Effect of auriculotherapy and intervention types on weight control

Abstract Background: Overweight and obesity characterized by abnormal or excessive fat accumulation, can cause many complications. Auriculotherapy, as the traditional Chinese technique, is widely applied in clinical trials for the management of body weight. The program aims to evaluate the effect and safety of auriculotherapy therapy and intervention types on weight control. Methods: All randomized controlled trials related to auriculotherapy targeting overweight and obesity will be searched in online databases, such as Medline, EMbase, Cochrane Central Register of Controlled Trials, AMED, CBM, Wanfang Data, and other databases from their inception to July 2019. The primary outcome is the difference in BMI from baseline to the end of studies. Secondary outcomes include the change of weight, percentage of body fat, waist circumference, serum lipid before and after treatment. Study selection, data extraction, and assessment of risk of bias will be performed independently by 2 reviewers. Comprehensive Meta-Analysis software (Version 3; Biostat Inc.) will be used for data synthesis. Results: This study will provide a comprehensive review of the available evidence for the treatment of obesity with auriculotherapy. Conclusion: The conclusion of this study will provide evidence to judge whether auriculotherapy is an effective therapeutic intervention for obesity. PROSPERO registration number: CRD42019136827.


Introduction
Overweight and obesity is a condition characterized by abnormal or excessive fat accumulation. [1] According to the World Health Organization (WHO) standard for Asians, people were classified as obese (BMI ≥ 25 kg/m 2 ), overweight (23 kg/m 2 BMI < 25 kg/ m 2 ), and normal weight (18.5 kg/m 2 BMI < 23 kg/m 2 ). [1,2] Worldwide, obesity is gradually becoming a major public health challenge. According to the epidemiological data, the prevalence of obese people has increased nearly three times since 1975. [3,4] In 2014, the number of obese populations in China is the largest in the world, even for morbid obesity, the number comes to the second rank. [5] Obesity can increase the incidence of many chronic conditions, such as diabetes, hypertension, cardiovascular diseases, and obstructive sleep apnea syndrome. [6][7][8] Obesity is also associated with the mortality. [9][10][11] It is estimated that about 4 million people died of overweight in 2015. [3] There are high direct and indirect health care costs for treating obesity. According to a survey, the economic loss of the world's overweight-related diseases in 2014 was estimated at $200 million. [12] At present, obesity has become the fourth world's major medical and social problems alongside AIDS, alcohol addiction and poison paralysis, and is the fifth largest risk of death worldwide. [9,13] Therefore, weight control is an important public health issue that needs to be addressed to improve the health of individuals and medical expenditures.
Currently, treatment options for obesity mainly include calorie restriction, exercise, lifestyle modification as well as medications and bariatric surgery. [14,15] The US Food and Drug Administration (FDA) has approved 5 weight loss drugs (orlistat, lorcaserin, naltrexone-bupropion, phentermine-topiramate, and liraglutide) for long-term management in obese or overweight individuals. [16] However, the side effects and instability limit the clinical application of these drugs, such as phentermine can cause insomnia, orlistat causes diarrhea, phentermine-topiramate can bring paresthesia, dizziness, taste disturbance, use liraglutide can cause nausea and vomiting. [17][18][19][20] Bariatric surgery may be the only long-term weight control therapy for the patient with morbid obesity but is hindered by heavily cost and possible postoperative complications such as anastomotic leakage and malnutrition. [21,22] As a result, more and more overweight and obese patients are seeking cheaper, more convenient and less side effects of complementary and alternative therapies.
Auriculotherapy, also called auricular acupoint pressure or ear stimulation, is a method of diagnosing and treating diseases by stimulation of specific acupoints on the external ear, includes electrical stimulation, acupoint acupressure, different type of needles, seeds, and magnetic balls. [23] Since it is thought that different auricular regions correspond to particular somatotopic areas of the body, auriculotherapy has been used as an effective treatment option for certain internal diseases including obesity. [24] According to traditional Chinese medicine (TCM) theory, obesity is related to the dysfunction of the spleen, stomach, and kidney. The main meridians of these organs are closely related to the ear. By stimulating corresponding auricular points, meridian, and collaterals could be activated to tonify and promote Qi, so as to regulate the function of the organs and reduce the weight. Experimental study suggests that auricular stimulation may be involved in several mechanisms of BW regulation, such as anorexigenic and orexigenic peptides, glucose metabolism, insulin resistance, lipid metabolism, and inflammatory markers. [25][26][27] The auricle nerve vessels are the most abundant, especially in the ear cavity and triangle nest, once stimulates the vagus nerve can affect the insulin value and suppress the appetite to achieve the purpose of weight loss. [25] Therefore, auriculotherapy for weight control has the support of TCM and western medicine theory.
Nowadays, there have been more and more clinical studies suggest that auriculotherapy has beneficial effects in the treatment of obesity. [28,29] There have been some systematic reviews published focusing on auricular acupoint stimulation in the treatment of obesity, but all of them, did not limit the control group to sham auriculotherapy, which could have led to the overestimation of the auriculotherapy effect due to the placebo effect. [30,31] Furthermore, these studies did not report the differences in the effect of auricular acupoint stimulation by different auriculotherapy types. [32,33] To the best of our knowledge, there is no systematic review has evaluated the pure effect of auriculotherapy for obesity. Hence, we conduct this systematic review to objectively evaluate the effect of pure auriculotherapy with that of sham auriculotherapy in the treatment for obesity and to compare the effect size of the treatments by auriculotherapy type.

