aspects of blood glucose, blood lipid,
and so on. Continuous variables, including FBG, 2hPG,
2.3.3. Assessment of Risk of Bias. Two independent in- HbA1c, TC, and CRP, were evaluated by weighted mean
vestigators (JK and GX) assessed the risk of bias in the differences (WMDs) and 95% confidence intervals (CIs). Di-
light of the Cochrane Collaboration’s Risk of Bias tool chotomous data, such as overall effective rate and risk ratio
4 Evidence-Based Complementary and Alternative Medicine

(RR) with 95% CI, was used to measure the treatment effect. 3.3. The Risk of Bias in the Analyzed Studies. We investigated
When important data was incomplete in the reported litera- the risk of bias for all the articles included in our analysis. All
ture, we contacted the authors by various means to get more the study items were randomly divided into a YQP group
relevant information. and a control group. The randomization of treatments was
not consistent when compared across the 10 articles; only
one study [42] was classified as low risk of bias because it was
2.3.5. Subgroup Analysis. The heterogeneity was assessed
randomized using a random number table; another study
by the I2 value. If the I2 value exceeds 50%, it means that
[48] did not include randomization and was therefore as-
there is significant statistical heterogeneity [30]. Subgroup
sociated with a high risk of bias; the other 8 studies did not
analysis was constructed to explore the potential causes of
mention the specific randomization method used; the risk of
heterogeneity. The subgroup analysis focused on the
bias for these papers was therefore determined as being
following factors: different ages (≥50 y or < 50 y), different
‘unclear.’ None of the RCTs reported allocation conceal-
control groups (metformin or other treatments), dura-
ment. In terms of performance bias, none of the 10 articles
tions of T2DM (≥10 y or < 10 y) or different regions, and
included in this analysis reported the blinding of the par-
so on.
ticipants or researchers. Therefore, we classified all 10 studies
as having a high risk of bias in this domain. With regard to
2.3.6. Sensitivity Analysis. When the outcomes were un- other biases, one study [40] did not report the treatment
stable, sensitivity analysis was carried out by removing duration; therefore the risk was classified as being high. The
studies with high risk of bias and recalculating the pooled complete and detailed analysis for the risk of bias is pre-
data to evaluate the robustness of merged results. sented in Figures 3 and 4.

2.3.7. Assessment of Publication Bias. Due to insufficient 3.4. Outcomes


included studies, there was no evaluation of publication bias
conducted in this study. 3.4.1. Fasting Blood Glucose. Nine studies involving 802
diabetic patients provided data on FBG before and after
3. Results intervention between treatment and control groups [40–48].
Using fixed effects model, the results suggested that YQP
3.1. Literature Search. Figure 2 shows the process used to plus conventional treatment might significantly reduce FBG
select studies for analysis. A total of 335 relevant literature in patients with T2DM (WMD � −0.83; 95% CI
articles were initially identified by our database searches; 168 [−1.01,−0.66], p < 0.00001; see Figure 5). And the hetero-
publications were excluded due to duplicate findings. Of the geneity was low (χ 2 � 15.63; p � 0.05,I2 � 49%; see Figure 5).
remaining 167 articles, some were excluded because they In subgroup analysis, there was no significant difference
failed to meet our specific inclusion criteria. For example, between subgroups of different ages (p � 0.14)and different
they were reviews or involved animal experiments, and fi- control treatments (p � 0.31) (Table 3, Supplementary
nally there were 19 literatures left. Then, after carefully Materials 1 and 2).
reading the full texts of these 19 articles, we removed non-
RCTs [31, 32], RCTs without treating DM [33], and the
articles lacking sufficient details on outcomes [34–39]. At 3.4.2. Two-Hour Postprandial Glucose. Eight
last, 10 clinical trials [40–49] were included in the meta- studies (including 689 patients) evaluated the effect of YQP
analysis. on 2hPG [42–49]. Results from pooled data analysis implied
a significant decrease in 2 hPG with low heterogeneity
(WMD � −1.40; 95% CI [−1.49, −1.31]; p < 0.00001; het-
3.2. Characteristics of the Included Studies. A total of 871 erogeneity: p � 0.19, I2 � 29%, fixed effects model; see Fig-
patients were included in the 10 studies, 455 in treatment ure 6). In subgroup analysis, there was no significant
groups and 416 in control groups. The mean age of the difference between subgroups of different ages (p � 0.19),
patients described in these 10 articles ranged from different control treatments (p � 0.64), and different courses
41.70 ± 11.05 years [43] to 69.30 ± 5.35 years [42]. The in- of treatment (p � 0.95) (Table 3, Supplementary Materials
tervention measure used for all treatment groups was the 3–5).
administration of YQP in combination with conventional
therapy. Of the 10 articles, 9 articles referred directly to
T2DM [41–49], while one article referred specifically to 3.4.3. Glycosylated Hemoglobin. A total of 6 studies in-
diabetic nephropathy [40]; we included this latter article cluding 572 participants reported HbA1c levels
because diabetic nephropathy was a common complication [40, 41, 44–47]. According to the random effects model, the
of diabetes. All 10 studies were carried out in China and were results showed that YQP combined with conventional
published between 2005 and 2021. The shortest and longest treatment could reduce the HbA1c levels of T2DM
treatment duration were 1 month [42, 49] and 3 months (WMD � −0.87; 95% CI [−1.26, −0.49]; p < 0.00001; see
[41, 43, 45, 48], respectively. Table 2 shows the detailed Figure 7). We found a significant heterogeneity among these
characteristics of the 10 studies that underwent final analysis researches (χ2 � 22.42, p � 0.0004, and I2 � 78%; see Figure 7);
herein. therefore, subgroup analysis was performed. Subgroup
Evidence-Based Complementary and Alternative Medicine 5

