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Review Intragastric botulinum toxin injection for weight loss: current trends, shortcomings and future perspective
Erfan Arabpour,orcid, Hadi Golmoradiorcid, Parya Mozafari Komesh Tapeorcid, Amir Sadeghi,orcid, Mohammad Abdehaghorcid, Pardis Ketabi Moghadamorcid, Mohammad Reza Zaliorcid

DOI: https://doi.org/10.5946/ce.2024.153
Published online: November 5, 2024

Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran

Correspondence: Amir Sadeghi Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Arabi Ave, Daneshjoo Blvd, Velenjak, Tehran 19839-63113, Iran E-mail: amirsadeghimd@yahoo.com
Correspondence: Erfan Arabpour Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Arabi Ave, Daneshjoo Blvd, Velenjak, Tehran 19839-63113, Iran E-mail: erfanarabpour1999@gmail.com
• Received: June 8, 2024   • Revised: June 22, 2024   • Accepted: June 27, 2024

© 2024 Korean Society of Gastrointestinal Endoscopy

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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  • The administration of botulinum toxin A (BTA) into the gastric wall has emerged as a novel endoscopic bariatric procedure. Although over 20 years have elapsed since the initial human trial of intragastric BTA injection, considerable debate remains surrounding the safety, efficacy, and procedural instructions of this approach. The current literature exhibits discrepancies in the methodologies employed across studies, including differences in the dosage of BTA administered, injection site, number and depth of injections, post-procedural dietary modifications, and follow-up duration. This study reviewed the state-of-the-art use of BTA for weight loss and focused on the clinical evidence of the therapeutic applications of BTA for obesity. Studies with consistent outcome measures and methodologies are necessary to thoroughly assess the potential effects of BTA on weight management.
  • Keywords: Botulinum toxins, type A; Endoscopic bariatrics; Obesity; Weight loss
Obesity is the leading cause of preventable death worldwide, second only to smoking.1 If the present patterns persist, the majority of the world’s population, exceeding 4 billion individuals, will grapple with either being overweight or obese by 2035. The prevalence of obesity is projected to rise to 1 in 4 people, in contrast to the current ratio of 1 in 7. The economic repercussions of obesity are anticipated to surpass a staggering 4 trillion United States dollars by 2035.2 This financial burden primarily stems from obesity-related comorbidities including hypertension, type 2 diabetes mellitus (DM), and cardiovascular diseases.3
High-intensity comprehensive lifestyle modifications, encompassing dietary changes, exercise, and behavioral therapy, are widely recommended as the initial approach to weight loss. However, these interventions typically result in a moderate weight loss of approximately 4% to a maximum of 10%.4 Additional weight-loss strategies are often necessary to achieve significant outcomes. Pharmacologic agents have been suggested as a treatment option for individuals who are obese (body mass index [BMI] ≥30 kg/m2) or overweight (BMI ≥27 kg/m2) and have complications related to excess adiposity. While weight loss medications can assist in achieving mild weight loss, individuals with a BMI ≥35 kg/m2 usually struggle to reach normal weight through medication alone. In cases where more substantial weight loss is required, bariatric surgery is considered for patients with a BMI ≥40 kg/m2 or a BMI ≥35 kg/m2 with obesity-related comorbidities (Table 1, Fig. 1).5,6
Given the limited effectiveness of lifestyle interventions and pharmacotherapy, as well as the obstacles associated with bariatric surgery, it is imperative to explore new treatment options for the increasing number of patients with obesity. The emerging field of endoluminal therapy offers the possibility of less invasive procedures that can cater to a broader range of individuals with obesity. There is a growing interest in utilizing endoscopic techniques, including restrictive procedures such as gastroplasty, implementation of space-occupying devices such as intragastric balloons (IGBs), malabsorptive techniques such as endoluminal devices, and injection of substances that can modify gastric motility and emptying.7
The administration of botulinum toxin A (BTA) into the gastric wall has emerged as a novel endoscopic treatment for obesity. By inducing temporary paralysis at the injection site, BTA can potentially delay gastric emptying (GE). This effect is achieved by inhibiting acetylcholine release at cholinergic neuromuscular junctions.8 In 2000, Gui et al.9 conducted a groundbreaking study demonstrating that intramuscular injections of BTA into the gastric wall of laparatomized rats significantly reduced their body weight and food intake. Following successful animal trials, endoscopic BTA injections have been explored as an alternative therapy for obesity in humans.
Although over 20 years have elapsed since the initial human trial of intragastric BTA injection (IBI), considerable debate remains surrounding the safety, efficacy, and procedural instructions of this approach. This review aimed to explore the current medical evidence regarding the use of IBI as a treatment for obesity.
A literature search was performed in PubMed, Scopus, and Google Scholar for articles published up to April 2024. Pertinent articles related to the respective sections were identified, and their bibliographies were utilized to conduct a recursive search. The search terms included “botulinum toxin”, “obesity”, and “weight loss” in addition to other relevant terms. Species and age filters were not used to comprehensively cover the evolution of IBI as a treatment for obesity. This review encompassed observational studies and clinical trials.
Currently, BTA is extensively used in clinical settings because of its ability to impede the contractions of smooth and striated muscles.10 It was initially theorized that the paralysis of the stomach muscles caused by BTA could result in weight loss by slowing down GE. Gui et al.9 conducted a pioneering study demonstrating that intramuscular administration of BTA into the gastric wall of laparotomized normal-weight rats significantly decreased their food consumption and body weight. This finding was later supported by similar results reported in Coskun et al.’s study11 on obese rats.
