Author’s Accepted Manuscript

Effect of Chinese herbal medicine on stroke

patients with type 2 diabetes

Fuu-Jen Tsai, Tsung-Jung Ho, Chi-Fung Cheng,

Xiang Liu, Hsinyi Tsang, Ting-Hsu Lin, Chiu-Chu
Liao, Shao-Mei Huang, Ju-Pi Li, Cheng-Wen Lin,
Jaung-Geng Lin, Jung-Chun Lin, Chih-Chien Lin,
Wen-Miin Liang, Ying-Ju Lin www.elsevier.com/locate/jep

PII: S0378-8741(16)32417-5
DOI: http://dx.doi.org/10.1016/j.jep.2017.02.024
Reference: JEP10728
To appear in: Journal of Ethnopharmacology
Received date: 16 December 2016
Revised date: 6 February 2017
Accepted date: 14 February 2017
Cite this article as: Fuu-Jen Tsai, Tsung-Jung Ho, Chi-Fung Cheng, Xiang Liu,
Hsinyi Tsang, Ting-Hsu Lin, Chiu-Chu Liao, Shao-Mei Huang, Ju-Pi Li, Cheng-
Wen Lin, Jaung-Geng Lin, Jung-Chun Lin, Chih-Chien Lin, Wen-Miin Liang and
Ying-Ju Lin, Effect of Chinese herbal medicine on stroke patients with type 2
d i a b e t e s , Journal of Ethnopharmacology,
http://dx.doi.org/10.1016/j.jep.2017.02.024
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Effect of Chinese herbal medicine on stroke patients with type 2
diabetes

Fuu-Jen Tsaia,b,c1, Tsung-Jung Hoa,d,e1, Chi-Fung Chengf1, Xiang Liug, Hsinyi Tsangg, Ting-Hsu Linb,

Chiu-Chu Liaob, Shao-Mei Huangb, Ju-Pi Lia,h, Cheng-Wen Lini, Jaung-Geng Lina, Jung-Chun Linjĭġ

Chih-Chien LinkĭġWen-Miin Liangf,*,ġYing-Ju Lina,b,*

a
School of Chinese Medicine, China Medical University, Taichung, Taiwan
b
Genetic Center, Department of Medical Research, China Medical University Hospital, Taichung,

Taiwan
c
Asia University, Taichung, Taiwan
d
Division of Chinese Medicine, China Medical University Beigang Hospital, Yunlin, Taiwan
e
Division of Chinese Medicine, Tainan Municipal An-Nan Hospital-China Medical University,

Tainan, Taiwan
f
Graduate Institute of Biostatistics, School of Public Health, China Medical University, Taichung,

Taiwan
g
National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda,

Maryland, USA
h
Rheumatism Research Center, China Medical University Hospital, Taichung, Taiwan
i
Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung,

Taiwan
j
School of Medical Laboratory Science and Biotechnology, College of Medical Science and

Technology, Taipei Medical University, Taipei, Taiwan

k
Department of Cosmetic Science, Providence University, Taichung, Taiwan

1
Fuu-Jen Tsai, Tsung-Jung Ho, and Chi-Fung Cheng contributed equally to this work.
1
wmliang@mail.cmu.edu.tw (W.-M. Liang)

yjlin.kath@gmail.com (Y.-J. Lin).

*
Corresponding authors. No. 91, Hsueh-Shih Road, Taichung, Taiwan. Tel.: +886 4 22053366; Fax:

+886 4 22053366.

Fuu-Jen Tsai, Tsung-Jung Ho, and Chi-Fung Cheng contributed equally to this work.

ABSTRACT

Ethnopharmacological relevance

Complications of type 2 diabetes (T2D) include stroke, which is a cerebrovascular disturbance

characterized by reduced blood flow in the brain, leading to death or physical disability. Chinese

herbal medicine (CHM) has been widely used in ancient China for the treatment of diabetes and

stroke by supplementing Qi and activating blood circulation.

Aim of the study

This study aimed to investigate the frequencies and patterns of CHM treatment for stroke patients

with T2D and the outcomes of long-term use in Taiwan.

Materials and methods

We identified 3,079 stroke patients (ICD-9-CM: 430-438) with T2D. We allocated 618 stroke

patients, matched for age, gender, and T2D-to-stroke duration, to both CHM and non-CHM groups.

Chi-square test, conditional multivariable logistic regression, Kaplan-Meier method, and the log-rank

test were used in this study.

Results

2
The CHM group was characterized by more cases of chronic obstructive pulmonary disease, ulcer

disease, hyperlipidemia, tobacco use, and higher income. The cumulative survival probability was

higher in the CHM group (P < 0.001, log rank test); after adjusting for comorbidities, income, and

urbanization level, this group also exhibited a lower mortality hazard ratio (0.37, 95% confidence

interval [0.25–0.55]). Shu-Jing-Huo-Xue-Tang, Xue-Fu-Zhu-Yu-Tang, and Du-Huo-Ji-Sheng-Tang;

and Dan-Shen, Niu-Xi, and Yan-Hu-Suo represented the top three formulas and herbs, respectively.

Conclusion

The use of CHM as adjunctive therapy may improve the overall survival (OS) of stroke patients with

T2D. The list of the comprehensive herbal medicines that they used might be useful in future

large-scale, randomized clinical investigations of agent effectiveness, safety, and potential

interactions with conventional treatments in stroke patients with T2D.

Keywords

Type 2 diabetes, stroke, Chinese herbal medicine.

1. Introduction

Type 2 diabetes (T2D) is a disorder of glucose metabolism characterized by pancreatic β-cell

dysfunction and insulin resistance as a result of uncontrolled hyperglycemia (Ashcroft and Rorsman,

2012). Excess glucose and its metabolites are considered to represent important inflammatory

stimulants and the resultant chronic inflammation is regarded as the subsequent driving force behind

diabetic complications (Navarro-Gonzalez et al., 2011). Notably, T2D is associated with chronic

multiple organ damage and failure. Diabetic complications include stroke, heart disease, retinopathy,

nephropathy, neuropathy, and peripheral circulatory disorders (Cade, 2008; Chen, S.Y. et al., 2016;

Lin et al., 2015; Pickup and Crook, 1998). Glycemic control with various antidiabetic medications

3
and disease complication monitoring are the major strategies for management of this condition. In

particular, blood glycemic levels can be controlled by lifestyle modification and/or treatment with

hypoglycemic, antihyperglycemic, insulin-sensitizing, and insulin secretion-enhancing medications

(Ahren, 2008; Cummins et al., 2010; Mikhail, 2008; Waugh et al., 2010). However, most patients

with T2D still develop complications regardless of intensive glycemic control (Stolar, 2010).

Furthermore, side effects following long-term use are also reported when diabetic patients are on a

regular medical regime (Zhou et al., 2016). Therefore, complementary and alternative medicines

have become increasingly popular as adjunctive treatments and have attracted considerable research

attention for the prevention or delay of diabetic complications and their progression.

Chinese herbal medicine (CHM) is a type of complementary and alternative medicine that has

been extensively utilized as a healthcare system for hundreds of years in Asian countries. In Taiwan,

CHM constitutes one of the important health care systems provided by the National Health Insurance

program and is widely used for medical treatment in addition to regular antidiabetic medications

(Hsu et al., 2014; Lee et al., 2016; Lin et al., 2015). The frequency of use, prescribing patterns, and

therapeutic effects of CHM as prescribed by licensed CHM practitioners in Taiwan have been

explored by population-based studies for several diseases included in the National Health Insurance

database (Chao et al., 2014; Chen et al., 2013; Chen et al., 2015; Chu et al., 2015; Hsu et al., 2014;

Lee et al., 2016; Lin et al., 2015). These reports have encouraged a search for alternative and

complementary therapies for the better management of diabetes and its complications. Furthermore,

in addition to the potential hypoglycemic effects of CHM, the identification of evidence-based effect

following long-term CHM treatment also warrants investigation.

