Curr Treat Options Gastro DOI 10.1007/s11938-015-0054-y
Endoscopy (I Waxman, Section Editor)
Endoscopic Bariatric Procedures Jacques Deviere, MD, PhD Address Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme University Hospital, Université Libre de Bruxelles, Route de Lennik 808, B-1070, Brussels, Belgium Email: [email protected]
* Springer Science+Business Media, LLC 2015
This article is part of the Topical Collection on Endoscopy Keywords Bariatrics I Transoral surgery I Endotherapy
Opinion statement Obesity is a pandemy which affects 600 million adults worldwide. Surgery is the only therapy which has been shown effective on the long term. Transoral surgery (or endotherapy) is particularly attractive in this group of patients and has the potential for offering a less invasive alternative. If the only treatment currently available in routine is balloon implantation, which is effective at short term but unfortunately associated with weight regain after removal in the majority of the cases, other techniques currently under development or clinical investigations might fine their place in future treatment armamentarium. They include restrictive procedures, involving plicature formation or tissue apposition in order to reduce the volume of the stomach, decrease its compliance, and favor an early satiety. Other techniques focus on malabsorption, either by bypassing the contact of food with the jejunum (a feature which also improves type 2 diabetes) or by emptying the stomach after food intake. Several techniques also allow performing gastrojejunal anastomoses. These could be particularly useful in designing hybrid procedures combining laparoscopic and transoral approach resulting in less invasive surgical procedures. Even if, currently, none of these techniques can be recommended outside clinical protocols, it becomes more and more obvious that some of them will find their place in the near future.
Introduction Obesity is the pandemic of the twenty-first century and a disease associated with considerable morbidity and mortality [1]. As of 2014, approximately 1.9 billion adults are overweight; and 600 million adults are obese [2]. This disease has seen its prevalence doubled over the last 20 years and also affects 42 million children under the age of 5 years [2].
Once considered a problem only in high-income countries, overweight and obesity are now dramatically on the rise in low- and middle-income countries, particularly in urban settings [2, 3]. The only effective therapy for morbid obesity (defined by Body Mass Index (BMI) of 40 kg/m2 or more, or by a BMI of 35 kg/m2 or more in the presence of co-
Endoscopy (I Waxman, Section Editor) morbidities) is currently surgery [4]. It has been shown effective on the long term and significantly reduces the risk of mortality associated with this disease. In the US, the number of indications for bariatric surgery has been multiplied by 5 between 1998 and 2005 [5], and the demand clearly surpasses the offer. Even if bariatric surgery induces excess weight loss ranging from 40 to 80 % with a reasonable complication rate, it is not always a Bdefinitive^ treatment for a Bchronic disease^ and a stepup approach, starting with restrictive procedures potentially followed by Roux en Y gastric bypass (RYGBP) are often considered. Repeated surgeries are, however, more difficult and associated with more complications [6, 7]. In addition, patients with milder obesity cannot always be managed by diet and physical examination and may benefit from medical help to change their behavior.
The pandemic and the demand for less invasive therapy for obesity led to emergence of endoscopic technologies potentially less invasive and with a lower morbidity. Indeed, endoluminal surgery, performed entirely through natural orifice, offers the potential for eliminating the trauma of abdominal incisions, particularly important in obese patients, possibly offering a lower risk approach which may expand interest among patients and physicians. It might find its place in the current armamentarium or morbid obesity treatment, extending indication to patients with severe co-morbidities, older age, or even non-morbid obese patients. This chapter describes the various endoluminal techniques which are currently under development, clinical evaluation, or offered in routine.
Endoscopic therapeutic options for endoluminal treatment of obesity Space-occupying devices The use of intragastric devices to induce weight loss in obese patients was first described in 1982 [8]. With a spherical shape and larger capacity than earlier models, the BioEnterics Intragastric Balloon (BIB, Apollo Endosurgery, Austin, TX) is the one which has been the most extensively studied (Fig. 1a). Balloon is a temporary nonsurgical option that can promote weight loss in obese patients by partially filling their stomach and inducing a sense of early satiety [9, 10]. One of the major drawbacks of balloon implantation is weight regain after removal. In this line, two recent studies help to better understand what can be expected from balloon implantation. Mathus-Vliegen et al. [11] included patients who had participated in a randomized, controlled trial comparing balloon versus sham for a 3month period, into an additional trial including 9 months of balloon treatment and follow-up for 1 year after removal. They excluded eight patients who had not met the weight loss goal during the first 3 months (n=5) or who did not tolerate the balloon (n=3). Although there was no difference between sham and balloon during the first 3 months, after 1 year of balloon treatment, a mean weight loss of 21.3 kg (17.1 %) was achieved in all patients, of which 12.6 kg (9.9 %) was maintained at the end of the second balloon-free year. Overall, 47 % of patients sustained a 10 % weight loss at the end of a 2-year follow-up. Although this study could not demonstrate an independent benefit of balloon treatment beyond diet, exercise, and behavioral therapy in the first treatment, balloon treatment for 1 year, in those patients who tolerated the treatment, resulted in substantial weight loss, a significant part of which was maintained during the first year after removal of the balloon. More recently, the
Endoscopic Bariatric Procedures Fig. 1. Endoscopic view of a BIB balloon filled with saline at the time of removal; a needle is inserted in the balloon to aspire its content. b Spatz adjustable balloon with its connecter allowing partial deflation or reinflation.
