Removable Transduodenal Bypass: Development of a New Endoscopic Concept

Overweight and obesity affect almost 60% of adults worldwide and have been rising constantly during the past decades. There has been no WHO-adjacent country who has managed to reach a steady state concerning obesity so far, aggravating obesity as a global health threat [1‒3]. The main global burden does not result from obesity directly; however, it does result from obesity-related health issues, such as nonalcoholic fatty liver disease (NAFLD), infertility, cardiovascular disease, cancer, diabetes mellitus type 2, and diseases of the musculoskeletal system as well as many more [4‒7].

The Look AHEAD trial clearly showed in 2013 that lifestyle modification does not have the ability to lead to a sufficient weight loss in obese patients with type 2 diabetes. Further, the trial showed that patients were only able to maintain a weight loss of 3.5% of total body weight over a mean follow-up of 9.6 years. It showed that cardiovascular events in diabetic patients could not be reduced through lifestyle intervention [8].

Bariatric surgery has long been proven to be the currently most effective therapy for weight reduction, improved overall survival, and reduced rate of obesity-related disease [9]. Worldwide, the most common primary procedures are sleeve gastrectomy, Roux-en-Y gastric bypass, and one-anastomosis gastric bypass [10].

During the past years, medication, specifically glucagon-like peptide 1 analogs (GLP-1 analogs), has taken a role in treatment of obesity and obesity-related disease. Liraglutide has the ability to create a mean weight loss of around 5–6% in diabetic and obese patients [11, 12], while new studies have shown that semaglutide can lead to a weight loss of up to 10–13% of total body weight [12, 13]. Both drugs have also shown to significantly reduce high blood pressure and type 2 diabetes when administered continuously [14].

Nevertheless, both current treatment options leave room for improvement. Surgery embodies an irreversible procedure that is effective in most cases but can also lead to adverse events or complications. Reversing bariatric surgical procedures is quite laborious and not always possible.

Further, using medication, to our knowledge, requires lifelong treatment if the effect should be maintained. Also, medication is not suitable for every patient, often causing side effects and therefore not being able to fulfill its full potential [14]. Therefore, endoscopic options for weight loss, type 2 diabetes control, and treatment of diseases secondary to obesity have been explored as an alternative treatment option over the past years.

EndoBarrier^®, for example, seemed to be a promising device for weight loss of up to 19% after 3–12 months of treatment [15, 16]. During a clinical trial in 2015, patient recruitment was terminated early due to an unexpected amount of liver abscesses (3.5%). Other adverse events, such as gastrointestinal bleeding and ulcerations, were also seen [17]. However, the mechanisms behind EndoBarrier have shown to reduce type 2 diabetes [15, 16] and improve biochemical markers of NAFLD [18] and hypertension [15].

Though mechanisms are not yet fully understood, weight loss, diabetic control, and reduction of hypertension seem to be achieved through avoiding contact of food to duodenal mucosa. This theory is supported by the REVITA-2 trial, which showed that duodenal mucosal resurfacing can reduce HbA1c significantly as well as reducing liver fat fraction in obese patients [19].

Since the concept of EndoBarrier seems to be a good base for endoscopic treatment of obesity and obesity-related diseases, through Trans-Duodenal Concepts^® (TDC), we aimed to create a device which lines the duodenum but prevents from adverse events seen during therapy with EndoBarrier. The implant development based on animal tests in minipigs will be described in the following. It is an example for an experimental concept development based on the analysis of clinical needs.

The development took place in 3 different stages. The implant development was based on a 60-cm-long foil tube which carries a semiflexible shaft at its tip. This shaft wears three ring-like balloons, made from thin polyurethane foil. One balloon aims to fixate the device in the duodenal bulb and the other concentric balloons are placed to fixate the implant in the gastric antrum and therefore slow down gastric emptying to the duodenum (Fig. 1). After definition of suitable dimensions, the device was implanted endoscopically into 8 pigs (20–40 kg). For implantation, the device was mounted on a flexible standard gastroscope. After the final position of the device was reached, the balloons were filled with room air. The filling tubes were placed in the stomach. In the further course, the pigs vomited up the filling tubes, leading to loss of volume in the balloons. Several attempts to fixate the tubes on the gastric mucosa with endoscopic clips were not successful.

The second generation of implants was therefore constructed with a ventil mechanism which closes the inlet of the shaft after the balloon has been filled (Fig. 2). Four pigs have so far received the new prototype. In all cases (apart from one, which was sacrificed due to an esophageal perforation), the device was implanted into the pigs successfully. The implant technique was changed compared with the previous experiments. For easier handling and implantation, the implant was mounted on a standard Savary bougie with 9 mm diameter. It was then inserted via an endoscopically implanted standard guide wire (Jagwire, BSCI). The procedure was monitored by the gastroscope which was inserted together with the bougie. The balloons were then filled with their standard volume of air, and the foil tube was extended by flushing water through the device and into the small bowel. The survival time of the pigs was 2–7 weeks. Autopsy revealed that in most cases, the foil tube everted through the shaft. Implant integrity, however, was given.

In the third generation of implants, we reduced the stiffness of the shaft between the two balloon-wearing tubes (Fig. 3). This prevented the eversion of the foil tube and led to a stabile position of the implant in the transpyloric position. The third generation of devices was tested on a total number of 6 pigs successfully.