The first application of BTA for managing obesity in humans was published in a case report by Rollnik et al.12 In this study, 100 U of BTA was injected into the antro-pyloric wall of an obese individual with a BMI of 31.4 kg/m2. Remarkably, this intervention resulted in a significant reduction of 8.9% in the individual’s total body weight after 4 months. These encouraging findings prompted further investigations into the potential of BTA as an intervention for obesity, leading to extensive research on IBI.
In the realm of medical science, it is common to find an agent that works; however, understanding how it works is less common. The mechanism by which BTA reduces body weight via intragastric injection is not completely understood. The use of BTA as a treatment for obesity is rooted in its ability to inhibit enteric cholinergic nerve terminals, resulting in delayed GE and an increased feeling of satiety.13 It has been hypothesized that certain individuals with obesity experience accelerated GE, which diminishes the usual signals of satiety triggered by the presence of food in the stomach.14 Research on GE in obesity has yielded inconclusive findings, with some studies reporting normal, delayed, or rapid GE in individuals with obesity. Discrepancies in these studies can be attributed to variations in inclusion criteria, dietary history, and the lack of standardized methods for measuring GE. However, a meta-analysis conducted by Yen et al.15 has confirmed the positive impact of IBI on prolonging gastric half-emptying time, with a mean difference (MD) of 11.37 minutes and a 95% confidence interval (CI) ranging from 3.69 to 19.06.
IBI may have a broader impact beyond inhibiting gastric muscle contraction, as it also influences gastrointestinal (GI) hormone levels. The relaxation of the fundus and proximal gastric body during the prandial and postprandial periods, along with the maintenance of intragastric pressure due to food accumulation, is referred to as gastric accommodation. This process is primarily associated with the fundus and is mediated through the vagal reflex pathway. Impaired gastric accommodation can lead to an early sensation of fullness and reduced food intake.16 Injection of BTA into the fundus can play a crucial role in disrupting gastric accommodation and suppressing the secretion of ghrelin, a hormone released from the gastric fundus that stimulates hunger, thereby promoting satiety. A study by Liu17 involved injecting 300 to 400 U of BTA into the fundus and antro-pyloric region of 126 patients with a BMI of 27 to 35 kg/m2 and assessed changes in GI hormones. This study revealed a significant decrease in ghrelin levels and highlighted the importance of fundus injections in achieving weight loss.
Currently, the most controversial issue regarding the use of intragastric botulinum injections for weight loss is its efficacy. Since its first application in 2003, an increasing number of studies have been published. However, as there is no consensus or approved protocol, the studies are heterogeneous in terms of population characteristics, dosage (100–1,000 IU) and location (antrum, body, and fundus) of injections, dietary interventions (with or without calorie restriction), follow-up time (5–24 weeks), and even outcomes (absolute weight loss, BMI, and hip circumference). This heterogeneity has led to inconsistent results in meta-analyses.
Our literature review revealed four meta-analyses that evaluated the efficacy of IBI for weight loss (Table 2).15,18-20 In 2015, Bang et al.18 pooled the results of five randomized controlled trials (RCTs) and concluded that IBI is an effective method for weight loss. However, only three of the five included studies compared the IBI and placebo groups. Bustamante et al.19 performed a meta-analysis based on stricter criteria than those of the other studies. After pooling the results of four RCTs, they found no significant differences in weight reduction between the IBI and placebo groups. Two recent meta-analyses attempted to compensate for the inconsistencies in previous studies using subgroup analyses. Chang et al.20 reported that IBI is not superior to saline in terms of weight loss or overall BMI changes. However, the subgroup analysis revealed that IBI is an effective method for weight loss in patients with BMI >40 kg/m2. A meta-analysis of six RCTs reported that although no difference in weight loss and BMI change was observed between the IBI and control groups, subgroup analyses revealed that IBI is effective ≥200 IU of botulinum is injected in multiple injection regions (antrum and other sites), along with a combined dietary calorie restriction.15 All four meta-analyses revealed serious heterogeneity in primary outcomes (I2=62%–89%). An interesting critical review by Theodoridis et al.21 reported poor quality for all the mentioned meta-analyses, except for Bustamante et al.’s study,19 which had high quality according to the assessment of multiple systematic reviews 2 score. It reported that, compared to placebo, IBI was not effective in reducing weight (MD, –2.41 kg; 95% CI, –5.21 to 0.38) and BMI (1.43 kg/m2, 95% CI, –3.04 to 0.18).
Overall, an overview of the trials on the efficacy of IBI reveals heterogeneity that makes combining and analying the results challenging (Table 3).17,22-46 Nevertheless, IBI is not an endoscopic bariatric procedure that can be effective for all individuals with obesity. Therefore, further trials with larger populations and transparent methodologies are required to establish accurate patient selection and precise injection protocols to obtain the optimum outcomes.
Most studies have focused on weight loss as the primary outcome. However, a recent study investigated the effects of IBI on the psychological symptoms and self-esteem of patients. A substantial cohort of 406 (369 female [90.9%] and 37 male) patients underwent IBI by injecting 500 U of BTA into 25 points in the fundus and antro-pyloric-pyloric region. After 6 months, psychological symptoms and self-esteem were reassessed using a standardized questionnaire. The study found that, following IBI treatment, patients exhibited reduced anxiety and depression alongside improvements in self-esteem. These findings suggest that IBI’s benefits extend beyond physical weight loss, potentially impacting mental well-being and self-perception, which can further influence weight management efforts.47