Records identified through database


searching (n = 313): Additional records identified through other
PubMed (n = 4); Cochrane (n = 3); Web of sources (n=22):
Science (n = 3); CNKI (n = 47); Wanfang Google Scholar (n=22)
data (n = 139); VIP (n = 49); Sino Med Patent Search and Analysis of National
(n = 68) Intellectual Property Administration (n=0)

A total of 335 of records 168 of duplicate


identified records removed

Records excluded (n=148):


Duplicates (n= 28);
Reviews (n= 56);
Records screened (n=167)
Animal experiments (n= 31);
Not using Yuquan Pill (n= 30);
Not included outcomes (n=3)

Full-text articles excluded (n=9):


Full-text articles assessed Not RCTs (n= 2)
for eligibility (n=19) Not treating DM (n= 1)
Lack of sufficient details on
outcomes (n= 6)

Studies included in qualitative


synthesis (n=10)

Figure 2: Flow diagram of studies selection process.

analyses according to different ages, control treatments, and regions showed no significant difference between groups (p
durations of disease showed no significant difference in in- for interaction � 0.84, 0.05, and 0.81, resp.) (Table 3, Sup-
tervention effect between groups (p for interaction � 0.11, plementary Materials 11–13).
0.74, and 0.26, resp.), and the significant heterogeneity was
still observed (Table 3, Supplementary Materials 6–8).
3.4.6. Overall Effective Rate. The overall effective rate was
divided into significant effective, effective, and ineffective
3.4.4. Total Cholesterol. Three studies involving 247 T2DM according to the degree of improvement of clinical symp-
evaluated the effect of adding YQP to conventional treatment toms and related indicators (mainly refers to blood glucose
on TC levels [45, 48, 49]. The combination therapy might level, including FBG, 2hPG, and HbA1c). Six researches that
significantly reduce the TC levels in T2DM patients compared involved 600 patients mentioned overall effective rate as
with control group (WMD � −0.50; 95% CI [−0.61, −0.39]; outcome [41, 43–47]. Since the absence of substantial het-
p < 0.00001, fixed effects model; see Figure 8) and with low erogeneity (χ 2 � 2.70, p � 0.75, and I2 � 0%; see Figure 10),
heterogeneity (χ 2 � 1.65, p � 0.44, and I2 � 0%; see Figure 8). In we used the fixed effects model for statistical analysis. The
subgroup analysis, there was no significant difference between results of the meta-analysis showed that YQP might result in
subgroups of different ages (p � 0.20) and different courses of a significant increase in overall effective rate compared with
treatment (p � 0.97) (Table 3, Supplementary Materials 9–10). conventional treatment (RR � 1.21; 95% CI [1.12, 1.31];
p < 0.00001; see Figure 10). Subgroup analyses by different
ages, control treatments, courses of treatment, and regions
3.4.5. C-Reactive Protein. Four studies explored CRP be- showed no significant difference in effect size (p for inter-
tween treatment group and control group [41, 43–45]. All action � 0.90, 0.79, 0.27, and 0.50, resp.) (Table 3, Supple-
the studies involving 406 T2DM patients showed that YQP mentary Materials 14–17).
plus conventional treatment might significantly reduce CRP
(WMD � −0.58; 95% CI [−0.88,−0.28]; p � 0.0002, random
effects model; see Figure 9). Significant heterogeneity was 3.4.7. Adverse Effects. Adverse effects were reported in 7 of
observed (χ 2 � 17.54, p � 0.0005, and I2 � 83%; see Figure 9). 10 studies. Three of them reported that no adverse effect
Subgroup analyses according to different ages, safety, and was found [42, 43, 48]. Four studies [41, 44, 45, 49]
6

Table 2: Characteristics of the studies included in this meta-analysis.


