Systematic review on gastric electrical stimulation in obesity treatment

Abstract

Introduction:

Obesity is a very common public health problem worldwide. However, there is a lack of effective therapies. Only a small portion of patients with morbid obesity are accepting bariatric surgery as the last option due to the risks associated with invasive therapy.

Areas covered:

In this paper, we review an emerging weight loss treatment: gastric electrical stimulation (GES). The feasibility of GES as a potential therapy for obesity is introduced. Methodologies and parameters of GES are presented. Several GES methods for treating obesity and their effects on food intake and body weight are presented. Possible mechanisms involved in the anti-obesity effect of GES are discussed. Finally, our comments on the potential of GES for obesity and expectations for future development of the GES therapy are provided. The PubMed central database was searched from inception to May 2019. The literature search used the following terms: “ Gastric electrical stimulation “ combined with “obesity” and “ Implantable gastric stimulation “ and “pharmaceutical therapy” and “bariatric surgery”.

Expert opinion:

There is a potential to use GES for treating obesity. However, more efforts are needed to develop appropriate stimulation devices and to design an adequate therapy for treating obesity in humans.

1. INTRODUCTION

Obesity is one of the most prevalent public health problems worldwide. The prevalence of obesity was 39.8% and affected about 93.3 millions of US adults in 2015~2016 [1]. Obesity-related complications such as cardiac diseases, stroke, type 2 diabetes and certain types of cancer are leading causes of preventable and premature death. The estimated annual medical cost of obesity in the United States was $147 billion in 2008 [2]; the medical cost for people who have obesity was $1,429 higher than those of normal weight [3]. Obesity is also associated with an increased prevalence of socioeconomic hardship due to a higher rate of disability, early retirement, and widespread discrimination [4].

The treatment of obesity can be classified into four categories: general interventions (diet and exercise), medical therapy, surgical therapy and other treatments.

Behavioral therapy Diet and Exercise are the most preferred general interventions for obesity. Modification of eating and physical activity behaviors is the main purpose of this treatment. Although a desirable body weight might be achieved by life style modification, relapse is still remaining as weak point of this intervention. It has been proven to be more difficult to maintain normal or acceptable body weight for patients who were treated with dietary restriction. About 50% of patients fail to maintain normal weight within one year after the treatment and almost all patients relapse within 5 years [5].

Medical therapy is often the first choice if the behavioral therapy fails. Overall, there is a lack of long-term efficacies [6, 7]. However, a recent meta-analysis included 28 randomized clinical trials in over 29,000 patients with obesity and reported that “orlistat, lorcaserin, naltrexone-bupropion, phentermine-topiramate, and liraglutide, compared with placebo, were each associated with achieving at least 5% weight loss at 52 weeks. Phentermine-topiramate and liraglutide were associated with the highest odds of achieving at least 5% weight loss” [7]. Side effects and long-term weight loss efficacies are two major factors to consider in the development and implementation of the medical therapy.

Surgical treatment is typically recommended for adults with a BMI ≥40 kg/m² without comorbid illness, or a BMI of 35 to 39.9 kg/m2 with at least one serious comorbidity, who have not met weight loss goals with diet, exercise, and drug therapy [8]. Several surgical procedures are being used clinically, the most common bariatric surgery procedures are gastric bypass, sleeve gastrectomy and biliopancreatic diversion with duodenal switch [9]. Among these various procedures, sleeve gastrectomy is more commonly performed bariatric procedure for obesity without diabetes, whereas Roux-en-Y gastric bypass has reliable hypoglycemic effect in addition to weight loss. A recent IFSO worldwide surgery in 2016 reported that the total number of bariatric/metabolic procedures in 2016 was 685, 874 and the most performed procedures was sleeve gastrectomy (53.6%) followed by Roux-en-Y gastric bypass (30.1%) and one-anastomosis gastric bypass (4.8%) [10].

Recently, gastric electrical stimulation (GES) has been introduced as a potential treatment option for obesity. Compared with the surgical treatment, GES is much less invasive, reversible and adjustable. The aim of this review is to review different methods of GES that have been applied for treating obesity and discuss pros, cons and feasibility of the GES therapy for obesity.

2. METHODS

The PubMed central database were searched from inception to May 2019 for relevant studies. The literature search used the following terms (with synonyms and closely related words): “Gastric electrical stimulation” combined with “obesity” and “ Implantable gastric stimulation “ and “weight loss treatment” and “bariatric surgery”. The selection was limited to English language documents. Table 1 shows the outcome of the search.

