Shenzhu Tiaopi granule combined with lifestyle intervention therapy for impaired glucose tolerance: A randomized controlled trial

Complementary Therapies in Medicine (2014) 22, 842—850

Available online at www.sciencedirect.com

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Shenzhu Tiaopi granule combined with lifestyle intervention therapy for impaired glucose tolerance: A randomized controlled trial Zhaohui Fang a,b,∗, Jindong Zhao a,b, Guobing Shi a, Yiqiong Shu a, Yingqun Ni a, Huan Wang a, Lei Ding a, Ruimin Lu a, Jiayun Li a, Xiaojin Zhu a, Senhua Cheng c, Xinyi Zhang a, Yan Liu d, Jun Wang e, Yuan Luo a, Qingyun Fan a, Chenglin Guo a, Ting Jiang a, Qian Wu a, Lihong Fan a, Hanpeng Ling a, Liqun Cui a, Yun Luo a, Hui Yang a, Robert M. Anderson b,f a

Department of Endocrinology, the First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei 230031, Anhui Province, China b Institute of Chinese Medicine Prevention and Therapy Diabetes Mellitus, Anhui Academy of Chinese Medicine, Hefei 230031, Anhui Province, China c Department of Endocrinology, Shangyu City Hospital of Chinese Medicine, Shangyu 312300, Zhejiang Province, China d Department of Endocrinology, the Second Affiliated Hospital of Anhui University of Chinese Medicine, Hefei 230031, Anhui Province, China e Department of Endocrinology, Wuhu City Hospital of Chinese Medicine, Wuhu 241000, Anhui Province, China f The Department of Learning Health Sciences, University of Michigan Medical School, Ann Arbor, MI, USA Available online 12 August 2014

KEYWORDS Impaired glucose tolerance (IGT); Spleen deficiency and damp overabundance syndrome (SDDOS);

Summary Objective: The purpose of the study was to evaluate the clinical effects of the Shenzhu Tiaopi granule (SZTP) combined with a lifestyle intervention in patients with impaired glucose tolerance (IGT), who also had a spleen deficiency and damp overabundance syndrome (SDDOS). Methods: After a one-month washout period, a total of 514 patients were randomly assigned to the control (lifestyle intervention) and experimental (SZTP plus lifestyle intervention) groups, with 257 patients in each group. Patients in the control group received

∗ Corresponding author at: Department of Endocrinology, the First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei 230031, Anhui Province, China. Tel.: +86 13965059097. E-mail address: [email protected] (Z. Fang).

http://dx.doi.org/10.1016/j.ctim.2014.08.004 0965-2299/© 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-SA license (http://creativecommons.org/licenses/by-nc-sa/3.0/).

The impact of Chinese Medicine combined with lifestyle intervention on impaired glucose tolerance Shenzhu Tiaopi granule (SZTP); Lifestyle

843

the lifestyle intervention (diet and exercise) for 12 months, while the patients in the experimental group were treated with SZTP plus the lifestyle intervention for 12 months. The Traditional Chinese Medicinal (TCM) symptom scores were observed in each group before and after treatment; the conversion rates from IGT to diabetes mellitus (DM) were also measured. Results: Following 12 months of treatment, the conversion rate from IGT to DM in the experimental group was significantly lower than in the control group (8.52% vs. 15.28%, P < 0.05). A significantly higher number of patients with IGT reverted to normal blood glucose levels in the experimental group than in the control group (42.15% vs. 32.87%, P < 0.05). In addition, after following the treatment for 12 months, the TCM symptoms of patients in the experimental group were markedly alleviated, as compared to the control group (P < 0.01). Conclusion: The combination of SZTP and lifestyle intervention showed a reduction in the conversion from IGT to DM, and an increase in the conversion from IGT to normal blood glucose levels. © 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-SA license (http://creativecommons.org/licenses/by-nc-sa/3.0/).