Number Duration of Gender
Author, year Age (T/C) Intervention (T) Intervention (C) Course Outcomes Region
(T/C) disease (T/C) (F/M)
Zheng and 46.84 ± 12.52/ 11.25 ± 9.72 y/ YQP (8 pills, tid)+metformin/
32/30 32/30 Metformin/gliclazide NR ①③ Hefei, Anhui
Huang, 2005 47.59 ± 11.98 11.82 ± 8.13 y gliclazide
Deng et al., 50 ± 11.6/ 3.68 ± 2.56 y/ Hangzhou,
60/30 51/39 YQP (6 g, qid)+acarbose (50 mg, tid) Acarbose (50 mg, tid) 12 w ①②⑤⑥⑦
2006 49.8 ± 12.1 3.43 ± 2.12 y Zhejiang
Zhao et al., 41.1 ± 10.4/ 5.2 ± 3.3 y/ YQP (8 pills, tid)+metformin Changsha,
48/46 53/41 Metformin (0.25 g, tid) 8w ①②③⑥
2008 42.3 ± 11.7 4.9 ± 3.2 y (0.25 g, tid) Hunan
Li and Wu, 51.5 ± 4/ 4.8 ± 0.9 y/ YQP (6 g, qid)+metformin (0.5 g,
50/50 53/47 Metformin (0.5 g, bid) 6w ①②③⑥ Weinan, Shanxi
2012 53.5 ± 5.5 5.1 ± 1.2 y bid)
49.1 ± 4.7/ 7.1 ± 0.6 y/ YQP decoction + hypoglycemic Zhengzhou,
Tian, 2013 30/30 28/32 Hypoglycemic drugs 4w ①②⑦
48.3 ± 5.4 6.6 ± 1 y drugs Henan
52.3 ± 5.1/ 9.5 ± 2.1 y/ Wulanchabu,
Zhu, 2015 37/32 41/28 YQP (6 g, qid)+acarbose (50 mg, tid) Acarbose (50 mg, tid) 4w ②④⑦
53.1 ± 3.4 10.5 ± 1.5 y Neimenggu
Metformin enteric
56.27 ± 6.6/ 5.56 ± 2.35 y/ YQP (6 g, qid)+metformin enteric
Wang, 2017 60/60 66/54 capsules (0.5 g, tid)+ 12 w ①③⑤⑥⑦ Tianjin
57.31 ± 4.2 5.45 ± 2.56 y capsules (0.5 g, tid)+ insulin
insulin
Jing et al., 46.87 ± 7.14/ YQP (6 g, qid)+metformin/ Metformin/gliclazide/
40/40 NR 55/25 12 w ①②④⑦ Taiyuan, Shanxi
2019 46.95 ± 7.54 gliclazide/insulin insulin
Xiao et al., 68.9 ± 5.2/ 5.9 ± 1.8 y/ YQP (6 g, qid)+saxagliptin (5 mg,
49/49 57/41 Saxagliptin (5 mg, qd) 12 w ①②③④⑤⑥⑦ Nanyang, Henan
2021 69.7 ± 5.5 5.6 ± 1.6 y qd)
Wan et al., 49.59 ± 5.37/ 5.14 ± 0.92 y/ YQP (6 g, qid)+dapagliflozin (10 mg, Dapagliflozin (10 mg, Zhengzhou,
49/49 58/40 12 w ①②③⑤⑥⑦
2021 49.65 ± 6.29 5.24 ± 0.84 y qd) qd) Henan
T: treatment group; C: control group; YQP : Yuquan Pill; F: female; M: male; NR: not reported; Y: year; W: week; ①: fasting blood glucose; ②: two-hour postprandial glucose; ③: glycosylated hemoglobin; ④: total
cholesterol; ⑤: c-reactive protein; ⑥: overall effective rate; ⑦: adverse effects.
Evidence-Based Complementary and Alternative Medicine
Evidence-Based Complementary and Alternative Medicine 7

Random sequence generation (selection bias)


Allocation concealment (selection bias)
Blinding of participants and personnel (performance bias)
Blinding of outcome assessment (detection bias)
Incomplete outcome data (attrition bias)
Selective reporting (reporting bias)
Other bias

0 25 50 75 100
(%)

Low risk of bias


Unclear risk of bias
High risk of bias
Figure 3: Risk of bias graph.

