A systematic review on use of Chinese medicine and acupuncture for treatment of obesityobr_

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1 obesity reviews doi: /j X x Obesity Treatment A systematic review on use of Chinese medicine and acupuncture for treatment of obesityobr_ Y. Sui 1 *, H. L. Zhao 1 *,V.C.W.Wong 2,N.Brown 3,X.L.Li 1, A. K. L. Kwan 2,H.L.W.Hui 2, E. T. C. Ziea 2 and J. C. N. Chan 1,4,5 1 Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, ; 2 Chinese Medicine Department, Hong Kong Hospital Authority, Hong Kong SAR, ; 3 Asia Diabetes Foundation, Hong Kong SAR, ; 4 Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong SAR, ; 5 Li Ka-shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, Received 3 October 2011; revised 25 November 2011; accepted 29 November 2011 Address for correspondence: Professor JCN Chan, Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong SAR,. jchan@cuhk.edu.hk Summary Obesity is a major health hazard and despite lifestyle modification, many patients frequently regain any lost body weight. The use of western anti-obesity drugs has been limited by side effects including mood changes, suicidal thoughts, and gastrointestinal or cardiovascular complications. The effectiveness and safety of traditional Chinese medicine including Chinese herbal medicine (CHM) and acupuncture provide an alternative established therapy for this medical challenge. In this systematic review, we used standard methodologies to search, review, analyse and synthesize published data on the efficacy, safety and relapse of weight regain associated with use of CHM and acupuncture. We also examined the rationale, mechanisms and potential utility of these therapies. A total of 12 electronic databases, including Chinese, English, Korean and Japanese, were searched up to 28 February Randomized controlled trials (RCTs) for CHM and/or acupuncture with comparative controls were considered. We used the to assess methodological qualities, the random effect model in the pooled analysis of therapeutic efficacy to adjust for heterogeneity and funnel plots to explore publication bias. After screening 2,545 potential articles from the electronic databases, we identified 96 RCTs; comprising of 49 trials on CHM treatment, 44 trials on acupuncture treatment and 3 trials on combined therapy for appraisal. There were 4,861 subjects in the treatment groups and 3,821 in the control groups, with treatment duration ranging from 2 weeks to 4 months. Of the 77 publications written in Chinese, 75 had a score <3, while 16 of the 19 English publications had a score of >3. Efficacy was defined as body weight reduction 2 kgor body mass index (BMI) reduction 0.5 kg/m 2. Compared with placebo or lifestyle modification, CHM and acupuncture exhibited respective risk ratio (RR) of 1.84 (95% CI: ) and 2.14 (95% CI: ) in favour of body weight reduction, with a mean difference in body weight reduction of 4.03 kg (95% CI: ) and 2.76 kg (95% CI: ) and a mean difference in BMI reduction of 1.32 kg m 2 (95% CI: ) and 2.02 kg m 2 (95% CI: ), respectively. Compared with the pharmacological treatments of sibutramine, fenfluramine or orlistat, CHM and acupuncture exhibited an RR of 1.11 (95% CI: ) and 1.14 (95% CI: ) in body weight reduction, mean difference in body weight reduction of 0.08 kg (95% CI: to 0.74) and 0.65 kg (95% CI: to 1.91), and mean difference in BMI reduction of 0.18 kg m 2 (95% CI: to 0.75) and 0.83 kg m 2 (95% CI: ), respectively. There *These authors contributed equally to the work. Hai-Lu Zhao s current affiliation is: Faculty of Basic Medicine, Guilin Medical College, Guilin ,. 409 obesity reviews 2012 International Association for the Study of Obesity 13, , May 2012

2 410 Therapeutic effect of TCM on obesity Y. Sui et al. obesity reviews were fewer reports of adverse effects and relapses of weight regain in CHM intervention studies conducted in than studies conducted outside. CHM and acupuncture were more effective than placebo or lifestyle modification in reducing body weight. They had a similar efficacy as the Western anti-obesity drugs but with fewer reported adverse effects. However, these conclusions were limited by small sample size and low quality of methodologies. Keywords: Acupuncture, Chinese herbal medicine, obesity, systematic review. obesity reviews (2012) 13, Introduction Obesity is associated with premature death and multiple morbidities including metabolic syndrome, cardiovascular disease, renal failure, sleep apnoea and some cancers. In high-risk subjects, a 5 10% reduction in body weight can reduce the risk of diabetes by 58% (1). Obesity is a state of positive energy balance, which can be corrected by caloric restriction and increased physical activity. While behavioural strategies can result in short-term weight loss, only 5 10% of subjects can maintain the weight loss for more than a few years (2). Metformin, a widely used anti-diabetic drug, induces 0.5 1% weight loss (3). Apart from metformin, nearly all western anti-obesity drugs, which can facilitate 3 5% weight loss, have adverse effects or body weight is regained upon cessation of therapy (4,5). Orlistat, a lipase inhibitor, acts locally at the gut but is poorly tolerated due to significant gastrointestinal side effects. Centrally acting drugs such as sibutramine increases risk of cardiovascular events, while rimonabant increases risk of negative moods and suicidal thoughts, and consequently both drugs have now been withdrawn from the market (6). Several peptides including glucagon like peptide 1 receptor agonist, amylin and leptin have promising weight-reducing effects, but all of them are injectables with uncertain long-term safety (7 9). As early as in the Han dynasty (BC ), traditional Chinese medicine (TCM) practitioners have reported symptoms, mechanisms and risk factors of obesity and used Chinese herbal medicine (CHM), acupuncture, lifestyle counselling, massage and qi-gong, either singly or in combination to control body weight. According to TCM theory, these recipes do not treat excess weight but focus on restoring internal balance to regulate food intake and body fat content. Despite their extensive use in current clinical practice, the evidence base for their use has not been subject to rigorous appraisal using international standards. Many systematic reviews in this area do not include clinical trials conducted in, especially those using traditional Chinese herbal recipes (10). Most authors also do not evaluate the rationale, safety and relapse of weight gain in these reviews. In this systematic review, we examined the efficacy, safety, rationale and incidence of relapse of weight gain using TCM to treat obesity, and their possible therapeutic values in this pandemic of obesity. Methods Inclusion criteria Study design Our review was restricted to randomized controlled trials (RCTs) that compared CHM/acupuncture or their variants with a control group. Here, a study that stated the phrase randomization was regarded as a randomized trial. No restriction was imposed on studies with respect to blinding and type of design such as parallel or cross-over. As the second phase of cross-over trials are usually excluded from reviews and meta-analyses in order to eliminate carry-over effects in the first phase arm, only the first phase results from the cross-over RCTs were analysed in this review. Cross-over RCTs of obesity without the first phase data were hereby excluded. Participant characteristics We included all participants irrespective of ages and sex, including overweight/obese children and adolescents. All appropriate definitions of overweight or obesity including body weight, body mass index (BMI) or percentage of weight excess compared with ideal weight were accepted. Pregnant and lactating women, patients with serious medical conditions, and secondary obesity such as druginduced obesity were excluded. Types of intervention Clinical trials evaluating all forms of CHM (specifically, herbal formula, single herb, herbal extractions, or com- 13, , May 2012 obesity reviews 2012 International Association for the Study of Obesity