same author reported the results of balloon therapy in a private practice setting [14], without intense dietary follow-up and suggested that balloon therapy has the potential, in this environment, to fill the therapeutic gap between pharmacotherapy and surgery. Another study looked at the long-term outcome after treatment with an intragastric balloon for 6 months, with no structured weight maintenance program after balloon removal. A hundred consecutive morbidly obese individuals were prospectively followed after BIB placement; 97 patients completed final follow up at a mean of 4.8 years while, after 6 months, 63 % of patients had more than 10 % baseline weight loss; there were only 28 % at final followup. At that time, 35 patients had undergone bariatric surgery and 34 patients had no significant weight change from baseline [12]. Imaz et al. [13] pooled 3,608 patients to estimate the effectiveness of BIB. The weight loss at balloon removal after 6 months was12.2% (32% excess weight loss (EWL)). A meta-analysis of two randomized controlled trials (RCTs) that compared balloon with placebo showed a benefit of balloon over placebo with a difference of 17% EWL. These studies confirm that balloon implantation is effective at short term and may be of some help in a minority of patients for long-term weight loss. It is a potential option for patients unwilling to undergo bariatric surgery or not candidate for bariatric surgery, and could also be used as a temporary measure in super-obese patients, in order to induce weight loss and decrease the risk of complications associated with further bariatric surgery. Because of these results and since no other endoscopic technique was available, the intragastric balloon market has been booming in Europe and Middle East over the last 10 years. Several different balloons have been developed without, up to now, dramatically improving the outcome in terms of weight loss and safety profile. Adjustable balloons (Spatz, Great Neck, NY, Fig. 1b), which can be reinflated (in case of decreased effect) or partially deflated (in case of intolerance) had shown initial promising results [15] but are associated with complications which require further improvement in design [16] (mainly at the level of anti-migration anchors). Air-inflated balloons (Heliosphere, Vienne, France) may be associated with a better tolerability but at the cost of a lower efficacy and a higher risk for spontaneous deflation [17] (and migration). Dual balloons connected to each other (ReShape Medical, San Clemente, CA) are designed to increase the total fluid volume, better fit with the stomach anatomy, and prevent balloon passage in the case of one of the two
Endoscopy (I Waxman, Section Editor) balloons deflating. These latter are the only ones currently available in the US, and the company submitted a PMA application on a RCT performed on 326 patients and showed that patients having the procedure lost more than twice as much weight as the sham–controlled subjects [18] at 6 months. Fifteen percent of the patients did not tolerate the balloon which had to be removed early. Their high cost compared with other available balloons limits their use in other parts of the world. Some of these new balloons are allowed to stay in place for 12 months. In the search for rendering intragastric balloons even less invasive, orally ingested balloons have been evaluated [19] and (too?) early commercialized. Although the principle is interesting, the risk of deflation limits their indwell duration to 3 months, and partial deflation may be associated with small bowel occlusion. Other swallowable balloons that degrade spontaneously and ensure homogeneous and fast deflation are now under investigation [20]. Several other space-occupying devices have been developed, two of them being still potentially under evaluation, although no recent clinical data are available. The transpyloric shuttle (Baronova, Goleta, CA) acts by transient occlusion of the pylorus (increasing the filling of the stomach) and the Satisphere (Endosphere, Redwood city, CA) aims to slow down the passage of food into the duodenum, increasing the satiety via stimulation of duodenal hormones. Although not really a space-occupying device, a new tool in the armamentarium of the endoscopist is the AspireAssist (Fig. 2) aspiration therapy system (Aspire Bariatrics, King of Prussia, Pennsylvania, USA). It involves the placement of a gastrostomy tube, similar to PEG placement and a siphon assembly to aspirate gastric contents 20 min after a meal. In a per-protocol analysis, body weight loss after a 4-week run-in period of a very low-calorie diet (and strict instructions about eating and chewing food) and 6 months of aspiration therapy was 16.5 % of initial weight and 40.8 % of EWL [21••]. Limitations of these techniques include social acceptability and the time necessary (45 min per day) for aspiration therapy [22]. It is, however, effective and might also have elective indications for management of super-obese patients [23]. A pivotal study is ongoing in the US.
Gastric restriction The major limitation of space-occupying devices is related, for most of them, to their limited duration of indwell. Any device inserted into the stomach or the duodenum will ultimately migrate and induce ulceration, mucosal hyperplasia, or even sometimes a perforation. Having suturing techniques which would allow reducing the volume of the stomach and result in long-lasting restriction of food intake might allow performing transoral procedures which would offer results similar to those of restrictive bariatric procedures without compromising further surgery if needed. One disadvantage of endoluminal approach is that suturing results in a mucosa-to-mucosa apposition while persistent suture/anastomosis requires serosa-to-serosa apposition. Therefore, several of the techniques described hereunder have shown only good shortterm results, and data about their mid- or long-term outcome are either disappointing or missing.
Endoscopic Bariatric Procedures Fig. 2. The Aspire Assist system includes gastrostomy includes a tube connected to gastrostomy (a), with a skin port (c) which can be connected to a dedicated pump in order to empty the stomach 20 min after the meals (b).