4. Discussion
Blinding of participants and personnel (performance bias)

4.1. Main Results. With the continuous development and wide


Blinding of outcome assessment (detection bias)

application of evidence-based medicine, systematic reviews and


Random sequence generation (selection bias)

meta-analyses have become a recognized and widely accepted


research method. Such studies can facilitate the evaluation of
Incomplete outcome data (attrition bias)
Allocation concealment (selection bias)

clinical evidence and serve as a strong foundation for evidence-


Selective reporting (reporting bias)

based decision making [50]. However, until now, there has


been no specific evaluation of the clinical evidence related to
the use of YQP for the treatment of T2DM.
A total of 335 relevant articles were retrieved in our initial
database searches. Ten of these articles were included in our
final meta-analysis after eliminating duplicate articles and
applying our specific exclusion criteria. Data analysis dem-
Other bias

onstrated that, compared to conventional treatment alone, the


coadministration of YQP and conventional medicine may be
more effective with regard to exerting effects on FBG, 2hPG,
Airong Tian.2013 + ? – ? + ? + HbA1c, TC, and CRP; there was also evidence for an im-
Baoli Zhu,2015 ? ? – ? ? ? ? provement in the overall effective rate. Our analyses also
showed that there was evidence for improvements in glucose
Chen Zhao,2008 ? ? – ? + ? +
and lipid metabolism and the inflammation associated with
Dongying Xiao,2021 ? ? – ? + ? + T2DM, at least to some extent. Next, we divided the par-
Hong Wan,2021 ? ? – ? + ? + ticipants into subgroups according to their specific charac-
Hua Wang,2017 ? ? – ? ? ? ? teristics (such as age and region) and differences with regard
Shuihua Li.2012 ? ? – ? ? ? ?
to control treatment and the duration of treatment. Com-
prehensive subgroup analysis was then performed on the basis
Xiaoqi Jing,2019 – ? – ? ? ? +
of these variables to explain or reduce the observed levels of
Yinquan Deng,2006 ? ? – ? + ? + heterogeneity. Although a series of subgroup analyses were
Yong Zheng,2005 ? ? – ? + ? – conducted in the present study, we identified high levels of
Zhao Gao 2015 ? ? – ? + ? + heterogeneity with regard to HbA1c and CRP data. The
combination of effect sizes using a random effects model did
Figure 4: Risk of bias summary. not reduce the observed heterogeneity or identify the source
of such heterogeneity. It was considered that it might be
related to the difference in origin, quality, and water content
reported the occurrence of general adverse effects. The of the Chinese herbs [51, 52] and further analysis could not be
most common adverse effect among these studies was conducted due to no specific details in the article.
abdominal discomfort [41, 44, 45, 49]. Headache, dizzi- When considering the statistical heterogeneity of meta-
ness, nausea, and hypoglycemia were also reported to analysis, it is important to consider two different components:
occur in the researches. No adverse effects were reported clinical heterogeneity and methodological heterogeneity. In our
in the remaining studies. meta-analysis, it is possible that different T2DM participants
8 Evidence-Based Complementary and Alternative Medicine

Experimental Control Weight Mean Difference Mean Difference


Study or subgroup
Mean SD Total Mean SD Total (%) IV, Fixed, 95% CI IV, Fixed, 95% CI
Airong Tian.2013 6.21 1.23 30 7.38 1.19 30 8.4 –1.17 [–1.78, –0.56]
Chen Zhao,2008 6.48 1.29 48 6.84 1.29 46 11.6 –0.36 [–0.88, 0.16]
Dongying Xiao,2021 6.38 1.2 49 6.96 1.34 49 12.4 –0.58 [–1.08, –0.08]
Hong Wan,2021 5.91 0.87 49 6.83 0.86 49 26.9 –0.92 [–1.26, –0.58]
Hua Wang,2017 5.33 1.27 60 6.53 1.72 60 10.8 –1.20 [–1.74, –0.66]
Shuihua Li.2012 7.67 2.25 50 7.88 2.31 50 3.9 –0.21 [–1.10, 0.68]
Xiaoqi Jing,2019 6.12 1.31 40 7.52 2.36 40 4.5 –1.40 [–2.24, –0.56]
Yinquan Deng,2006 7.12 1.3 60 7.55 1.11 30 11.9 –0.43 [–0.95, 0.09]
Yong Zheng 2005 5.28 1.08 32 6.56 1.21 30 9.6 –1.28 [–1.85, –0.71]
Total (95% CI) 418 384 100.0 –0.83 [–1.01, –0.66]
Heterogeneity: chi2 = 15.63, df = 8 (P = 0.05); I2 = 49%
Test for overall effect: Z = 9.21 (P < 0.00001) –2 –1 0 1 2
Favours (experimental) Favours (control)

Figure 5: Forest plot for FBG.