As discussed above, obesity may not be an adequate factor to determine a patient’s candidacy for IBI. One of the proposed mechanisms by which IBI promotes weight loss is through the inhibition of stomach muscle contraction, reduction of GE, and decrease in satiety. Therefore, it can be hypothesized that patients with rapid GE may benefit more from IBI than those with delayed GE Consequently, baseline gastric scintigraphy before IBI can be utilized as a screening tool or predictor of IBI success. A well-designed RCT is required to confirm this hypothesis. However, delayed GE is not the only proposed mechanism of IBI for treating obesity. Even if this hypothesis is valid, it may not be sufficient as a sole screening tool.
Any deterioration in the function of the pyloric muscle has the potential to affect GE. Two studies with relatively large populations (178 and 77 patients) assessed the association between pylorus tone and success of IBI treatment. They had a relatively similar definition of normotonic pylorus. When pyloric ring contraction was not detected within one minute, tactile stimulation was administered to the pyloric ring using the head of the endoscope for an additional 30 s. If the endoscopists did not observe any contractions even after the tactile stimulus, it was considered indicative of a hypotonic pylorus. BMI was assessed before and 6 months after IBI. Both studies reported a significant reduction in the BMI of patients with normotonic pylorus (p<0.05), whereas patients with hypotonic pylorus showed no significant change in BMI (p>0.05).24,48 It can be concluded that, in addition to gastric scintigraphy, the endoscopic view of pylorus and its contractions could also be used as a predictor of IBI success.
DM, especially when poorly controlled, alters GI motility, which can be seen as gastroparesis.49 Many studies have excluded patients with DM because of altered GI motility. However, reports have suggested that IBI is not only associated with significant weight loss but may also have the potential to reduce the need for diabetic medications.26 Despite this, no research is currently available that specifically investigates the effectiveness of IBI in patients with DM compared with individuals without DM. It appears that the degree of control of DM is more significant than its mere presence, and future studies should consider the complications associated with DM, particularly gastroparesis, when designing research protocols.
Although almost all trials on the efficacy of IBI for weight loss included patients with BMI >30 kg/m2, a recent study focused on patients who are overweight. The study included 40 patients with BMI 25 to 30 kg/m2. A total dose of 300 U (150 U for the fundus and 150 U for the body and antrum) was injected, and diet control (300 calories less than the daily requirements) was implemented. After a 6-month follow-up, weight loss was significant (BMI reduced from 27.2±2.5 kg/m2 to 24.1±2.4 kg/m2). The authors concluded that IBI, mainly focusing on the fundus, yields successful weight loss results, and IBI with diet control is an effective treatment option.50 However, this study lacked a control group (placebo injection with dietary restriction), and it is unclear whether the observed weight loss is due to IBI or dietary interventions.
The appropriate therapeutic dosage of BTA remains a topic of debate. The lack of significant findings on the overall body weight reduction in the studies prompts an inquiry into the sufficiency of the BTA dosage administered. Across the various trials, the dosage of BTA administered varied from 100 U to 1,000 U.
A small pilot study was conducted to investigate the effective dose of BTA, focusing on different doses and the number of injection sites. The study involved 12 participants with a BMI ≥40 kg/m2 categorized into four groups. Each group received one of the following treatments in the antro-pyloric-pyloric region: a total dose of 200 U BTA injected into eight sites, a total dose of 200 U BTA injected into 16 sites, a total dose of 300 U BTA injected into 16 sites, or a total dose of 300 U BTA injected into 24 sites. After 12 weeks, no significant differences were observed in total body weight or GE for solids and semi-solids diets among the groups. It is important to note that the study used rigorous exclusion criteria, and its main limitations included a small sample size and the absence of a control group.28 Similarly, another study investigated the effect of different BTA doses on overall body weight reduction and GE. These findings indicate that increasing the dosage of BTA does not result in an increase in total body weight loss.29 Topazian et al.30 found that administering a higher dose of BTA (500 U) did not increase adverse events; however, it was associated with a reduced effect on GE time compared to the 300 U BTA group. However, there is growing evidence that a total dosage of less than 200 U may not be sufficient to achieve considerable weight loss.
In conclusion, increasing the dose of BTA in future trials is unlikely to enhance evidence supporting the effective use of BTA for obesity treatment. However, a minimum dose of 200 U (as opposed to 100 U used in most previous trials) may be necessary to achieve considerable weight loss.
Another debate regarding the application of IBI is the optimum number and location of injections. BTA is usually injected in a circular manner (at least four for each area); the number of injections depends on the selected anatomical sites. Acetylcholine-mediated gastric antral contraction is essential for the passage of food into the duodenum.51 In the first studies evaluating the efficacy of IBI for obesity, the antro-pyloric-pyloric region was the only injection site.29,32,33 Trials have since been initiated to consider the fundus as an injection site. While the fundus does not have a role in food propulsion as the antrum does, the rationale for including the fundus is its role in gastric accommodation and regulation of gastric capacity, which induces early satiety. Although a Chinese study, including 126 patients with BMI 27 to 35 kg/m2, emphasized the role of fundus injection for weight loss, there was no fundal-sparing population in the control group.17 To the best of our knowledge, no well-designed study has conducted a head-to-head comparison of injections with or without including the fundus. However, the results of meta-analyses have supported extensive (the fundus and body rather than the antrum only) and multiple (>10) injections to achieve significant weight loss.15,18