Contents Introduction.............................................................................................................. Subjects and methods.................................................................................................... Diagnosis criteria.................................................................................................... Selection criteria.................................................................................................... Exclusion criteria.................................................................................................... Criteria for withdrawing patients from the study .................................................................... Sample size and statistical analysis ........................................................................... Treatment regimen ........................................................................................... Variables assessed ............................................................................................ Evaluation of efficacy......................................................................................... Results ................................................................................................................... Procedure and subjects.............................................................................................. Comparison of baseline characteristics .............................................................................. Comparison of baseline clinical symptoms ........................................................................... Comparisons of conversion rate ..................................................................................... Comparisons of levels of FPG, 2 hPG and HbA1c ..................................................................... Comparisons of cardiovascular risk factors and serum lipid levels ................................................... Comparisons of efficacy and scores on single TCM symptom ......................................................... Comparisons of safety evaluation and adverse events ............................................................... Discussion ................................................................................................................ Conflict of interest ....................................................................................................... Acknowledgements....................................................................................................... References ...............................................................................................................

Introduction With the rapid of economic development around the world resulting in reduced levels of physical activity and changes in dietary habits, the incidence and prevalence of diabetes Mellitus (DM) has been rising. The prevalence of diabetes is the third highest among non-infectious diseases in China.1 Chinese people are experiencing steady improvements in living standards, changes in dietary habits. There is also an accelerated pace of life, as well as an increase in sedentary lifestyle. Also the population of China is rapidly aging. The age-standardized prevalence of DM and impaired glucose tolerance (IGT) (sometimes referred to as pre diabetes [PD]) among Chinese over age 20 were reported as 9.7% and 15.5% in 2008,2 and were significantly increased to 11.6% and 50.1% in 2013.3 In China, approximately 148 million people were diagnosed with IGT indicates impaired glucose regulation

843 844 844 844 844 844 844 845 845 845 845 845 846 846 846 846 847 848 848 848 849 849 849

during the PD stage.2 Moreover, the prevalence of IGT has increased faster than that of DM. Thus, IGT has become one of the immediate public health concerns in China. According to the reports of the International Diabetes Federation (IDF) and American Diabetes Association (ADA), most patients with type 2 diabetes mellitus (T2DM) and some patients with type 1 diabetes mellitus are present with IGT before the onset of DM. Currently, several large-scale clinical trials had been conducted to determine whether lifestyle or drug intervention can delay or reverse the development and progression of DM.4—6 Of these studies, ‘The Da Qing IGT and Diabetes Study’, is the first international, randomized clinical trial, designed to assess the effects of lifestyle intervention on the prevention of DM in patients with IGT. That study demonstrated the vital role of lifestyle intervention in the prevention of overt DM in patients with IGT. During a 6-year follow-up study, the diet

844 intervention group, the exercise intervention group, and the diet combined exercise intervention combined group exhibited a 35%, 46%, and 41% reduction in the incidence rate of DM respectively, when compared with the control group. Moreover, a 43% reduction in the incidence rate and a 3.6-year delay of the onset of overt DM were observed in the lifestyle intervention group, during a 20-year follow-up period.7 However, for most patients staying with a lifestyle intervention over a long period of time is very difficult. In addition to lifestyle interventions, treatment with medications, such as acarbose, metformin, etc., can also be used to prevent or delay the onset of IGT. The Diabetes Prevention Program,8,9 Finnish Diabetes Prevention Study,10 and Study to Prevent Non-Insulin-Dependent Diabetes trial (STOP-NIDDM)11 have shown that the above drugs can reduce the risk of developing overt T2DM to varying degrees. In Traditional Chinese Medicine (TCM), based on the clinical symptoms, IGT is categorized as ‘‘spleen pyretic abundance’’. Traditional Chinese Medicine interventions for IGT are intended to prevent DM. Based on clinical observations and TCM experience the symptoms of IGT are viewed as spleen deficiency and damp overabundance syndrome (SDDOS). It is well known that many active components used in TCM, including polysaccharides, glycosides, flavonoids, alkaloids and terpenoids, have a hypoglycemic activity. It has been suggested that Shenzhu Tiaopi granule (SZTP) can help strengthen the spleen and remove the dampness. The SZTP is mainly composed of codonopsis pilosula, rhizoma dioscoreae, rhizoma atractylodis, poria cocos, pericarpium citri reticulatae, and radix glycyrrhizae preparata. The dose is respectively 15 g, 12 g, 10 g, 10 g, 6 g, 6 g. The component of these herbs have found to be effective in lowering blood glucose.12—18 Here we report the results of a randomized controlled trial to assess the efficacy of SZTP combined with lifestyle intervention in the prevention and treatment of IGT in patients with SDDOS.