Among the complications of T2D, stroke represents a cerebrovascular disturbance yielding

reduced blood flow in the brain, resulting in death or physical disability (Tsai et al., 2016). The

current management of stroke is to stabilize patient vital signs and reduce brain damage. However,

although the mortality associated with stroke has decreased through advances in clinical medicine,

4
the long-term neurological disability remains high (Feigin et al., 2015), significantly negatively

impacting the life quality and economic loads of the patients and their families. Furthermore,

long-term disability and high recurrence rates of stroke remain unsolved and have led to the search

for complementary and alternative therapies to assist with these issues (Mukherjee and Patil, 2011).

For example, acupuncture has been shown to alleviate shoulder pain, dysphagia, muscle spasticity,

and joint pain after stroke (Lee et al., 2012; Long and Wu, 2012; Zhao et al., 2009). It was also

shown to reduce the risk of stroke recurrence with a hazard ratio (HR) of 0.88 (95% CI, 0.84-0.91)

(Shih et al., 2015). In addition, stroke patients who underwent acupuncture treatment showed a lower

incidence of acute myocardial infarction than those who did not, with a HR of 0.86 (95 % CI,

0.80-0.93) (Chuang et al., 2015). Furthermore, CHM practitioners prescribe CHM formulas and

single herbs based on the individual clinical presentation of each stroke patient (Chang et al., 2016;

Chen et al., 2012; Lo et al., 2003). Chinese herbal medicine (CHM) has been widely used in ancient

China for the management of diabetes and stroke, through supplementing Qi and activating blood

circulation (Du et al., 2015). However, there remains a lack of nationwide population-based

ethnopharmacological surveys on CHM usage and the long-term treatment effects on stroke patients

with T2D.

To better understand the effects of CHM therapy and its long-term treatment in stroke patients

with T2D, we utilized a population-based database to investigate the demographic characteristics,

overall survival, and CHM prescribing patterns for these patients. By using this large-scale

population-based analysis, we were further able to investigate whether the integration of CHM and

regular antidiabetic medications improved the overall survival (OS) of stroke patients with T2D.

2. Materials and methods

2.1 Data sources

5
 The National Health Insurance (NHI) program provides a unique database; the National Health

Insurance Research database (NHIRD; http://nhird.nhri.org.tw/), which was initiated in 1995 in

Taiwan. This program provides insurance for almost the entire population and the associated

comprehensive is available for research purposes to scientists in Taiwan. In this study, the data were

retrieved from the ‘Longitudinal Health Insurance Database (LHID2000 and LHID2005)’. Each

sub-database comprises a random sample of 1 million individuals registered in the NHIRD in 2000

or 2005, respectively. LHID2000 and LHID2005 contain detailed medical records for every

individual including age, gender, diagnoses, prescriptions, records of clinical visits and

hospitalizations, inpatient orders, ambulatory care, and sociodemographic factors. The database also

provides longitudinally linked data for the 1996–2012 period. The study population underwent a

standard diagnosis protocol according to the International Classification of Disease, 9 th Revision,

Clinical Modification (ICD-9-CM). This study was designed as a population-based retrospective

analysis to explore the effect of CHM treatment on the OS rate of patients with T2D plus stroke. All

data for each individual are decoded and therefore we could not obtain their informed consent. This

study was evaluated and approved by the Institutional Review Board of the China Medical

University Hospital.

2.2 Identification of stroke patients with T2D

We designed a national population-based study to investigate two cohorts of 1 million random

individuals selected from the NHI program in Taiwan. We identified 187,465 patients with diabetes

(ICD-9-CM 250) entered into the database between 1998 and 2012 (Figure 1). The ICD-9-CM for

stroke was 430–438. Excluded individuals included those younger than 20 years of age, without

stroke complication, or who experienced stroke before 1999 or after 2010. Individuals receiving a

stroke diagnosis within one year of diabetes diagnosis and those diagnosed with cancer prior to the

incidence of stroke were also excluded, as were patients who passed away within one year after

6
stroke and those taking CHM fewer than 28 days within the first year after stroke. Finally, 3,079

study subjects were included in the study.

Subjects diagnosed with stroke one year after diabetes diagnosis were included in the study.

Individuals with a cumulative number of CHM treatment days of more than 28 within the first year

after their stroke diagnosis were defined as CHM users (n = 858, Figure 1). Study subjects who did

not experience any CHM use were defined as non-CHM users (n = 2,221). Furthermore, to reduce

bias owing to confounding variables, non-CHM users were selected 1:1 after frequency matching for

age, gender, and duration from diabetes to stroke. For matched study subjects, 618 subjects were

selected for each group (Table 1). The date on which the criterion of 28 CHM prescription

cumulative days was accomplished was designated as the index date. The study end was defined as:

date of death, date of withdrawal from the NHI program, or date of termination of follow-up

(December 31, 2012).

Demographic characteristics for the study subjects are shown in Table 1. These included age,

gender, duration from diabetes to stroke, income, and urbanization level. Urbanization levels in

Taiwan are divided into five strata according to the Taiwan National Health Research Institute

publications, with levels 1 and 5 referring to the most and least urbanized communities,

respectively(Lin et al., 2013). We also identified the comorbidities that had been diagnosed in the

study subjects before their diagnosis of stroke. These comorbidities were COPD (ICD-9-CM 490–

496), hepatitis (ICD-9-CM 070), ulcer disease (ICD-9-CM 531–534), chronic kidney disease

(ICD-9-CM 582, 583–583.7, 585, 586, and 588), hyperlipidemia (ICD-9-CM 272), obesity

(ICD-9-CM 278 and 278.01), alcohol-related illness (ICD-9-CM 303, 305, 305.01, 305.02, 305.03,

and V11.3), and tobacco use (ICD-9-CM 305.1).

2.3 Chinese herbal medicine

All medicine codes for CHM, including herbal formulas and single herbs, were collected,

7
grouped, and listed on the Taiwan NHI website

(http://www.nhi.gov.tw/webdata/webdata.aspx?menu=21&menu_id=713&webdata_id=932). For the

CHM users, the frequencies of users, person-year, frequency of prescription, percentage of usage

person, average drug dose per day, and average duration for prescription were calculated from the

index date to the study end (Table 3). Herbal formulations are usually obtained from traditional

Chinese medicine classics or ancient medical books. Herbal formulations constitute a combination of

more than two herbs (Table 3), created by knowledgeable traditional Chinese medicine practitioners.

These formulas have been used for more than hundreds of years in China. Single herbs were usually

from plant, animal, or mineral sources and could be mixed with other single herbs to create a herbal

formula. In Taiwan, herbal formulas and single herbs are all manufactured by pharmaceutical

manufacturers with Good Manufacturing Practice certification. These pharmaceutical manufacturers

are Sun Ten Pharmaceutical Co. Ltd. (http://www.sunten.com.tw/), Chuang Song Zong

Pharmaceutical Co. Ltd. (http://www.csz.com.tw/), Shang Chang Pharmaceutical Co. Ltd.

(http://www.herb.com.tw/about_en.php), KO DA Pharmaceutical Co. Ltd.

(http://www.koda.com.tw/), and Kaiser Pharmaceutical Co. Ltd (http://www.kpc.com/).