The EndoCinch Suturing System (C.R. Bard, Murray Hill, NJ) was initially designed for the endoscopic treatment of gastroesophageal reflux disease (GERD). This system allows the placement of series of stitches in the lower esophagus to create a pleat in the sphincter. Although associated with encouraging early results, the EndoCinch for the treatment of GERD has been called into question due to the lack of retention of plications in the long term [24], an observation that is probably related to the fact that most of these stitches are placed in the submucosa. Fogel et al. [25] first described the use of this technology for the treatment of obesity in 64 patients. His technique consisted in the deployment of seven sutures in a continuous and cross-linked design from the proximal fundus to the distal body. The result of the treatment is suggested to be a significant decrease in distensibility of the stomach. The procedure was performed ambulatory, and out of the 59 patients followed for 12 months, the percentage excess weight loss reported was 21 % at 1 month and 58 % at 12 months. Only a minority of patients (N=14) underwent repeated endoscopy in the follow-up. In 11 of them,
Endoscopy (I Waxman, Section Editor) the suture line was reported as completely or partially intact. Unfortunately, limited information on endoscopic or radiological follow-up was provided, the study having been performed without institutional review board submission and with commercial products, making it difficult to understand the extent of stomach restriction. Using a modified version of the device (Restore Suturing System Bard-Davol, Warwick, RI), Brethauwer et al. [26] reported feasibility and efficacy in a pilot multicentric study involving 18 patients. The observed EWL at 12 months was 27 %, and dehiscence of the sutures was observed in 13/18 cases. No other clinical data were published since then. The Overstich (Apollo Endosurgery) is another suturing system which also allows the endoscopist to reload the suture without removing the scope. Multiple sutures have been placed in a pilot study on four patients with successful apposition of gastric wall [27]. No data are, however, available on clinical mid-term outcome. Safestich (Miami, FL) is developing a dedicated instrument (Intraluminal Gastroplasty Device) which is not fixed at the endoscope and designed to suture the two sides of the stomach which are captured by suction and sutured after mucosal excision [28]. Only this small pilot study reported persistence of the suture up to 2 years in three patients. This principle of using a dedicated device which accommodates an endoscope and uses suction for apposition of the gastric walls was the fundamental originality of the transoral gastroplasty System (Satiety, Inc, Palo Alto, CA), a technique now abandoned but which is, to date, the one with most clinical data available in the area of endoluminal restrictive treatment. The system consisted in a flexible 18-mm-diameter shaft device allowing suction of the anterior and posterior walls of the stomach which were stapled with a stapler similar to those used in laparoscopic surgery, allowing a suture involving two serosa-to-serosa appositions. Two pilot studies had demonstrated EWL of 25 % and 46 % at 6 months [29, 30]. A multicentric European study [31] performed on 67 patients confirmed the effectiveness at 1 year with 45 % EWL and reported only two mild complications. A multicentric randomized sham–controlled study was then performed in 11 (ten US) centers, comparing the active and sham procedure (2.1 ratio) in a series of 275 patients. After completion of this study, the technique was shown superior to placebo, but two severe complications were observed. Additional data requested by the Food and Drug Administration (FDA) could not be provided due to lack of financing; the company was bankrupted and its assets sold to another major medical device company. Interestingly, the latter refused to provide data for publication of this trial. Besides this last ethical concern, the major lessons from this experience were that these advanced transoral procedures, unlike laparoscopic interventions, were not more difficult to perform in the heavily obese, were associated with fast recovery, could be performed on an outpatient basis, and, importantly, do not compromise or render more difficult further surgery if needed [32]. Another technique for endoluminal gastric restriction is the creation of multiple plicatures in the stomach wall. The POSE system (USGI) is a dedicated flexible device (Fig. 3) in which an endoscope is inserted and
Endoscopic Bariatric Procedures Fig. 3. The POSE system is a dedicated flexible device (a), accommodating the endoscope and special grasping and suturing device (b), allowing performance of transmural plicatures which are placed in the antrum and the fundus (c).
allows performing plicatures with serosa-to-serosa apposition. By placing it into the antrum and the fundus, it reduces the compliance of the stomach and favors early satiety. The device obtained the CE-Mark in Europe and two independent studies months [33, 34•], performed with the commercial device showed promising outcomes in terms of weight loss (45 % and 49 % EWL at 6 and 12 months, respectively). These studies were, however, associated with intense dietary follow-up, and the real efficacy of this technique will be further explored in a multicentric, sham–controlled trial which is currently ongoing in the US. Finally, another procedure, now abandoned, also provided interesting data for future development of these technologies. Transoral Endoscopic Restrictive Implants System (TERIS, Barosense, Redwood City, CA) was seen as
Endoscopy (I Waxman, Section Editor) Fig. 4. The Endomina platform is a universal self-assembling platform which can be adapted into the stomach to any endoscope and allowing performance of both plicatures and wall-towall sutures.
an endoscopic equivalent to gastric banding. It consisted in a proximal implant attached to the stomach wall through plicatures and anchors. A phase I pilot trial [35] reported successful placement in 12 of 13 patients but with significant complications and EWL of 28 % at 3 months, suggesting that technical improvements were obviously needed, but also that it could become another option in the endoscopic armamentarium. The major drawback was, however, migration of the implants, stressing the fact that even tight attachments do not avoid migration of a foreign body attached to the gastric wall and submitted to mechanical constrains. The same company came back with a similar instrument redesigned to only perform plicatures [36]. In a way similar to the POSE procedure, more than ten plicatures per patient were made in 17 patients, without severe complications and a reported EWL of 35 % at 1 year. Despite that, the company closed up and sold its assets for lack of financing. Finally, combining transmural suturing of the gastric wall with plicatures and apposition of these plicatures in order to reduce the volume and distensibility of the stomach is the principle followed by the Endomina (Fig. 4) universal platform [37] (Endotools SA, Gosselies, Belgium). These double plicatures, apposing each other, persist in animal models, but human data are still pending.
Malabsorption/metabolic endoscopy These techniques have to be put in line with the development of metabolic surgery and particularly with the clinical observation that bypassing the proximal bowel improves type 2 diabetes and induces weight loss, a feature which, at least in part, explains the greater improvement of diabetes observed in patients undergoing a laparoscopic RYGBP, for the same weight loss, compared with a purely restrictive procedure [38, 39].