Subjects and methods The First Affiliated Hospital of Anhui University of Chinese Medicine Ethics Committee (Hefei, China) approved the protocols in this study (Approval ID: 2011AH-001-04).

Diagnosis criteria In the current study, IGT was defined (per the criteria of the World Health Organization for the diagnosis and classification of DM [1999]) as a 2-h postprandial blood glucose (2 hPG) ≥7.8 mmol/L but <11.1 mmol/L in the presence of a fasting plasma glucose (FPG) concentration <7.0 mmol/L. The TCM standard of SDDOS was established based on the national standard of the People’s Republic of China (GB/T, l6751.2-1997) and the characteristics of SDDOS symptoms.19 The primary symptoms included the following: (1) fatigue; (2) heavy sensation in the body and fullness in the epigastria and abdomen, and (3) stickiness but without desire to drink, or thirst with desire to drink. The secondary symptoms were as follows: (1) overweight or obesity; (2) shortness of breath and disinclination to talk;

Z. Fang et al. (3) blood stagnation, nausea and vomiting; (4) spontaneous sweating or sweating during the night; (5) viscous, loose bowels or constipation; (6) pale tongue with white or greasy coating, accompanied with indentation; and (7) relaxed and soft pulse. Patients exhibiting at least two of the primary symptoms and three of the secondary symptoms were diagnosed as having SDDOS. The standard of TCM symptomatic scores is: (1) primary symptoms: 0 = none, 2 = slight, 4 = moderate, 6 = severe; (2) secondary symptoms: 0 = none, 1 = slight, 2 = moderate, 3 = severe; (3) condition of tongue: 0 = absence, 1 = presence; and (4) condition of pulse: 0 = absence, 1 = presence.

Selection criteria Patients were screened according to the criteria of: meeting both the western medical diagnostic criteria for IGT and the TCM diagnostic criteria for SDDOS; confirmed diagnosis of IGT in suspicious cases, followed by one-month washout period; male or female between the ages of 25 and 70; had not been treated for IGT previously; had not participated in any other clinical trials during the last three months; and gave voluntary informed consent.

Exclusion criteria Patients were excluded if they had: acute cardiocerebrovascular events during the last six months; severe liver or kidney dysfunction; malignancy; psychiatric disorders; and with complications of other endocrine diseases; serious primary diseases. Pregnant or lactating women were also excluded.

Criteria for withdrawing patients from the study Patient were withdrawn from the study if they: were unable or unwilling to adhere to study protocols, dropped out of the study, or suffered a severe adverse event that prevented them for adhering to study protocols e.g. heart attack. Sample size and statistical analysis The incidence rate of patients with IGT who converted to overt DM was the primary endpoint of the study. The sample size was calculated using Statistic Package for Social Science (SPSS) version 17.0 statistical software (version 17.0, SPSS Inc, Chicago, IL, USA) with an equal number of patients in each group (two-tailed test, power = 0.80, ˛ = 0.05). According to the previous reports, the incidence rates of patients with IGT who converted to overt DM in the control and test groups were assumed to be 46.0% and 32.8%, respectively,7,11 and the required sample sizes were then estimated to be 214 patients in each group. The expected dropout rate was <20%, the study investigators therefore decided to enroll 514 patients. Statistical analyses were performed using SPSS version 17.0 statistical software. Normally distributed measurement data were expressed as means and standard deviations (mean ± standard deviation SD). The effective rates between groups were compared with the Chi-square test. The differences before and after treatment were compared