3 obesity reviews Therapeutic effect of TCM on obesity Y. Sui et al. 411 pounds including herbs and other supplements) and/or acupuncture (specifically, classical body/auricular acupuncture, electroacupuncture, laser acupuncture, acupressure and catgut implantation) used alone or in combination were included. Studies with co-interventions, such as massage or weight loss devices, were included if they were given to both groups. Other comparators include non-pharmacological (no treatment, placebo/sham treatment, lifestyle modification of diet or physical exercise) and pharmacological treatments (another CHM or standard Western drugs). Outcome measures The primary outcomes include change in body weight, BMI, waist circumference, hip circumference and body fat percentage. Secondary outcomes included enhanced biophysical functions (blood lipids, blood glucose, insulin sensitivity, appetite), adverse effects and relapse of weight regain post intervention. Exclusion criteria Exclusions include preclinical studies (e.g. in vitro/in vivo animal studies), case reports, case series, self-control and non-randomized controlled trials, as well as, trials that compared different forms or points of acupuncture without a non-acupuncture comparative arm or they included herbal ingredients not considered as Chinese herbs. Search methods for identification of studies Data sources The following data sources were searched up to 28 February 2010: (i) English data sources: Cochrane Library, MEDLINE, Allied and Complementary Medicine Database; (ii) Chinese data sources: Chinese Biomedical Literature Database, Chinese Medical Current Contents, Traditional Chinese Medical Literature Analysis and Retrieval System; (iii) Japanese database: Japan Science and Technology Information Aggregator Electronic; (iv) Korean databases: National Assembly Library and KoreaMed; (v) other online databases including the reference lists of clinical trials registered at the National Institutes of Health and World Health Organization clinical trial databases. Searching key words We followed the research strategy using the key words of (i) acupuncture OR electroacupuncture OR acupressure OR meridian OR acupoint ; (ii) Chinese herbal medicine OR Chinese formula OR Chinese remedy OR Medicinal plants OR Plant extract OR Phytotherapy OR Integrative medicine ; (iii) obesity OR weight loss OR weight control OR weight reduction OR overweight ; (iv) randomized controlled trial OR controlled clinical trial OR clinical trial. Data collection and analysis Selection of studies Two reviewers scanned the title and abstract of every record retrieved from the literature searches. All potentially relevant articles were investigated as full text in English or Chinese. For ambiguous or missing information, we contacted the author where possible. For duplicate publications, the original publication was used. Data extraction This included descriptions of studies (author, publication year, location, blinding), characteristics of participants (age, gender, number, diagnosis), details of intervention and control (ingredients/points of each formulae/acupuncture, dosage, type of preparation, frequency of treatment, duration, follow-up period, co-interventions such as diet or physical exercise), score of quality assessment, outcome measures (discrete and continuous data), type and frequency of adverse events, and any relapse of weight regain. Measures of potential publication bias and treatment efficacy We used Review Manager (version 5, The Nordic Cochrane Centre, Copenhagen, Denmark) to assess treatment efficacy and publication bias. The relative strength of treatment effects was illustrated by forest plots (or blobbogram). We checked the existence of publication bias or systematic heterogeneity using funnel plots as visual aids. A symmetric inverted funnel indicates that publication bias is unlikely, while an asymmetric funnel signifies the possibility of either publication bias or a systematic difference between smaller and larger study effects. The I 2 statistic was used to measure clinical heterogeneity and the random effect model was selected when I 2 > 50%. For discrete data, the risk ratio (RR) was calculated. A RR larger than one indicated greater reduction of body weight or BMI in the treatment group than in the control group, defined as loss of body weight 2 kg or BMI 0.5 kg m 2. For continuous data, mean differences of changes in body weight and BMI between treatment and control groups were calculated. For publications providing only pre- and post-treatment values, mean change was calculated by subtracting post- from pre-measurements and standard deviation (SD) for change was estimated by the given SD of pre- and post-treatment (11). A positive value of mean difference (MD) indicated a greater reduction of body weight or BMI in the treatment group than in the control group. Weighted mean differences of body weight reduction and related parameters were analysed by a general linear model using SPSS 10.0 obesity reviews 2012 International Association for the Study of Obesity 13, , May 2012

4 412 Therapeutic effect of TCM on obesity Y. Sui et al. obesity reviews software (Statistics Package for the Social Sciences for Windows, 2000, SPSS, Chicago, IL, USA) between treatment and control groups. Thirty-one studies provided information of dropout or withdrawal, including 13 (68.4%) publications written in English and 18 (23.4%) publications written in Chinese. Results Study description Number of included RCTs and patients We selected 2,545 potentially relevant publications and excluded 1,755 due to non-clinical nature after scanning titles and abstracts. We retrieved the remaining 790 publications for detailed evaluation. Among them, 694 publications were excluded for the following reasons: reviews (174), self-control studies (335), studies of secondary obesity (10), non-randomized studies (64), acupuncture studies comparing different points or methods (102), animal studies (8), and cross-over study without phase 1 results (1). A total of 96 randomized controlled studies were selected which included trials on CHM (49 publications, 2,297 in treatment groups and 1,971 in control groups, Table 1), acupuncture (44 publications, 2,421 in treatment groups and 1,746 in control groups, Table 2) and combined therapy of CHM and acupuncture (C+A, 3 publications, 143 in treatment groups and 104 in control groups, Table 3). The control groups included nonpharmacological interventions (no treatment, placebo, lifestyle modification or weight loss devices), or pharmacological (another type of CHM or Western drugs). Tables 1 and 2 exhibit eight RCTs with reported status of relapse of weight gain after treatment. Categories of RCTs Among the 49 trials on CHM, 3 involved single herb, 6 used herbal extracts, 8 reported compounds of several plants with or without food supplements, and 32 described Chinese herbal formulae. In the 44 trials on acupuncture, 27 used classical body acupuncture, 4 used auricular acupuncture, and 13 used both body and auricular acupuncture. In these 96 selected studies, 73 were conducted in mainland, 4 in Taiwan, 10 in USA, 2 in Cameroon, 1 in Japan, 1 in Korea, 1 in India and 1 in Australia. Methodological quality The scoring system was used to evaluate methodological quality based on randomization, blinding and description of withdrawal. The score varied from 1 to 5. Most of the publications written in Chinese (75 of 77, 97.4%) had low scores of less than 3, while most of the English publications (16 of 19, 84.2%) had high scores of 3 or higher. Thirteen studies (56.5%) conducted outside were designed as double blinding, while 67 studies (91.8%) conducted in used open design. CHM treatment Improvement in obesity evaluated by RR The trials using non-pharmacological comparators were divided into (i) no treatment; (ii) placebo and (iii) co-intervention (both treatment and control groups were given drugs with weight reducing effects, e.g. metformin in diabetic patients). In most studies, efficacy was defined as body weight reduction 2 kg or BMI reduction 0.5 kg m 2. Five trials compared CHM treatment versus no treatment with a RR of weight reduction in favour of CHM (RR = 1.82, 95% CI = ) in a randomized effect model. Two studies compared CHM versus placebo (RR = 2.52, 95% CI = ), whereas two other studies compared CHM versus co-interventions (RR = 1.58, 95% CI = ). Combining these nine trials using a randomized effect model (Supporting Information Fig. S1a, A) yielded an RR of weight reduction in favour of CHM (pooled RR = 1.84, 95% CI = ) with heterogeneity (I 2 = 91%). The funnel plot indicated an insufficient number of trials, and of those available they were shown to have both small sample size and small effect sizes (Supporting Information Fig. S1a, B). In trials using pharmacological comparators, eight studies compared CHM versus the Western drug, fenfluramine with similar effects between both groups (RR = 1.10, 95% CI = ). One study compared CHM versus metformin in diabetic patients with a significant difference in body weight in favour of CHM (RR = 1.21, 95% CI = ). Combining these nine trials using a randomized effect model (Supporting Information Fig. S1b, A) showed a similar effect between CHM and Western drugs (pooled RR = 1.11, 95% CI = ) with heterogeneity (I 2 = 82%) due to an insufficient number of studies combined with small sample size and relatively small effects (Supporting Information Fig. S1b, B). Reduction in severity of obesity measured by a mean difference Patients treated with CHM had a greater body weight reduction when compared with no-treatment (MD = 5.82 kg, 95% CI = ) and placebo treatment (MD = 3.19 kg, 95% CI = ) (Supporting Information Fig. S2a). Similar body weight change was observed with CHM when compared with fenfluramine (MD = kg, 95% CI =-1.34 to 1.12) and metformin (MD = 0.33 kg, 95% CI =-2.67 to 3.33) (Supporting Information Fig. S2b). Subjects treated with CHM had a greater BMI reduction than those without treatment 13, , May 2012 obesity reviews 2012 International Association for the Study of Obesity