Endoscopic Bariatric Procedures Fig. 5. The duodenal jejunal bypass sleeve is a Teflon sheet fixed to a metallic anchor (a) and deployed from the duodenum into the proximal part of the jejunum (b). It allows avoidance of contact of food with duodenal and proximal jejunal mucosa.
EndoBarrier (GI Dynamics, Lexington, MA, USA) is a duodenal–jejunal bypass sleeve (DJBS) made from a Teflon liner and delivered endoscopically to the duodenal bulb (Fig. 5), which has shown promise and efficacy in the management of obesity and associated diabetes. When deployed, it mimics the mechanical manipulation of RYGB surgery by creating a mechanical barrier that allows food to bypass the duodenum and proximal jejunum without mixing with bile and pancreatic secretion until more distally in the gut, thus potentially altering the incretin–anti-incretin system procedure [39]. The device is left in place for a maximum of 3 to 6 months and is removed with a dedicated and relatively easy system. Three early trials demonstrated the potential benefit of DJBS. In the first one [40], it was successfully deployed in 12 patients in less than 30 min (and required approximately 40 min to be removed). With the exception of pain prompting early removal, it was associated with a significant drop in HbA1C, compared with a control group. A second multicenter trial, from Chile, showed, at 12 weeks, a weight loss significantly higher in 24 patients treated with the EndoBarrier system compared with the diet control group in a preoperative setting [41]. The last available study is a sham–controlled trial with 21 patients treated and 26 undergoing the sham procedure, with a 12 weeks study design. Excess weight loss (11.9 % versus 2.7 %) and loss of more than 10 % excess weight (62 % versus 17 % of patients) were all in favor of the DJBS. However, eight subjects terminated earlier because of GI bleeding (N=3) or device intolerance (pain and/or vomiting, N=4) and an
Endoscopy (I Waxman, Section Editor) unrelated preexisting illness (N=1), showing that more technological developments are still to be done [42]. In most of the series published so far, complications prompting early removal, including some more severe, were the major concerns related with this technique. Their frequency led some experts to state that it was not ready for clinical use. However, a more recent RCT on 77 patients showed an independent benefit over dietary support in terms of diabetes improvement and weight loss with only 9 % early explants for mild complications [43•]. Another study suggested that diabetes improvement may persist after sleeve removal. This prompted the company to start a sham–controlled RCT in the US, but unfortunately, the FDA halted this trial for major complications (including liver abscess), further showing that the safety profile of this duodenal implant has to be improved. Remodelling the enteroinsular endocrine regulation for treating type 2 diabetes is also the target of a new technology called Bduodenal resurfacing^ (Fractyl, Boston, MA) where sequential submucosal injections and mucosal ablation (by transient heating) are performed in the third part of the duodenum (below the papilla). The destroyed duodenal mucosa is then regenerated with potentially different endocrine capabilities, and, in a first pilot study performed in Chile, this led to a significant improvement of type 2 diabetes. A multicentric study is ongoing in Europe. If these data are confirmed, it could open a new era for endotherapy of diabetes, and the concept is very attractive due to the lack of implant. Another area with possible developments in the near future is the transoral creation of anastomoses either using Natural Orifice Transluminal Endoscopic Surgery techniques [44] which might become easier with the development of new dedicated stents [45••] (XLumina, CA) or by using magnets as already demonstrated in clinical studies for treating gastric outlet obstruction [46] but which might become easier to use with self-assembling technologies, also allowing immediate functionality after placement[47•]. These technologies could prompt the design of either entirely peroral procedures or hybrid peroral/laparoscopic procedures facilitating the performance of bypass.
Conclusions Mechanisms of bariatric procedures are complex and involve modulation of the neurohormonal mechanisms that regulate appetite, satiety, glucose metabolism, energy utilization, and feeding behavior [48]. Transoral procedures offer the possibility to further unravel these mechanisms in the light of clinical observations. If restrictive surgical procedures are supposed to mainly act by increasing the resistance to the passage of food and thereby inducing weight loss because of noxious symptoms, this effect is much less obvious with the endoluminal procedures which aim to appose tissues or perform plicatures. Limiting the distensibility of the stomach and further modulating Ghrelin response to fasting or postprandial Ghrelin inhibition and/or stimulation of appetite frenators such as peptide YY or glucagon-like peptide 1, or increasing vagal stimulation are potential mechanisms of action. Understanding the physiological effect of the new
Endoscopic Bariatric Procedures technologies, at the level of neurohormonal mediators will be, in our view, one of the key factors that might allow in the future designing the most effective treatment option. Several technical challenges also remain, mainly in terms of persistence of the anatomical changes created and prevention of complications associated with the treatment. An optimal technique would probably benefit of several of the multiple inventions which took place in this area over the last 15 years. There is no doubt that we need better, less invasive, endoscopic techniques for the management of the obesity pandemic. One of the hurdles we might face is related to the difficulty and cost of proving clinical efficacy which prompt some interesting technologies to disappear for lack of financing. In this line, another concern is that, in case of bankruptcy, the intellectual property is acquired by major medical devices companies which do not seem very keen in pursuing development. Hopefully, obesity (and diabetes) is affecting so many peoples around the world that search for an effective therapy is still pursued by enthusiastic groups of engineers and physicians, and there is no doubt that endoscopic approach will play a growing role in the future management of this disease.
