The small bowel is a prime target for bariatric and metabolic endoscopic therapies. New insights into the mechanisms of action of surgical therapies have led to new endoscopic therapies for obesity, type 2 diabetes mellitus, and the metabolic syndrome. The development of endoluminal sleeves that bypass the proximal duodenum have replicated some of the effects of surgical bypass procedures. The endoscopic dual-path enteral bypass has created new and treatment options for these conditions. Duodenal mucosal resurfacing offers significant promise for diabetes management. It is hoped that a durable endoscopic therapy for these conditions will be defined and optimized.
Key points
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The small bowel is important in the management of obesity, type 2 diabetes mellitus, and metabolic syndrome. Bariatric surgical therapies have focused on the small bowel for decades.
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New understanding of the mechanisms of obesity and type 2 diabetes mellitus as they relate to the small bowel have led to the development of endoscopic bariatric therapies that focus in this region.
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Endoluminal sleeves function by bypassing the proximal duodenum and have been shown to be effective in the short-term management of obesity and diabetes.
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Dual-path enteral bypass functions by delivering enteral contents rapidly to the ileum and represents a new treatment of both obesity and diabetes.
Introduction
The small bowel plays a significant role in weight management and management of type 2 diabetes mellitus (T2DM). Manipulation of the small bowel has been used in surgical weight loss procedures for decades and was initially established by creating malabsorption to facilitate weight loss. Further work has identified other mechanisms of action that are becoming key to understanding the role of the small bowel in obesity and T2DM. Key clinical observations in patients who had gastric bypass showed that weight loss and reversal of diabetes can occur and are largely caused by the bypass of the proximal small bowel. Recent reviews of the physiology of small bowel manipulation have identified several possible mechanisms of action for small bowel devices that lead to weight loss and control of T2DM. Two main mechanisms of action for procedures and surgeries of the small bowel to affect obesity and T2DM are foregut exclusion and rapid delivery of food to the ileum. Both have been implicated in invoking an incretin pathway for improvement in obesity and resolution of T2DM but understanding of these mechanisms is far from complete. These concepts and the surgical therapies are expanded on elsewhere (see Zubaidah Nor Hanipah and Philip R Schauer’s article, “ Surgical Treatment of Obesity and Diabetes ”; and Lee M. Kaplan’s article, “ What Bariatric Surgery Can Teach Us About Endoluminal Treatment of Obesity and Metabolic Disorders ,” in this issue). Endoscopic bariatric therapies that target the small bowel and have been used in humans include endoluminal sleeves, duodenal mucosal resurfacing, and partial stream intestinal bypass procedures. Duodenal mucosal resurfacing are the focus of a following article in this series (see Alan D. Cherrington and colleagues’ article, “ Hydrothermal Duodenal Mucosal Resurfacing: Role in the Treatment of Metabolic Disease ,” in this issue). The remaining 2 approaches have been used both in animal studies and in humans and have been found to be effective in the treatment of obesity and T2DM.
Introduction
The small bowel plays a significant role in weight management and management of type 2 diabetes mellitus (T2DM). Manipulation of the small bowel has been used in surgical weight loss procedures for decades and was initially established by creating malabsorption to facilitate weight loss. Further work has identified other mechanisms of action that are becoming key to understanding the role of the small bowel in obesity and T2DM. Key clinical observations in patients who had gastric bypass showed that weight loss and reversal of diabetes can occur and are largely caused by the bypass of the proximal small bowel. Recent reviews of the physiology of small bowel manipulation have identified several possible mechanisms of action for small bowel devices that lead to weight loss and control of T2DM. Two main mechanisms of action for procedures and surgeries of the small bowel to affect obesity and T2DM are foregut exclusion and rapid delivery of food to the ileum. Both have been implicated in invoking an incretin pathway for improvement in obesity and resolution of T2DM but understanding of these mechanisms is far from complete. These concepts and the surgical therapies are expanded on elsewhere (see Zubaidah Nor Hanipah and Philip R Schauer’s article, “ Surgical Treatment of Obesity and Diabetes ”; and Lee M. Kaplan’s article, “ What Bariatric Surgery Can Teach Us About Endoluminal Treatment of Obesity and Metabolic Disorders ,” in this issue). Endoscopic bariatric therapies that target the small bowel and have been used in humans include endoluminal sleeves, duodenal mucosal resurfacing, and partial stream intestinal bypass procedures. Duodenal mucosal resurfacing are the focus of a following article in this series (see Alan D. Cherrington and colleagues’ article, “ Hydrothermal Duodenal Mucosal Resurfacing: Role in the Treatment of Metabolic Disease ,” in this issue). The remaining 2 approaches have been used both in animal studies and in humans and have been found to be effective in the treatment of obesity and T2DM.