An ultrasound guide can ensure the endoscopist that the medication is injected into the muscularis propria of the gastric wall, which is the primary site of action of BTA. Moreover, during injection into the fundus, which is anatomically near the diaphragm muscle and carries a risk of respiratory depression, an ultrasound guide can increase the safety and accuracy of injections. The literature review revealed that among the three studies that utilized endoscopic ultrasound (EUS)-guided injection, two reported significant weight loss after EUS-guided IBI34,35 and one reported no effect.36 None of the studies were designed to assess whether an ultrasound guide could enhance the outcome of IBI owing to the lack of a proper control group. A meta-analysis compared the EUS-guided studies with the no EUS-guided studies and found no significant difference in the absolute weight loss (MD, –0.65 kg; 95% CI, –2.7 to 1.4).15 The available evidence does not support any additional benefits of EUS-guided IBI over the conventional method.
It can be hypothesized that by increasing satiety, IBI increases the patients' compliance with dietary restrictions, and that applying calorie restrictions following IBI will result in further weight loss. Although several studies restricted the calorie intake of participants, only two studies aimed to assess the role of calorie restriction in the outcomes of IBI. In the first study, 300 U of BTA was injected into the antrum, body, and fundus of 49 patients with obesity, and a low-calorie, high-protein diet (40% carbohydrates, 30% protein, and 30% fat) was recommended. The control group consisted of 28 patients who were on a low-calorie, high-protein diet. The percentage of weight loss from baseline was assessed after 12 weeks, and the IBI group showed significantly greater weight loss (11.5%) than that of the control group (1.8%).37 In the second study, patients with grade II obesity were categorized into three groups: (1) IBI alone (n=20), (2) IBI+ calorie restriction (n=40), and (3) calorie restriction alone (n=23). Patients in the IBI groups received injections of 200 U of BTA into the antrum, fundus, and cardia, along with a dietary intervention including a 1,000-kcal high-protein diet (35% protein, 25% carbohydrate, and 40% lipid). After 6 months, weight loss and treatment adaptation were significantly higher in group 2 (p<0.01).26 It can be inferred that the implementation of IBI aids in the adjustment to the new dietary pattern and that the combination of IBI and calorie restriction potentially produces a mutually beneficial outcome.
The durability of the effects of IBI is a common concern among patients. The effects of IBI typically appear within the first week after injection. Patients experience early satiety, with symptoms typically emerging around the third day.28 Nevertheless, it is essential to note that these effects are not permanent. The trials that successfully demonstrated a significant total body weight loss exhibited varying durations of the weight loss effect, typically lasting for 1 to 2 months.13,38 This duration aligns with the therapeutic effect observed in other GI disorders, such as achalasia, when treated with BTA therapy.52 A systematic review revealed a mere inclination towards a reduced overall weight loss when the follow-up period was ≤8 weeks, suggesting that the long-term sustainability of the impact on weight loss remains uncertain.15
The sustainability of weight loss through IBI remains uncertain, raising questions regarding the effectiveness of repeated interventions and the optimal timing for such repetitions.
Safety is a paramount consideration for IBI, similar to other medical treatments. Following the procedure, some patients may experience mild GI symptoms such as bloating, postprandial fullness, and nausea. However, these symptoms typically subside within the initial days of the procedure, without requiring any interventions.28 Although extremely rare, there are case reports of gastric necrosis, perforation, and bezoar formation necessitating surgical intervention.53-55 The primary concern associated with IBI is the potential risk of iatrogenic botulism. Despite not being identified in previous IBI trials, the European Centre for Disease Prevention and Control reported a sudden surge in botulism cases associated with IBI between late February 2023 and March 10, 2023, with 67 cases reported in Turkey (n=53), Germany (n=12), Austria (n=1), and Switzerland (n=1).56 This indicates that iatrogenic botulism is a rare yet severe adverse event of IBI, underscoring the importance of educating patients about the alarm signs. However, the risk factors contributing to the development of iatrogenic botulism remain unclear. It is uncertain whether patient demographics, BTA dosage, injection site, or the number and depth of injections play a role in the occurrence of botulism. Establishing a comprehensive multinational registry of IBI is imperative to ascertain the precise incidence rate and risk factors associated with this potentially catastrophic adverse event.
The efficacy of IBI compared to other endoscopic bariatric procedures is unclear. A prospective case-matched study compared the safety and efficacy of IBI with those of an IGB (88 patients in each group). After 6 months, although both groups demonstrated significant weight loss, which was more significant in the IGB group (15.6 vs. 9.3 kg, p<0.001), the incidence of postoperative complications was significantly lower (9% vs. 30%, p=0.001) and the duration was shorter (0.7 vs. 5.2 days, p<0.001) in the IBI group. Researchers determined that IBI is a safe and efficient intervention for mild obesity. Despite greater weight reduction in the IGB cohort, the IBI group exhibited superior outcomes in terms of the percentage of excess weight loss, postoperative complications, and symptom duration.44 In line with this study, Kanlioz et al.57 reported similar results, demonstrating higher efficacy but more complications with IGB than with IBI. Except for IGB, no comparative trials have examined IBI using other endoscopic bariatric procedures. To address this knowledge gap, future studies should include an arm for endoscopic sleeve gastroplasty, aspiration therapy, transpyloric shuttling, and other methods.