Compliance with Ethics Guidelines Conflict of Interest Jacques Deviere is a consultant for and patent holder with Endotools Therapeutics. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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Endoscopy (I Waxman, Section Editor)
Endoscopic Bariatric Procedures Jacques Deviere, MD, PhD Address Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme University Hospital, Université Libre de Bruxelles, Route de Lennik 808, B-1070, Brussels, Belgium Email: [email protected]
* Springer Science+Business Media, LLC 2015
This article is part of the Topical Collection on Endoscopy Keywords Bariatrics I Transoral surgery I Endotherapy
Opinion statement Obesity is a pandemy which affects 600 million adults worldwide. Surgery is the only therapy which has been shown effective on the long term. Transoral surgery (or endotherapy) is particularly attractive in this group of patients and has the potential for offering a less invasive alternative. If the only treatment currently available in routine is balloon implantation, which is effective at short term but unfortunately associated with weight regain after removal in the majority of the cases, other techniques currently under development or clinical investigations might fine their place in future treatment armamentarium. They include restrictive procedures, involving plicature formation or tissue apposition in order to reduce the volume of the stomach, decrease its compliance, and favor an early satiety. Other techniques focus on malabsorption, either by bypassing the contact of food with the jejunum (a feature which also improves type 2 diabetes) or by emptying the stomach after food intake. Several techniques also allow performing gastrojejunal anastomoses. These could be particularly useful in designing hybrid procedures combining laparoscopic and transoral approach resulting in less invasive surgical procedures. Even if, currently, none of these techniques can be recommended outside clinical protocols, it becomes more and more obvious that some of them will find their place in the near future.
Introduction Obesity is the pandemic of the twenty-first century and a disease associated with considerable morbidity and mortality [1]. As of 2014, approximately 1.9 billion adults are overweight; and 600 million adults are obese [2]. This disease has seen its prevalence doubled over the last 20 years and also affects 42 million children under the age of 5 years [2].
Once considered a problem only in high-income countries, overweight and obesity are now dramatically on the rise in low- and middle-income countries, particularly in urban settings [2, 3]. The only effective therapy for morbid obesity (defined by Body Mass Index (BMI) of 40 kg/m2 or more, or by a BMI of 35 kg/m2 or more in the presence of co-
Endoscopy (I Waxman, Section Editor) morbidities) is currently surgery [4]. It has been shown effective on the long term and significantly reduces the risk of mortality associated with this disease. In the US, the number of indications for bariatric surgery has been multiplied by 5 between 1998 and 2005 [5], and the demand clearly surpasses the offer. Even if bariatric surgery induces excess weight loss ranging from 40 to 80 % with a reasonable complication rate, it is not always a Bdefinitive^ treatment for a Bchronic disease^ and a stepup approach, starting with restrictive procedures potentially followed by Roux en Y gastric bypass (RYGBP) are often considered. Repeated surgeries are, however, more difficult and associated with more complications [6, 7]. In addition, patients with milder obesity cannot always be managed by diet and physical examination and may benefit from medical help to change their behavior.
The pandemic and the demand for less invasive therapy for obesity led to emergence of endoscopic technologies potentially less invasive and with a lower morbidity. Indeed, endoluminal surgery, performed entirely through natural orifice, offers the potential for eliminating the trauma of abdominal incisions, particularly important in obese patients, possibly offering a lower risk approach which may expand interest among patients and physicians. It might find its place in the current armamentarium or morbid obesity treatment, extending indication to patients with severe co-morbidities, older age, or even non-morbid obese patients. This chapter describes the various endoluminal techniques which are currently under development, clinical evaluation, or offered in routine.
Endoscopic therapeutic options for endoluminal treatment of obesity Space-occupying devices The use of intragastric devices to induce weight loss in obese patients was first described in 1982 [8]. With a spherical shape and larger capacity than earlier models, the BioEnterics Intragastric Balloon (BIB, Apollo Endosurgery, Austin, TX) is the one which has been the most extensively studied (Fig. 1a). Balloon is a temporary nonsurgical option that can promote weight loss in obese patients by partially filling their stomach and inducing a sense of early satiety [9, 10]. One of the major drawbacks of balloon implantation is weight regain after removal. In this line, two recent studies help to better understand what can be expected from balloon implantation. Mathus-Vliegen et al. [11] included patients who had participated in a randomized, controlled trial comparing balloon versus sham for a 3month period, into an additional trial including 9 months of balloon treatment and follow-up for 1 year after removal. They excluded eight patients who had not met the weight loss goal during the first 3 months (n=5) or who did not tolerate the balloon (n=3). Although there was no difference between sham and balloon during the first 3 months, after 1 year of balloon treatment, a mean weight loss of 21.3 kg (17.1 %) was achieved in all patients, of which 12.6 kg (9.9 %) was maintained at the end of the second balloon-free year. Overall, 47 % of patients sustained a 10 % weight loss at the end of a 2-year follow-up. Although this study could not demonstrate an independent benefit of balloon treatment beyond diet, exercise, and behavioral therapy in the first treatment, balloon treatment for 1 year, in those patients who tolerated the treatment, resulted in substantial weight loss, a significant part of which was maintained during the first year after removal of the balloon. More recently, the
Endoscopic Bariatric Procedures Fig. 1. Endoscopic view of a BIB balloon filled with saline at the time of removal; a needle is inserted in the balloon to aspire its content. b Spatz adjustable balloon with its connecter allowing partial deflation or reinflation.