5 obesity reviews Therapeutic effect of TCM on obesity Y. Sui et al. 413 Table 1 Characteristics of RCTs using Chinese herbal medicine in the treatment of obesity Basic information Study design Results (compared with control) Adverse effects No. of relapse after Tr. Author, year, location Blinding/ Patient no. in Tr/Ct Tr; daily dose (duration/follow-up after Tr. ) Ct; daily dose With benefits No effect Tr (frequency) Ct (frequency) Tr/Ct Boozer et al. (20), 2001, USA DB/4 24/24 Ephedra 72 mg, caffeine 240 mg Placebo BW, WC, HC, BMI, BL, BG BP Symptoms of nervous (37), gastrointestinal (10), dry mouth (11) Symptoms of nervous (28), gastrointestinal (9), Dry mouth (4) Coffey et al. (21), 2004, USA DB/3 42/42 Ma huang 250 mg, Kola not 500 mg, White willow bark 200 mg (12 weeks/0) Placebo BW, WC, BMI BF, BP Exacerbated depression, atrial fibrillation (NR) Exacerbated depression, atrial fibrillation (NR) Garrison and Chambliss (22), 2006, USA DB/3 8/10 Proprietary M. officinalis and P. amurense extract; 250 mg (6 weeks/0) Placebo BW, NR Heartburn, shaking hands, fatigue, headache (NR), et al. None Greenway et al. (37), 2004, USA DB/4 12/19 Herbal supplement containing caffeine and ephedra; 2 pills (12 weeks/0) Placebo BW BL Symptoms of respiratory (11), gastrointestinal (2), headache (2), et al. Symptoms of respiratory (8), pain (3), gastrointestinal (5), et al. Hackman et al. (24), 2006, USA DB/4 19/23 Multinutrient supplement containing ephedra 40 mg and caffeine 100 mg (9 m/0) Placebo BW, BF BP Dizziness (5), dry mouth (14), headache (16), insomnia (7), nervousness (13), palpitation (13), et al. Dizziness (3), dry mouth (4), fatigue (4), headache (13), insomnia (2), nausea (3), et al. Hioki et al. (38), 2004, Japan DB/4 41/40 Ephedrine 24 mg, caffeine 280 mg (24 weeks/0) Placebo NR BW, BMI, BF Loose bowels (3) None Kuriyan et al. (39), 2007, USA DB/3 25/25 Caralluma fimbriata extract; 1 g (60 d/0) Placebo WC BW, HC, BMI, BF, BL, BG Mild symptoms of the gastrointestinal tract (6) Mild symptoms of the gastrointestinal tract (5) Oben et al. (40), 2007, Cameroon DB/3 Cissus quadrangularis 15 mg, green tea extract 200 mg, AlbumaSoy 0.12 mg Placebo BW BMI, BF NR NR Oben et al. (23), 2008, Cameroon DB/3 24/24 Cissus quadrangularis 150 mg, Irvingia gabonensis 250 mg (10 weeks/0) Placebo BW, WC, BF, BG NR Headache (4), lack of sleep (4), gas (5) Headache, lack of sleep, gas (NR) Preuss et al. (41), 2004, India DB/4 18/16 HCA-SX 4,667 mg, niacin-bound chromium 4 mg, Gymnema sylvestre extract 400 mg Placebo BW, BL NR Leg cramps (2), mild diarrhoea (5), mild gas (10) Diarrhoea (9), gas (4), increased appetite (1), et al. obesity reviews 2012 International Association for the Study of Obesity 13, , May 2012

6 414 Therapeutic effect of TCM on obesity Y. Sui et al. obesity reviews Table 1 Continued Basic information Study design Results (compared with control) Adverse effects No. of relapse after Tr. Author, year, location Blinding/ Patient no. in Tr/Ct Tr; daily dose (duration/follow-up after Tr. ) Ct; daily dose With benefits No effect Tr (frequency) Ct (frequency) Tr/Ct Udani and Singh (42), 2007, USA DB/4 White bean extract; 1,000 mg (14 weeks/0) Placebo NR BW, WC None None Udani et al. (43), 2004, USA DB/4 14/13 White bean extraction; 1,500 mg Placebo BL BW, WC, HC, BF Tension headache (1) Abdominal pain, bloating, gas (1) Chen and Zhu (44), 2008, Open/1 50/51 Asparagus; 0.5 g (6 weeks/0) Placebo BW, WC, BF HC NR NR Du et al. (45), 2008, Open/0 106/50 NR; 5 g (2 weeks/0) Placebo BW, WC NR None None He et al. (46), 2007, Open/1 23/22 NR; (10 weeks/0) Placebo WC, HC, BMI, NR Nausea (1) Nausea Hong et al. (47), 2005, Open/1 24/21 Astragali Radix, Coptidis Rhizoma, Rhei Rhizoma, Puerariae Radix, et al.; 1 potion (4 weeks/0) Metformin; 1g BMI, BL, BG, BI, IS NR NR NR Hu (48), 2008, Open/1 32/32 Astragali Radix, Codonopsitis Radix, Poria, Atractylodis Ovatae Rhizoma, et al.; 1 potion (6 weeks/0) Co-treatment BMI, BL, BG, BI, IS NR NR NR Jiao et al. (49), 2001, Open/1 50/50 Anthraquinone, glycoprotein, tenin, amino acids; g (12 weeks/0) Fenfluramine; mg NR BW, WC NR NR Jiao et al. (49), 2001, Open/1 137/135 Anthraquinone, Glycoprotein, Tenin, Amino acids; 5 pills (12 weeks/0) None BW, WC NR NR NR Jiao et al. (49), 2001, Open/1 50/50 Anthraquinone, Glycoprotein, Tenin, Amino acids; g (12 weeks/0) Xiaopangmei; tablets BW, WC NR NR NR Jiao et al. (49), 2001, Open/1 45/42 Containing Rhei Rhizoma 1 g; 6 15 pills (4 weeks/0) Fenfluramine; mg NR BW, BF Abdominal pain (NR) Abdomal pain, anorexia, depression 13, , May 2012 obesity reviews 2012 International Association for the Study of Obesity