Sánchez-Torralvo et al.45 evaluated the role of IBI as a bridge therapy before bariatric surgery. The patients on the bariatric surgery waitlist were randomized into the IBI and placebo groups. Seven to eight months before surgery, the patient underwent upper endoscopy. In the IBI group, 200 U of BTA was injected at 16 points into the gastric wall (fundus and antro-pyloric region), whereas in the placebo group, physiological saline was injected using the same protocol as used for the placebo group. Weight reduction was evaluated upon admission and at 4 and 12 weeks after surgery. The average weight loss percentage on the day of surgery was –7.6% for the IBI group compared to –4.5% for the placebo group (p=0.013). The weight loss percentage appeared to be consistently higher in the IBI group 1 month after surgery (–15.2% vs. –12.7%, p=0.07) and leveled off at 3 months (–21.6% for both groups). The researchers suggested that IBI is effective in achieving substantial weight loss, particularly in individuals with a BMI of ≥50 kg/m2, and administering IBI before bariatric surgery can enhance weight loss during the perioperative period. However, it is crucial to consider the presence of lead-time bias when drawing conclusions from these findings. Although weight loss was more pronounced in the IBI group during the immediate postoperative period, it ultimately became comparable 3 months after surgery, which suggests that there is no additional benefit of preoperative IBI in patients undergoing bariatric surgery. Thus, IBI may be a treatment option for patients who refuse bariatric surgery and may not enhance the effects of bariatric surgery.
Pharmacological treatments for obesity, particularly the use of glucagon-like peptide-1 agonists, are becoming increasingly popular due to their easy administration, high efficacy, and few side effects.58 In a study conducted by Gameel et al.,59 the efficacies of IBI and liraglutide in weight loss were compared. The study included 20 patients in each group who were closely monitored for 16 weeks with dietary and exercise guidance. The findings of the study revealed that both IBI and liraglutide demonstrated significant efficacy in promoting weight loss, with no discernible superiority of one method over the other. Moreover, a large-scale study by the same group investigated the impact of a combination of liraglutide and IBI on weight loss in patients with obesity (BMI >30 kg/m2). The study included 541 patients in the IBI+liraglutide group (group I) and 160 in the IBI alone group (group II). BTA (500 U) was injected into 24 sites in the fundus and antro-pyloric region. Liraglutide treatment was initiated at 0.6 mg per day and increased to 1.2 mg per day after 1 week. A low-calorie diet was administered to all the patients based on their comorbidities. After 6 months of follow-up, both groups experienced a significant weight loss (24.9 kg and 9.8 kg for groups I and II, respectively); however the weight loss was more significant in group I than in group II (p<0.001). No significant differences in adverse effects were observed between the groups (31.8% and 25% for groups I and II, respectively). The investigators proposed IBI plus liraglutide therapy to be safer and more effective for weight loss than IBI alone.46 Further studies, with direct comparisons of IBI and various pharmacological agents in terms of efficacy, safety, and cost are needed to shed light on this aspect.
In light of the discussed findings, one must ponder upon the following question: What lies ahead of IBI regarding its potential for weight loss?
The current literature shows discrepancies in various aspects. There is variability in the methodologies employed across studies, including differences in the dosage of BTA administered, injection site, number and depth of injections, post-procedural dietary modifications, and follow-up duration. Furthermore, the measured outcomes vary, with some studies focusing on GE whereas others prioritizing satiety or weight loss. Additionally, the follow-up duration varies significantly, which is essential to consider because of the temporary nature of the effects of BTA treatment. Future research should investigate the quantitative GI factors that can predict treatment success. Additionally, it remains uncertain whether repeated injections have a lasting effect. Evaluating the cost-to-benefit ratio is crucial when considering long-term treatment through repeated injections. If IBI is considered for patients who are ineligible for or refuse surgery, its efficacy and cost need to be compared with those of pharmaceutical options. Finally, adverse events should not be disregarded. Establishing an international database is imperative for understanding severe adverse events, such as iatrogenic botulism. Studies with consistent outcome measures and methodologies are necessary to thoroughly assess the potential effects of BTA on weight management.
Fig. 1.
Management of patients who are overweight and those who are obese. BMI, body mass index; DM, diabetes mellitus. a)Pharmacotherapy and endoscopic procedures of no more than 5% weight loss in three to six months with lifestyle intervention alone.
ce-2024-153f1.jpg
Table 1.
Adiposity-related complications
Mild to moderate complications Severe complications
Metabolic syndrome Non-alcoholic fatty liver disease Myocardial infarction
Uncomplicated diabetes mellitus Polycystic ovary syndrome Heart failure
Prediabetes Stable cardiovascular disease Cerebral vascular accident
Dyslipidemia Gastroesophageal reflux disease Diabetic complications
Hypertension Depression Incapacitating osteoarthritis
Osteoarthritis Infertility Significant psychopathology
Sleep disorder Hypogonadism Significant functional limitations
Asthma Headache
Table 2.
A summary of meta-analyses on the efficacy of IBI in obesity
Study Bang et al.18 Bustamante et al.19 Chang et al.20 Yen et al.15
Publication year 2015 2017 2020 2022
Included studies 5 RCTs, 2 non-RCTs 4 RCTs 5 RCTs 6 RCTs
No. of participants (IBI/control) 115 (79/36) 142 (72/70) 174 (88/86) 226 (116/110)
Heterogeneity of primary outcome (I2, %) 67 89 87 62
Results IBI is effective for weight loss. Wide area injection (including body or fundus) and multiple injections (>10) are associated with better outcomes. IBI alone is not effective for the primary treatment of obesity. IBI is not superior to saline in absolute weight loss or BMI change. Patients with BMI ≥40 kg/m2 may benefit from IBI. IBI is effective for obesity treatment, and adequate doses (≥200 U), multiple gastric injection regions, and combined diet control are crucial.
AMSTAR 2 quality score Critically low High Low Critically low