Table 1:

Search outcomes

Key words (combined with obesity)	All articles	Retrieved Articles
Obesity and diet	67596	8
pharmaceutical therapy	4448	2
Bariatric surgery	29880	3
Gastric electrical stimulation	128	11
Implantable gastric stimulation	60	19
Epidemiology	94353	4
Guidelines	9987	3

Articles were excluded if 1) they did not meet the selection criteria outlined in Table 2; 2) they were duplicate publications; 3) guidelines with unclear methodologies.

Table 2:

Selection Criteria

Area Covered	Obesity and diet, pharmaceutical therapy, gastric electrical stimulation, implantable gastric stimulation and other treatments for obesity
Relevance	Introduced novel devices, provided detailed information about related devices, showed relevant information about discussing point.
Outcomes	Clinical effectiveness (e.g. reduced body weight; improved quality of life) and safety Guidelines
Study Design	Health care assessments, systematic reviews, meta-analyses, randomized controlled trials (RCTs), nonrandomized studies, evidence-based guidelines,

3. FOOD INTAKE AND GASTROINTESTINAL MOTILITY

In the brain-gut axis, the most influential organ involving food intake and nutrient metabolism is the gut. The gut communicates with the brain via both neural and hormonal signals triggered by the mechanical (motility) actions of the gut. Therefore, gastrointestinal motility plays a regulatory role in food intake. In addition to neural and hormonal regulations, the stomach is the most influential organ in the process of satiation. Gastric accommodation and emptying are two main functions of the stomach to influence satiety or appetite that determines the amount of food intake of a subsequent meal. A reduced gastric accommodation and delayed gastric emptying lead to a reduced or delayed intake of a subsequent meal [11, 12].

Upon food ingestion, the proximal stomach relaxes to accommodate the ingested food, a physiological process called gastric accommodation. Gastric accommodation is controlled by a vago-vagal reflex triggered by meal ingestion and mediated by the activation of inhibitory nitrergic motor neurons in the gastric wall which produce fundic relaxation. Gastric accommodation to a meal consists of relaxation of the proximal stomach, providing the meal with a reservoir and enabling a volume increase without a rise in gastric pressure [11). Whereas, the function of the distal stomach, the antrum, is to generate peristalsis to push the ingested food through the pylorus to the duodenum, a process called gastric emptying. Gastric emptying is determined by the propulsive antral contractions and the appreciate opening of the pylorus. The frequency and coordination of the antral contractions are determined by the gastric pace-making activity [12] that is also called the slow wave due to its slow rhythm (3 cycles/min). Disruption of this pace-making activity impairs antral contractions and leads to delayed gastric emptying [12].

A number of studies have investigated the difference in gastric emptying between lean and obese subjects. There is no statistical difference in the size of the stomach or gastric accommodation between lean and obese subjects. However, Intervention-induced delayed gastric emptying was found to be linked to increased satiety, reduced food intake and/or weight loss [11, 12]. GES with optimized parameters was found that the GES-induced increase in gastric volume was inversely correlated with the reduced amount of food intake in dogs [13,14]. Furthermore, it was also found that GES activates satiety neurons in the ventromedial hypothalamus in a similar way of intragastric balloon [15]. GES has also been shown to delay gastric emptying associated with reduced food intake as well as weight loss in rats and humans [16–17].

4. GASTRIC ELECTRICAL STIMULATION

Different methods of GES have been introduced and studied for different applications. We classified GES methods in two ways: based on stimulus configurations and based on the effect of GES on gastric motility.

Based on the pulse width, GES can be classified as long pulses, short pulses and pulse trains [18]. Long-pulse stimulation is most frequently reported in the literature, but mostly limited to animals. It is able to entrain intrinsic gastric pace-making activity called the slow wave due to its low frequency (3 waves/min). In this method, the electrical stimulus is composed of repetitive single pulses with a pulse width in the order of milliseconds (10–600 ms). It is also called low frequency/high energy GES [19, 20]. In contrast to long-pulse stimulation, Short-pulse stimulation has substantially shorter pulse width in the order of a few hundred microseconds (μs). In pulse trains, the stimulus is composed of repetitive trains of short pulses with on and off periods. Recently, various implantable pulse generators have been developed and frequently used in nerve stimulation, capable of generating pulse trains with a pulse width of > 1ms [21,22].

According to the effects of GES on gastric motility, GES can be classified into three categories:

Any method of GES that enhances gastric motility is called excitatory GES or eGES. According to this definition, eGES is able to pace gastric slow waves, enhance gastric contractions and/or accelerate gastric emptying. In this method, the frequency of the stimulation should be the same as or slightly higher than the frequency of the gastric slow waves and long pulses are used. This method is typically used for treating gastric motility disorders such as gastroparesis [23–25]. However, no implantable device is available to evaluate the long-term efficacy of treatment.

