Can gastric botulinum toxin A injection be used as minimally invasive procedure in the short-term treatment of obesity?

BACKGROUND/AIM: Gastric botulinum toxin A (BTX-A) injection is a type of endoscopic obesity treatment option that delays gastric emptying. However, there is little and contradictory information concerning the treatment efficacy of BTX-A injection. This study evaluated the treatment efficacy of BTX-A injection in the treatment of obesity.
MATERIALS AND METHODS: This was an open-label, prospective study of obese individuals with a body mass index >30 kg/m2 admitted to our clinic. The sample consisted of 72 consecutive treatment-naive patients with obesity divided into age-sex-matched three groups: gastric BTX-A injection (study group), calorie-restricted (15-20 Kcal/kg) diet (control) and bariatric surgery (BS) (control) groups. İn the study group, 200 IU BTX-A was injected to the antrum and corpus endoscopically. The study and control groups were compared for their total body weight loss (TBWL) and excess body weight loss (EBWL) at the 6th month.
RESULTS: Gastric BTX-A injection therapy was applied to 24 patients. The mean age was 39.1 ± 9.1/years. 54.1% of the patients (n = 13) was female. At the 6th month, the mean TBWL and EBWL of patients were; 10% ±4.1 and 37.2% ±13.9 for gastric BTXA injection group, 5% ±2.3 and 20.2% ±9.3 for diet group, 30.7% ±5.3 and 66.9% ±14.4 for BS group. Patients who underwent gastric BTX-A injection lost weight more effectively than patients who were on diet alone, while BS patients lost weight more effectively than those who had gastric BTX-A injection (P < 0.001). In the gastric BXT-A injection group, the first 3-month delta EBWL and TBWL (change of EBWL and TBWL percentages) were found significantly higher than the 3-6th month and 6-12th month (P = 0.001 and P < 0.001).
CONCLUSION: Gastric BTX-A injection is a minimally invasive and short-term effective method that can be used in the treatment of obesity.

INTRODUCTION

Obesity is a serious health problem with an increased global prevalence.[1] It is also associated with reduced levels of quality of life and increased rates of morbidity and mortality. Some of the obesity-related health problems are hypertension, type 2 diabetes, dyslipidaemia, cardiovascular diseases, non-alcoholic fatty liver disease, degenerative joint disease, gastroesophageal reflux disease and malignancies.[2]

Reducing more than 10% of total body weight significantly reduces obesity-related risks. Treatments for obesity are diet and lifestyle changes as well as exercise, pharmacotherapy, endoscopy and surgical intervention.[3] Lifestyle changes, diet and pharmacotherapy often have limited efficacy or fail to achieve treatment goals,[4] while bariatric surgery (BS) is highly effective.[5] However, BS is a treatment option only for patients with a body mass index (BMI) of 40 kg/m2 or ≥35 kg/m2 and obesity-related morbidities. However, most patients do not prefer to undergo surgery because it is an invasive intervention that may cause morbidities.

Endoscopic treatments are safer, minimally invasive, reversible and cost-effective compared to surgical treatments. Endoscopic therapies for obesity are categorised as space-occupying devices, sleeve gastrectomy, malabsorption and methods to regulate gastric emptying.[6]

Gastric botulinum toxin A (BTX-A) injection is a type of treatment for obesity that delays gastric emptying. However, there is little and contradictory information concerning the efficacy of BTX-A injection. This study evaluated the efficacy of BTX-A in the treatment of obesity.

MATERIALS AND METHODS

This was an open-label, prospective study on obese individuals with a BMI >30 kg/m2. The sample consisted of 72 consecutive treatment-naive people with obesity admitted to the gastroenterology department of the Health Sciences University Umraniye Training and Research Hospital between January 2019 and February 2020.

The exclusion criteria were being pregnant, having a metabolic disease that prevents weight loss, a history of gastrointestinal surgery, malignancy or alcohol use and having been on a diet or medication/herbal therapy to lose weight in the last 3 months.

All patients in the study group were evaluated endoscopically and confirmed that there was not any pathology (ulcer, malignancy, stenosis, erosive/reflux esophagitis, etc.) before the procedure. In addition, the patients were not receiving antiaggregant or anticoagulant therapy.

Prior to intervention, demographic and basal blood data (total blood count, haemoglobin A1c, thyroid-stimulating hormone, liver and kidney functions, lipid profiles and HOMA-IR) were recorded.