The impact of Chinese Medicine combined with lifestyle intervention on impaired glucose tolerance by paired t-test. The ranked data were compared using the Ridit test. P < 0.05 was considered to be statistically significant. Treatment regimen After one-month washout period, enrolled patients were randomized to the control or experimental groups, in a 1:1 ratio. Patients in the control group received a lifestyle intervention for 12 months, based on the Chinese guidelines prevention and treatment of T2DM20 and dietary advice for treatment of T2DM in adults.21 These patients were encouraged to consume more vegetables, control their intake of alcohol, and reduce their intake of simple sugars. Meanwhile, they were taught and encouraged to increase the amount of their leisure physical exercise by at least once a day. The patients in the experimental group received 8.8 g of oral SZTP (offered by the Pharmaceutical Formulations Center of the First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Anhui, China [Lot, BZ20080027]) twice daily plus lifestyle intervention for 12 months. All the investigators were trained and certified before the study. Variables assessed The variables assessed included general demographic information, as well as the levels of FPG, 2 hPG, glycosylated hemoglobin A1c (HbA1c), triglycerides (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), and low density lipoprotein cholesterol (LDL-C) in both the groups. The levels of FPG, 2 hPG and HbA1c was assessed every three months, whereas the other variables were measured before and after the treatment. The symptoms according to the TCM; conditions of tongue and pulse were also recorded for all patients. Patient safety variables included physical examination, routine blood and urine tests, liver and kidney functions, and electrocardiogram (ECG) measurements. Evaluation of efficacy Evaluation of treatment efficacy. The primary clinical efficacy of the two treatments was evaluated by changes in the laboratory examination of IGT before and after treatment in both the groups.22,23 There were three assessment levels, including: significant impact, modest impact and no impact, which were defined as follows: significant impact: an FPG <7.0 mmol/L and a 2 hPG <7.8 mmol/L after treatment; modest impact: an FPG <7.0 mmol/L and a 2 hPG ≥7.8 mmol/L but <11.1 mmol/L after treatment; and no impact: an FPG ≥7.0 mmol/L or a 2 hPG ≥11.1 mmol/L after treatment. The change in a single TCM symptom was considered as secondary variables (for the efficacy of TCM), which were classified as: (1) significant impact: original symptoms disappeared or were improved by two grades; (2) modest impact: original symptoms were improved by one grade but did not disappear; and (3) no impact: there were no changes in original symptoms. Another secondary efficacy evaluation of TCM symptoms was defined as follows: (1) high impact: TCM symptoms completely or largely disappeared, and the TCM symptomatic scores decreased by ≥90%; (2) modest impact: clinical symptoms were obviously improved with symptomatic

845

Assessed for eligibility (n=617) Excluded (n=103) Did not meet inclusion criteria (n=91) Declined to participate (n=12)

Randomized (n=514)

Allocated to the control group (n=257)

Lost to follow-up (n=41)

Analyzed (n=216)

Allocated to the experimental group (n=257)

Lost to follow-up (n=34)

Analyzed (n=223)

Figure 1 The consort flow diagram of the randomized controlled trial.

scores decreased by ≥70% but less than <90%; (3) minor impact: clinical symptoms were improved to some extent, with symptomatic scores decreased by ≥30% but less than <70%; and (4) no impact: clinical symptoms were not obviously improved or even aggravated, with symptomatic scores decreased by <30%.

Results Procedure and subjects After signing informed consent, patients at high risk of DM were screened by finger-prick blood glucose level measurements by glucometer (ONE TOUCH-ULTRA, Johnson and Johnson, Co, USA) at four community health service centers in Hefei, Anhui, China, resulting in the identification of 1814 suspicious cases of IGT all told. All of these suspicious IGT patients underwent an oral glucose tolerance test (OGTT) with 75 g glucose on the next day at the Experiment Center of the First Affiliated Hospital of Anhui University of Chinese Medicine, Anhui, China, and 1496 cases were diagnosed by oxidase assay in 2—3 ml venous blood collection. There were 617 patients who had SDDOS, There were 879 patients with other syndromes. For example Qi and Yin deficiency syndrome, blood stasis syndrome, deficiency of both Yin and Yang syndrome. TCM syndrome type is diagnosed by professor of medicine. The same professor of medicine examined the patients at the beginning and at the end of the study. With the OGTT test after a one-month washout period a total of 514 patients were diagnosed with SDDOS IGT (Fig. 1). Patients were re-examined each month by a community doctor according the study protocol to assess the indexes described in the ‘‘Variables assessed’’ section. The community followed-up with the study participants each week by telephone or by a home visit to monitor and record the conditions their degree of compliance with the lifestyle intervention and medication regimen. The community doctor also discussed and helped resolve problems patients

846 Table 1

Z. Fang et al. Comparison of baseline demographic characteristics in the two groups.

Variable

Lifestyle intervention group (n = 257)

SZTP plus lifestyle intervention group (n = 257)