Table 3: Subgroup analysis for outcomes.


p value for
Number of comparisons Results p value for overall effect I2
subgroup difference
FBG WMD (95%CI)
All comparisons 9 −0.84 [−1.10, −0.58] <0.00001 49%
Age 0.14
<50 y 5 −0.94 [−1.17, −0.71] <0.00001 49%
≥50 y 4 −0.67 [−0.95, −0.38] <0.00001 47%
Different control treatment 0.31
Metformin 3 −0.68 [−1.03, −0.34] 0.0001 67%
Other treatments 6 −0.89 [−1.10, −0.68] <0.00001 42%
2hPG
All comparisons 8 −1.39 [−1.58, −1.20] <0.00001 29%
Age 0.19
<50 y 4 −1.60 [−1.91, −1.29] <0.00001 0%
≥50 y 4 −1.38 [−1.47, −1.29] <0.00001 43%
Different control treatment 0.64
Metformin 2 −1.53 [−1.93, −1.13] <0.00001 0%
Acarbose 2 −1.38 [−1.48, −1.29] <0.00001 73%
Other treatments 4 −1.49 [−1.79, −1.19] <0.00001 43%
Course of treatment 0.95
<8 w 3 −1.39 [−1.49, −1.30] <0.00001 0%
≥8 w 5 −1.38 [−1.65, −1.12] <0.00001 56%
HbA1c
All comparisons 6 −0.87 [−1.26, −0.49] <0.00001 78%
Age 0.11
<50 y 3 −1.09 [−1.38, −0.80] <0.00001 10%
≥50 y 3 −0.61 [−1.12, −0.11] 0.02 78%
Different control treatment 0.74
Metformin 3 −0.84 [−1.31, −0.37] 0.0005 74%
Other treatments 3 −1.01 [−1.86, −0.15] 0.02 83%
Duration of disease 0.26
<10 y 5 −0.82 [−1.22, −0.42] 0.0004 81%
≥10 y 1 −1.60 [−2.91, −0.29] 0.02 NA
TC
All comparisons 3 −0.50 [−0.61, −0.39] <0.00001 0%
Age 0.20
<50 y 1 −1.02 [−1.83, −0.21] 0.01 NA
≥50 y 2 −0.49 [−0.60, −0.38] <0.00001 0%
Course of treatment 0.97
<8 w 1 −0.50 [−0.68, −0.32] <0.00001 NA
≥8 w 2 −0.50 [−0.64, −0.36] <0.00001 40%
CRP
All comparisons 4 −0.58 [−0.88, −0.28] 0.0005 83%
Evidence-Based Complementary and Alternative Medicine 9

Table 3: Continued.
p value for
Number of comparisons Results p value for overall effect I2
subgroup difference
Age 0.84
<50 y 1 −0.55 [−0.69, −0.41] <0.00001 NA
≥50 y 3 −0.61 [−1.18, −0.05] 0.03 88%
Safety 0.05
No adverse effects 1 −1.13 [−1.49, −0.77] <0.00001 NA
Adverse effects occurring 3 −0.62 [−0.97, −0.26] 0.0007 89%
Region 0.81
Henan province 2 −0.81 [−1.38, −0.25] 0.005 88%
Other provinces 2 −0.69 [−1.52, 0.14] 0.10 94%
Overall effective rate RR (95%CI)
All comparisons 6 1.21 [1.12, 1.31] <0.00001 0%
Age 0.90
<50 y 2 1.22 [1.08, 1.38] 0.001 0%
≥50 y 4 1.21 [1.09, 1.34] 0.0002 0%
Different control treatment 0.79
Metformin 3 1.20 [1.08, 1.34] 0.001 0%
Other treatments 3 1.23 [1.10, 1.37] 0.0003 0%
Course of treatment 0.27
<8 w 1 1.10 [0.92, 1.33] 0.30 NA
≥8 w 5 1.24 [1.14, 1.35] <0.00001 0%
Region 0.50
Henan province 2 1.18 [1.06, 1.30] 0.002 0%
Other provinces 4 1.24 [1.11, 1.38] 0.0001 0%
FBG, fasting blood glucose; 2hPG, two-hour postprandial glucose; HbA1c, glycosylated hemoglobin; TC, total cholesterol; CRP, c-reactive protein; Y, year; W,
week.