Study registration
PROSPERO registration number is CRD42019136827. This protocol is reported in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) statement guidelines. [34] The review will be conducted in accordance with the PRISMA guidelines and follows the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions. [35,36] If we refine the procedures described in this protocol, we will update the record in the PROSPERO and disclose them in future publications related to this study.

2.2.
Inclusion criteria for study selection 2.2.1. Types of study. In order to evaluate the pure effect of auriculotherapy in the treatment of obesity, we will just include the randomized clinical trials (RCT) that compared auriculotherapy (auricular acupuncture or auricular acupressure or auricular acupuncture with electrical stimulation) with sham auriculotherapy or placebo or no treatment (waiting list control). Completed and ongoing trials will be included. Owing to the language restriction of our researchers, we will limit the language of search literature to Chinese and English. If the study was designed as a cross-over trial, only the first phase results will be analyzed in order to eliminate carry-over effects.
Trials will be excluded as follows: (1) studies that involved a combination of auriculotherapy with other treatments, such as moxibustion, massage, cupping, and drugs or Chinese herbs; (2) comparing auriculotherapy with other forms of acupuncture or other treatment; (3) quasi-randomized trials and case reports; (4) only providing the information of effective rate and not providing the data of BMI from baseline to the end of studies.

Types of participants.
Trials including patients who meet the diagnostic criteria of overweight or obese and age were greater than 18 years will be included. All eligible study participants will be included in this review regardless of their race or gender. Trials including participants who are not appropriate to receive auriculotherapy, such as pregnant or lactating women, and those were secondary obesity or with additional severe diseases will be excluded.

Types of intervention.
The experimental group should be treated with auriculotherapy including auricular acupuncture or auricular acupressure or auricular acupuncture with electrical stimulation, and acupoints used according to TCM nomenclature. The types of seed used and the duration of treatment will be unlimited. Auriculotherapy combined with other conventional therapy should be excluded.
To evaluate the true effect of auriculotherapy on obesity, we will limit the interventions in the control groups to sham auriculotherapy or no treatment or placebo. Studies involving auriculotherapy for weight a control but without control arm will be excluded. In addition, studies involving sham auricular acupuncture for weight control that was not masked from participants in the control group will also be excluded.  BMI is an index defined by one's weight in kilogram divided by height in meter square (kg/m 2 ). The secondary outcomes include the change of weight, percentage of body fat (BFP), WC, serum lipid (such as cholesterol and triglyceride) before and after treatment, adverse events will also be measured as secondary outcomes for safety assessment.

Data sources
Our systematic review will search all RCTs for auriculotherapy on weight control, electronically and manually, regardless of publication status, till 31th July 2019.

Search strategy
The search strategy will be followed the PRISMA guidelines. The key search terms are ("obesity" OR "overweight" OR "weight reduction") AND ("auricular acupuncture" OR "auricular acupressure" OR "auricular pressing" OR "auricular needle" OR "auricular plaster") AND ("randomized"). The search strategy will be adapted to different databases demands. Search strategy in PubMed is shown in Table 1.
2.5. Data collection and analysis 2.5.1. Selection of studies. In the literature screening process, search results will be imported from the original databases to Endnote V.X9 and repetitive studies will be deleted by the software. Two reviewers will independently screen all retrieval research, read the title, abstract and keywords to determine which studies meet the inclusion criteria. We will obtain the full text of all relevant studies for further evaluation. Studies excluded after reading the full text will be recorded and explained. The selection results will be cross-checked by the 2 reviewers. Any disagreement will be resolved by consensus. Further argument will be arbitrated by a third reviewer. The primary selection process is shown in a PRISMA flow chart (Fig. 1).