T value

P value

Male:female Age (mean ± SD, year) Disease duration (mean ± SD, month) Height (mean ± SD, cm) Body weight (mean ± SD, kg) BMI (mean ± SD, kg/m2 ) Wc (mean ± SD, cm) Hc (mean ± SD, cm) FPG (mean ± SD, mmol/l) 2 hPG (mean ± SD, mmol/l) HbA1c (mean ± SD, %) TG (mean ± SD, mmol/L) TC (mean ± SD, mmol/L) HDL-C (mean ± SD, mmol/L) LDL-C (mean ± SD, mmol/L) SBP (mean ± SD, mmHg) DBP (mean ± SD, mmHg) Family history of hypertension [n (%)] Family history of diabetes mellitus [n (%)] History of smoking [n (%)] History of drinking [n (%)]

142:115 54.61 ± 10.51 5.08 ± 10.56 163.05 ± 8.18 67.53 ± 11.02 25.33 ± 3.21 90.71 ± 8.15 97.96 ± 6.81 5.70 ± 0.55 9.23 ± 0.81 6.06 ± 0.55 1.59 ± 0.72 5.28 ± 1.14 1.38 ± 0.54 2.44 ± 0.53 131.79 ± 16.16 84.24 ± 6.70 65 (25.29) 30 (11.67) 130 (50.58) 158 (61.47)

136:121 54.95 ± 9.50 3.73 ± 7.22 163.43 ± 8.29 67.67 ± 10.77 25.27 ± 3.14 89.69 ± 8.83 97.18 ± 7.58 5.71 ± 0.52 9.30 ± 0.95 6.13 ± 0.60 1.58 ± 0.78 5.30 ± 1.16 1.45 ± 0.65 2.47 ± 0.94 130.62 ± 15.57 84.29 ± 7.40 61 (23.73) 33 (12.84) 125 (48.63) 161 (62.64)

0.282 −0.378 1.681 −0.638 −0.173 0.272 1.260 1.223 −0.019 −0.910 −1.460 0.062 −0.098 −1.088 −0.389 1.023 −0.080 0.168 0.163 0.195 0.074

0.595 0.705 0.093 0.524 0.863 0.786 0.208 0.222 0.985 0.363 0.145 0.950 0.922 0.277 0.697 0.307 0.936 0.758 0.788 0.724 0.856

SZTP, ShenZhu TiaoPi granule; BMI, body mass index; Hc, hip circumference; Wc, waist and hip circumference; FPG, fasting blood glucose; 2 hPG, 2-h postprandial blood glucose; HbA1c, glycosylated hemoglobin; TG, triglyceride; TC, total cholesterol; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; SBP, systolic blood pressure; DBP, diastolic blood pressure.

were having complying with the study protocol of the group to which they were assigned. These weekly visits ensured a high degree of compliance with the study protocols.

Comparison of baseline characteristics At the end of the clinical trial, 439 out of 514 patients had completed the study. A total of 75 patients were lost to follow-up during the 12 months of the study, which included 41 in the control group and 34 in the experimental group; no significant differences were observed in the drop out rates between the two groups (15.95% vs. 13.23%; P > 0.05). Five patients were dissatisfied with the treatment process, 11 patients failed to complete the course of follow-up appointments, and 27 patients decided that it would take a long time before the onset of DM and did not wish to continue with treatment for their IGT, 18 of the patients worked and were unable to make time for the study, 14 patients noted adverse events. Thus, the analysis included 216 patients in the control group and 223 patients in the experimental group (Fig. 1). There were no significant differences between the two groups in their baseline characteristics including age, sex ratio, disease duration, height, body weight, body mass index (BMI), hip circumference (Hc), waist circumference (Wc), FPG, 2 hPG, HbA1c, TG, TC, HDL-C, LDL-C, systolic blood pressure (SBP), and diastolic blood pressure (DBP) (Table 1).

Comparison of baseline clinical symptoms At study entry, obesity and fatigue were the symptoms reported most frequently. In all 514 patients assessed 299 (58.17%) were obese and 281 (54.67%) patients, reported feeling fatigued. The most common symptoms of SDDOS at baseline were stickiness but without desire to drink (49.03%), thirsty with desire to drink (41.83%), and fullness in the epigastria of abdomen, (41.25%). Shortness of breath and disinclination was only noted in 112 patients (21.79%) (Table 2).