Endoluminal sleeves
Duodenal Jejunal Bypass Liner
In an attempt to mimic the small bowel bypass of the Roux-en-Y gastric bypass procedures without surgery, Rodriquez-Grunert and colleagues described an endoluminal sleeve device that could be deployed endoscopically with anchors in the duodenum that essentially provided a lumen within the lumen of the proximal small bowel, prohibiting contact between the mucosa and ingested contents. The sleeve also did not allow bile and pancreatic secretions to contact the food stream until the end of the sleeve some 60 cm downstream from the major papilla. The resulting bypass of proximal small bowel mucosa had a profound effect on glucose metabolism and led to weight loss and improvement of T2DM. This device was brought to further human trials and marketed outside the United States as the EndoBarrier (GI Dynamics, Lexington MA). The system consists of a 60-cm Teflon polymer sleeve, a nitinol crown anchoring system at the proximal end with barbs that penetrate the duodenal wall, and is designed to be deployed in the duodenal bulb ( Fig. 1 A ). The sleeve is encapsulated in a delivery system that is introduced over a guidewire into the duodenum. The EndoBarrier is deployed with endoscopic and fluoroscopic guidance to direct placement of the anchoring system into the duodenal bulb and allow the deployed sleeve to cover the proximal small bowel ( Fig. 1 B). While the device is in place, contents from the stomach pass through the lumen of the sleeve and are delivered into the proximal small bowel without contact with the mucosa or digestive enzymes from the biliary tree or pancreas. The sleeves were left in place for varying time intervals (3–12 months) and then removed endoscopically with a retrieval device that collapses the nitinol anchor into an endoscopic hood to protect the gastrointestinal (GI) tract as it is withdrawn. The early clinical experience with the device in open-label trials has been encouraging, with excess weight loss (EWL) in the 25% to 35% range when the sleeve is left in place longer than 3 months. Investigators also noticed a prompt and significant improvement in hemoglobin A1c (HbA1c) levels. This finding led to additional studies, including randomized controlled trials, which typically result in less weight loss than open-label studies. The results of the reported trials were reviewed in a meta-analysis by Abu Dayyeh and colleagues in 2015. This meta-analysis showed that, in the open label studies, more than 25% EWL was achieved with the device. Three studies enrolling 105 patients achieved an EWL of 35.3% (95% confidence interval [CI], 24.6–46.1) at 12 months. Four randomized controlled trials compared 12 to 24 weeks of treatment with the EndoBarrier duodenal jejunal bypass liner (90 subjects) with a sham or control arm (84 subjects). The mean EWL difference compared with a control group was significant at 9.4% (95% CI, 8.26–10.65). Even with short-term (3-month) use the glycosylated hemoglobin was significantly improved compared with controls. Patient tolerance of the device has been variable and early removal is necessary for symptoms in a percentage of patients. Complications related to the sleeve were reported in all the trials. The cumulative complication rate for the clinical trials analyzed in the meta-analysis included 271 implanted patients and reported serious adverse events, including sleeve migration (4.9%), GI bleeding (3.86%), sleeve obstruction (3.4%), liver abscess (0.126%), cholangitis (0.126%), acute cholecystitis (0.126%), and esophageal perforation (0.126%) (secondary to trauma from an uncovered barb at withdrawal).
Although the device has been used widely outside the United States, it has not been approved to be marketed for clinical use in the United States by the US Food and Drug Administration (FDA). A pivotal multicenter randomized controlled trial was initiated in the United States in 2013. However, this 21-center trial had enrollment suspended in March 2015 because of a safety issue with an increased incidence of hepatic abscesses being reported. According to a press release on the GI Dynamics Web site, the trial was placed on hold when 4 cases of hepatic abscess were noted in the 325 randomized subjects. Negotiations with the FDA on a mitigation plan stalled and the trial has not been restarted as of the date of submission of this article. Results from the incompletely enrolled trial are difficult to interpret and have been presented in abstract form.
The device is still being sold and used outside the United States with reported good results. A recent report describes improvement in liver function in subjects with nonalcoholic fatty liver disease treated with the EndoBarrier. A single center also reported its site experience with the device, identifying the side effects seen with clinical use of the EndoBarrier. Eighty percent of patients designated to receive the device were able to complete the prescribed therapy without premature removal or a complication. The same center recently reported its patients’ experience 12 months after the EndoBarrier had been removed. Fifty-nine patients completed the 12-month follow-up after explantation. During this period, body weight increased by 5.6 kg (standard deviation [SD], 6.4 kg) ( P <.001) and HbA1c level increased from 65 mmol/mol (SD, 17 mmol/mol) to 70 mmol/mol (SD, 20 mmol/mol) ( P <.001). Body weight remained 8.0 kg (SD, 8.6 kg) ( P <.001) lower than before implantation; that is, corresponding with a net total body weight loss of 7.4% (SD, 7.6%) ( P <.001) ( Fig. 2 ). The investigators call for a change in strategy to maintain the benefits of the EndoBarrier in their patients.