During the past years, several devices using the concept of duodenal lining have been developed by different manufacturers. Keyron^® has presented a model combining a gastric balloon with duodenal lining presented as ForePass^® which has been tested on rodents and has shown a decrease in NAFLD and type 2 diabetes, for example [20]. Another device presented by Metamodix^® called EndoSleeve^® is secured via the pyloric muscle through a stenting device connected to a duodenal liner. Clinical studies have not yet been published [21]. A third duodenal lining system presented on the market is NobiX^® by Allevetix^®, which uses a stenting system within the most oral part of the duodenum as well as a gastric fixation device to secure the lining system. Results have also not yet been published [22].

Again, also duodenal mucosal resurfacing seems to be a feasible approach toward reduction of obesity-related disease with a proven dose effect upon intensification [19]. The current development of all these devices and methods shows the relevance and demand for nonsurgical but effective alternative weight loss procedures to currently available solutions of surgery and medication.

Through TDC, we aim to take hazards for adverse events seen in previous devices into account and to modify these to create a safe and reliable device. Design and functionality have been modified thoroughly and seem safe and feasible for clinical trials on humans. Implantation has been optimized and simplified for uncomplicated use.

In the past, all published works regarding endoscopic devices for diabetes control and weight loss have been based on clinical results. Within the time of observation, we did not see bleedings or perforations. Due to different eating habits, physiological function, upright position, and slightly different anatomy, the efficacy of the transduodenal barrier in terms of improvement of diabetes metabolism and weight reduction cannot be proven in an animal experiment. Therefore, we aim to continue research with application of the transduodenal barrier in human studies. Based on previous clinical results with the EndoBarrier, successful function of the barrier can be expected.

However, the balloons aim to avoid risk for bleeding and perforation, as was seen in EndoBarrier, which was fixed in place by sharp barbs. As several clinical cases showed, these might cause ulceration and bacterial transmission. Further, we expect to avoid liver abscesses for the same reason.

In addition, we hope to reduce peristaltic waves directing food transport toward the duodenum and therefore delay gastric emptying through the slightly larger, 60-mL balloon used on the gastric side of the device. The pyloric tube is designed to be soft while still allowing gastric emptying through plastic ring reinforcement to maintain the risk for stomach and duodenal ulceration as low as possible. During the trials performed on minipigs during the past years, we have faced some technical challenges, which has led to further development and maturing of the product design.

We still do see technical challenges with possible leakage of the balloons; therefore, a second safety balloon is implanted into the gastric balloon. Further, bowel obstruction has been a major concern upon implant of the device into minipigs. However, since this has never been a major problem with previous devices, we expect the device to act in a different manner than in pigs and similarly to EndoBarrier when used on the human.

However, we do expect there to be a certain level of intolerance in patients receiving TDC as a therapeutic device, specifically nausea, vomiting, and possibly pain directly after device implantation. In analogy to gastric balloon implantation, we expect these symptoms to pass after a few days or weeks.

So far, the device was not tested on animals with type 2 diabetes mellitus or NAFLD. Therefore, remission of these comorbidities is yet to be investigated.

Further, the minipigs used for testing the device were not obese. Due to this reason and due to the necessity of explant of the device in case of a weight loss of more than 10% according to FELASA regulations or in case of stress in the animal, true weight loss could not be determined. We see difficulties in determining true weight loss in animals since the important factor of disease understanding and the understanding of the device and therefore stress production and management are essential for potential long-term use and success of the device. For this, testing in the human model is essential. However, we see potential use for TDC not only in primary reduction of weight, NAFLD, type 2 diabetes, or hypertension but also as a complimentary therapy to surgery or conservative therapeutic options in terms of multimodal therapeutic concepts. Further trials are needed for clinical evaluation.

We see TDC as a promising device based on a proven, effective concept for reduction of obesity and obesity-related disease. However, TDC has never been implanted into human patients. Therefore, clinical trials are needed for evidence of possible effect and safety in humans. A clinical case series is already in preparation, aiming to implant first TDC devices before the end of 2023.

The authors thank Dieter Fornoff, Andreas Ries, and Maher Kasraoui for prototype development and manufacturing. Animal testing was performed in Fördergemeinschaft für Innovative Medizin Beichlingen, Germany (Dr. Frank Pölzing); mfd Diagnostics GmbH Wendelsheim, Germany (Dr. Bernd Lecher); and IHU Strasbourg (Amelie Gressier and Fanelie Wanert).

This study was performed in line with the principles of animal protection (FELASA). The test was approved by Freistaat Thüringen, Landesamt für Verbraucherschutz, Reg. Nr. 08-001/16; Rheinland-Pfalz, Landesuntersuchungsamt, Reg. Nr. G 17 – 15 – 087; IHU Reg. Nr. DXP22-54.

Georg Kähler is the founder and shareholder of Trans-Duodenal Concepts GmbH. The other authors have no relevant financial or nonfinancial interests to disclose.

All costs for manufacturing of the prototypes and animal testings were covered by Trans-Duodenal Concepts GmbH, Mannheim, Germany.

All authors contributed to the study conception and design. Concept development and engineering were performed by Prof. Dr. med. Georg Kähler.

Data and materials can be obtained from the endoscopic department, department of surgery of the Medical Faculty Mannheim.