IBI, intragastric botulinum toxin injection; RCT, randomized controlled trial; BMI, body mass.

Table 3.
Summary of published human studies of IBI for weight loss
Study Publication year Country Study design Population (kg/m2) Number (BTA/control) Follow-up duration BTA dosage(U) Injections no./locations EUS-guided Diet Results Side effects
Albani et al.29 2005 Italy Open-label 38.2≤BMI≤56.7 8 (8/NA) 16 wk 500 10/antrum No NR IBI is effective for weight loss independent of changes in hunger or satiety Nausea in one (12.5%) patient
García-Compean et al.32 2005 Mexico Clinical trial BMI over 30 12 (12/NA) 12 wk 100 8/antropyloric No NR IBI does not seem to reduce body weight or induce changes in GE in patients with obesity NR
Gui et al.33 2005 Italy RCT BMI≥30 14 (10/4) 5 wk 133, 200 8/antrum No NR IBI is an effective method for weight loss, and BTA has potential activity as a clinical tool for gastric motility and possibly for manipulation of appetite NR
Júnior et al.28 2006 Brazil Pilot study BMI ≥40 12 (12/NA) 12 wk 200, 300 8, 16, 24/antropyloric No NR No significant change in weight before and after the IBI NR
Foschi et al.22 2007 Italy RCT BMI ≥35 with 2 complications of obesity or BMI≥40 without complications 24 (12/12) 8 wk 200 12/antrum, fundus No 1200 kcal diet Greater weight loss, BMI reduction, early satiety and delayed GE in IBI group NR
Mittermair et al.23 2007 USA RCT 30≤BMI≤35 10 (5/5) 6 mo 200 16/antrum, body No NR IBI does not appear to reduce body weight NR
Topazian et al.35 2008 USA Pilot study BMI≥30 10 (10/NA) 16 wk 100, 300 5/antrum Yes NR Beneficial effects of 300 U BTA (not 100 U) on weight loss and satiation was observed Diarrhea in two (20%) patients
Foschi et al.25 2008 Italy RCT 35≤BMI<40 with two complications of obesity or BMI >40 30 (18/12) 8 wk 200 20/antrum, fundus No 1,200 kcal liquid diet IBI makes weight loss easier and decreases GE and capacity NR
Li et al.27 2012 China RCT BMI>28 19 (9/10) 12 wk 200, 300 20/antrum, body, fundus No NR Endoscopic multiple punctures of BTA with fundic injections could potentially lead to weight loss and a decrease in BMI by slowing down GE. The impact of BTA on ghrelin levels might also play a role in suppressing appetite NR
Topazian et al.30 2013 USA RCT BMI ≥30 and body weight ≥85 kg 60 (45/15) 24 wk 100, 300, 500 15/antrum Yes NR Injections of 300 U of BTA into gastric antral muscularis propria under EUS guidance may induce delays in GE, but they do not cause body weight loss NR
Chen et al.31 2016 Norway RCT 35≤ BMI ≤44 20 (10/10) 6 mo NR NR/antrum No NR Reduced body weight is associated with increased satiety in IBI group Dumping syndrome in one (10%) patient after 12 mo
de Moura et al.36 2019 Brazil RCT BMI>50 32 (16/16) 24 wk 200 40/antrum, body Yes In the first 14 days, a restricted liquid diet of up to 700 kcal/day; days 15-25, up to 800 kcal/day; day 26 through the end of the 6-month, up to 1000 kcal/day IBI is not an effective way for weight loss NR
Durmus et al.44 2019 Turkey Clinical trial Patients with obesity 52 (26/26) 3 mo 100 NR/NR No Healthy eating habit The intragastric balloon is a more efficient treatment than IBI, although it has more complications NR
Gameel et al.34 2020 Egypt Open-label BMI ≥30 25 (25/NA) 16 wk 100 5/antrum, pyloric ring Yes NR IBI seems to be effective for weight loss NR
Ferhatoglu et al.26 2020 Turkey Observational study BMI≥30 87 (44/43) 6 mo 100 20/pyloric ring, fundus, cardia No 1000 kcal restricted diet The pairing of a calorie-restricting diet with IBI would become a popular bariatric therapy for patients with obesity NR
Kanlioz et al.24 2020 Turkey Observational study BMI≥25 178 (178/ NA) 6 mo 200 20/antrum No Hypocaloric diet No significant decrease in BMI was observed NR
Kaya et al.38 2020 Turkey Pilot study BMI≥25 56 (56/ NA) 6-9 mo 250 10/antrum No 1200 kcal diet IBI can be beneficial in weight loss Abdominal pain and vomiting in one (1.8%) patient
Liu et al.17 2020 Taiwan Observational study 27≤BMI≤30 126 (126/ NA) 6 mo 300, 400 NR/fundus, body, antrum No 300 kcal less than their daily requirement IBI, especially on fundus, is an effective method for weight loss. Alterations in ghrelin and other incretins, along with delayed GE, are the keys to decreasing eating amount and reaching early satiety NR
30≤BMI≤35
Sánchez-Torralvo et al.45 2022 Spain RCT BMI>40 or BMI >35 with comorbidities 52 (28/24) 24 wk 200 16/antrum, fundus No 1500 kcal Mediterranean diet IBI is an effective and safe procedure to achieve moderate weight loss and improve quality of life NR
Şen et al.39 2021 Turkey Observational study 26≤BMI≤31.6 13 (13/NA) 6 mo 300 24/antrum, body, fundus No 1200-calorie low-carbohydrates diet IBI as a weight loss therapy does not provide significant results Total gastric necrosis in one patient (7.6%)
Abesadze et al.40 2021 Georgia Open-label Women of reproductive age with 25<BMI<40 32 (32/NA) 12 wk 1000 NR No NR IBI is an effective and safe method in young overweight, class I-II obese women. Endocrine disorders are not contraindications for the procedure NR
Hsu et al.37 2022 Taiwan Clinical trial BMI>25 71 (49/22) 12 wk 300 30/antrum, body, fundus No Low-calorie high-protein diet IBI is more effective than diet control alone Nausea (4%), diarrhea (2%), constipation (24.4%), urinary disorder (2%), and abdominal pain (2%)
Özdil et al.41 2022 Turkey Pilot study BMI>30 72 (24/48) 6 mo 200 NR/antrum, fundus No Calorie-restricted (15–20 kcal/kg) diet IBI is a minimally invasive and temporary effective method to be used in the treatment of obesity NR
Tayyem et al.42 2022 Jordan Prospective cohort BMI>25 176 (88/88) 6 mo 100 6/antrum, cardia, fundus No 1200–1300 kcal/day IBI is a minimally invasive, effective, and safe procedure capable of suppressing appetite and promoting weight loss Nausea, vomiting, and abdominal pain (9%)
Altunal et al.46 2023 Turkey Retrospective cohort BMI>30 701 (160/541) 3 mo 500 25/fundus No NR IBI combined with liraglutide is a safe method that provides a more effective weight loss than IBI alone Nausea (9.4%), vomiting (7%), abdominal pain (1.7%), flatulence (7.8%), diarrhea (1%), and constipation (9.4%)
Köseoğlu et al.43 2024 Turkey Clinical trial BMI >25 with at least one obesity-related complication or BMI >30 without obesity-related complications 82 (82/NA) 6 mo 200 14/antrum, incisura angularis, body No No IBI is associated with a significant weight loss in obese patients, although the weight loss is not constant NR