2.4 Data analysis

The demographic characteristics of CHM and non-CHM users were compared for categorical

variables. These categorical data include age, gender, duration from diabetes to stroke, comorbidities

(COPD), hepatitis, ulcer disease, chronic kidney disease, hyperlipidemia, obesity, alcohol-related

illness, and tobacco use), income, and urbanization level. Chi-squared tests were used to detect

differences between CHM and non-CHM users (Table 1). Categorical data are shown as absolute

numbers and percentages. Assessment of HRs of mortality in stroke patients with T2D was

performed by using a Cox proportional hazard model with the adjustments of CHM use,

comorbidities, income, and urbanization level (Table 2). The frequency and usage patterns of the top

8
12 most common herbal formulas and single herbs used are shown in Table 3. The Kaplan-Meier

method was used to estimate cumulative survival probability (Figure 2). The log-rank test was used

to explore the effect of CHM on the OS rate of stroke patients with T2D. All P-values less than 0.05

were considered to be statistically significant. All data management and statistical analyses were

performed using SAS software (version 9.4; SAS Institute, Cary, NC, USA).

3. Results

3.1 Characteristics of stroke patients with T2D

The recruitment flowchart of study subjects is shown in Figure 1. In our study cohort, there

were 3,079 patients who experienced stroke one year after a diagnosis of diabetes in Taiwan from

1999 to 2009. Among these, 858 (27.9%) were assigned to the CHM group and 2,221 (72.1%) were

in the non-CHM group. The characteristics of the CHM versus the non-CHM group are shown in

Table 1 for all subjects. Statistically significant differences between the two groups were found for

age, gender, duration from diabetes to stroke, comorbidities (chronic obstructive pulmonary disease

(COPD), hepatitis, ulcer disease, hyperlipidemia, and obesity), and income (P < 0.05). The CHM

group was characterized as younger, female, with a longer time interval between diabetes and

diagnosis of stroke, more cases of COPD, hepatitis, ulcer disease, hyperlipidemia, and obesity, and

with a higher income. After matching these two groups for age, gender, and duration from diabetes to

stroke, frequency matched CHM and non-CHM users were compared (Table 1). No differences were

found in the distribution of baseline characteristics except for comorbidities and income. There were

significant differences in the frequency distributions for COPD, ulcer disease, hyperlipidemia,

tobacco use, and income (P < 0.05).

3.2 Survival analysis according to CHM usage

The cumulative survival probability for stroke patients with T2D between matched CHM and

9
non-CHM users is shown though a Kaplan-Meier survival graph (Figure 2). A difference was

identified in the survival probability between these two groups (P < 0.001, log rank test), with the

cumulative survival probability being higher in CHM than in non-CHM users. Also, as shown in

Table 2, after adjusting for comorbidities, income, and urbanization level, the CHM users showed a

lower mortality HR (0.37, 95% confidence interval [CI 0.25–0.55]) when compared with the

non-CHM users.

3.3 Most commonly prescribed Chinese herbal formula and single herb among stroke patients

with T2D

The top 12 Chinese herbal formulas and single herbs prescribed for the stroke patients with T2D

for CHM users are listed in Table 3. The composition of these herbal formulas and single herbs is

also displayed. According to the percentage of usage person, Shu-Jing-Huo-Xue-Tang (36.6%) was

the most commonly prescribed herbal formula, with an average daily dosage of 4.1g. The second and

third most common formulas were Xue-Fu-Zhu-Yu-Tang (30.7%) and Du-Huo-Ji-Sheng-Tang

(30.6%) with average daily dosages of 3.5 and 4.2 g, respectively. The top 12 single herbs used for

stroke patients are also listed in Table 3. Dan-Shen (Rx. Salviae miltiorrhizae, 35.9%) was the most

commonly prescribed single herb, with an average daily dosage of 1.1g, followed by Niu-Xi (Rx.

Achyranthis bidentatae, 31.4%), and Yan-Hu-Suo (Rz. Corydalis, 31.2%) with average daily dosages

of 1 and 1.2 g, respectively. The HR against mortalities of the stroke patients following division into

subgroups according to use of these herbs are shown in Table 4. As indicated, among these 12 herbal

formulas and 12 single herbs, all achieved a P value < 0.05 and the HR for mortality risk among

CHM users was lower when compared to that of non-CHM users.

4. Discussion

Currently, there are no data regarding the use of complementary alternative medicine for the

10
treatment of stroke patients with T2D. To our knowledge, this is the first nationwide

population-based pharmaco-epidemiological study related to CHM use. In this retrospective study,

we revealed that CHM plays an important role in the treatment of T2D patients suffering from stroke,

and that CHM treatment is associated with a reduction in the risk of mortality. The cumulative

survival probability was also higher in CHM users than in non-CHM users. The herbal formulas and

single herbs most commonly used by CHM users were identified; notably, these products showed a

reduction in the mortality HR. Thus, our results suggest that CHM treatment is associated with a

lower risk of mortality among stroke patients with T2D.

During 1 year before the index date, regular medications for diabetes, hypertension, and

hyperlipidemia were taken by the patients of both groups (Table S1). Concerning antidiabetic

medications, biguanides, alpha glucosidases, thiazolidinediones, and insulin were used equally

between the two groups, while sulfonylureas were used more commonly by patients in the non-CHM

group. In contrast, antihypertensive medications including beta blocking agents, calcium channel

blockers, angiotensin converting enzyme inhibitors, and angiotensin II receptor blocking agents were

more commonly used by patients in the CHM group. With regard to antihyperlipidemic medications,

more patients in the CHM group used statins. Overall, our findings showed that CHM users suffered

from more severe hypertension and hyperlipidemia than non-CHM users did. We also recorded the

regular medications taken by the patients in the two groups from the index date to 365 days (1 year)

after the index date (Table S2). As shown in the table, more patients in the non-CHM group used

biguanides, sulfonylureas, and insulin. There was no significant difference between the two groups in

the usage of antihypertensive or antihyperlipidemic medications. Our results suggested that the usage

of regular antidiabetic, antihypertensive, and antihyperlipidemic drugs was reduced for CHM users

after the index date. This benefit might have been mediated through the components of CHM, which

are primarily plant substances. These medicinal plants show antidiabetic and anti-inflammatory

activities, inhibit abdominal fat accumulation, and attenuate oxidative stress (Kim et al., 2012; Lau et

11
al., 2012; Raoufi et al., 2015; Tam et al., 2011; Zhao et al., 2012). These pharmacological benefits

might explain the reason for the lower mortality HR observed in CHM users (Table S3-S6).

Furthermore, when mortality risk in the CHM users was stratified according to the type of the

herbs used, all of the most commonly used herbal formulas and single herbs demonstrated a

protective effect. The pharmaco-epidemiological data of these products provide us with the clinical

information necessary to further investigate their pharmacological activities in T2D patients suffering

from stroke. The most commonly used herbal formula was Shu-Jing-Huo-Xue-Tang, followed by

Xue-Fu-Zhu-Yu-Tang and Du-Huo-Ji-Sheng-Tang, all of which demonstrated lower HR of mortality.

Shu-Jing-Huo-Xue-Tang can invigorate blood, relax the channels, treat blood stagnation resulting

from wind-cold-dampness, and alleviate severe pain in the muscles, joints, and nerves (Kanai et al.,

2003). This formula has also been used for the treatment of gout, mucous cysts of the knees,

lumbago, sciatica, numbness in the legs, purpura, hemiplegia, hypertension, and postpartum pain due

to thrombosis. It is derived from the classic Chinese literature, Wan-Bing-Hui-Chun, edited by Dr.