Informed consent was obtained from the subjects for the intervention and anaesthesia. They were sedated (2 mg/kg propofol) for the procedure performed by an experienced gastroenterologist using Fujinon (Fujifilm Tokyo, Japan) VP-4450 HD, Fujinon EG 590WR gastroscope and Pentax EPK i7010; EG-2990Zi gastroscope. Each 100 U-10 ml (Allergan Botox ®1 vial) was diluted with 0.9% saline (200 U BTX-A in total) and injected semicircularly into the antrum-corpus junction, distal to the corpus (100 U), and into the fundus–corpus junction, proximal to the corpus (100 U) with 1–3-cm intervals using a 23G Carr-Locke injection needle.

All patients, in the study group, were checked and examined regarding post-procedural complications. Furthermore, at the post-procedure 2nd week, they were called on the phone to check whether they presented any post-procedural symptoms (abdominal pain, vomiting, newly developed reflux, etc.). After the procedure, they were put on a diet prescribed typically to post-sleeve gastrectomy patients. Without calorie restriction, the subjects were put on an only-fluid diet for a week after the procedure, then moved onto a semi-solid diet for 2–4 weeks and then returned to their regular diet after the 6th week. They were followed up at 3-month intervals for weight loss.

The bariatric group consisted of 24 sleeve gastrectomy patients (age and gender matched) followed up regularly in the diet polyclinic after being operated by an experienced general surgeon. The diet group consisted of 24 patients (age and gender matched) without comorbid diseases who were on a calorie-restricted diet (15–20 kcal per kilo) in the diet outpatient clinic.

The total body weight loss (TBWL) and excess body weight loss (EBWL) values of the gastric BTX-A injection group were recorded and compared at 3-month intervals for 12 months. Furthermore, the gastric BTX-A injection and control groups were compared for their TBWL and EBWL at the 6th month.

The study was approved by the ethics committee of the Health Sciences University Umraniye Training and Research Hospital (Date: 18 March 2020 and No: B.10.1.TKH.4.34.H. GP. 0.01/69).

Statistical analysis

The data were analysed using the Statistical Package for the Social Sciences (SPSS version 25.0) at a significance level of 0.05 and a confidence interval of 95%. Mean (median for non-normally distributed data), frequency and percentage were used for descriptive analysis. The Shapiro–Wilk test was used for normality testing because the sample size of each group was smaller than 50. A Student's t-test was used for normally distributed data, while the Mann–Whitney U-test was used for non-normally distributed data. For normally distributed data, a one-way analysis of variance and post hoc test were used to compare the means of continuous variables between more than two groups. For non-normally distributed data, Kruskal–Wallis test was used to compare the means of continuous variables between more than two groups. On the other hand, Friedman test was also used for non-normally distributed data to find out the differences between two or more groups of a dependent variable. The Chi-square and Fisher's exact tests were used to compare the categorical data.

RESULTS

The average age of the patients who received BTX-A injection (n = 24) was 39.1 ± 9.1 years. All study groups were similar in terms of baseline demographic features and laboratory values. The bariatric group had a significantly higher mean BMI than the gastric and diet groups (P < 0.001). The baseline characteristics of the patients are shown in Table 1. The 6th-month TBWL and EBWL values of all groups are shown in Table 2 and Figure 1. The 6th-month TBWL and EBWL values of the gastric BTX-A injection group are shown in Figure 2.

Table 1

Baseline characteristics of gastric botulinum toxin A, diet and bariatric surgery groups