IBI, intragastric botulinum toxin injection; BTA, botulinum toxin A; EUS, endoscopic ultrasound; BMI, body mass index; NA, not applicable; NR, not reported; GE, gastric emptying; RCT, randomized clinical trial.

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      Intragastric botulinum toxin injection for weight loss: current trends, shortcomings and future perspective
      Image
      Fig. 1. Management of patients who are overweight and those who are obese. BMI, body mass index; DM, diabetes mellitus. a)Pharmacotherapy and endoscopic procedures of no more than 5% weight loss in three to six months with lifestyle intervention alone.

      Fig. 1.

      Intragastric botulinum toxin injection for weight loss: current trends, shortcomings and future perspective
      Mild to moderate complications Severe complications
      Metabolic syndrome Non-alcoholic fatty liver disease Myocardial infarction
      Uncomplicated diabetes mellitus Polycystic ovary syndrome Heart failure
      Prediabetes Stable cardiovascular disease Cerebral vascular accident
      Dyslipidemia Gastroesophageal reflux disease Diabetic complications
      Hypertension Depression Incapacitating osteoarthritis
      Osteoarthritis Infertility Significant psychopathology
      Sleep disorder Hypogonadism Significant functional limitations
      Asthma Headache
      Study Bang et al.18 Bustamante et al.19 Chang et al.20 Yen et al.15
      Publication year 2015 2017 2020 2022
      Included studies 5 RCTs, 2 non-RCTs 4 RCTs 5 RCTs 6 RCTs
      No. of participants (IBI/control) 115 (79/36) 142 (72/70) 174 (88/86) 226 (116/110)
      Heterogeneity of primary outcome (I2, %) 67 89 87 62
      Results IBI is effective for weight loss. Wide area injection (including body or fundus) and multiple injections (>10) are associated with better outcomes. IBI alone is not effective for the primary treatment of obesity. IBI is not superior to saline in absolute weight loss or BMI change. Patients with BMI ≥40 kg/m2 may benefit from IBI. IBI is effective for obesity treatment, and adequate doses (≥200 U), multiple gastric injection regions, and combined diet control are crucial.
      AMSTAR 2 quality score Critically low High Low Critically low
      Study Publication year Country Study design Population (kg/m2) Number (BTA/control) Follow-up duration BTA dosage(U) Injections no./locations EUS-guided Diet Results Side effects
      Albani et al.29 2005 Italy Open-label 38.2≤BMI≤56.7 8 (8/NA) 16 wk 500 10/antrum No NR IBI is effective for weight loss independent of changes in hunger or satiety Nausea in one (12.5%) patient
      García-Compean et al.32 2005 Mexico Clinical trial BMI over 30 12 (12/NA) 12 wk 100 8/antropyloric No NR IBI does not seem to reduce body weight or induce changes in GE in patients with obesity NR
      Gui et al.33 2005 Italy RCT BMI≥30 14 (10/4) 5 wk 133, 200 8/antrum No NR IBI is an effective method for weight loss, and BTA has potential activity as a clinical tool for gastric motility and possibly for manipulation of appetite NR
      Júnior et al.28 2006 Brazil Pilot study BMI ≥40 12 (12/NA) 12 wk 200, 300 8, 16, 24/antropyloric No NR No significant change in weight before and after the IBI NR
      Foschi et al.22 2007 Italy RCT BMI ≥35 with 2 complications of obesity or BMI≥40 without complications 24 (12/12) 8 wk 200 12/antrum, fundus No 1200 kcal diet Greater weight loss, BMI reduction, early satiety and delayed GE in IBI group NR
      Mittermair et al.23 2007 USA RCT 30≤BMI≤35 10 (5/5) 6 mo 200 16/antrum, body No NR IBI does not appear to reduce body weight NR
      Topazian et al.35 2008 USA Pilot study BMI≥30 10 (10/NA) 16 wk 100, 300 5/antrum Yes NR Beneficial effects of 300 U BTA (not 100 U) on weight loss and satiation was observed Diarrhea in two (20%) patients
      Foschi et al.25 2008 Italy RCT 35≤BMI<40 with two complications of obesity or BMI >40 30 (18/12) 8 wk 200 20/antrum, fundus No 1,200 kcal liquid diet IBI makes weight loss easier and decreases GE and capacity NR
      Li et al.27 2012 China RCT BMI>28 19 (9/10) 12 wk 200, 300 20/antrum, body, fundus No NR Endoscopic multiple punctures of BTA with fundic injections could potentially lead to weight loss and a decrease in BMI by slowing down GE. The impact of BTA on ghrelin levels might also play a role in suppressing appetite NR
      Topazian et al.30 2013 USA RCT BMI ≥30 and body weight ≥85 kg 60 (45/15) 24 wk 100, 300, 500 15/antrum Yes NR Injections of 300 U of BTA into gastric antral muscularis propria under EUS guidance may induce delays in GE, but they do not cause body weight loss NR