7 obesity reviews Therapeutic effect of TCM on obesity Y. Sui et al. 415 Table 1 Continued Basic information Study design Results (compared with control) Adverse effects No. of relapse after Tr. Author, year, location Blinding/ Patient no. in Tr/Ct Tr; daily dose (duration/follow-up after Tr. ) Ct; daily dose With benefits No effect Tr (frequency) Ct (frequency) Tr/Ct Li et al. (50), 2007, Open/1 25/25 Rhei Rhizoma, Polygoni Multiflori Radix, Scutellariae Radix, Alisma lanceolatum; 6 g None BW, WC, HC, BMI, BF, BG, BI BL Mild symptoms of the gastrointestinal tract (2) None Li (51), 2007, Open/1 46/48 Rhei Rhizoma, Cassiae Torae Semen, Bupleuri Radix, Rhizoma pinelliae; 12 g (12 weeks/0) None BMI, BG, BI, NR NR NR Pan et al. (52), 2005, DB/3 41/41 Lotus rhizome, Green tea, Radix notoginseng; 18 g (7 weeks/0) Placebo BW, WC, HC, BMI, BF NR Irritability (1), nausea (2) Irritability (1), nausea (1), constipation (2) Shi et al. (53), 2005, Open/1 32/30 Atractylodis Rhizoma, Coicis Semen, Dioscorea Rhizoma, Phellodendri Cortex, et al.; 1 potion Metformin; 0.75 g NR BW, WC, HC, BL, BG NR NR Sun and Ma (54), 2006, Open/1 52/20 Gysum Fibrosum, Gardeniae Fructus, Coptidis Rhizoma, Astragali Radix, et al.; 1 potion (4 weeks/0) None BW NR None None Tan et al. (55), 1999, Open/1 30/30 Crataegi Fructus, Poria, Folium Nelumbinis, Citri Exocarpium, Panax ginseng; 18 g Shanzhajing; 3 tablets BW, BMI, BL NR NR NR Tan et al. (56), 2006, Open/2 32/32 Astragali Radix, Poria, Atractylodis Rhizoma, Aurantii Fructus, et al.; 1 potion (4 weeks/0) Xiaoke Pill; 20 pills BW, BL BG None None Tang (57), 2007, Open/1 120/120 Rhei Rhizoma, Aurantii Fructus, Sieb etzucc, Dioscorea Rhizoma, Crataegi Fructus, et al.; 9 g (24 weeks/0) Placebo BMI, BL, BG, BP NR NR NR obesity reviews 2012 International Association for the Study of Obesity 13, , May 2012

8 416 Therapeutic effect of TCM on obesity Y. Sui et al. obesity reviews Table 1 Continued Basic information Study design Results (compared with control) Adverse effects No. of relapse after Tr. Author, year, location Blinding/ Patient no. in Tr/Ct Tr; daily dose (duration/follow-up after Tr. ) Ct; daily dose With benefits No effect Tr (frequency) Ct (frequency) Tr/Ct Wang and Cheng (58), 2007, Open/1 31/29 Gastrodiae Rhizome, Alisma lanceolatum, Atractylodis Ovatae Rhizoma, Rhizoma pinelliae, et al.; 1 potion None BL, BG, BP BW, WC, BMI NR NR Wang et al. (59), 2007, Open/1 60/60 Crataegi Fructus, Folium Nelumbinis, Alisma lanceolatum; 18 g (26 weeks/0) Placebo BW, BL NR None None Wang et al. (60), 2009, Open/2 37/34 Astragali Radix, Dioscorea Rhizoma, Polygonati Huangjing Rhizoma, et al.; NR None BMI, BP BL, BP NR NR Wang (12), 2006, Open/1 80/76 Rhei Rhizoma, Gardeniae Fructus, Aurantii Fructus, Astragali Radix, et al.; 22 g (4 weeks/3 m) Fenfluramine; 20 mg BW NR Mild symptoms of the gastrointestinal tract (10) Mild symptoms of the gastrointestinal tract (12) 0/within 1 month Wei et al. (61), 2008, Open/1 30/30 Astragali Radix, Lycii Fructus, Crataegi Fructus, Citri Exocarpium, Rhei Rhizoma; 1 potion (12 weeks/0) None BW, BL NR NR NR Xi et al. (62), 1989, Open/1 55/55 Astragali Radix, Alisma lanceolatum, Folium Nelumbinis, Rhei Rhizoma, et al.; ml (4 weeks/0) Fenfluramine; 60 mg NR BW, BL NR NR Xiao et al. (63), 2008, Open/1 50/49 Folium Nelumbinis, Atractylodis Rhizoma, Poria, Rhizoma pinelliae, et al.; 3 6 potion (4 weeks/0) Fangfeng Tongsheng Pill; g BW, BMI NR NR NR 13, , May 2012 obesity reviews 2012 International Association for the Study of Obesity

9 obesity reviews Therapeutic effect of TCM on obesity Y. Sui et al. 417 Table 1 Continued Basic information Study design Results (compared with control) Adverse effects No. of relapse after Tr. Author, year, location Blinding/ Patient no. in Tr/Ct Tr; daily dose (duration/follow-up after Tr. ) Ct; daily dose With benefits No effect Tr (frequency) Ct (frequency) Tr/Ct Xie (64), 2008, Open/1 40/40 Rehmanniae Radix Conquita, Dioscorea Rhizoma, Poria, Phellodendri Cortex, et al.; 300 ml (4 weeks/0) Fenfluramine; 10 mg BL, BG BW, BMI Diarrhoea, bloating (3) Dry mouth, constipation (11); headache, anorexia (2) Yang (65), 2003, Open/1 88/46 Astragali Radix, Poria, Rhizoma pinelliae, Citri Exocarpium, et al.; 1 potion (12 weeks/0) Metformin; 1g BG NR NR NR Le et al. (66), 2002, Open/1 64/53 Folium Nelumbinis, Crataegi Fructus, Atractylodis Rhizoma, Coicis Semen, et al.; ml Tianyan Jianfei Tea; NR BW, BMI, BF Nausea, abdominal pain, diarrhoea, dizziness (7) Nausea, abdominal pain, diarrhoea, dizziness (7) Zhang et al. (67), 2006, Open/1 48/48 Fangji Radix, Astragali Radix, Atractylodis Ovatae Rhizoma, Ziziphi Fructus, Poria, et al.; NR (4 weeks/0) Co-treatment BW, BMI, BL NR None None Zhang et al. (68), 2007, Open/1 66/66 Codonopsitis Radix, Atractylodis Ovatae Rhizoma, Puerariae Radix, Poria, et al.; 1 potion (12 weeks/0) None BW NR NR NR Zhao et al. (13), 2002, Open/1 90/29 Poria, Cinnamomi Ramulus, Atractylodis Ovatae Rhizoma,Crataegi Fructus, et al.; 1 (12 weeks/1 year) Fenfluramine; mg NR BW, WC, BL None Fatigue, drowsiness, abdomen discomfort 0/14 Zhao et al. (69), 2007, Open/1 40/40 NR (12 weeks/0) Ziyin Qingre Recipe; NR BW, BMI, BG NR None None Zhou et al. (70), 2003, Open/1 50/50 NR; 4 pills Jianfei Tea; 2 packets BW, BMI NR Polyuria (NR) None obesity reviews 2012 International Association for the Study of Obesity 13, , May 2012