	Gastric BTX-A (n=24)	Diet (n=24)	Bariatric surgery (n=24)	P
Age	39.1±9.1	42 (IQR: 10)*	40.2±7.7	0.605**
Male, n (%)	11 (45.8)	9 (37.5)	8 (33.3)	0.664**
Female, n (%)	13 (54.2)	15 (62.5)	16 (66.7)
BMI (kg/m2)	34.9±3.9	33.1 (IQR: 6.55)*	46.9±4.3	<0.001**
Creatinine	0.83±0.1	0.79±0.1	0.79 (IQR: 0.19)*	0.811**
Glucose (mg/dl)	92.7±7.6	93.9±9.9	91.5 (IQR: 5)*	0.967**
HOMA-IR	2.56 (IQR: 1.43)*	2.93 (IQR: 1.19)*	3.17 (IQR: 1.81)*	0.089**
HbA1c (mmol/mol)	5.7±0.2	5.8±0.3	5.9±0.3	0.242***
Total cholesterol (mg/dl)	203.3±35.3	182.9±45.9	189.4±26	0.152***
HDL (mg/dl)	41.5 (IQR: 6.25)*	40.8±4.2	42 (IQR: 10.5)*	0.149**
LDL (mg/dl)	134.9±30.3	128.4±28.1	124.7±21.1	0.413***
Triglyceride	166.8±64.6	186±47.4	148±66.3	0.097***
TSH	1.5421±0.43	1.5438±0.37	1.4625±0.44	0.745***
ALT	30.5 (IQR: 11.50)*	29.2±7.7	30 (IQR: 15.75)*	0.920**
AST	27±8	27.7±6.1	29 (IQR: 10)*	0.764**
Haemoglobin	13.9±1.3	13.1 (IQR: 1.75)*	13.7±1	0.549**

*Median values, **Kruskal–Wallis H test, ***One-way ANOVA test. BMI: Body mass index, HOMA-IR: Homoeostatic model assessment of insulin resistance, HDL: High-density lipoprotein, LDL: Low-density lipoprotein, TSH: Thyroid-stimulating hormone, ALT: Alanine aminotransferase, AST: Aspartate aminotransferase, BTX-A: Botulinum toxin A, IQR: Interquartile range, HbA1c: Haemoglobin A1c, ANOVA: Analysis of variance

Table 2

Comparison of total body weight loss and excess body weight loss values of all groups at the 6th month

Weight loss	Gastric BTX-A	Diet	Bariatric surgery	P
TBWL month 3 (%)	7.1 (İQR: 3.9)*	4.75±2.2	18.55 (İQR: 6.2)*	<0.001**
EBWL month 3 (%)	26.2 (İQR: 17.2)*	19.47±9.3	39.0 (İQR: 14.3)*	<0.001**
TBWL month 6 (%)	10±4.1	5±2.3	30.7±5.3	<0.001***
EBWL month 6 (%)	37.2±13.9	20.2±9.3	66.9±14.4	<0.001***

*Median, **Kruskal–Wallis test, ***One-way ANOVA test. BTX-A: Botulinum toxin A, TBWL: Total body weight loss, EBWL: Excess body weight loss, IQR: Interquartile range, ANOVA: Analysis of variance

Figure 1

Comparison of treatment efficacy

Figure 2

The 6th-month TBWL and EBWL values of the gastric BTX-A injection group. TBWL: Total body weight loss, EBWL: Excess body weight loss, BMI: Body mass index

At the 3rd and 6th months, TBWL-EBWL values were the highest in the BS group (P < 0.001) than others. At the 3rd and 6th months, TBWL-EBWL values of the gastric BTX-A injection group were higher than the diet group (P = 0.044, P = 0.038 and P = 0.016, P = 0.040, respectively).

In the gastric BXT-A injection group, the first 3-month delta EBWL (change percentages of EBWL) was found significantly higher than the 3–6th month and 6–12th month (P = 0.001 and P < 0.001) [Figure 3]. Furthermore, the first 3-month delta TBWL (change percentages of TBWL) was found significantly higher than the 3–6th month and 6–12th month (P = 0.001 and P < 0.001) [Figure 4].

Figure 3

Comparison of delta excess body weight loss (change percentages of excess body weight loss) values of patients who received gastric BXT-A injection according to 3-month intervals. Friedman test

Figure 4

Comparison of delta total body weight loss (change percentages of excess body weight loss) values of patients who received gastric BXT-A injection according to 3-month intervals. Friedman test

At the 12th month, EBWL and TBWL values of the gastric BTX-A injection group were found to be 38.1 ± 19.1 and 10.3 ± 5.8, respectively. The gastric BTX-A injection group subjects had no complication or new symptoms, during post-procedure follow-up.

DISCUSSION

Endoscopic bariatric and metabolic treatments (EBMTs) are cost-effective, minimally invasive, reversible and physiological methods developed in recent years to bridge the gap between medical and surgical treatments.[7] They are also pre-surgical bridge therapies. There is a wide range of endoscopic treatments, and many more are under development. One of those treatments is gastric BTX-A injection.