Data extraction and management.
The following data will be extracted from the selected studies by 2 reviewers independently using a predefined data acquisition form: the characteristics of the study (publication year, nationality, journal, study design), participants (sample size, age, sex, height, weight, BMI), intervention (duration, frequency, types of auriculotherapy, types of control group), weight-related outcomes (the difference in BMI, the change of weight, BFP, waist circumference, and serum lipid), adverse reactions and other information. Any discrepancy noticed in the process of data extraction will be resolved through discussion and the suggestion of a third reviewer. For publications with insufficient or ambiguous data, we will attempt to obtain information from the corresponding authors by e-mail or telephone.

Assessment of risk of bias and
reporting of study quality. The authors will assess the study quality by using the checklist developed by the Cochrane Collaboration's bias risk assessment tool which evaluates the presence of potential selection bias (random sequence generation and allocation concealment), performance bias (blinding of investigators and participants), detection bias (blinding of outcome assessors), attrition bias (incomplete outcome data), reporting bias (selective reporting) and possible other sources of bias (funding bias). [36] Risk bias of trials was graded as high, low or unclear risk. If inconsistent results appear, the final decisions will be made by the third author.
2.5.4. Measures of treatment effect. Data analysis and quantitative data synthesis will be performed using Comprehensive Meta-Analysis software (Version 3; Biostat Inc.). For continuous data, we will use the standardized mean difference (SMD) along with its 95% confidence intervals to measure the therapeutic effect, whereas dichotomous data will be presented as relative risk (RR) with 95%CI for analysis.

Assessment of heterogeneity.
Heterogeneity between studies will be assessed using the I 2 test. The study is not considered to have large heterogeneous if the I 2 test is less than 50%. However, when the I 2 values higher than 50%, there is substantial heterogeneity among the trials, we will search for possible causes from a clinical and methodological perspective, and provide a descriptive analysis or subgroup analysis to explore the possible causes of heterogeneity. Meanwhile, the corresponding P values will also be taken into account. The results will be discussed according to the different heterogeneity.
2.5.6. Assessment of reporting biases. We will use funnel charts to visually inspect publication biases. If a sufficient number of included studies (more than 10 trials) are available, the funnel Table 1 Search strategy used in PubMed database. plot will be used to assess the reported bias. If the funnel plot is found to be asymmetrical, analyze the cause using Egger regression test. We will include all eligible trials regardless of the quality of the method.
2.5.7. Data synthesis. We will use Comprehensive Meta-Analysis software (Version 3; Biostat Inc.) for all statistical analysis. In order to maximize information, data on outcomes reported by single studies or in a descriptive way will be reported narratively. If the I 2 test is less than 50%, the fixed effects model will be used for data synthesis. If considerable heterogeneity is observed, data will be pooled using the randomeffects model.

Subgroup analysis.
In the present study, the heterogeneity will significant with respect to the auriculotherapy types, subjects, treatment period, etc. Therefore, subgroup analysis will be employed according to different types of auriculotherapy, the initial BMI of patients, different treatment duration, or frequency, different control groups (sham auriculotherapy or placebo), different outcomes, and so on.
2.5.9. Sensitivity analysis. Multiple sensitivity analysis will be performed to assess the robustness of the summary estimates and to detect if any particular study accounted for a large proportion of heterogeneity. These will be based on different statistical approach, different heterogeneity quality and different sample size. The meta-analysis will be reused, and more inferior quality studies will be excluded. The results will be compared and discussed according to the results.
2.5. 10. Grading the quality of evidence. The GRADE approach will be used to rate the quality of evidence of estimates derived from this study. [37] In this approach, direct evidence from RCTs starts at high quality and can be downgraded based on the risk of bias, indirectness, imprecision, inconsistency (or heterogeneity), and/or publication bias to levels of moderate, low, and very low quality. [38] 3. Discussion Overweight and obese problem is a pandemic public health issue in the world, with more medical costs and seriously affect the quality of people's life. Therefore, several interventions have been explored, such as lifestyle intervention, pharmaceutical, and bariatric surgery treatments. People can reduce 5% to 10% of initial weight through intensive lifestyle intervention by changes diet and physical activity, [39,40] but long-term weight maintenance is difficult. Meanwhile, pharmaceutical and bariatric surgery treatments are effective for some overweight and obese people but are expensive and often accompanied by adverse side effects.
With the development of complementary and alternative medicine, auriculotherapy has been widely applied in clinic especially in Asian countries. And it is widely used in the regulation of obesity. As mentioned in the preceding texts, the previous reviews did not separate the pure effect of auriculotherapy from other interventions and sham auriculotherapy. Therefore, the effect of auriculotherapy may have been overestimated in the meta-analysis due to the placebo effect. In this study, we will objectively evaluate the pure effect of auriculotherapy for obesity, and also examined the effect of auriculotherapy on obesity by different types, hoping to provide convincing evidence for patients and clinicians during the decision-making process.