10 418 Therapeutic effect of TCM on obesity Y. Sui et al. obesity reviews Table 1 Continued Basic information Study design Results (compared with control) Adverse effects No. of relapse after Tr. Author, year, location Blinding/ Patient no. in Tr/Ct Tr; daily dose (duration/follow-up after Tr. ) Ct; daily dose With benefits No effect Tr (frequency) Ct (frequency) Tr/Ct Zhu et al. (71) 1997 Open/1 100/50 Anthraquinone, Rhei Rhizoma, Glycoprotein, Triazole, Polysaccharide; NR (10 d/0) Placebo BW, WC NR Skin flash, itch (2) None Gao et al. (72), 1999, SB/1 46/20 Haidong flower; 2 g (4 weeks/0) Fenfluramine; 20 mg BF, BL BW, WC, HC Bloating (2) Diarrhoea, anorexia, drowsiness (several) Li et al. (73), 2004, SB/1 64/40 Codonopsitis Radix, Atractylodis Ovatae Rhizoma, Polygoni Multiflori Radix, et al.; 9 g Fenfluramine; 60 mg NR BW, WC, HC, BMI, BF Diarrhoea (2) Diarrhoea Lian et al. (74), 2008, SB/1 101/101 Coptidis Rhizoma, Anemarrhenae Rhizoma, Rhei Rhizoma, et al.; 200 ml (12 weeks/0) Metformin; 750 mg BL BW, WC, BMI, BG NR NR Yang and Xiong (75), 2003, SB/1 35/20 Rhizoma pinelliae,poria, Alisma lanceolatum, Magnoliae Cortex, et al.; 6 g (12 weeks/0) None BW NR Diarrhoea (NR) None BF, body fat; BG, blood glucose; BI, blood insulin; BL, blood lipids; BMI, body mass index; BP, blood pressure; BW, body weight; Ct, control; DB, double blinding; HC, hip circumferences; IS, insulin sensitivity; NR, not reported; RCT, randomized controlled trial; SB, single blinding; Tr, treatment; WC, waist circumferences. 13, , May 2012 obesity reviews 2012 International Association for the Study of Obesity

11 obesity reviews Therapeutic effect of TCM on obesity Y. Sui et al. 419 Table 2 Characteristics of RCTs using acupuncture in the treatment of obesity Basic information Study design Results (compared with control) Adverse effects No. of relapse after treatment Author year location Blinding/ Patient no. in Tr/Ct Tr; frequency (duration/follow-up after Tr. ) Ct; daily dose With benefits No effect Tr (frequency) Ct (frequency) Tr/Ct Huang et al. (76), 2004, DB/2 30/30 BPs: Tianshu, Quchi, Hegu, Taichong, Sanyinjiao et al. EPs: Jidian, spleen, mouth, et al.; 1 per 3 d (12 weeks/0) None BW NR None None Xiao (77), 2004, DB/1 32/30 BPs: Zusanli, Sanyinjiao, Yinlingquan, Fenglong, Shuifen, Tianshu; 3 per week Orlistat; 360 mg BW NR NR Bloating, diarrhoea Xu (78), 1991, Taiwan Open/2 19/20 BPs: Shuifen, Qihai, Siman, Sanyinjiao, Fenglong, Zusanli; 2 per week (6 weeks/0) Diet, PE; NR NR BW, WC, HC, BMI, BF, BL, BG Skin bruise (3) None Zeng and Nie (79), 2006, Open/1 25/25 BPs: Tianshu, Guanyuan, Zhongwan, Qihai, et al.; EPs: Shenmen, endocrine, spleen, et al.; 1 per 2 d None BMI NR NR NR Allison et al. (80), 1995, USA SB/2 35/34 EPs: Six strategically placed points; 3/d (12 weeks/0) Placebo NR BW, BF, BP Redness, pain, bleeding (NR) Redness, pain, bleeding (NR) Elder et al. (25), 2007, USA SB/3 27/24 BPs: Jianjing, Jingming, Yintang; 1/d (24 weeks/0) Self-directed support; NR BW NR None None Fewer/NR Hsieh (81), 2007, Taiwan SB/2 27/28 EPs: Shenmen, mouth, stomach, endocrine, small intestine; 1 per week Placebo BMI NR NR NR Hsu et al. (82), 2005, Taiwan Open/3 24/22 BPs: Qihai, Shuifen, Shuidao, Siman, Zusanli, Fenglong and Sanginjao; 2 per week (6 weeks/0) Diet, PE; NR BW, WC, BMI NR Ecchymosis (2); abdominal discomfort (1) None Kim et al. (83), 2007, Korea SB/2 18/18 BPs: Dadun, Jingqu, Shangqiu, Yinbai; retained Placebo NR BF, BL NR NR Richards and Marley (15), 1998, Australia DB/5 28/32 EPs: Shenmen, Stomach; 2/d (4 weeks/12 weeks, with treatment) Placebo BW NR Inter-current illness (1) None obesity reviews 2012 International Association for the Study of Obesity 13, , May 2012

12 420 Therapeutic effect of TCM on obesity Y. Sui et al. obesity reviews Table 2 Continued Basic information Study design Results (compared with control) Adverse effects No. of relapse after treatment Author year location Blinding/ Patient no. in Tr/Ct Tr; frequency (duration/follow-up after Tr. ) Ct; daily dose With benefits No effect Tr (frequency) Ct (frequency) Tr/Ct Cui and Lu (84), 2005, Open/2 30/30 BPs: Fenglong, Quchi, Neiguan, Hegu, Zhongwan, et al. EPs: Shenmen, lung, large intestine, et al.; 5 per week Co-treatment BW NR NR NR Dai (85), 2006, Open/1 48/48 BPs: Zhongwan, Tianshu, Jianfeixue, Shangjuxu, Neiting; 1 per 2 d None BMI NR NR NR Shan et al. (86), 2008, Open/2 72/40 BPs: Xiawan, Daheng, Qihai, Tianshu, Zusanli, Fenglong, Taichong, Jianfeixue; NR (10 30 d/0) None BW NR NR NR Dong (87), 2005, Open/2 30/28 BPs: Guanyuan, Xuehai, Pishu, Weishu, Zhongwan; 1 per d (40 d/0) Sibutramine; 10 mg BF BW Dry mouth, constipation, anorexia (NR) Dry mouth, constipation, anorexia (NR) Fan et al. (88), 2005, Open/1 50/50 BPs: Xuehai, Sanyinjiao, Tianshu, Zusanli, Hegu; 1 per 2 d (4 weeks/0) Diet, PE; NR BW, BL NR NR NR Han et al. (89), 2008, Open/1 50/30 BPs: Zhongwan, Fenglong, Quchi, Zusanli; NR (12 weeks/0) Sibutramine; 10 mg BW, WC, BL BMI NR NR He et al. (90), 2008, Open/2 40/40 BPs: Tianshu, Guanyuan, Sanyinjiao, Fenglong, Zusanli; EPs: Shenmen, endocrine, spleen, stomach, triple burner, et al.; 1 per 2 d Sibutramine; 10 mg WC, HC BW, BMI None Insomnia, palpitation Jin et al. (91) 2009 Open/1 40/40 BPs: Dazhui, Zhongwan, Qihai, Daimai, Shuifen, Zhongji, et al.; 5 per week (60 d/0) None BW WC, HC, BMI None None 13, , May 2012 obesity reviews 2012 International Association for the Study of Obesity