and different intervention measures may lead to a certain 4.3. Strengths and Limitations. Our study has several ad-
extent of clinical heterogeneity. Methodological hetero- vantages. For example, this is the first systematic review to
geneity may be caused by differences in trial design and investigate the efficacy and safety of YQP for the treatment
poor methodological quality, such as the inappropriate use of T2DM. Furthermore, we used a wide range of search
of blinding methods and hidden differences in allocation. terms to conduct a comprehensive and systematic search of
In the present study, our subgroup analysis was based on a established national and international databases. When
range of factors, including age, course of disease, inter- missing or unclear data were evident, we actively contacted
vention measures, and the treatment duration; these an- the authors to obtain relevant information. Secondly, in
alyses involved post hoc analysis, thus reducing the order to provide a comprehensive description of the use of
reliability of our subgroup analysis. YQP in the treatment of T2DM, this study was conducted
in strict accordance with established methodology for
systematic reviews. The results were carefully interpreted to
4.2. Certainty of the Evidence. We used GRADEpro software ensure accuracy and avoid misleading conclusions. Thirdly,
to assess the certainty of the evidence that was analyzed in this systematic review and meta-analysis described and
this study. Figure 11 showed that the FBG, 2hPG, and the evaluated the present clinical trials on YQP for T2DM,
effective rate had a moderate quality of evidence, while filling the blank in existing knowledge. We found that,
HbA1c and TC in RCTs had a low certainty of evidence, compared with conventional treatment, the combined use
and CRP had a very low certainty of evidence. The observed of YQP and conventional medicine could improve glucose
reduction in the certainty of evidence was mainly attributed and lipid metabolism and inflammation, associated with
to the high risk of bias in the studies analyzed, inconsis- T2DM. The results of this study provide new treatment
tency between the included studies, and the imprecision of options for T2DM. YQP may improve the inflammatory
the findings. Specifically, this is due to the low methodo- condition of diabetes, which is the pathological basis and
logical quality of the included studies, the high heteroge- key factor of multiple complications of diabetes. It has far-
neity of some studies, and the small sample size of some reaching influence, extensive research prospects, and im-
studies. The poor methodological quality of some of the portant research significance, and it is worth further in-
included studies was indicated by unclear randomization vestigation. Although our current research is limited, we
allocation and blinding strategies. As a direct result of these believe that, with the continuous development and pro-
factors, our current findings should be considered cau- motion of traditional Chinese medicine, the importance of
tiously for clinical practice. Additional and more stan- YQP for T2DM will become increasingly prominent. We
dardized RCTs are now needed to fully validate the effects hope that our study may provide new directions, ideas, and
of YQP on T2DM. methods for the study of T2DM.
10 Evidence-Based Complementary and Alternative Medicine

Experimental Control Weight Mean Difference Mean Difference


Study or subgroup
Mean SD Total Mean SD Total (%) IV, Fixed, 95% CI IV, Fixed, 95% CI
Airong Tian.2013 8.08 1.36 30 9.26 1.41 30 1.6 –1.18 [–1.88, –0.48]
Baoli Zhu,2015 8.1 0.26 37 9.5 0.13 32 84.2 –1.40 [–1.50, –1.30]
Chen Zhao,2008 8.13 1.69 48 9.62 2.13 46 1.3 –1.49 [–2.27, –0.71]
Dongying Xiao,2021 9.79 1.53 49 10.83 1.68 49 1.9 –1.04 [–1.68, –0.40]
Hong Wan,2021 7.11 0.82 49 8.94 1.26 49 4.3 –1.83 [–2.25, –1.41]
Shuihua Li.2012 11.22 1.13 50 12.77 1.24 50 3.5 –1.55 [–2.02, –1.08]
Xiaoqi Jing,2019 7.56 1.63 40 8.87 2.96 40 0.7 –1.31 [–2.36, –0.26]
Yinquan Deng,2006 8.3 1.06 60 9.16 1.32 30 2.6 –0.86 [–1.40, –0.32]
Total (95% CI) 363 326 100.0 –1.40 [–1.49, –1.31]
Heterogeneity: chi2 = 9.89, df = 7 (P = 0.19); I2 = 29%
Test for overall effect: Z = 31.44 (P < 0.00001) –2 –1 0 1 2
Favours (experimental) Favours (control)

Figure 6: Forest plot for 2hPG.

Experimental Control Weight Mean Difference Mean Difference


Study or subgroup
Mean SD Total Mean SD Total (%) IV, Random, 95% CI IV, Random, 95% CI
Chen Zhao,2008 4.68 0.77 48 5.65 0.57 46 21.6 –0.97 [–1.24, –0.70]
Dongying Xiao,2021 6.85 0.66 49 7.23 0.7 49 21.7 –0.38 [–0.65, –0.11]
Hong Wan,2021 6.71 1.26 49 8.09 1.67 49 15.6 –1.38 [–1.97, –0.79]
Hua Wang,2017 6.02 1.37 60 7.25 1.54 60 16.8 –1.23 [–1.75, –0.71]
Shuihua Li.2012 6.52 1.22 50 6.83 1.18 50 17.8 –0.31 [–0.78, 0.16]
Yong Zheng 2005 6.68 2.51 32 8.28 2.73 30 6.4 –1.60 [–2.91, –0.29]
Total (95% CI) 288 284 100.0 –0.87 [–1.26, –0.49]
Heterogeneity: Tau2 = 0.16, chi2 = 22.42, df = 5 (P = 0.0004); I2 = 78%
Test for overall effect: Z = 4.42 (P < 0.00001) –2 –1 0 1 2
Favours (experimental) Favours (control)

Figure 7: Forest plot for HbA1c.