Comparisons of conversion rate Following 12 months of treatment, the conversion rate of IGT to DM in the experimental group was significantly lower than that in the control group (15.28% vs. 8.52%, P < 0.05). The rate of conversion from IGT to normal blood glucose tolerance was significantly higher in the experimental group as compared to that in the control group (42.15% vs. 32.87%, P < 0.05) (Table 3).

Comparisons of levels of FPG, 2 hPG and HbA1c After 12 months of treatment, the levels of 2 hPG and HbA1c were reduced in both the experimental and control group compared with those scores at baseline. However

The impact of Chinese Medicine combined with lifestyle intervention on impaired glucose tolerance Table 2

847

Comparison of clinical symptoms in the two groups [n (%)].

Symptom, n (%)

Lifestyle intervention group (n = 257)

SZTP plus lifestyle intervention group (n = 257) Formatting problem

Total n (%)

Fatigue Heavy sensation in the body Fullness in the epigastria and abdomen Stickiness but without desire to drink Thirsty with desire to drink Obesity Shortness of breath and disinclination to talk Stagnancy Spontaneous sweating Loose bowels Constipation Symptom scores

137 (53.31%) 119 (46.30%)

144 (56.03%) 88 (53.31%)

281 (54.67%) 207 (40.27%)

103 (40.08%)

109 (53.31%)

212 (41.25%)

126 (49.03%)

126 (53.31%)

252 (49.03%)

105 (40.86%)

110 (53.31%)

215 (41.83%)

146 (56.80%) 53 (20.62%)

153 (53.31%) 59 (53.31%)

299 (59.53%) 112 (21.79%)

95 (36.96%) 61 (23.74%) 95 (36.96%) 89 (34.63%) 9.61 ± 2.57

96 (53.31%) 54 (53.31%) 105 (53.31%) 72 (53.31%) 9.66 ± 2.33

191 (37.16%) 115 (22.37%) 200 (38.91%) 161 (31.32%)

SZTP, ShenZhu TiaoPi granule.

Table 3

Comparison of conversion rate of IGT to DM or normal blood glucose tolerance in the two groups.

Group

n (%)

2

P value

Lifestyle intervention group (n = 216) SZTP plus lifestyle intervention group (n = 223) Lifestyle intervention group (n = 216) SZTP plus lifestyle intervention group (n = 223)

33 (15.28%) 19 (8.52%)* 71 (32.87%) 94 (42.15%)*

4.798

0.028

4.030

0.045

SZTP, ShenZhu TiaoPi granule. * P < 0.05 vs. the control group after 12 months of treatment.

those before and after treatment differences were not statically significant (P > 0.05). However, the 2 hPG before levels and after levels differences the levels in the experimental group were significantly lower compared those in the control group. (P < 0.01) (Table 4).

Comparisons of cardiovascular risk factors and serum lipid levels After 12 months of treatment, the baseline values of cardiovascular risk factors such as body weight, BMI and Wc

Table 4

were reduced numerically more in the experimental group compared to the control group. However, there were no statically significant differences in all the above factors between the two groups (P > 0.05). Furthermore, after 12 months of treatment, change from baseline in the levels of Hc, SBP and DBP in both the groups were not significant (P > 0.05). In the experimental group, the TG levels were numerically reduced in comparison with that at baseline, whereas there were no statistically significant differences observed between the two groups (P > 0.05). In addition, in the experimental group, there were no discernable changes in the

Comparison of levels of blood sugar after treatment in the two groups (mean ± SD).

Index

FPG (mmol/l) 2 hPG (mmol/l) HbA1c (%)

Lifestyle intervention group

SZTP plus lifestyle intervention group

Before treatment (n = 257)

After treatment (n = 216)

Before treatment (n = 257)

After treatment (n = 223)

5.70 ± 0.81 9.23 ± 0.81 6.06 ± 0.55

5.60 ± 0.77 8.88 ± 1.92 5.84 ± 0.59

5.71 ± 0.90 9.30 ± 0.95 6.13 ± 0.60

5.52 ± 0.82 8.35 ± 1.54** 5.73 ± 0.66

SZTP, ShenZhu TiaoPi granule. ** P < 0.01 vs. the control group after 12 months of treatment.