Any method of GES that has no effects on gastric motility is called neutral GES or nGES. In this method, short pulses are usually used as stimuli of GES. Even though nGES does not change gastric motility, it typically affects neural activities [26]. One of this method called Enterra therapy has been used clinically for the treatment of nausea and vomiting in patients with gastroparesis [27]. Any method of GES may be called nGES if it uses short pulses or trains of short pulses with a width of < 1ms, since with these parameters, GES does not alter gastric motility.

Any method of GES that inhibits gastric motility is called inhibitory GES or iGES. The inhibitory effect may include suppression of gastric tone, contractions and/or emptying. Both long pulse GES and pulse train GES that inhibit motility can be called iGES. In iGES, the stimulation frequency in case of repetitive long pulses or the frequency of pulse trains in case of pulse train stimulation is at least 50% higher than the normal frequency of gastric slow waves and the pulse width is >1ms. It is believed that inhibition of gastric motility would reduce food intake, therefore iGES is expected to be a potential therapy for obesity.

5. GASTRIC ELECTRICAL STIMULATION FOR OBESITY

The first GES method used to treat obesity was the device called implantable gastric stimulation (IGS). It uses trains of short pulses and almost has no effects on gastric motility. However, it changes central neuronal and hormonal activities. The second GES device that was used clinically to patients with obesity was called Tantalus. Tantalus was designed to improve gastric motility. The third GES device used for treating obesity was called Closed-Loop Gastric Electrical Stimulation System (abiliti® system) that delivered electrical stimulation upon food intake.

5.1. Implantable gastric stimulation

In the IGS method, trains of short-pulses were used with the following parameters: the duration of the train of 2s, the off period of 3s, pulse frequency of 40 Hz, pulse width of 300 μs and pulse amplitude of 6–10 mA. In clinical studies, a pair of electrodes for stimulation was placed on the serosa of gastric body in the middle of the lesser curvature.

The IGS method was shown to exert no effects on gastric contraction, gastric emptying or gastric tone in canine studies performed in our lab [26]. Therefore, the IGS can be classified as nGES. Although the IGS was reported to alter hormonal signals in the hypothalamus [28] and observed to reduce appetite in patients with obesity, several studies have shown that the IGS-induced satiety was not strong enough to alter eating behaviors of patients with obesity clinically [29].

5.2. Tantalus

The Tantalus system was developed based on the hypothesis that the enhancement of gastric contractions at early stage of food ingestion increases satiety and thereby reduces food intake [30]. According to a simultaneous increase of impedance in gastric fundic and a decrease in gastric slow wave frequency, food intake was automatically detected. Upon the detection of each intrinsic slow wave, the system delivers a train of pulses with a train duration of 1.2s, pulse frequency of 83Hz, pulse width of 6ms and pulse amplitude from 6–10mA.

In a clinical study among patients with morbid obesity, a 17% of excess weight loss in 12 patients after 20 weeks, 27% of excess weight loss in 9 patients after 52 weeks were observed with the Tantalus therapy [30]. However, a significant increase in gastric emptying, which was believed to reduce satiety and thereby increase food intake, was reported in 12 patients with obesity treated with the Tantalus system [30]. The mechanism of anti-obesity effect of Tantalus system remained unclear. In another clinical study, sixty one patients with type 2 diabetes were recruited and the Tantalus-DIAMOND® GES device were implanted for meal-mediated antral electrical stimulation up to 36 months. As a result, Tantalus-DIAMOND® Gastric Electrical Stimulation showed chronic effects such as improvement in glycemic control, a decrease in body weight, and a decrease in systolic blood pressure [31]. Also, it was assumed that this was through a gut-brain interaction that modulates effects on the liver and pancreatic islets [32–33].

5.3. Closed-loop gastric electrical stimulation system

The Closed-loop gastric electrical stimulation system (abiliti® system) consists of a trans gastric sensor that is used to detect food intake and a pair of stimulation electrodes placed at the lesser curvature over the vagus. The electrical impulses produced by the stimulator is sent to the stimulation electrode when food intake is detected. The system also includes a 3D accelerometer used to record physical activity and a telemetry link that enables data download for patient monitoring. The device is implanted under a laparoscopic procedure. The food sensor is inserted in the body-fundus region, about 3 cm from the greater curvature. The stimulation electrode is fixed on the anterior wall of the stomach approximately 4 cm distal to the gastroesophageal junction and 1.5 cm from the lesser curvature. The device is programmed to deliver a mild stimulation at meal times.