Experimental Control Weight Mean Difference Mean Difference


Study or subgroup
Mean SD Total Mean SD Total (%) IV, Fixed, 95% CI IV, Fixed, 95% CI
Baoli Zhu,2015 3.8 0.28 37 4.3 0.46 32 36.6 –0.50 [–0.68, –0.32]
Dongying Xiao,2021 4.12 0.32 49 4.6 0.39 49 61.5 –0.48 [–0.62, –0.34]
Xiaoqi Jing,2019 4.85 1.21 40 5.87 2.32 40 1.9 –1.02 [–1.83, –0.21]
Total (95% CI) 126 121 100.0 –0.50 [–0.61, –0.39]
Heterogeneity: chi2 = 1.65, df = 2 (P = 0.44); I2 = 0%
Test for overall effect: Z = 8.80 (P < 0.00001) –1 –0.5 0 0.5 1
Favours (experimental) Favours (control)

Figure 8: Forest plot for TC.

Experimental Control Weight Mean Difference Mean Difference


Study or subgroup
Mean SD Total Mean SD Total (%) IV, Random, 95% CI IV, Random, 95% CI
Dongying Xiao,2021 2.26 0.81 49 3.39 1.02 49 22.4 –1.13 [–1.49, –0.77]
Hong Wan,2021 1.38 0.37 49 1.93 0.36 49 30.9 –0.55 [–0.69, –0.41]
Hua Wang,2017 0.79 0.58 60 1.07 0.43 60 29.6 –0.28 [–0.46, –0.10]
Yinquan Deng,2006 6.87 1.15 60 7.31 1.18 30 17.0 –0.44 [–0.95, 0.07]
Total (95% CI) 218 188 100.0 –0.58 [–0.88, –0.28]
Heterogeneity: Tau2 = 0.07, chi2 = 17.54, df = 3 (P = 0.0005); I2 = 83%
Test for overall effect: Z = 3.76 (P = 0.0002) –1 –0.5 0 0.5 1
Favours (experimental) Favours (control)

Figure 9: Forest plot for CRP.

Although we made every effort to be rigorous and this meta-analysis was small and of low quality; these factors
accurate in our research process, some limitations should be led to a low degree of certainty in terms of evidence.
taken into account. First, the number of studies included in Consequently, our results should be interpreted with
Evidence-Based Complementary and Alternative Medicine 11

Experimental Control Weight Risk Ratio Risk Ratio


Study or subgroup
Events Total Events Total (%) M-H, Fixed, 95% CI M-H, Fixed, 95% CI
Chen Zhao,2008 44 48 34 46 15.9 1.24 [1.02, 1.50]
Dongying Xiao,2021 47 49 41 49 18.8 1.15 [1.00, 1.31]
Hong Wan,2021 47 49 39 49 17.9 1.21 [1.03, 1.40]
Hua Wang,2017 53 60 42 60 19.2 1.26 [1.04, 1.53]
Shuihua Li.2012 43 50 39 50 17.9 1.10 [0.92, 1.33]
Yinquan Deng,2006 48 60 17 30 10.4 1.41 [1.01, 1.98]
Total (95% CI) 316 284 100.0 1.21 [1.12, 1.31]
Total events 282 212
Heterogeneity: chi2 = 2.70, df = 5 (P = 0.75); I2 = 0%
0.5 0.7 1 1.5 2
Test for overall effect: Z = 4.86 (P < 0.00001)
Favours (experimental) Favours (control)

Figure 10: Forest plot for overall effective rate.

Certainty assessment No of studies Effect


Certainty Importance
No of Study Risk of Other Yuquan Control Relative Absolute
Inconsistency Indirectness Imprecision
studies design bias considerations pill treatment (95% CI) (95% CI)