848 Table 5

Z. Fang et al. Comparison of baseline after treatment in the two groups (mean ± SD).

Index

Body weight (kg) BMI (kg/m2 ) Wc (cm) Hc (cm) SBP (mmHg) DBP (mmHg) TC (mmol/L) TG (mmol/L) HDL-C (mmol/L) LDL-C (mmol/L)

Lifestyle intervention group

SZTP plus lifestyle intervention group

Before treatment (n = 257)

Before treatment (n = 257)

67.53 25.33 90.71 97.96 131.79 84.24 5.28 1.59 1.38 2.44

± ± ± ± ± ± ± ± ± ±

11.02 3.21 8.15 6.81 16.16 6.70 1.14 0.72 0.54 0.53

After treatment (n = 216) 67.02 24.97 90.35 97.86 131.03 83.88 5.24 1.56 1.45 2.40

± ± ± ± ± ± ± ± ± ±

9.68 2.86 7.77 6.68 16.87 6.99 1.11 0.69 0.70 0.56

67.67 25.27 89.69 97.18 130.62 84.29 5.30 1.58 1.45 2.47

± ± ± ± ± ± ± ± ± ±

10.77 3.14 8.83 7.58 15.57 7.40 1.16 0.78 0.65 0.94

After treatment (n = 223) 66.81 24.76 88.97 96.97 129.79 83.84 5.24 1.49 1.90 2.42

± ± ± ± ± ± ± ± ± ±

10.22 2.72 8.12 7.17 15.20 7.20 1.13 0.75 0.51 0.86

SZTP, ShenZhu TiaoPi granule; BMI, body mass index; Hc, hip circumference; Wc, waist and hip circumference; SBP, systolic blood pressure; DBP, diastolic blood pressure. TG, triglyceride; TC, total cholesterol; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol.

levels of TC, HDL-C and LDL-C before and after treatment (Table 5).

Comparisons of efficacy and scores on single TCM symptom After 12 months of treatment, the symptoms of ‘fatigue and stickiness but without desire to drink’ were significantly more improved in the experimental group compared with the control group (P < 0.01). Moreover, there was a significant improvement in the symptoms including ‘heavy sensation in the body, fullness in the epigastria and abdomen, obesity, as well as loose bowels’ (P < 0.05). The total efficacy rate in the experimental group was superior to that in the control group after 12 months of treatment (86.78% vs. 81.48%), with significant difference ( = 3.131, P < 0.05). At baseline, there were no significant differences in terms of the TCM symptomatic scores between the two treatment groups (P > 0.05). After 12 months of treatment, the TCM symptomatic scores in the control and experimental groups were 4.81 ± 2.23 and 3.55 ± 1.86, respectively, which decreased significantly (P < 0.01) compared to the baseline values. Furthermore, the scores above improved significantly (P < 0.05) in the experimental group as compared to the control group after treatment (Table 6).

Comparisons of safety evaluation and adverse events Following the treatment for 12 months, AEs were noted in 14 patients, including five in the control group and nine in the experimental group. Of which, 13 patients experienced gastrointestinal reactions, and one patient had pruritus. There were no significant (P > 0.05) differences in the incidence of AEs between the two groups. All reported AEs were mild moderate in severity; no serious AEs were reported. Eight patients were withdrawn from the study due to these AEs.

Discussion IGT has been considered as an intermediate metabolic state between normal blood glucose levels and DM, and a transient stage in the development of DM from normal glucose tolerance. IGT is characterized by an increase in the postprandial glucose levels. The reduction in second-phase insulin secretion and peripheral insulin resistance (IR) in skeletal muscle provide a common mechanism for the pathogenesis of IGT; IGT is reported to be closely related to the function of pancreas. In the present study, the male patients were 1.18 times higher in number than those of the female patients (54.09% vs. 45.91%), indicating that the prevalence of IGT was higher in males, which could be viewed as a consequence of their irregular lifestyle and higher levels of work pressure.3,24 The living habits of males maybe affect their health, for example, smoking, consumption of alcohol drinking, lack of exercise, and poor dietary habits.3,24 There were: 51 patients aged ≤40 years (9.92%); 116 patients aged 41—50 (22.57%), 168 patients aged 51—60 (32.68%)and 178 patients aged 61—70 (34.63%). The study comprised 346 (67.31%) patients with in the age range of 51—70 years were at particularly high risk for IGT confirming the results of a previous study conducted in China that showed IGT is age dependent.25 In all 514 patients with IGT, a total of 126 (24.51%) patients had a family history of hypertension. This indicates that periodic follow-up should be conducted for those patients in order to prevent more severe morbidity caused by hypertension. Consistent with the results obtained from the previous studies, the most common clinical symptom reported in the enrolled patients was obesity (59.53%). The results of this study show that compared with the lifestyle intervention alone, lifestyle intervention combined with TCM therapy was more effective in reversing IGT to normal glucose tolerance there by reducing the onset of DM. It is also suggested that the DM was unlikely to be well controlled with lifestyle interventions alone because of the of the difficulty patients suffering from obesity, IGT or type 2