BTX-A is a neurotoxic protein produced by Clostridium botulinum, a Gram-positive anaerobic bacterium.[8] It inhibits the release of acetylcholine (Ach), which is responsible for neurotransmission in the central and peripheral nervous systems.[9] In vitro and in vivo studies have shown that BTX-A also reduces cholinergic transmission by inhibiting the release of Ach in the gastrointestinal smooth muscle.[1011] BTX-A is the most potent muscle contraction inhibitor. Gastric BTX-A injection inhibits the interdigestive migrating motor complexes originating in the antrum and enabling the passage of solid food towards the pylorus,[12] thereby interfering with gastric emptying and also inhibiting the secretion of ghrelin, a potent hormone of gastric fundus origin that stimulates appetite.[13] These effects are associated with reduced stomach capacity, loss of appetite and increased satiety.[14] BTX-A is also an option for the treatment of some gastrointestinal disorders (cricopharyngeal achalasia, achalasia, sphincter of Oddi dysfunction, gastroparesis, pelvic floor dyssynergia and chronic idiopathic anal pain and anal fissure).[15]

Gui et al. reported that rats who received gastric BTX-A consumed less food and lost more weight than those who underwent a sham procedure.[12] Çoşkun et al. also observed more delayed gastric emptying and greater weight loss in rats who received gastric BTX-A than in controls.[16]

Clinical trials report contradictory results on the efficacy of gastric BTX-A, but they have methodological differences. The treatment efficacy of gastric BTX-A may depend on the patient characteristics, dose and number of injections, procedure, body site and post-procedural diet.[17]

We followed up the gastric group subjects for 6 months to determine the treatment efficacy of gastric BTX-A. They had a mean TBWL of 10 ± 4.1% and EBWL of 37.2% ±13.9 in the 6th month. Studies report conflicting results on post-gastric BTX-A weight loss. A meta-analysis of eight trials has revealed that wide-area injections, including the fundus or body rather than the antrum only, and multiple injections (>10) are associated with weight loss.[18]

All trials that have reported the efficacy of BTX-A in weight loss and delayed gastric emptying have tested a dose of 200 U.[192021] We used the same dose and administered multiple injections semicircularly into the antrum–corpus junction, distal to the corpus (100 U), and into the fundus–corpus junction, proximal to the corpus (100 U). The injection site was 16–20 sites, and the distance between every two injection points was 1 cm. We think that its administration to a wide area of the stomach may be effective even at low doses. Furthermore, we did not find any data regarding the dose application of botulinum toxin adjusted on the patient weight. There is no weight-dependent dose calculation in other areas of the use of botulinum toxin A injection, either. In addition, in our study, patients with high BMI had higher EBWL and TBWL values.

The groups were demographically and clinically similar. As an indication for operation, the bariatric group had a higher BMI than the others. We found that the bariatric group had the highest EBWL and TBWL, followed by the gastric BTX-A injection and diet groups (P < 0.001).

As far as we know, the effect of BTX-A injection lasts for 3–6 months. However, there is no data on the long-term efficacy of gastric BTX-A injection.[14] In our study, we found that the amount of weight loss in the first 3 and 6 months was greater than in the second 3 and 6 months (P < 0.001), probably because the effect of gastric BTX-A diminishes with time. In addition, we found that at the end of the follow-up period (12 months), the TBWL and EBWL values of the patients were similar to the results at the 6th month. Patients did not gain weight after the 6th month until the 1-year follow-up.

Our study results also showed that the gastric BTX-A injection was significantly more effective only than the diet group. İn the other hand, we already had been thought that BS is more effective than gastric BTX-A injection in the treatment of obesity. We wanted to compare our results with sleeve gastrectomy, which is a common and more effective treatment modality in our country. BS is the gold standard treatment for obesity. However, gastric BTX-A injection may be a promising option for patients who cannot undergo surgery. Therefore, prospective placebo-controlled studies should be carried out to assessing gastric BTX-A injection therapy.

This study has some limitations. Some of them are the absence of a placebo arm, the diets that are not similar between all groups and the inability to monitor ghrelin levels in patients who received gastric BTX-A injection.

CONCLUSION

The development of new endoscopic techniques and improvement in existing designs suggest an increasingly important role of the endoscopist in the treatment of obesity. Gastric BTX-A injection is a minimally invasive and short-term effective method to be used in the treatment of obesity.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.