Ting-xian Gong in 1587, and is composed of 17 single herbs. This formula has been used for the

treatment of chronic pain syndromes over hundreds of years. Recently, it has been shown to have

pharmacological activities including anti-inflammatory and analgesic activities in rheumatoid

arthritis (Chou et al., 1993), antihypersensitivity activity in chronic constriction injury (CCI)-

neuropathic rats (Shu et al., 2010), and analgesic activity via increasing blood circulation (Kanai et

al., 2003). This formula has been commonly used for the treatment of ischemic stroke patients in

Taiwan (Hung, I.L. et al., 2015). Moreover, the pre-treatment of animals by this formula in a model

of ischemia-reperfusion injury was shown to improve skeletal muscle blood vessel microcirculation,

decrease skeletal muscle oxidative injury, and enhance antioxidant enzymes’ activities (Tong et al.,

2012). It has also been used to treat other conditions including fractures (Liao et al., 2015), breast

cancer (Tsai et al., 2014), and prostate cancer (Lin et al., 2012). However, no antidiabetic activities

were reported for Shu-Jing-Huo-Xue-Tang.

12
 Xue-Fu-Zhu-Yu-Tang and Du-Huo-Ji-Sheng-Tang were the second and the third most commonly

used formulas, respectively, by stroke patients with T2D in our study. Xue-Fu-Zhu-Yu-Tang is

derived from the classic Chinese literature, Yi-Lin-Gai-Cuo: Correcting the Errors in the Forest of

Medicine, written by Dr. Qing-ren Wang in 1830, and is composed of 11 single herbs. It enhances

blood circulation, reduces chest pain, and counteracts blood stasis. This formula has been used in

conditions of blood stagnation in the heart, chest, or diaphragm, and blood stasis in children, usually

when fever, pain, and insomnia develop after trauma. It is a famous traditional Chinese herbal

formula that has been used for treating cardiovascular diseases and related illnesses in China for

centuries (Liu et al., 2004). Currently, Xue-Fu-Zhu-Yu-Tang has also been used to treat ischemic

heart disease (Hung, Y.C. et al., 2015), hyperlipidemia (Chu et al., 2015), platelet aggregation

(Huang et al., 2014), migraine (Chang et al., 2014), and prostate cancer (Lin et al., 2012). However,

similar to Shu-Jing-Huo-Xue-Tang, no antidiabetic activities have been reported for

Xue-Fu-Zhu-Yu-Tang. Du-Huo-Ji-Sheng-Tang is derived from the classic Chinese literature,

Beiji-Qian-Jin-Yao-Fang: Essential Formulas for Emergencies [Worth] a Thousand Pieces of Gold,

written by Dr. Simiao Sun in the Sui and Tang dynasty, and is composed of 15 single herbs. It

alleviates pain due to wind and dampness, relieves painful obstruction, supplies Qi, enhances blood

circulation, and tonifies the liver and kidney. It has also been used for treating osteoarthritis (Chen et

al., 2011; Chen et al., 2014), osteoporosis (Shih et al., 2012), rheumatoid arthritis (Chen, Y. et al.,

2016; Zhao et al., 2013), rheumatic back pain, and sciatica. Neither anti-stroke nor antidiabetic

activities have been reported for Du-Huo-Ji-Sheng-Tang.

Dan-Shen is composed of Salvia miltiorrhiza Bunge, family Lamiaceae. It is a very famous

traditional Chinese herb used to treat bleeding disorders and blood stasis (Zhou et al., 2005). Our

results suggested that Dan-Shen is the most commonly used single herb for the treatment of stroke

patients with T2D. This finding is consistent with the results of previous studies. Hung et al. suggest

that Dan-Shen is the most frequently prescribed single herb for ischemic stroke patients (Hung, I.L.

13
et al., 2015). Dan-Shen demonstrates beneficial effects in central nervous system neuronal injury and

degeneration in several animal models (Hugel and Jackson, 2014; Lee et al., 2013; Zhu et al., 2013)

as well as protective effects on the cardiovascular system (Hu et al., 2012; Jiang et al., 2013; Woo et

al., 2013; Yang et al., 2012; Zhang et al., 2014). Furthermore, an active component (SalB) from

Dan-Shen exhibits antioxidant and antidiabetic activities by affecting insulin sensitivity and glycogen

synthesis (Cai et al., 2014; Huang, M. et al., 2015; Lian et al., 2015; Raoufi et al., 2015). Niu-Xi

(Achyranthes bidentata Blume, family Amaranthaceae, 31.4%), and Yan-Hu-Suo (Corydalis

yanhusuo (Y.H.Chou & Chun C.Hsu) W.T.Wang ex Z.Y.Su & C.Y.Wu, family Papaveraceae, 31.2%)

are the second and the third most commonly used single herbs, respectively. Niu-Xi has been used to

invigorate blood and treat blood stasis. Niu-Xi enhances neuronal growth in vitro, promotes

peripheral nerve regeneration (Cheng et al., 2014; Wang et al., 2013a) and exhibits a neuroprotective

effect in animal models of cerebral ischemia (Shen et al., 2013; Yu et al., 2014). Furthermore, Niu-Xi

inhibits the production of advanced glycation end products and their accumulation in the brain tissue,

and improves learning and memory capabilities in ovariectomized rats (Wang et al., 2013b).

Yan-Hu-Suo has been found to treat peptic ulcer (Huang, C.Y. et al., 2015), improve neurological

status, and reduce the area of cerebral infarct in a rat model of ischemia-reperfusion injury (Liao et

al., 2001). Interestingly, its methanolic extract and alkaloidal components inhibit diabetes

complications, including cataract, through inhibiting the aldose reductase enzyme (Kubo et al., 1994).

However, there is no information regarding the therapeutic effect of these herbal formulas and single

herbs in stroke patients with T2D. To our knowledge, this is the first study to demonstrate that CHM

adjunctive therapy might be beneficial for better survival among these patients.

4.1 Limitations

The results of clinical research using the National Health Insurance Research database in Taiwan

might provide further evidence regarding the CHM therapeutic effect. The main limitation of this

14
study is the lack of data on blood chemistry in the National Health Insurance Research database in

Taiwan. Despite this, our results indicate that CHM reduces the risk of mortality in stroke patients

with T2D. Our study further provides a comprehensive list of CHM products that might be useful for

future investigation of their safety and efficacy. Functional characterization of their protective effects

on brain endothelial cells is also warranted. Furthermore, additional large-scale, randomized clinical

trials should be performed in order to determine the effectiveness and safety of these herbal

medicines and to evaluate their potential interactions with conventional treatments.

5. Conclusion

By reviewing the National Health Insurance Research Database (NHIRD), we were able to

investigate the mechanism of action of CHM in the treatment of disease. The CHM users showed a

lower mortality HR when compared with the non-CHM users. In the CHM group,

Shu-Jing-Huo-Xue-Tang, Xue-Fu-Zhu-Yu-Tang, and Du-Huo-Ji-Sheng-Tang were the top three

formulas taken, whereas Dan-Shen, Niu-Xi, and Yan-Hu-Suo were the top three single herbs. Thus,

the use of CHM as adjunctive therapy may improve the overall survival (OS) of stroke patients with

T2D. Our study provides a list of the comprehensive herbal medicines that they used that might be

useful in future large-scale, randomized clinical investigations of their effectiveness, safety, and

potential interactions with conventional treatments in stroke patients with T2D.

