21/01/2025
The availability of endoluminal bariatric and metabolic therapies (EBMTs) approved by the Food and Drug Administration (FDA) for obesity has increased significantly. In this article, part 2 of a series, Dilhana S. Badurdeen, M.B.B.S., M.D., discusses small bowel EBMTs, including the duodenojejunal bypass sleeve, duodenal mucosal resurfacing or ablation, pharmacological duodenal exclusion therapy, duodenal mucosal electroporation therapy, and gastric mucosal ablation.
Dr. Badurdeen and Vivek Kumbhari, M.B., Ch.B., Ph.D., gastroenterologists at Mayo Clinic in Florida, are co-authors of a review article published in a 2023 issue of Current Opinion in Gastroenterology that summarizes the current state of EBMTs.
"The aims of small bowel endoluminal bariatric and metabolic therapies vary," explains Dr. Badurdeen. "Some of these therapies attempt to prevent the passage of ingested nutrients to the proximal small intestine, replicating the effects of gastric bypass surgery. Others are designed to target duodenal mucosal cells, with the goal of modifying the incretin pathway to enhance insulin sensitivity."
Duodenojejunal bypass sleeve
The duodenojejunal bypass sleeve is an endoscopically inserted implant that prevents nutrient digestion and absorption at the proximal small intestine. Using a self-expandable metal stent, the endoscopist anchors the device to the duodenal bulb and places a Teflon sleeve into the proximal small bowel.
"A number of studies have investigated the safety and efficacy of this treatment for patients with poorly controlled diabetes mellitus," explains Dr. Badurdeen. "Although this device has demonstrated the potential to address obesity and metabolic disorders by targeting the proximal small intestine, it has not yet obtained FDA approval. More information will be available after the completion of another multicenter study in the United States."
Duodenal mucosal resurfacing (DMR)
Also known as duodenal mucosal ablation, this is an endoscopic technique that involves mucosal injection, lifting and ablation with a device that targets the distal 10 cm of duodenal mucosa after the major papilla. Several models of this device are available, some of which are FDA approved for adults with inadequately controlled type 2 diabetes (T2DM) on long-acting insulin. Other models are undergoing clinical trials for patients with suboptimally controlled T2DM.
"DMR appears to improve glycemic control independent of weight loss," explains Dr. Badurdeen. "Participants in a multicenter study had decreases in HbA1c and fasting blood sugar levels, which were maintained at 12 months, and improvements in insulin resistance."
Pharmacological duodenal exclusion therapy
This approach involves the use of a proprietary pH-activated mucin complexing polymer that is designed to enhance the duodenum's natural mucous barrier. The polymer is not absorbed and provides a temporary barrier that replicates duodenal exclusion physiology.
"This approach is aiming for results similar to gastric bypass surgery," explains Dr. Badurdeen. "A phase 1 randomized double-blinded safety clinical trial demonstrated that the polymer was safe at doses up to 6 grams per day, with some mild to moderate adverse effects reported, mostly at higher doses," explains Dr. Badurdeen. "Although the researchers observed a significant reduction in postprandial glucose levels on day 1, that reduction was not sustained through day 5, with similar results observed for postprandial bile acid increases. Results from a phase 2 double-blinded, randomized clinical trial that are not yet published may provide additional insights."
Duodenal mucosal electroporation therapy
This approach — also known as re-cellularization via electroporation therapy (ReCET) — uses pulsed electric fields targeting the duodenal mucosa. The goal is to improve regulation of blood glucose and insulin levels by inducing controlled electroporation and apoptosis of duodenal cells, which then regenerate and restore their original function. Read more about the preliminary results from the REGENT-1-US trial and Mayo Clinic researchers' involvement in the development and testing of the ReCET procedure here.
Gastric mucosal ablation (GMA)
Also called gastric mucosal devitalization (GMD), this minimally invasive bariatric procedure is designed to emulate the weight-independent metabolic effects of laparoscopic sleeve gastrectomy (LSG). During GMA, the endoscopist selectively ablates the gastric mucosal cells, inducing weight loss by manipulating metabolic pathways.
In an article published in Obesity Surgery in 2022, Drs. Badurdeen and Kumbhari and colleagues determined the optimal ablation parameters and that the optimal percent surface area to ablate is 70%. Overall, they observed an improvement in glucose and lipid metabolism and favorable cardiovascular changes in the animals that were randomized to GMD.
Drs. Badurdeen and Kumbhari and others are now conducting clinical trials to assess the feasibility and safety of GMA. In the COMET EF — Step 1 study, the researchers assessed the histopathological outcome and safety of ablation in combination with submucosal saline injection. They successfully performed ablation on stomach tissue sites that were resected 3 to 5 days later during planned sleeve gastrectomy in six research participants with obesity.
The Comet EF — Step 2 is a prospective, single-arm pilot study conducted at two sites. This study is designed to determine if ablating up to 70% of the gastric mucosa in a two-step procedure is technically feasible, safe and tolerable as a therapeutic approach for patients with obesity. Research participants are adults with class 1 to class 3 obesity who receive two treatment sessions, eight weeks apart. The researchers will note the total body weight loss at six months after the last treatment session.