The impact of Chinese Medicine combined with lifestyle intervention on impaired glucose tolerance Table 6 Symptom

849

Comparison of efficacy on single TCM symptom before and after treatment in the two groups. Lifestyle intervention group (n = 216)

SZTP plus lifestyle intervention group (n = 223)

n

n

Excellence Effect Invalid Efficacy rate (%)

Fatigue 115 41 Heavy sensation in 35 96 the body Fullness in the 34 92 epigastria and abdomen Stickiness but without 97 41 desire to drink Thirst with desire to 93 37 drink Obesity 113 56 Shortness of breath 20 44 and disinclination to talk 85 39 Stagnancy Spontaneous sweating 46 17 Loose bowels 72 29 Constipation 84 33 Curative effect 216 100 Scores

Excellence Effect Invalid Efficacy rate (%)

49 37

25 24

78.26 75.00

120 82

61 41

45 30

14 11

88.33** 86.58*

36

22

76.08

99

48

38

13

86.86*

31

25

74.22

111

61

34

12

88.78**

30

26

72.04

92

41

33

18

80.43

31 11

26 13

76.99 70.45

110 46

69 30

27 7

14 9

87.27* 80.43

27 19 30 32 68

19 10 13 19 48

77.64 78.26 81.94 77.38 77.32% 4.81 ± 2.23

84 49 49 26 91 49 64 30 223 123

25 15 34 24 84

10 8 8 10 16

88.09 83.67 91.20* 84.37 86.78%** 3.55 ± 1.86*,

SZTP, ShenZhu TiaoPi granule. * P < 0.05 vs. the control group after 12 months of treatment. ** P < 0.01 vs. the control group after 12 months of treatment.  P < 0.01 vs. that before treatment.

diabetes have in losing weight and/or increasing their level of physical activity. These observations support the need to develop a comprehensive plan with multiple strategies to prevent and treat DM. The patients whose blood glucose levels returned to normal are still at higher risk of developing IGT and/or overt type 2 diabetes. Therefore in addition to long-term follow-up and assessment these patients should be provided with further health education. This would help in evaluating the long-term efficacy of TCM in combination with western medicine in the treatment of patients with IGT and it would provide the foundation for the development further feasible and effective strategies for the preventing and treating of IGT. There were no significant differences in incidence of adverse events (P > 0.05) between the two groups. None of the patients reported any serious adverse events (SAE). Following the 12-month treatment period, there were no noticeable changes in the related indices of routine blood and urine tests, kidney function tests and ECG in both the groups, suggesting the tolerability of these treatment regimens in the selected population is high. In addition, there were no significant differences regarding the dropout rate between the experimental group and control groups (15.95% vs. 13.23%, P > 0.05). However, there are some limitations of the current study. The duration of follow-up was not enough to assess the longterm efficacy of the experimental approach, which warrants further follow-up studies to verify the efficacy of the experimental approach. Based on the available data, we plan to

further our understanding TCM and western medicine in relation to IGT, in order to develop more innovative approaches in using TCM prevent and treat of IGT. Meanwhile, consensus from the experts about efficacy of the approach used in the experimental group can help us optimize our current treatment regimens. We also hope to achieve more representative results through a national study, which would be greatly beneficial in the using TCM to prevent and treat IGT.

Conflict of interest The authors declare that they have no conflict of interest.

Acknowledgements The study was supported by the State Administration of Traditional Chinese Medicine, Administration of Traditional Chinese Medicine of Anhui province, the 38th Research Institute of China Electronic Technology Corporation, as well as the three community health service centers in Hefei, Anhui Province, China, including Xiyuan avenue, Wulitun avenue, Tongling Road avenue (Grant no. 201007004).

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