Author contributions

FJT, TJH, WML, and YJL conceived and designed the experiments. CFC, THL, CCL, and SMH

performed the experiments. CFC, YTS, WKC, and JHC analysed the data. CHK, XL, HT, JPL, CWL,

JGL, YHL, JCL, and CCLin contributed reagents/materials/analysis tools. WML and YJL wrote the

manuscript. All the authors have read and approved the final manuscript.

15
Conflict of interest statement

The authors have no conflict of interest to disclose.

Acknowledgements

This study was supported by grants from the China Medical University (CMU102-PH-01 and

CMU100-S-01), the China Medical University Hospital (DMR-105-031, DMR-105-098, and

DMR-106-155), the National Science Council, the Ministry of Science and Technology, Taiwan

(MOST 103-2320-B-039 -006 -MY3 and MOST 105-2314-B-039-037-MY3), and China Medical

University under the Aim for Top University Plan of the Ministry of Education, Taiwan. This study

was based in part on data from the National Health Insurance Research Database provided by the

Bureau of National Health Insurance, Department of Health and managed by National Health

Research Institutes. The interpretation and conclusions contained herein do not represent those of

National Health Insurance Administration, Department of Health or National Health Research

Institutes. The authors wish to thank the Division of Chinese Medicine, China Medical University,

Beigang Hospital, for administrative assistance and consultation, and the Aim for Top University

Plan of the Ministry of Education, Taiwan, at the China Medical University. We also thank Dr.

Kuan-Teh Jeang and Willy W.L. Hong for their technical help and suggestions.

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Figure Legends

Figure 1. Flow diagram showing the protocol for enrollment of study subjects.

Figure 2. Kaplan-Meier survival probability of stroke patients with T2D according to Chinese

herbal medicine (CHM) use.

22
Table 1 Demographic characteristics of total subjects and frequency matched subjects with stroke patients with T2D according to CHM usage.
Total subjects ġ Matched subjects
non-CHM
CHM group non-CHM group CHM group
Characteristics group
N=858 N=2,221 p value N=618 N=618 p value
N (%) N (%) ġ N (%) N (%)
Age <0.001 0.838
<60 yrs 212 ( 24.71%) 339 ( 15.26%) 141 ( 22.82%) 138 ( 22.33%)
>=60 yrs 646 ( 75.29%) 1882 ( 84.74%) 477 ( 77.18%) 480 ( 77.67%)
Gender <0.001 1
Male 430 ( 50.12%) 1339 ( 60.29%) 331 ( 53.56%) 331 ( 53.56%)
Female 428 ( 49.88%) 882 ( 39.71%) 287 ( 46.44%) 287 ( 46.44%)
Duration from diabetes to stroke 0.017 0.902
1~3 years 231 ( 26.92%) 696 ( 31.34%) 193 ( 31.23%) 191 ( 30.91%)
>=3 years 627 ( 73.08%) 1525 ( 68.66%) 425 ( 68.77%) 427 ( 69.09%)
COPD 0.043 <0.001
No 537 ( 62.59%) 1476 ( 66.46%) 385 ( 62.3%) 445 ( 72.01%)
Yes 321 ( 37.41%) 745 ( 33.54%) 233 ( 37.7%) 173 ( 27.99%)
Hepatitis <0.001 0.088
No 785 ( 91.49%) 2116 ( 95.27%) 569 ( 92.07%) 584 ( 94.5%)
Yes 73 ( 8.51%) 105 ( 4.73%) 49 ( 7.93%) 34 ( 5.5%)
Ulcer disease <0.001 <0.001
No 454 ( 52.91%) 1461 ( 65.78%) 329 ( 53.24%) 422 ( 68.28%)
Yes 404 ( 47.09%) 760 ( 34.22%) 289 ( 46.76%) 196 ( 31.72%)
Chronic kidney disease 0.55 0.409
No 763 ( 88.93%) 1958 ( 88.16%) 547 ( 88.51%) 556 ( 89.97%)

23
 Yes 95 ( 11.07%) 263 ( 11.84%) 71 ( 11.49%) 62 ( 10.03%)
Hyperlipidemia <0.001 <0.001
No 319 ( 37.18%) 1207 ( 54.34%) 235 ( 38.03%) 313 ( 50.65%)
Yes 539 ( 62.82%) 1014 ( 45.66%) 383 ( 61.97%) 305 ( 49.35%)
Obesity 0.003 0.058
No 850 ( 99.07%) 2217 ( 99.82%) 612 ( 99.03%) 617 ( 99.84%)
Yes 8 ( 0.93%) 4 ( 0.18%) 6 ( 0.97%) 1 ( 0.16%)
Alcohol-related illness 0.84 0.78
No 848 ( 98.83%) 2197 ( 98.92%) 612 ( 99.03%) 611 ( 98.87%)
Yes 10 ( 1.17%) 24 ( 1.08%) 6 ( 0.97%) 7 ( 1.13%)
Tobacco use 0.057 0.019
No 849 ( 98.95%) 2211 ( 99.55%) 610 ( 98.71%) 617 ( 99.84%)
Yes 9 ( 1.05%) 10 ( 0.45%) 8 ( 1.29%) 1 ( 0.16%)
INCOME <0.001 0.02
<NT20000 391 ( 45.57%) 1227 ( 55.25%) 283 ( 45.79%) 316 ( 51.13%)
NT20000~NT30000 290 ( 33.80%) 732 ( 32.96%) 209 ( 33.82%) 211 ( 34.14%)
NT30000~NT40000 125 ( 14.57%) 166 ( 7.47%) 85 ( 13.75%) 52 ( 8.41%)
>=NT40000 52 ( 6.06%) 96 ( 4.32%) 41 ( 6.63%) 39 ( 6.31%)
Urbanization level 0.056 0.184
1 305 ( 35.55%) 813 ( 36.61%) 218 ( 35.28%) 251 ( 40.61%)
2 243 ( 28.32%) 526 ( 23.68%) 166 ( 26.86%) 135 ( 21.84%)
3 80 ( 9.32%) 202 ( 9.10%) 59 ( 9.55%) 58 ( 9.39%)
4 98 ( 11.42%) 269 ( 12.11%) 75 ( 12.14%) 67 ( 10.84%)
5 132 ( 15.38%) 411 ( 18.51%) ġ ġ 100 ( 16.18%) 107 ( 17.31%) ġ ġ
ġ

24
CHM, Chinese herbal medicine; T2D, type 2 diabetes; COPD, chronic obstructive pulmonary disease.

Chi-squared tests were used to detect differences between CHM and non-CHM users.

Table 2 Hazard ratios for mortality according to CHM user, comorbidities, income, and urbanization level among frequency matched subjects

with stroke patients with T2D

Hazard ratio (95%CI) p value

CHM user (Yes v.s. No) 0.37 (0.25 - 0.55) <0.001
Comorbidities
COPD (Yes v.s. No) 1.74 (0.98 - 3.11) 0.06
Hepatitis (Yes v.s. No) 0.50 (0.12 - 2.11) 0.348
Ulcer disease (Yes v.s. No) 0.92 (0.52 - 1.62) 0.77
Chronic kidney disease (Yes v.s. No) 1.56 (0.74 - 3.28) 0.238
Hyperlipidemia (Yes v.s. No) 0.75 (0.44 - 1.29) 0.297
Income (ref: NT30000~NT40000)
<NT20000 1.29 (0.40 - 4.16) 0.666
NT20000~NT30000 0.84 (0.23 - 3.12) 0.799
>=NT40000 1.84 (0.25 - 13.33) 0.546
Urbanization level (ref: 3)
3
1 0.27 (0.09 - 0.74) 0.012
2 0.25 (0.09 - 0.68) 0.007
4 0.61 (0.20 - 1.85) 0.382
ġ 5 0.41 (0.14 - 1.17) 0.094
25
CHM, Chinese herbal medicine; T2D, type 2 diabetes; CI, confidence interval; COPD, chronic obstructive pulmonary disease.