13 obesity reviews Therapeutic effect of TCM on obesity Y. Sui et al. 421 Table 2 Continued Basic information Study design Results (compared with control) Adverse effects No. of relapse after treatment Author year location Blinding/ Patient no. in Tr/Ct Tr; frequency (duration/follow-up after Tr. ) Ct; daily dose With benefits No effect Tr (frequency) Ct (frequency) Tr/Ct Ke and Chen (14), 2008, Open/2 36/30 BPs: Zhongwan, Shuifen, Tianshu, Daimai, Qihai, Guanyuan, Shuidao; 1 per week (8 weeks/6 months) Sibutramine; 10 mg WC, BMI BW, BL Fewer More Fewer/ More Lei (92), 2006, Open/1 130/30 BPs: Zhongwan, Taibai, Pishu, Sanyinjiao, Zusanli, et al.; NR (30 d/0) None BW NR NR NR Lei and Hua (93), 2005, Open/1 120/60 BPs: Zhongwan, Liangmen, Qihai, Guanyuan, Neiting, et al. EPs: endocrine, subcortex, sympathetic, et al.; 1 per 2 d (30 d/0) Orlistat; 360 mg BW NR None None Li and Deng (94), 2004, Open/1 93/30 BPs: Pishu, Weishu, Sanjiaoshu, Tianshu, Shuidao, et al. EPs: hunger, lung, spleen, kindy, triple burner, endocrine, abdomen; 1 per 2 d (40 d/0) Placebo BW NR NR NR Li and Wang (16), 2006, Open/3 55/30 BPs: Sanyinjiao, Tianshu, Zusanli; EPs: hunger, Cubcortex, Shenmen; 1/d (70 d/4 week) None BW, BMI, BL NR NR NR Stable/NR Li and Wu (95), 2006, Open/1 80/80 BPs: Tianshu, Daheng, Zhongwan, Xiawan, Qihai, et al. EPs: sympathetic, abdomen, brain, hunger, et al.; 2 4 per week (12 weeks/0) None BW, BMI BF NR NR Li (17), 2005, Open/2 59/40 BPs: Chengman, Liangmen, Huaroumen, Tianshu, Shuidao, et al.; 1 per 7 d (4 weeks/0.5 1 year) Sibutramine; 10 mg BW NR NR NR 0/3 Luo and Li (96), 2007, Open/1 20/20 BPs: Liangqiu, Xuehai, Zhigou, Waiguan, Sanyinjiao, et al.; 1 per 2 d (48 d/0) None BW NR NR NR obesity reviews 2012 International Association for the Study of Obesity 13, , May 2012

14 422 Therapeutic effect of TCM on obesity Y. Sui et al. obesity reviews Table 2 Continued Basic information Study design Results (compared with control) Adverse effects No. of relapse after treatment Author year location Blinding/ Patient no. in Tr/Ct Tr; frequency (duration/follow-up after Tr. ) Ct; daily dose With benefits No effect Tr (frequency) Ct (frequency) Tr/Ct Luo (97), 2007, Open/1 30/30 BPs: Zhongwan, Tianshu, Guanyuan, Shangjuxu, Zusanli, Sanyinjiao; 1 per 2 d None BMI, BL NR NR NR Ma et al. (98), 2006, Open/2 100/50 BPs: Zhongwan, Tianshu, Fenglong, Quchi, Zusanli; 1 per 2 d (12 weeks/0) Sibutramine; 10 mg WC, BF, BL NR None None Mi (99), 2005, Open/2 80/40 BPs: Zusanli, Sanyinjiao, Neiting, Liangqiu, Shangjuxu, et al.; 1 per 2 d (12 weeks/0) None BMI NR NR NR Nie et al. (100) 2007 Open/2 80/70 BPs: Umbilical 8 points; 1 per 2 d (40 d/0) Sibutramine; 10 mg WC, HC BW, BMI, BF NR NR Ouyang et al. (101), 2009, Open/1 22/24 BPs: Zhongwan, Xiawan, Tianshu, Daheng, Qihai, et al.; 1 per 2 d (12 weeks/0) Metformin; 1.5 g BMI, BF BL, BG NR NR Su et al. (102), 2007, Open/2 108/108 BPs: Guanyuan, Sanyinjiao; EPs: Endocrine, Shenmen, Spleen; 1 per 2 d (4 weeks/0) Another CHM; 1 potion BW NR NR NR Tan (103), 2009, Open/1 45/45 BPs: Tianshu, Huaroumen, Wailing, Daimai, Suifen, Sanyinjiao; 1 per 2 d (30 d/0) Jianfei capsule; 2 BW NR NR NR Tu (104), 2006, Open/1 73/39 BPs: Taichong, Neiting, Taixi, Sanyinjiao, Zusanli, et al.; 1 per 2 d (45 d/0) None BMI NR NR NR Wang and Cheng (105), 2006, Open/1 30/29 BPs: Baihui, Quchi, Taichong, Zusanli; 1 per 2 d None; 10 mg BW, WC, BMI, BL, BG, BP BI, IS NR NR Wang et al. (106), 2005, Open/1 70/46 BPs: Ten points around navel; 1 per 2 d Diet, PE; NR BW NR NR NR Wang et al. (107), 2009, Open/1 48/44 EPs: hunger, endocrine, spleen, stomach, lung, Shenmen; NR (12 weeks/0) Sibutramine; 10 mg NR BW, WC, HC, BMI, BF None None 13, , May 2012 obesity reviews 2012 International Association for the Study of Obesity

15 obesity reviews Therapeutic effect of TCM on obesity Y. Sui et al. 423 Table 2 Continued Basic information Study design Results (compared with control) Adverse effects No. of relapse after treatment Author year location Blinding/ Patient no. in Tr/Ct Tr; frequency (duration/follow-up after Tr. ) Ct; daily dose With benefits No effect Tr (frequency) Ct (frequency) Tr/Ct Wang (108), 2001, Open/1 60/60 BPs: Tianshu, Huaroumen, Wailing, Xiawan, Shimen; 1 per 2 d (30 d/0) Jianfei Tea; NR BW, BMI NR NR NR Wang et al. (109), 2005, Open/1 91/58 BPs: Zhongwan, Shuifen, Qihai, Tianshu, Wailing, et al. EPs: Endocrine, Kidney, Hunger, et al.; 1 per week Fenfluramine; 40 mg BW NR None Nausea, diarrhea Wang (110), 2006, Taiwan Open/1 20/20 BPs: Tianshu, Daheng, Zhongwan, Guanyuan, Shuifen, et al.; 1 per week (6 weeks/0) Co-treatment; NR BMI NR NR NR Xu (18), 2005, Open/1 215/92 BPs: Zhigou, Siman, Guanyuan, Daimai, Xuehai, et al. EPs: mouth, stomach, spleen, kidney, endocrine, et al.; 1/d (60 d/no statement) Liujunzi Decoction; NR BMI NR NR NR Fewer/NR Yi et al. (19), 2009, Open/1 73/55 BPs: Zhongwan, Qihai, Huaroumen, Pishu, Weishu, et al.; 1/d (39 d/6 m) Slimming instrument; NR BW NR Menstruation disorder (1) None 2/3 Zhang and Cui (111), 2007, Open/2 32/32 BPs: Zhongwan, Guanyuan, Tianshu, Shuifen, Zusanli, et al.; 5 per week None BW NR NR NR Tong et al. (112), 2006, SB/1 26/15 BPs: Abdominal 8 points, ST36,SP9; 1 per 2 d (80 d/0) Placebo WC, BMI NR NR NR BF, body fat; BG, blood glucose; BI, blood insulin; BL, blood lipids; BMI, body mass index; BP, blood pressure; BPs, body points; BW, body weight; Ct, control; DB, double blinding; EPs, ear points; HC, hip circumferences; IS, insulin sensitivity; NR, not reported; PE, physical exercises; RCT, randomized controlled trial; SB, single blinding; Tr, treatment; WC, waist circumferences. obesity reviews 2012 International Association for the Study of Obesity 13, , May 2012