same author reported the results of balloon therapy in a private practice setting [14], without intense dietary follow-up and suggested that balloon therapy has the potential, in this environment, to fill the therapeutic gap between pharmacotherapy and surgery. Another study looked at the long-term outcome after treatment with an intragastric balloon for 6 months, with no structured weight maintenance program after balloon removal. A hundred consecutive morbidly obese individuals were prospectively followed after BIB placement; 97 patients completed final follow up at a mean of 4.8 years while, after 6 months, 63 % of patients had more than 10 % baseline weight loss; there were only 28 % at final followup. At that time, 35 patients had undergone bariatric surgery and 34 patients had no significant weight change from baseline [12]. Imaz et al. [13] pooled 3,608 patients to estimate the effectiveness of BIB. The weight loss at balloon removal after 6 months was12.2% (32% excess weight loss (EWL)). A meta-analysis of two randomized controlled trials (RCTs) that compared balloon with placebo showed a benefit of balloon over placebo with a difference of 17% EWL. These studies confirm that balloon implantation is effective at short term and may be of some help in a minority of patients for long-term weight loss. It is a potential option for patients unwilling to undergo bariatric surgery or not candidate for bariatric surgery, and could also be used as a temporary measure in super-obese patients, in order to induce weight loss and decrease the risk of complications associated with further bariatric surgery. Because of these results and since no other endoscopic technique was available, the intragastric balloon market has been booming in Europe and Middle East over the last 10 years. Several different balloons have been developed without, up to now, dramatically improving the outcome in terms of weight loss and safety profile. Adjustable balloons (Spatz, Great Neck, NY, Fig. 1b), which can be reinflated (in case of decreased effect) or partially deflated (in case of intolerance) had shown initial promising results [15] but are associated with complications which require further improvement in design [16] (mainly at the level of anti-migration anchors). Air-inflated balloons (Heliosphere, Vienne, France) may be associated with a better tolerability but at the cost of a lower efficacy and a higher risk for spontaneous deflation [17] (and migration). Dual balloons connected to each other (ReShape Medical, San Clemente, CA) are designed to increase the total fluid volume, better fit with the stomach anatomy, and prevent balloon passage in the case of one of the two
Endoscopy (I Waxman, Section Editor) balloons deflating. These latter are the only ones currently available in the US, and the company submitted a PMA application on a RCT performed on 326 patients and showed that patients having the procedure lost more than twice as much weight as the sham–controlled subjects [18] at 6 months. Fifteen percent of the patients did not tolerate the balloon which had to be removed early. Their high cost compared with other available balloons limits their use in other parts of the world. Some of these new balloons are allowed to stay in place for 12 months. In the search for rendering intragastric balloons even less invasive, orally ingested balloons have been evaluated [19] and (too?) early commercialized. Although the principle is interesting, the risk of deflation limits their indwell duration to 3 months, and partial deflation may be associated with small bowel occlusion. Other swallowable balloons that degrade spontaneously and ensure homogeneous and fast deflation are now under investigation [20]. Several other space-occupying devices have been developed, two of them being still potentially under evaluation, although no recent clinical data are available. The transpyloric shuttle (Baronova, Goleta, CA) acts by transient occlusion of the pylorus (increasing the filling of the stomach) and the Satisphere (Endosphere, Redwood city, CA) aims to slow down the passage of food into the duodenum, increasing the satiety via stimulation of duodenal hormones. Although not really a space-occupying device, a new tool in the armamentarium of the endoscopist is the AspireAssist (Fig. 2) aspiration therapy system (Aspire Bariatrics, King of Prussia, Pennsylvania, USA). It involves the placement of a gastrostomy tube, similar to PEG placement and a siphon assembly to aspirate gastric contents 20 min after a meal. In a per-protocol analysis, body weight loss after a 4-week run-in period of a very low-calorie diet (and strict instructions about eating and chewing food) and 6 months of aspiration therapy was 16.5 % of initial weight and 40.8 % of EWL [21••]. Limitations of these techniques include social acceptability and the time necessary (45 min per day) for aspiration therapy [22]. It is, however, effective and might also have elective indications for management of super-obese patients [23]. A pivotal study is ongoing in the US.
Gastric restriction The major limitation of space-occupying devices is related, for most of them, to their limited duration of indwell. Any device inserted into the stomach or the duodenum will ultimately migrate and induce ulceration, mucosal hyperplasia, or even sometimes a perforation. Having suturing techniques which would allow reducing the volume of the stomach and result in long-lasting restriction of food intake might allow performing transoral procedures which would offer results similar to those of restrictive bariatric procedures without compromising further surgery if needed. One disadvantage of endoluminal approach is that suturing results in a mucosa-to-mucosa apposition while persistent suture/anastomosis requires serosa-to-serosa apposition. Therefore, several of the techniques described hereunder have shown only good shortterm results, and data about their mid- or long-term outcome are either disappointing or missing.
Endoscopic Bariatric Procedures Fig. 2. The Aspire Assist system includes gastrostomy includes a tube connected to gastrostomy (a), with a skin port (c) which can be connected to a dedicated pump in order to empty the stomach 20 min after the meals (b).