Models adjusted for CHM use, comorbidities, income, and urbanization level.

Cox's proportional hazards model was applied in this analysis.

Urbanization level 1 referring to the most urbanized communities and level 5 referring to the least urbanized communities.

26
Table 3 Twelve most common herbal formulas and single herbs for frequency matched subjects with stroke patients with T2D.
Av
g.
dr Averag
Num ug e
Compos Frequ Frequen Percen
ber do duratio
Chinese ition Composition Composition (botanical plant name, ency Person cy of tage of
Formulas of se n for
name (Pin-yin ((latin name) family name) of -year prescrip usage
herb pe prescri
name) user tions person
s r ption
da (days)
y
(g)
12.
Total 618 3068.7 22355 100 7.8
4
Herbal formula
617 3065.8 21449 99.8 9.6 7.8
(Pin-yin name)
Radix
Angelica sinensis (Oliv.) Diels,
Dang-Gui Angelicae
family Apiaceae
Sinensi
Radix
Paeonia lactiflora Pall., family
Bai-Shao Paeoniae
Paeoniaceae
Alba
๤࿶ࢲ Chuan-Xio Rhizoma Ligusticum sinense Oliv., family
Shu-Jing-Huo-Xue- 17 226 1276.6 1300 36.6 4.1 7.8
Ո෯! ng Chuanxiong Apiaceae
Tang
Radix Rehmannia glutinosa (Gaertn.) DC.,
Di-Huang
Rehmanniae family Plantaginaceae
Semen Prunus persica (L.) Batsch, family
Tao-Ren
Persicae Rosaceae
Rhizoma Atractylodes macrocephala Koidz,
Bai-Zhu
Atractylodis family Compositae

27
 Wolfiporia extensa (Peck) Ginns,
Fu-Ling Poria
family Polyporaceae
Radix
Achyranthes bidentata Blume,
Niu-Xi Achyranthis
family Amaranthaceae
Bidentatae
Wei-Ling- Radix Clematis chinensis Osbeck, family
Xian Clematidis Ranunculaceae
Radix
Han-Fang Stephania tetrandra S.Moore,
Stephaniae
-Ji family Menispermaceae
Tetrandrae
Rhizoma seu
Qiang-Hu Notopterygium oviforme Shan,
Radix
o family Apiaceae
Notopterygii
Radix
Fang-Fen Saposhnikovia divaricata (Turcz.)
Saposhnikovi
g Schischk, family Apiaceae
ae
Long-Dan- Radix Gentiana lutea L., family
Cao Gentianae Gentianaceae
Radix Angelica dahurica (Hoffm.) Benth.
Bai-Zhi Angelicae & Hook.f. ex Franch. & Sav., family
Dahuricae Apiaceae
Pericarpium
Citrus reticulata Blanco, family
Chen-Pi Citri
Rutaceae
Reticulatae
Radix
Glycyrrhiza uralensis Fisch., family
Gan-Cao Glycyrrhizae
Leguminosae
Preparata
Rhizoma
Sheng-Jia Zingiber officinale Roscoe, family
Zingiberis
ng Zingiberaceae
Recens
Semen Prunus persica (L.) Batsch, family
Ո۬೴ 11 Tao-Ren 190 1068.1 1049 30.7 3.5 9.2
Xue-Fu-Zhu-Yu-Tan Persicae Rosaceae

28
 g ྿෯! Flos Carthamus tinctorius L., family
Hong-Hua
Carthami Compositae
Radix
Angelica sinensis (Oliv.) Diels,
Dang-Gui Angelicae
family Apiaceae
Sinensi
Chuan-Xio Rhizoma Ligusticum sinense Oliv., family
ng Chuanxiong Apiaceae
Radix Paeonia anomala subsp. veitchii
Chi-Shao Paeoniae (Lynch) D.Y.Hong & K.Y.Pan,
Rubra family Paeoniaceae
Chuan-Ni Radix Achyranthes bidentata Blume,
u-Xi Cyathulae family Amaranthaceae
Radix Bupleurum chinense DC., family
Chai-Hu
Bupleuri Apiaceae
Radix Platycodon grandiflorus (Jacq.)
Jie-Geng
Platycodi A.DC., family Campanulaceae
Fructus Gardenia jasminoides J.Ellis, family
Zhi-Zi
Gardeniae Rubiaceae
Sheng-Di- Radix Rehmannia glutinosa (Gaertn.)
Huang Rehmanniae DC.), family Plantaginaceae
Radix
Glycyrrhiza uralensis Fisch., family
Gan-Cao Glycyrrhizae
Leguminosae
Preparata
Radix Angelica dahurica (Hoffm.) Benth.
Bai-Zhi Angelicae & Hook.f. ex Franch. & Sav., family
Dahuricae Apiaceae
Herba cum Asarum sieboldii Miq., family
ᐱࢲ஌ Xi-Xin
Radix Asari Aristolochiaceae
Du-Huo-Ji-Sheng-T 15 189 1007.3 1083 30.6 4.2 9.1
ғ෯! Radix
ang Fang-Fen Saposhnikovia divaricata (Turcz.)
Saposhnikovi
g Schischk., family Apiaceae
ae
Radix Gentiana crassicaulis Duthie ex
Qin-Jiao
Gentianae Burkill, family Gentianaceae
29
 Macrophyllae

Taxillus chinensis (DC.) Danser,

Sang-Ji-S Herba Taxilli
family Loranthaceae
heng
Eucommiae Eucommia ulmoides Oliv., family
Du-Zhong
cortex Eucommiaceae
Radix
Achyranthes bidentata Blume,
Niu-Xi Achyranthis
family Amaranthaceae
Bidentatae
Cinnamomi Cinnamomum cassia (L.) J.Presl,
Rou-Gui
cortex family Lauraceae
Radix Angelica dahurica (Hoffm.) Benth.
Bai-Zhi Angelicae & Hook.f. ex Franch. & Sav., family
Dahuricae Apiaceae
Chuan-Xio Rhizoma Ligusticum sinense Oliv., family
ng Chuanxiong Apiaceae
Radix Rehmannia glutinosa (Gaertn.) DC.,
Di-Huang
Rehmanniae family Plantaginaceae
Radix
Paeonia lactiflora Pall., family
Bai-Shao Paeoniae
Paeoniaceae
Alba
Radix Panax ginseng C.A.Mey., family
Ren-Shen
Ginseng Araliaceae
Wolfiporia extensa (Peck) Ginns,
Fu-Ling Poria
family Polyporaceae
Radix
Glycyrrhiza uralensis Fisch., family
Gan-Cao Glycyrrhizae
Leguminosae
Preparata
‫ؿ‬ᛰҒ Radix
Paeonia lactiflora Pall., family
Shao-Yao-Gan-Cao- 2 Bai-Shao Paeoniae 184 1026 840 29.8 3.1 7.1
૛෯! Paeoniaceae
Tang Alba