16 424 Therapeutic effect of TCM on obesity Y. Sui et al. obesity reviews Table 3 Characteristics of RCTs using combined therapy (Chinese herbal medicine plus acupuncture) for obesity Basic information Study design Results (compared with control) Adverse effects No. of relapse after treatment Author year location Blinding/ Patient no. in Tr/Ct Tr; daily dose (duration/follow-up after treatment ) Ct; daily dose With benefits No effects Tr (frequency) Ct (frequency) Tr/Ct Tang and Fan (113), 2009, Huang (114), 2009, Liu et al. (115), 2009, DB/1 38/26 Rhizoma pinelliae, Poria, Codonopsitis Radix, et al.; BPs: Zhongwan, Tianshu, Shuidao, Sanyinjiao; 1 per 2 d (2 months/0) Open/2 50/50 BPs: Zhongwan, Qihai, Liangmen, Tianshu, Geshu, Fenglong; NR (12 weeks/0) Open/2 55/28 BPs: Zhongwan, Daheng, Shuifen, Tianshu, Qihai, et al.; 1 per 2 d Co-treatment; 750 mg Orlistat; 120 mg Sibutramine; 10 mg BW, BMI, BL, BI, BP WC NR None Nausea, stomach pain (3) BW, HC, BMI, BL None Diarrhoea (23), headache (3) NR BW NR NR BF, body fat; BG, blood glucose; BI, blood insulin; BL, blood lipids; BMI, body mass index; BP, blood pressure; BPs, body points; BW, body weight; Ct, control; DB, double blinding; HC, hip circumferences; IS, insulin sensitivity; NR, not reported; RCT, randomized controlled trial; SB, single blinding; Tr, treatment; WC, waist circumferences. (MD = 1.20 kg m 2, 95% CI = ), treated with placebo (MD = 1.00 kg m 2, 95% CI = ) or receiving metformin as co-treatment (MD = 2.26 kg m 2, 95% CI = ) (Supporting Information Fig. S3a). Patients treated with CHM had similar BMI change compared to those treated with fenfluramine (MD = 0.17 kg m 2, 95% CI =-0.56 to 0.90) or metformin (MD = 0.20 kg m 2, 95% CI =-0.71 to 1.11) (Supporting Information Fig. S3b). Combining all data yielded an MD in body weight reduction of 2.93 kg (95% CI = ) and BMI reduction of 1.36 kg m 2, 95% CI = ) in favour of CHM treatment with statistical heterogeneity across trials (body weight reduction: I 2 = 97%, BMI reduction: I 2 = 96%). The funnel plot demonstrated no apparent asymmetry, suggesting that publication bias was not likely (Supporting Information Figs S1a 3b, B). For parameters related to body weight reduction, the CHM-treated group had greater reduction in blood lipids and glucose levels (Supporting Information Table S1). There was no difference in the weighted mean difference of these parameters between subjects treated with CHM or Western drugs. Acupuncture treatment Improvement in obesity evaluated by RR The comparators to acupuncture treatment included (i) no treatment; (ii) placebo of sham acupuncture; (iii) co-intervention; (iv) lifestyle modification (including diet and physical exercise). In 11 trials, acupuncture was associated with greater weight loss than no treatment (RR = 2.76, 95% CI = ) using the random effect model. Compared to sham operation (RR = 1.61, 95% CI = ), co-interventions (RR = 1.56, 95% CI = ), and lifestyle modification (RR = 1.48, 95% CI = ), acupuncture showed greater efficacy in body weight reduction. Combining data of these 15 trials in a random effect model yielded a RR of weight reduction in favor of acupuncture (pooled RR = 2.14, 95% CI = ) (Supporting Information Fig. S4a, A), with heterogeneity (I 2 = 88%) due to an insufficient number of trials combined with small sample sizes and effect (Supporting Information Fig. S4a, B). There were 11 trials using Western drugs as comparators including sibutramine (n = 8 studies), fenfluramine (n = 1) and orlistat (n = 2). Acupuncture showed greater efficacy in weight reduction than sibutramine (RR = 1.06, 95% CI = ), fenfluramine (RR = 1.17, 95% CI = ) and orlistat (RR = 1.54, 95% CI = ). The combined analysis in a random effect model showed greater efficacy in favour of acupuncture (Supporting Information Fig. S4b, A) compared to Western drugs (pooled RR = 1.14, 95% CI = ) with heterogeneity (I 2 = 76%) due to insufficient number of studies combined with small sample sizes and effects (Supporting Information Fig. S4b, B). Reduction in severity of obesity measured by a weighted mean difference Subjects treated with acupuncture showed a greater body weight reduction than no-treatment (MD = 4.10 kg, 95% 13, , May 2012 obesity reviews 2012 International Association for the Study of Obesity

17 obesity reviews Therapeutic effect of TCM on obesity Y. Sui et al. 425 CI = ), placebo treatment (MD = 1.65 kg, 95% CI = ) (Supporting Information Fig. S5a, A), metformin (MD = 1.53 kg, 95% CI = ) (Supporting Information Fig. S5b, A), but similar when compared with fenfluramine (MD =-0.26 kg, 95% CI =-1.20 to 0.68). Similarly, BMI reduction was greater in patients treated with acupuncture than those who received no treatment (MD = 2.65 kg m 2, 95% CI = ), placebo (MD = 2.01 kg m 2, 95% CI = ) (Supporting Information Fig. S6a, A) or sibutramine (MD = 0.83 kg m 2, 95% CI = ) (Supporting Information Fig. S6b, A). Combining all data yielded an MD in body weight reduction of 1.85 kg (95% CI = ) and BMI reduction of 1.42 kg m 2 (95% CI = ) in favour of acupuncture. There was statistical heterogeneity (body weight reduction: I 2 = 69%, BMI reduction: I 2 = 84%) with an insufficient number of trials combined with small sample and effect size (Supporting Information Figs S5a 6b, B). In the analysis between acupuncture and control groups, acupuncture demonstrated greater reductions in body weight, BMI, waist circumference and blood total cholesterol in comparison to lifestyle modification or no treatment, and similar effects when compared to sibutramine, fenfluramine or orlistat (Supporting Information Table S2). Combined treatment of CHM and acupuncture In one study, combined treatment of CHM and acupuncture showed a tendency of greater efficacy in reducing weight than non-pharmacological control (RR = 1.25, 95% CI = ) (Supporting Information Fig. S7). Two other studies compared combined treatment versus Western drugs (orlistat and sibutramine) with similar weight loss (RR = 1.01, 95% CI =-2.24 to 4.26) (Supporting Information Fig. S8). No mean difference in body weight was calculated due to small trial number. Safety (adverse events) CHM treatment There were 28 studies which reported adverse events (Supporting Information Table S3): 7 trials reported no adverse events and 21 reported more frequent adverse effects in the treated groups than control groups. The majority of adverse effects were gastrointestinal symptoms (treatment: 15 trials, 71.4%; control: 15 trials, 88.2%), such as nausea, diarrhoea, constipation and dry mouth. Uncommon adverse effects included headache (treatment: 3 trials, 14.3%; control: 7 trials, 41.2%), insomnia (treatment: 2 trials, 9.5%; control: 2 trials, 11.8%) and anorexia (treatment: 0; control: 2 trials, 11.8%). The adverse effects caused by CHM formula were usually mild and tolerable and did not result in treatment withdrawal. In USA and Japan, trials which used compounds containing ephedrine and caffeine showed more severe adverse effects with premature in 17 patients. In the control group, most of the adverse effects were reported in patients treated with the Western drug, fenfluramine. Acupuncture Adverse events were monitored in 16 studies of acupuncture (Supporting Information Table S3). Ten trials reported no adverse events, and six reported mild adverse effects. The most frequently reported adverse effects were symptoms of local skin reactions after acupuncture such as skin bruises, redness and pain (treatment: 3 trials, 50.0%; control: 1 trial, 14.3%). Symptoms of the gastrointestinal tract were reported in 2 (33.3%) acupuncture trials and 5 control trials using Western drugs (71.4%). Insomnia, headache and anorexia were very uncommon adverse effects, and only reported in 1 control trial. The adverse effects caused by acupuncture were mild and tolerable with no premature withdrawal. Relapse of weight gain Eight studies (12 19) reported status of relapse of weight gain after treatment although no formal definition of relapse was given. The observation period lasted between 2 months and 1 year. Description of follow-up procedures and the number of patients who relapsed after the treatment are listed in Tables 1 and 2. In a 3-month study which compared a herbal formula versus fenfluramine, none of the 90 patients treated with herbal mixture regained weight compared to 14 of 29 patients who relapsed after fenfluramine treatment (13). In another 4-week study which compared acupuncture (59 patients) and sibutramine (40 patients), no relapse was observed in the acupuncture group at 6 and 12 months after stopping the treatment compared to three relapses in the control group (17). Most studies reported fewer relapses in the CHM or acupuncture treatment groups but more relapses in the control (placebo or Western drug) groups, although these rates were poorly quantified. Biophysical functions In studies where measurements were made, blood lipids, blood glucose, blood pressure and insulin sensitivity were usually improved by CHM or acupuncture treatment. Reduced hunger sensation and improved satiety were reported in the active treatment groups for four of the five CHM studies (80% improvement), and three acupuncture studies (100% improvement), but not in the control groups. Some studies also reported improved selfsatisfaction and quality of life after weight loss, such as feelings of refreshment and reduction of weakness. obesity reviews 2012 International Association for the Study of Obesity 13, , May 2012