      Chen et al.31 2016 Norway RCT 35≤ BMI ≤44 20 (10/10) 6 mo NR NR/antrum No NR Reduced body weight is associated with increased satiety in IBI group Dumping syndrome in one (10%) patient after 12 mo
      de Moura et al.36 2019 Brazil RCT BMI>50 32 (16/16) 24 wk 200 40/antrum, body Yes In the first 14 days, a restricted liquid diet of up to 700 kcal/day; days 15-25, up to 800 kcal/day; day 26 through the end of the 6-month, up to 1000 kcal/day IBI is not an effective way for weight loss NR
      Durmus et al.44 2019 Turkey Clinical trial Patients with obesity 52 (26/26) 3 mo 100 NR/NR No Healthy eating habit The intragastric balloon is a more efficient treatment than IBI, although it has more complications NR
      Gameel et al.34 2020 Egypt Open-label BMI ≥30 25 (25/NA) 16 wk 100 5/antrum, pyloric ring Yes NR IBI seems to be effective for weight loss NR
      Ferhatoglu et al.26 2020 Turkey Observational study BMI≥30 87 (44/43) 6 mo 100 20/pyloric ring, fundus, cardia No 1000 kcal restricted diet The pairing of a calorie-restricting diet with IBI would become a popular bariatric therapy for patients with obesity NR
      Kanlioz et al.24 2020 Turkey Observational study BMI≥25 178 (178/ NA) 6 mo 200 20/antrum No Hypocaloric diet No significant decrease in BMI was observed NR
      Kaya et al.38 2020 Turkey Pilot study BMI≥25 56 (56/ NA) 6-9 mo 250 10/antrum No 1200 kcal diet IBI can be beneficial in weight loss Abdominal pain and vomiting in one (1.8%) patient
      Liu et al.17 2020 Taiwan Observational study 27≤BMI≤30 126 (126/ NA) 6 mo 300, 400 NR/fundus, body, antrum No 300 kcal less than their daily requirement IBI, especially on fundus, is an effective method for weight loss. Alterations in ghrelin and other incretins, along with delayed GE, are the keys to decreasing eating amount and reaching early satiety NR
      30≤BMI≤35
      Sánchez-Torralvo et al.45 2022 Spain RCT BMI>40 or BMI >35 with comorbidities 52 (28/24) 24 wk 200 16/antrum, fundus No 1500 kcal Mediterranean diet IBI is an effective and safe procedure to achieve moderate weight loss and improve quality of life NR
      Şen et al.39 2021 Turkey Observational study 26≤BMI≤31.6 13 (13/NA) 6 mo 300 24/antrum, body, fundus No 1200-calorie low-carbohydrates diet IBI as a weight loss therapy does not provide significant results Total gastric necrosis in one patient (7.6%)
      Abesadze et al.40 2021 Georgia Open-label Women of reproductive age with 25<BMI<40 32 (32/NA) 12 wk 1000 NR No NR IBI is an effective and safe method in young overweight, class I-II obese women. Endocrine disorders are not contraindications for the procedure NR
      Hsu et al.37 2022 Taiwan Clinical trial BMI>25 71 (49/22) 12 wk 300 30/antrum, body, fundus No Low-calorie high-protein diet IBI is more effective than diet control alone Nausea (4%), diarrhea (2%), constipation (24.4%), urinary disorder (2%), and abdominal pain (2%)
      Özdil et al.41 2022 Turkey Pilot study BMI>30 72 (24/48) 6 mo 200 NR/antrum, fundus No Calorie-restricted (15–20 kcal/kg) diet IBI is a minimally invasive and temporary effective method to be used in the treatment of obesity NR
      Tayyem et al.42 2022 Jordan Prospective cohort BMI>25 176 (88/88) 6 mo 100 6/antrum, cardia, fundus No 1200–1300 kcal/day IBI is a minimally invasive, effective, and safe procedure capable of suppressing appetite and promoting weight loss Nausea, vomiting, and abdominal pain (9%)
      Altunal et al.46 2023 Turkey Retrospective cohort BMI>30 701 (160/541) 3 mo 500 25/fundus No NR IBI combined with liraglutide is a safe method that provides a more effective weight loss than IBI alone Nausea (9.4%), vomiting (7%), abdominal pain (1.7%), flatulence (7.8%), diarrhea (1%), and constipation (9.4%)
      Köseoğlu et al.43 2024 Turkey Clinical trial BMI >25 with at least one obesity-related complication or BMI >30 without obesity-related complications 82 (82/NA) 6 mo 200 14/antrum, incisura angularis, body No No IBI is associated with a significant weight loss in obese patients, although the weight loss is not constant NR
      Table 1. Adiposity-related complications

      Table 2. A summary of meta-analyses on the efficacy of IBI in obesity

      IBI, intragastric botulinum toxin injection; RCT, randomized controlled trial; BMI, body mass.

      Table 3. Summary of published human studies of IBI for weight loss

      IBI, intragastric botulinum toxin injection; BTA, botulinum toxin A; EUS, endoscopic ultrasound; BMI, body mass index; NA, not applicable; NR, not reported; GE, gastric emptying; RCT, randomized clinical trial.

      Table 1.

      Table 2.

      Table 3.

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