30
 Radix
Glycyrrhiza uralensis Fisch., family
Gan-Cao Glycyrrhizae
Leguminosae
Preparata
Radix
Shu-Di-H Rehmannia glutinosa (Gaertn.) DC.,
Rehmanniae
uang family Plantaginaceae
Preparata
Shan-Zhu- Cornus officinalis Siebold & Zucc.,
Fructus Corni
Yu family Cornaceae
Rhizoma Dioscorea opposita Thunb., family
Ϥ‫ښ‬Ӧ Shan-Yao
Liu-Wei-Di-Huang- 6 Dioscoreae Dioscoreaceae 182 1064.9 1014 29.4 4 8.6
㲢Τ!!
Wan Wolfiporia extensa (Peck) Ginns,
Fu-Ling Poria
family Polyporaceae
Mu-Dan-P Cortex Paeonia officinalis L., family
i Moutan Paeoniaceae
Rhizoma Alisma plantago-aquatica L., family
Ze-Xie
Alismatis Alismataceae
Radix
Shu-Di-H Rehmannia glutinosa (Gaertn.) DC.,
Rehmanniae
uang family Plantaginaceae
Preparata
Shan-Zhu- Cornus officinalis Siebold & Zucc.,
Fructus Corni
Yu family Cornaceae
Rhizoma Dioscorea opposita Thunb., family
Shan-Yao
Dioscoreae Dioscoreaceae
ᔮғ๝ Rhizoma Alisma plantago-aquatica L., family
Ji-Sheng-Shen-Qi-W 10 Ze-Xie 165 913 1216 26.7 4.3 9.8
਻Τ! Alismatis Alismataceae
an Radix
Paeonia lactiflora Pall., family
Bai-Shao Paeoniae
Paeoniaceae
Alba
Mu-Dan-P Cortex Paeonia officinalis L., family
i Moutan Paeoniaceae
Cinnamomi Cinnamomum cassia (L.) J.Presl,
Rou-Gui
cortex family Lauraceae

31
 Radix Aconiti
Astragalus propinquus Schischkin,
Zhi-Fu-Zi Lateralis
family Leguminosae
Preparata
Chuan-Ni Radix Achyranthes bidentata Blume,
u-Xi Cyathulae family Amaranthaceae
Che-Qian- Semen Plantago depressa Willd., family
Zi Plantaginis Plantaginaceae
Pueraria montana var. lobata
Radix
Ge-Gen (Wild.) Sanjappa & Pradeep, family
Puerariae
Leguminosae
Herba Ephedra distachya L., family
Ma-Huang
Ephedrae Ephedraceae
Cinnamomi Cinnamomum cassia (L.) J.Presl,
Gui-Zhi
ramulus family Lauraceae
Radix
Paeonia lactiflora Pall., family
လਥ෯! 7 Bai-Shao Paeoniae 161 897.4 712 26.1 4.7 6.4
Ge-Gen-Tang Paeoniaceae
Alba
Rhizoma
Sheng-Jia Zingiber officinale Roscoe, family
Zingiberis
ng Zingiberaceae
Recens
Fructus Ziziphus jujuba Mill., family
Da-Zao
Jujube Rhamnaceae
Radix
Glycyrrhiza uralensis Fisch., family
Gan-Cao Glycyrrhizae
Leguminosae
Preparata
Radix
Glycyrrhiza uralensis Fisch., family
Gan-Cao Glycyrrhizae
Leguminosae
Preparata
‫ݼ‬Ғ૛
11 Radix Panax ginseng C.A.Mey., family 154 855.9 912 24.9 3.7 8.7
Zhi-Gan-Cao-Tang ෯! Ren-Shen
Ginseng Araliaceae
Radix Salviae Salvia miltiorrhiza Bunge, family
Dan-Shen
Miltiorrhizae Lamiaceae

32
 Cinnamomi Cinnamomum cassia (L.) J.Presl,
Gui-Zhi
ramulus family Lauraceae
Sheng-Di- Radix Rehmannia glutinosa (Gaertn.)
Huang Rehmanniae DC.), family Plantaginaceae
Mai-Men- Radix Ophiopogon japonicus (Thunb.) Ker
Dong Ophiopogonis Gawl., family Asparagaceae
Colla Corii
E-Jiao Equus asinus L., family Equidae
Asini
Huo-Ma-R Semen Cannabis sativa L., family
en Cannabis Cannabaceae
Rhizoma
Sheng-Jia Zingiber officinale Roscoe, family
Zingiberis
ng Zingiberaceae
Recens
Fructus Ziziphus jujuba Mill., family
Da-Zao
Jujube Rhamnaceae
White
Wine
Radix
Angelica sinensis (Oliv.) Diels,
Dang-Gui Angelicae
family Apiaceae
Sinensi
Radix
Paeonia lactiflora Pall., family
Bai-Shao Paeoniae
Paeoniaceae
Alba
у‫ښ‬೮ Wolfiporia extensa (Peck) Ginns,
Jia-Wei-Xiao-Yao-S 10 Fu-Ling Poria 153 831.8 787 24.8 3.2 8.6
ᇿණ! family Polyporaceae
an
Rhizoma
Atractylodis Atractylodes macrocephala Koidz.,
Bai-Zhu
Macrocephal family Compositae
ae
Radix Bupleurum falcatum L., family
Chai-Hu
Bupleuri Apiaceae

33
 Mu-Dan-P Cortex Paeonia officinalis L., family
i Moutan Paeoniaceae
Fructus Gardenia jasminoides J.Ellis, family
Zhi-Zi
Gardeniae Rubiaceae
Radix
Glycyrrhiza uralensis Fisch., family
Gan-Cao Glycyrrhizae
Leguminosae
Preparata
Herba
Mentha arvensis L., family
Bo-He Menthae
Lamiaceae
Haplocalycis
Rhizoma
Sheng-Jia Zingiber officinale Roscoe, family
Zingiberis
ng Zingiberaceae
Recens
Radix Rehmannia glutinosa (Gaertn.) DC.,
Di-Huang
Rehmanniae family Plantaginaceae
Radix
Shu-Di-H Rehmannia glutinosa (Gaertn.) DC.,
Rehmanniae
uang family Plantaginaceae
Preparata
Herba Dendrobium moniliforme (L.) Sw.,
Shi-Hu
Dendrobii family Orchidaceae
Tian-Men- Radix Asparagus cochinchinensis (Lour.)
Dong Asparagi Merr., family Asparagaceae
Ғ៛໯! 10 Mai-Men- Radix Ophiopogon japonicus (Thunb.) Ker 153 820.9 775 24.8 3.6 7.4
Gan-Lu-Yin
Dong Ophiopogonis Gawl., family Asparagaceae
Huang-Qi Radix Scutellaria baicalensis Georgi,
n Scutellariae family Lamiaceae
Herba
Yin-Chen- Artemisia capillaris Thunb., family
Artemisiae
Hao Compositae
Scopariae
Fructus
Citrus aurantium L., family
Zhi-Shi Aurantii
Rutaceae
Immaturus