In a clinical study in 34 patients with morbid obesity, GES with the Closed-Loop Gastric Electrical Stimulation System reduced food intake by producing an early sensation of fullness and satiety, resulting in a mean excess weight loss (EWL) of 28.7% at 12 month and this effect was stable to 27 months with EWL of 27.5% [34]. However, this was not a placebo-controlled study.

5.4. Inhibitory gastric electrical stimulation

The iGES method is proposed as an anti-obesity therapy by inhibiting gastric motility. However, implantable device has never been developed. Both long pulse and pulse train were used in iGES. Reduced food intake and weight loss were reported in rats and dogs treated with iGES [16,26]. Acute iGES using temporary mucosal electrodes was also fond to reduce food intake in healthy volunteers [17, 18]. Due to problems of current imbalance and electrode corrosion with long pulses, pulse train iGES is expected to be more suitable for treating obesity. When GES is performed using pulse trains, effects of iGES on gastric motility are determined by the pulse width, frequency and trains/min [35–37].

5.5. Vagal nerve blockade (vBLOC) therapy for obesity

Although vagal nerve stimulation does not belong to gastric electrical stimulation, it is included in this review as this is the only FDA approved implantable device for treating obesity. The device is called Maestro Rechargeable System or vBLOC implying the block of vagal nerve. It consists of two implantable parts: two leads that are placed around the anterior and posterior vagal trunks near the esophagogastric junction by laparoscopic surgery and a rechargeable pulse generator implanted subcutaneously on the thoracic wall [38–39]. The implantable pulse generator requires wireless charging approximately two times weekly. In the ReCharge Trial, which was a prospective, randomized, controlled trial, vBLOC showed clinically significant weight loss and improvements in obesity-related cardiovascular risk factors, healthy eating behaviors, and quality of life through 2 years follow-up [40]. A total of 239 patients with a BMI between 35 and 45 kg/m2 were randomized to vBLOC and sham control group in 2:1 ratio. The subcutaneous neuroregulator was implanted in the sham control group without any connected electrodes. All devices were programmed to deliver charges for at least 12 hours a day. Mean %EWL was 24.4% for the vBLOC group and 15.9% for the sham group at 12 months. After 24 months, 76% of vBLOC participants were remained in the trial and had a mean %EWL of 21% [40–41].

6. MECHANISMS OF GES FOR OBESITY

Possible mechanisms of GES for obesity may involve gastric motility, neurons in the hypothalamus via the vagal and spinal afferent pathways and certain central and gastrointestinal hormones.

6.1. Inhibitory effects of iGES on gastric motility

iGES has been reported to inhibit gastric tone, antral contractions and gastric emptying. In a canine study, the pulse train GES increased gastric volume at a pulse width of 2ms (p=0.018) and 4ms (p=0.05), but not at a pulse width of 0.21 ms, 0.45 ms or 1ms. Similar inhibitory effects on gastric tone were observed with iGES using long pulses [13, 14]. Both methods of iGES using long pulses and pulse trains were found to exert inhibitory effects on antral contractions mediated via the sympathetic mechanism [42]. Various studies have reported inhibitory effects of iGES on gastric emptying in both animals and humans [28,43–45]. Gastric emptying of both liquids and solids was reported to be significantly decreased with iGES [17,18, 46]. Conceptually, the inhibition of gastric motility suppresses food intake and results in weight loss.

6.2. Excitatory effect of eGES on gastric motility

As mentioned earlier, the Tantalus system was designed and believed to enhance gastric contractions by synchronizing each stimulus with the spontaneous intrinsic gastric contraction. Although no data have been reported in the literature on the actual enhancement of gastric contractions, accelerated gastric emptying of solids was reported in patients with obesity treated with the Tantalus system [29]. However, it remains unclear why the acceleration of gastric emptying might lead to a reduced food intake or wright loss.

6.3. Central neuronal effects of GES

Unlike gastric motility, central neuronal activities can be changed by both nGES (such as IGS) and iGES (such as Tantalus system). This is because the central nervous system responds to electrical stimulation faster. However, enhanced central effects with GES was observed in a comparative study when pulse width was increased from 0.3ms to 3ms [47].

Involvement of vagal afferent pathway:

A recent study using various GES methods in a rodent model has shown that GES with either long pulses or trains of short pulses could activate neurons responsive to gastric distention in the nucleus tractus solitarii, thereby suggesting the involvement of the vagal afferent pathway [48].