The EndoCinch Suturing System (C.R. Bard, Murray Hill, NJ) was initially designed for the endoscopic treatment of gastroesophageal reflux disease (GERD). This system allows the placement of series of stitches in the lower esophagus to create a pleat in the sphincter. Although associated with encouraging early results, the EndoCinch for the treatment of GERD has been called into question due to the lack of retention of plications in the long term [24], an observation that is probably related to the fact that most of these stitches are placed in the submucosa. Fogel et al. [25] first described the use of this technology for the treatment of obesity in 64 patients. His technique consisted in the deployment of seven sutures in a continuous and cross-linked design from the proximal fundus to the distal body. The result of the treatment is suggested to be a significant decrease in distensibility of the stomach. The procedure was performed ambulatory, and out of the 59 patients followed for 12 months, the percentage excess weight loss reported was 21 % at 1 month and 58 % at 12 months. Only a minority of patients (N=14) underwent repeated endoscopy in the follow-up. In 11 of them,
Endoscopy (I Waxman, Section Editor) the suture line was reported as completely or partially intact. Unfortunately, limited information on endoscopic or radiological follow-up was provided, the study having been performed without institutional review board submission and with commercial products, making it difficult to understand the extent of stomach restriction. Using a modified version of the device (Restore Suturing System Bard-Davol, Warwick, RI), Brethauwer et al. [26] reported feasibility and efficacy in a pilot multicentric study involving 18 patients. The observed EWL at 12 months was 27 %, and dehiscence of the sutures was observed in 13/18 cases. No other clinical data were published since then. The Overstich (Apollo Endosurgery) is another suturing system which also allows the endoscopist to reload the suture without removing the scope. Multiple sutures have been placed in a pilot study on four patients with successful apposition of gastric wall [27]. No data are, however, available on clinical mid-term outcome. Safestich (Miami, FL) is developing a dedicated instrument (Intraluminal Gastroplasty Device) which is not fixed at the endoscope and designed to suture the two sides of the stomach which are captured by suction and sutured after mucosal excision [28]. Only this small pilot study reported persistence of the suture up to 2 years in three patients. This principle of using a dedicated device which accommodates an endoscope and uses suction for apposition of the gastric walls was the fundamental originality of the transoral gastroplasty System (Satiety, Inc, Palo Alto, CA), a technique now abandoned but which is, to date, the one with most clinical data available in the area of endoluminal restrictive treatment. The system consisted in a flexible 18-mm-diameter shaft device allowing suction of the anterior and posterior walls of the stomach which were stapled with a stapler similar to those used in laparoscopic surgery, allowing a suture involving two serosa-to-serosa appositions. Two pilot studies had demonstrated EWL of 25 % and 46 % at 6 months [29, 30]. A multicentric European study [31] performed on 67 patients confirmed the effectiveness at 1 year with 45 % EWL and reported only two mild complications. A multicentric randomized sham–controlled study was then performed in 11 (ten US) centers, comparing the active and sham procedure (2.1 ratio) in a series of 275 patients. After completion of this study, the technique was shown superior to placebo, but two severe complications were observed. Additional data requested by the Food and Drug Administration (FDA) could not be provided due to lack of financing; the company was bankrupted and its assets sold to another major medical device company. Interestingly, the latter refused to provide data for publication of this trial. Besides this last ethical concern, the major lessons from this experience were that these advanced transoral procedures, unlike laparoscopic interventions, were not more difficult to perform in the heavily obese, were associated with fast recovery, could be performed on an outpatient basis, and, importantly, do not compromise or render more difficult further surgery if needed [32]. Another technique for endoluminal gastric restriction is the creation of multiple plicatures in the stomach wall. The POSE system (USGI) is a dedicated flexible device (Fig. 3) in which an endoscope is inserted and
Endoscopic Bariatric Procedures Fig. 3. The POSE system is a dedicated flexible device (a), accommodating the endoscope and special grasping and suturing device (b), allowing performance of transmural plicatures which are placed in the antrum and the fundus (c).
allows performing plicatures with serosa-to-serosa apposition. By placing it into the antrum and the fundus, it reduces the compliance of the stomach and favors early satiety. The device obtained the CE-Mark in Europe and two independent studies months [33, 34•], performed with the commercial device showed promising outcomes in terms of weight loss (45 % and 49 % EWL at 6 and 12 months, respectively). These studies were, however, associated with intense dietary follow-up, and the real efficacy of this technique will be further explored in a multicentric, sham–controlled trial which is currently ongoing in the US. Finally, another procedure, now abandoned, also provided interesting data for future development of these technologies. Transoral Endoscopic Restrictive Implants System (TERIS, Barosense, Redwood City, CA) was seen as
Endoscopy (I Waxman, Section Editor) Fig. 4. The Endomina platform is a universal self-assembling platform which can be adapted into the stomach to any endoscope and allowing performance of both plicatures and wall-towall sutures.
an endoscopic equivalent to gastric banding. It consisted in a proximal implant attached to the stomach wall through plicatures and anchors. A phase I pilot trial [35] reported successful placement in 12 of 13 patients but with significant complications and EWL of 28 % at 3 months, suggesting that technical improvements were obviously needed, but also that it could become another option in the endoscopic armamentarium. The major drawback was, however, migration of the implants, stressing the fact that even tight attachments do not avoid migration of a foreign body attached to the gastric wall and submitted to mechanical constrains. The same company came back with a similar instrument redesigned to only perform plicatures [36]. In a way similar to the POSE procedure, more than ten plicatures per patient were made in 17 patients, without severe complications and a reported EWL of 35 % at 1 year. Despite that, the company closed up and sold its assets for lack of financing. Finally, combining transmural suturing of the gastric wall with plicatures and apposition of these plicatures in order to reduce the volume and distensibility of the stomach is the principle followed by the Endomina (Fig. 4) universal platform [37] (Endotools SA, Gosselies, Belgium). These double plicatures, apposing each other, persist in animal models, but human data are still pending.
Malabsorption/metabolic endoscopy These techniques have to be put in line with the development of metabolic surgery and particularly with the clinical observation that bypassing the proximal bowel improves type 2 diabetes and induces weight loss, a feature which, at least in part, explains the greater improvement of diabetes observed in patients undergoing a laparoscopic RYGBP, for the same weight loss, compared with a purely restrictive procedure [38, 39].