18 426 Therapeutic effect of TCM on obesity Y. Sui et al. obesity reviews Table 4 The 10 most frequently used herbs and acupuncture points Herbs, n = 98 (name in pinyin) Frequency in 32 recipes (%) Body points, n = 85 (name in pinyin) Frequency in 44 trials (%) Auricular points, n = 33 Frequency in 15 trials (%) Scutellariae Radix (Huangqi) 14 (43.6) Zusanli 36 (81.8) Hunger 12 (85.7) Crataegi Fructus (Shanzha) 13 (40.6) Sanyinjiao 36 (81.8) Shenmen 12 (85.7) Rhei Rhizoma (Dahuang) 12 (37.5) Tianshu 34 (77.3) Spleen 12 (85.7) Atractylodis Ovatae Rhizoma (Baizhu) 10 (31.3) Fenglong 33 (75.0) Stomach 11 (78.6) Alisma lanceolatum (Zexie) 10 (31.3) Zhongwan 30 (68.2) Endocrine 11 (78.6) Poria (Fuling) 10 (31.3) Qihai 27 (61.4) Large intestine 9 (60) Folium Nelumbinis (Heye) 9 (28.1) Quchi 26 (59.1) Mouth 8 (57.1) Atractylodis Rhizoma (Cangzhu) 8 (25.0) Yinlingquan 23 (52.3) Lung 8 (57.1) Salviae Miltiorrhizae Radix (Danshen) 8 (25.0) Pishu 22 (50.0) Triple warmer 8 (57.1) Citri Exocarpium (Chenpi) 7 (21.9) Shuifen 22 (50.0) Sympathetic 6 (42.9) Rationale for choices of CHM and acupuncture A total of 98 herbs, 85 body points and 33 auricular points were used in these studies. The 10 most frequently used herbs and points are listed in Table 4. The most frequently used herbs were further categorized and analysed for the combination of a classic formula (Supporting Information Table S4). TCM diagnosis was reported in 33 publications. Most of these studies claimed that the causes of simple obesity were phlegm dampness (Tanshi, 87.9%) and spleen deficiency (Pixu, 84.8%). Other diagnoses were stomach heat (Weire, 54.5%), liver depression (Ganyu, 33.3%) and kidney deficiency (Shenxu, 30.3%). Accordingly, most of the therapies focused on eliminating dampness (Huashi, 63.2%), invigorating spleen (Jianpi, 68.4%) and benefiting Qi to activate blood circulation (Yiqi-HuoXue, 42.1%). Other therapies of clearing stomach (Qingwei, 21.1%), invigorating kidney (Bushen, 21.1%) and dispersing stagnated liver (Shugan, 5.3%) were less frequently proposed. Discussion In this systematic review of peer-reviewed articles published in English and Chinese, we have identified 49 randomized studies using CHM, 45 acupuncture and 3 combination treatments to treat obesity, with or without active comparators. A total of 4,885 subjects in the treatment groups and 3,821 in the control groups were evaluated and the duration of studies ranged from 2 weeks to 4 months. The majority of these studies were conducted in mainland. Using standard critique criteria, studies performed outside had a higher methodological quality than those conducted within. Despite the small sample size and methodological limitations, analysis of the pooled data showed a consistent superior effect of CHM and acupuncture, compared to Western drugs and lifestyle modification, in reducing body weight with improved metabolic profiles. We have tried to identify all RCTs of CHM and acupuncture for weight reduction although this might be limited by incomplete citation tracking, as with most systematic reviews. We were able to review trials conducted and published in and English-speaking countries and a few studies conducted in Korea and Japan but written in English. We were not able to include all studies from Korea and Japan written in their native language although TCM and acupuncture are widely used in these two countries. Overall, the herbal formulae used in studies conducted in showed good tolerability. By contrast, CHM intervention used in studies conducted outside tended to have more adverse effects (20 24). These differences might be due to the more rigorous methodology with better data documentation in studies conducted in the West. However, insufficient compliance to the principles of TCM during selection of herbal compounds may be another explanation. In, the philosophy of TCM emphasizes on personalized therapy, where the types of symptoms and signs judged by TCM doctors formed the basis for selection of herbs. Therefore, despite having the same clinical diagnosis (e.g. obesity), depending on the symptoms and signs, different patients may be given different TCM treatments. By contrast, Western doctors are more likely to prescribe similar medications to patients with the same clinical diagnosis, albeit with different subphenotypes. In trials conducted in, the TCM doctors adhered to this principle but less often in trials conducted outside. This difference in therapeutic approach may partly explain the lower efficacy and higher incidence of adverse effects with CHM in these latter trials. On the other hand, most of the trials conducted in had suboptimal design, often due to lack of information on blinding, method of randomization and reasons of. These methodological deficiencies may contribute to the lower incidence of adverse effects and better tolerability of CHM in trials conducted in. Despite these limitations, the overall data suggest that CHM and acupuncture were better tolerated than Western drugs, with reportedly less weight gain after treatment (12 14,17,18,22,25). Taken together, these preliminary results 13, , May 2012 obesity reviews 2012 International Association for the Study of Obesity