Central neuronal effects:

A recent study reported that all three methods of GES (short pulse, long pulse and trains of short pulses) were able to activate gastric distention-responsive neurons in the paraventricular nucleus. However, in gastric distention-inhibitory neurons (one specific type of neurons), opposite effects were noted between GES using trains of short pulses with different parameters used for treating obesity and gastroparesis [49]. These results suggest possible distinct central mechanisms with different methods of GES. Similar central neuronal effects of GES were also found in the hippocampus and the ventromedial nucleus [15, 50].

Central humoral effects:

A few studies investigated central humoral mechanisms of IGS and reported a decrease in orexigenic peptides and an increase in anorexigenic peptides. After 2-hr GES using trains of short pulses, neurons expressing orexin was significantly decreased in the supraoptic nucleus and the lateral hypothalamic area, whereas neurons expressing oxytocin and cholecystokinin were increased in the paraventricular nucleus and hippocampus, respectively [28, 49–50].

7. EXPERT OPINION

Although GES has a great potential for treating obesity, no device has been approved by the FDA up till now. While a number of medical devices have been developed and numerous efforts have been made to commercialize these devices for treating obesity, there are fundamental problems with GES for obesity in comparison with other successful neuromodulation therapies, such as deep brain stimulation for Parkinson disease, vagal nerve stimulation for epilepsy, spinal cord stimulation for neuropathic pain and sacral nerve stimulation for overactive bladder. In all these clinically approved neuromodulation methods, electrical stimulation is uniquely applied to nerves. The nerve, no matter which kind, has a short time constant and therefore responds to electrical stimulation quickly. That is, short pulses in the order of a few hundred microseconds are sufficient for neuromodulation. By carefully examining all published studies, one could easily conclude that none of stimulation pulses has been of a width wider than 1ms.

GES is, however, different from other neuromodulation methods. When an electrical stimulus is applied to the seromuscular layer of the gastric wall, it interacts with the intrinsic enteric nerves, the extrinsic autonomic nerve, the interstitial cells of Cajal and the smooth muscle. Their combined responses to the stimulation determine the final outcomes. Therefore, stimulation parameters have been carefully selected in order to achieve expected outcome. Moreover, the stomach has its own electrical rhythm and this must be also taken into consideration whether the stimulation should be designed to enhance or disrupt this intrinsic electrical activity.

Among the three devices or therapies that have been introduced for treating obesity, there are some pros and cons in their designs and hypotheses. The IGS therapy was successful in altering neuronal and hormonal activities in the central nervous system. However, it does not alter functions of the gastric smooth muscle and therefore does not change gastric motility since the device is not able to deliver any pulses wider than 0.6ms. Consequently, the stimulation-induced central changes (such as increased satiety and reduced appetite) are not sufficient to overcome the desire of the patient to eat more foods. The Tantalus system is capable of delivering wider pulses in the order of a few milliseconds and altering gastric motility functions. However, the therapy was designed to enhance gastric emptying; it is unclear why acceleration of gastric emptying might lead to reduced food intake. The closed-loop gastric electrical stimulation system has an advantage of performing closed-loop electrical stimulation; mainly delivering electrical stimuli only upon food intake. This is a unique and necessary feature required for GES. However, it is unclear whether the system is capable of delivering wider pulses to alter gastric motility functions.

Based on our numerous preclinical studies, iGES is believed to be an appropriate therapy for obesity as this method is designed to suppress food intake and induce postprandial satiety by interrupting the normal gastric pace-making activity and therefore inhibiting antral contractions and delaying gastric emptying. However, no medical device is currently available to perform iGES and therefore no long-term clinical data is available to support that the animal data can be accurately translated into humans and iGES is indeed a viable therapy for obesity. Table 3 lists main features of these three methods and their pros and cons.

Table 3:

Comparison among different GES methods

Name	IPG	Motility	CNS	On-demand	Weight loss
IGS	Inadequate	No effect	Induce satiety	N/A	Mild
Tantalus	Adequate	Enhanced	Not clear	N/A	Mild
Abiliti	Inadequate	No data	No data	Yes	Mild
iGES	Not available	Inhibitory	Induce satiety	Need to add	Substantial

IPG: implantable pulse generator; CNS: central nervous system; on-demand: GES delivered upon food intake.

In conclusion, there is a great potential to use GES for treating obesity. However, more efforts are needed to determine best stimulation parameters and treatment regimens, to develop appropriate stimulation device and to conduct adequate clinical trials using the appropriate methods and devices.

Article Highlights.

• Gastric electrical stimulation (GES) is an emerging weight loss treatment.

• Compared with the surgical treatment, GES is much less invasive, reversible and adjustable.

• Brain-gut axis plays an important role in therapeutic mechanism of GES.

• There is a great potential to use GES for treating obesity.

• developing appropriate stimulation device and design an adequate therapy for treating obesity in humans are essential.