Fasting blood glucose


MD 0.84
lower ⊕⊕⊕
randomised a
9 serious not serious not serious not serious none 418 384 - (1.1 CRITICAL
trials MODERATE
lower to
0.58 lower)
Two-hour postprandial glucose
MD 1.39
lower ⊕⊕⊕
randomised
8 seriousa not serious not serious not serious none 363 326 - (1.58 MODERATE
CRITICAL
trials
lower to
1.2 lower)
Glycosylated hemoglobin
MD 0.87
lower
randomised ⊕⊕
6 seriousa seriousb not serious not serious none 288 284 - (1.26 LOW
CRITICAL
trials
lower to
0.49 lower)
Total cholesterol
MD 0.5
lower ⊕⊕
randomised a seriousc
3 serious not serious not serious none 126 121 - (0.61 LOW IMPORTANT
trials
lower to
0.39 lower)
C-reactive protein
MD 0.58
lower ⊕
randomised a b c
4 serious serious not serious serious none 218 188 - (0.88 VERY LOW IMPORTANT
trials
lower to
0.28 lower)
Effective rate
157 more
RR 1.21 per 1,000
randomised a 282/316 212/284 ⊕⊕⊕
6 serious not serious not serious not serious none (1.12 to (from 90 IMPORTANT
trials (89.2%) (74.6%) MODERATE
1.31) more to
231 more)

Figure 11: Certainty of evidence: Yuquan Pill compared to control treatment for T2DM. CI, confidence interval; MD, mean difference; RR,
risk ratio. a Randomization allocation and the blinding are unclear in articles. b There is serious heterogeneity among the studies included in
the analysis of this outcome. c Results are imprecise since the study included relatively few studies and few patients.

caution. Secondly, there were some defects in the included In addition, the safety of YQP remains unclear because
articles with regard to RCT design. Certain methodologies some studies did not report adverse events; thus, adverse
related to random sequence generation, the allocation events could not be systematically collated and analyzed. In
concealment, and blinding were generally poor. Only one subgroup analyses, the cutoff points for age and duration of
study [42] clearly reported the generation of random se- disease are mainly based on related studies, and more
quences. Furthermore, none of the RCTs involved alloca- biological basis is needed. Although we performed sub-
tion concealment or the blinding of participants or group analyses for each outcome, the source of hetero-
researchers. This may have led to the overestimation of geneity was not fully identified. Due to the limited number
efficacy. Thirdly, since patients were only recruited from of studies included in this meta-analysis, we were unable to
Chinese hospitals, our study may not be globally repre- conduct meta-regression analysis to further explore the
sentative and lacks clinical applicability. Whether YQP can source of heterogeneity. Furthermore, we were unable to
be applied to other ethnic groups remains to be elucidated. apply funnel plots to evaluate publication bias.
12 Evidence-Based Complementary and Alternative Medicine

5. Conclusion Technology Development Fund of Hospital of Chengdu


University of Traditional Chinese Medicine (21HL04).
In conclusion, this systematic review and meta-analysis
evaluates the efficacy and safety of YQP on T2DM for the Supplementary Materials
first time. We showed that, compared with conventional
treatment, the combined administration of YQP and con- Supplementary Material 1: Subgroup analysis for FBG (age).
ventional medicine may improve glucose and lipid meta- Supplementary Material 2: Subgroup analysis for FBG
bolism and the inflammatory conditions in patients with (different control treatment). Supplementary Material 3:
T2DM. However, due to the poor quality of these studies, the Subgroup analysis for 2hPG (age). Supplementary Material
evidence remains very uncertain. Therefore, our results 4: Subgroup analysis for 2hPG (different control treatment).
should be interpreted with caution and applied cautiously in Supplementary Material 5: Subgroup analysis for 2hPG
clinical practice. In the future, more multicenter, large-scale, (course of treatment). Supplementary Material 6: Subgroup
and high-quality RCTs will be needed to fully determine the analysis for HbA1c (age). Supplementary Material 7: Sub-
clinical efficacy and safety of YQP for the treatment of group analysis for HbA1c (different control treatment).
T2DM. Supplementary Material 8: Subgroup analysis for HbA1c
(duration of disease). Supplementary Material 9: Subgroup
Abbreviations analysis for TC (age). Supplementary Material 10: Subgroup
analysis for TC (course of treatment). Supplementary Ma-
2hPG: 2-hour postprandial glucose terial 11: Subgroup analysis for CRP (age). Supplementary
CFDA: China Food and Drug Administration Material 12: Subgroup analysis for CRP (safety). Supple-
CIs: Confidence intervals mentary Material 13: Subgroup analysis for CRP (region).
CNKI: China National Knowledge Infrastructure Supplementary Material 14: Subgroup analyses for overall
CQVIP: VIP information resource integration service effective rate (age). Supplementary Material 15: Subgroup
platform analyses for overall effective rate (different control treat-
CRP: c-Reactive protein ment). Supplementary Material 16: Subgroup analyses for
GRADE: Grading of recommendations assessment, overall effective rate (course of treatment). Supplementary
development, and evaluation Material 17: Subgroup analyses for overall effective rate
HbA1c: Glycated hemoglobin (region). (Supplementary Materials)
FBG: Fasting blood glucose
OGTT: Oral glucose tolerance test References
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