Endoscopic Bariatric Procedures Fig. 5. The duodenal jejunal bypass sleeve is a Teflon sheet fixed to a metallic anchor (a) and deployed from the duodenum into the proximal part of the jejunum (b). It allows avoidance of contact of food with duodenal and proximal jejunal mucosa.
EndoBarrier (GI Dynamics, Lexington, MA, USA) is a duodenal–jejunal bypass sleeve (DJBS) made from a Teflon liner and delivered endoscopically to the duodenal bulb (Fig. 5), which has shown promise and efficacy in the management of obesity and associated diabetes. When deployed, it mimics the mechanical manipulation of RYGB surgery by creating a mechanical barrier that allows food to bypass the duodenum and proximal jejunum without mixing with bile and pancreatic secretion until more distally in the gut, thus potentially altering the incretin–anti-incretin system procedure [39]. The device is left in place for a maximum of 3 to 6 months and is removed with a dedicated and relatively easy system. Three early trials demonstrated the potential benefit of DJBS. In the first one [40], it was successfully deployed in 12 patients in less than 30 min (and required approximately 40 min to be removed). With the exception of pain prompting early removal, it was associated with a significant drop in HbA1C, compared with a control group. A second multicenter trial, from Chile, showed, at 12 weeks, a weight loss significantly higher in 24 patients treated with the EndoBarrier system compared with the diet control group in a preoperative setting [41]. The last available study is a sham–controlled trial with 21 patients treated and 26 undergoing the sham procedure, with a 12 weeks study design. Excess weight loss (11.9 % versus 2.7 %) and loss of more than 10 % excess weight (62 % versus 17 % of patients) were all in favor of the DJBS. However, eight subjects terminated earlier because of GI bleeding (N=3) or device intolerance (pain and/or vomiting, N=4) and an
Endoscopy (I Waxman, Section Editor) unrelated preexisting illness (N=1), showing that more technological developments are still to be done [42]. In most of the series published so far, complications prompting early removal, including some more severe, were the major concerns related with this technique. Their frequency led some experts to state that it was not ready for clinical use. However, a more recent RCT on 77 patients showed an independent benefit over dietary support in terms of diabetes improvement and weight loss with only 9 % early explants for mild complications [43•]. Another study suggested that diabetes improvement may persist after sleeve removal. This prompted the company to start a sham–controlled RCT in the US, but unfortunately, the FDA halted this trial for major complications (including liver abscess), further showing that the safety profile of this duodenal implant has to be improved. Remodelling the enteroinsular endocrine regulation for treating type 2 diabetes is also the target of a new technology called Bduodenal resurfacing^ (Fractyl, Boston, MA) where sequential submucosal injections and mucosal ablation (by transient heating) are performed in the third part of the duodenum (below the papilla). The destroyed duodenal mucosa is then regenerated with potentially different endocrine capabilities, and, in a first pilot study performed in Chile, this led to a significant improvement of type 2 diabetes. A multicentric study is ongoing in Europe. If these data are confirmed, it could open a new era for endotherapy of diabetes, and the concept is very attractive due to the lack of implant. Another area with possible developments in the near future is the transoral creation of anastomoses either using Natural Orifice Transluminal Endoscopic Surgery techniques [44] which might become easier with the development of new dedicated stents [45••] (XLumina, CA) or by using magnets as already demonstrated in clinical studies for treating gastric outlet obstruction [46] but which might become easier to use with self-assembling technologies, also allowing immediate functionality after placement[47•]. These technologies could prompt the design of either entirely peroral procedures or hybrid peroral/laparoscopic procedures facilitating the performance of bypass.
Conclusions Mechanisms of bariatric procedures are complex and involve modulation of the neurohormonal mechanisms that regulate appetite, satiety, glucose metabolism, energy utilization, and feeding behavior [48]. Transoral procedures offer the possibility to further unravel these mechanisms in the light of clinical observations. If restrictive surgical procedures are supposed to mainly act by increasing the resistance to the passage of food and thereby inducing weight loss because of noxious symptoms, this effect is much less obvious with the endoluminal procedures which aim to appose tissues or perform plicatures. Limiting the distensibility of the stomach and further modulating Ghrelin response to fasting or postprandial Ghrelin inhibition and/or stimulation of appetite frenators such as peptide YY or glucagon-like peptide 1, or increasing vagal stimulation are potential mechanisms of action. Understanding the physiological effect of the new
Endoscopic Bariatric Procedures technologies, at the level of neurohormonal mediators will be, in our view, one of the key factors that might allow in the future designing the most effective treatment option. Several technical challenges also remain, mainly in terms of persistence of the anatomical changes created and prevention of complications associated with the treatment. An optimal technique would probably benefit of several of the multiple inventions which took place in this area over the last 15 years. There is no doubt that we need better, less invasive, endoscopic techniques for the management of the obesity pandemic. One of the hurdles we might face is related to the difficulty and cost of proving clinical efficacy which prompt some interesting technologies to disappear for lack of financing. In this line, another concern is that, in case of bankruptcy, the intellectual property is acquired by major medical devices companies which do not seem very keen in pursuing development. Hopefully, obesity (and diabetes) is affecting so many peoples around the world that search for an effective therapy is still pursued by enthusiastic groups of engineers and physicians, and there is no doubt that endoscopic approach will play a growing role in the future management of this disease.
Compliance with Ethics Guidelines Conflict of Interest Jacques Deviere is a consultant for and patent holder with Endotools Therapeutics. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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