34
 Folium Eriobotrya japonica (Thunb.) Lindl.,
Pi-Pa-Ye
Eriobotryae family Rutaceae
Radix
Glycyrrhiza uralensis Fisch., family
Gan-Cao Glycyrrhizae
Leguminosae
Preparata
Herba
Mentha arvensis L., family
Bo-He Menthae
Lamiaceae
Haplocalycis
Chuan-Xio Rhizoma Ligusticum sinense Oliv., family
ng Chuanxiong Apiaceae
Radix Angelica dahurica (Hoffm.) Benth.
Bai-Zhi Angelicae & Hook.f. ex Franch. & Sav., family
Dahuricae Apiaceae
Rhizoma seu
Qiang-Hu Notopterygium oviforme Shan,
Radix
o family Apiaceae
Notopterygii
Herba cum Asarum sieboldii Miq., family
οᨚૡ Xi-Xin
Radix Asari Aristolochiaceae
Chuan-Xiong-Cha-T 10 149 857.1 847 24.1 4.3 6.3
ፓණ! Rhizoma Cyperus rotundus L., family
iao-San Xiang-Fu
Cyperi Cyperaceae
Herba Nepeta tenuifolia Benth., family
Jing-Jie
Schizonepetae Lamiaceae
Radix
Saposhnikovia divaricata (Turcz.)
Fang-Fen Saposhnikovi
Schischk., family Apiaceae
g ae
Radix
Glycyrrhiza uralensis Fisch., family
Gan-Cao Glycyrrhizae
Leguminosae
Preparata
Folium
Camellia sinensis (L.) Kuntze,
Lu-Cha Camelliae
family Theaceae
Sinensis
Radix Astragalus propinquus Schischkin,
ံ໚ᗋ 7 Huang-Qi 144 774 762 23.3 4.2 9.1
Bu-Yang-Huan-Wu- Astragali family Leguminosae
35
 Tang ϖ෯! Radix
Angelica sinensis (Oliv.) Diels,
Dang-Gui Angelicae
family Apiaceae
Sinensi
Chuan-Xio Rhizoma Ligusticum sinense Oliv., family
ng Chuanxiong Apiaceae
Radix Paeonia anomala subsp. veitchii
Chi-Shao Paeoniae (Lynch) D.Y.Hong & K.Y.Pan,
Rubra family Paeoniaceae
Semen Prunus persica (L.) Batsch, family
Tao-Ren
Persicae Rosaceae
Flos Carthamus tinctorius L., family
Hong-Hua
Carthami Compositae
Pheretima Pheretima posthuma, family
Pheretima
posthuma Megascolecidae
Single herbs
595 2949.1 17669 96.3 4 8.1
(Pin-yin name)
Radix Salviae Salvia miltiorrhiza Bunge, family
Dan-Shen Ϗୖ! 1 Dan-Shen 222 1210.7 1545 35.9 1.1 11.2
Miltiorrhizae Lamiaceae
Radix
Achyranthes bidentata Blume,
Niu-Xi Фጣ! 1 Niu-Xi Achyranthis 194 1029.4 1144 31.4 1 8.3
family Amaranthaceae
Bidentatae
Corydalis yanhusuo (Y.H.Chou &
Yan-Hu-S Rhizoma
‫ۯ‬च઩! 1 Chun C.Hsu) W.T.Wang ex Z.Y.Su & 193 1069 819 31.2 1.2 7.8
Yan-Hu-Suo uo Corydalis
C.Y.Wu, family Papaveraceae
Bulbus
Fritillaria cirrhosa D.Don, family
Bei-Mu ‫!҆ن‬ 1 Bei-Mu Fritillariae 182 972.6 1021 29.4 1 7.3
Liliaceae
Cirrhosae
Huang-Qi Radix Scutellaria baicalensis Georgi,
Huang-Qin 㲢᭷! 1 176 963.9 1029 28.5 1.1 9.2
n Scutellariae family Lamiaceae
Pueraria montana var. lobata
Radix
Ge-Gen လਥ! 1 Ge-Gen (Willd.) Sanjappa & Pradeep, 176 958 824 28.5 1.1 8.4
Puerariae
family Leguminosae

36
 Mai-Men- Radix Ophiopogon japonicus (Thunb.) Ker
ഝߐо! 1 164 902.9 768 26.5 1 7.5
Mai-Men-Dong Dong Ophiopogonis Gawl., family Asparagaceae
Radix Platycodon grandiflorus (Jacq.)
Jie-Geng ਧఒ! 1 Jie-Geng 162 880.8 914 26.2 1 6.6
Platycodi A.DC., family Campanulaceae
Tian-Hua- Radix Trichosanthes kirilowii Maxim.,
Ϻ޸ણ! 1 159 895.8 872 25.7 1.3 8.8
Tian-Hua-Fen Fen Trichosanthis family Cucurbitaceae
Radix Panax notoginseng (Burkill)
San-Qi ΟΎ! 1 San-Qi 154 834.4 805 24.9 1.1 8.8
Notoginseng F.H.Chen, family Araliaceae
Radix et Rheum palmatum L., family
Da-Huang ε໳! 1 Da-Huang 151 833.1 1337 24.4 0.8 8.5
Rhizoma Rhei Polygonaceae
Eucommiae Eucommia ulmoides Oliv., family
Du-Zhong ‫׹‬Ҹ! 1 Du-Zhong 149 780.1 1029 24.1 1.1 9
cortex Eucommiaceae

*Sorted by percentage of usage person

Information are obtained from the websites (http://www.theplantlist.org/; http://mpns.kew.org/mpns-portal/searchName;

http://www.ipni.org/;http://www.americandragon.com/index.htm; http://old.tcmwiki.com/; http://www.shen-nong.com/eng/front/index.html).

37
Table 4 Hazard ratios and 95% confidence intervals of mortality risk associated with
cumulative use of herbal formula and single herbs among stroke patients with T2D.
Non-CHM user
Formulas CHM user (e/n) HR (95% CI)
(e/n)

Total
Herbal formula
Shu-Jing-Huo-Xue-Tang 27/226 47/226 0.38 (0.19-0.63)***

Xue-Fu-Zhu-Yu-Tang 13/190 41/190 0.15 (0.09-0.36)***

Du-Huo-Ji-Sheng-Tang 18/189 37/189 0.36 (0.17-0.68)**

Shao-Yao-Gan-Cao-Tang 22/184 38/184 0.43 (0.22-0.78)**

Liu-Wei-Di-Huang-Wan 20/182 37/182 0.32 (0.14-0.62)**

Ji-Sheng-Shen-Qi-Wan 15/165 32/165 0.37 (0.17-0.70)**

Ge-Gen-Tang 18/161 33/161 0.22 (0.11-0.48)***

Zhi-Gan-Cao-Tang 18/154 37/154 0.30 (0.15-0.61)**

Jia-Wei-Xiao-Yao-San 18/182 44/182 0.20 (0.10-0.40)**

38
 Gan-Lu-Yin 17/153 37/153 0.24 (0.11-0.52)***

Chuan-Xiong-Cha-Tiao-San 11/149 29/149 0.23 (0.11-0.56)***

Bu-Yang-Huan-Wu-Tang 12/144 28/144 0.37 (0.18-0.72)**

Single herbs

Dan-Shen 16/222 37/222 0.26 (0.12-0.49)***

Niu-Xi 23/194 44/194 0.27 (0.12-0.50)***

Yan-Hu-Suo 21/193 38/193 0.29 (0.17-0.50)**

Bei-Mu 19/182 38/182 0.28 (0.13-0.53)***

Huang-Qin 8/176 36/176 0.14 (0.08-0.32)***

Ge-Gen 19/162 39/162 0.29 (0.13-0.60)**

Mai-Men-Dong 14/164 32/164 0.37 (0.19-0.73)**

Jie-Geng 17/176 42/176 0.20 (0.10-0.41)***

Tian-Hua-Fen 15/159 34/159 0.17 (0.08-0.41)***

San-Qi 17/154 31/154 0.27 (0.15-0.50)**

Da-Huang 13/151 36/151 0.26 (0.14-0.51)***

39
 Du-Zhong 16/149 31/149 0.32 (0.16-0.62)**

HR, hazard ratio; 95%CI, 95% confidence interval; CHM, Chinese herbal medicine; e, frequency of mortality; n, total number.

HR represented adjusted hazard ratio adjusted for age, gender, comorbidities, income, and urbanization level.

Cox's proportional hazards model was applied in this analysis.

*p < 0.05; **p < 0.01; ***p < 0.001.

40
41
42