Endoscopic small bowel therapies for type 2 diabetes

Abstract

Type 2 diabetes is a global epidemic despite current medical treatments. Many patients are not responsive to medications, and patients with obesity are hesitant about bariatric surgery. Studies investigating the metabolic effects of Roux‐en‐Y gastric bypass have increasingly demonstrated that the duodenum plays a key role in the pathophysiology of type 2 diabetes. This has led to the emergence of small bowel endoscopic therapies for type 2 diabetes. These therapies include procedures such as duodenal ablation, luminal liners, endoscopic bypasses, and endoscopic injections.

INTRODUCTION

Currently, >400 million people worldwide have type 2 diabetes (T2D), with approximately 90% of cases occurring in individuals who are overweight or obese. The global incidence of T2D is rising at an alarming pace, with projections estimating that 552 million individuals will be affected by 2030. ¹ The initial approach to managing T2D involves lifestyle modifications, including dietary changes and increased physical activity. However, as the disease progresses, patients often require pharmacological interventions, including daily insulin administrations, for glycemic control. Despite the use of lifestyle modifications and pharmacologic therapies, fewer than half the individuals with T2D are able to achieve goal glycated hemoglobin (HgbA1C) levels. ² , ³ Although there is no definitive cure for T2D, various treatment strategies aim to regulate blood glucose levels and mitigate disease complications.

The duodenum plays a critical role in glucose homeostasis, serving as a primary site for nutrient sensing, digestion, and absorption, which directly influence the hormonal and neural pathways involved in appetite regulation and metabolic control. The duodenal mucosa contains enteroendocrine L cells and K cells, which secrete glucagon‐like peptide 1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP) in response to nutrient intake. GLP‐1 suppresses glucagon secretion, delays gastric emptying, and enhances satiety by acting on receptors in the hypothalamus, thereby playing a crucial role in appetite regulation. GIP, on the other hand, stimulates insulin secretion from pancreatic beta cells following a meal, enhancing the body's ability to regulate postprandial glucose levels. Together, GLP‐1 and GIP, collectively known as incretins, enhance insulin secretion and contribute to glucose homeostasis. Their effect on glucose metabolism is known as the “incretin effect.” ⁴

In individuals with obesity, dysregulated duodenal nutrient signaling results in impaired incretin responses, decreased insulin sensitivity, and altered gut hormone secretion, all of which contribute to excessive energy intake and metabolic dysfunction. ⁵ Furthermore, obesity‐associated duodenal inflammation and mucosal hyperplasia impairs nutrient sensing and promotes the release of pro‐inflammatory cytokines, exacerbating insulin resistance and metabolic dysfunction. ⁶

Given the dysregulation of the duodenum in metabolic disease such as T2D, it has become a target for therapeutic interventions aimed at restoring normal nutrient signaling and improving metabolic outcomes. Procedures such as Roux‐en‐Y gastric bypass (RYGB) have exemplified the improvement of metabolic dysfunction, especially diabetes, by bypassing the duodenum and improving insulin resistance. ⁷ Studies have compared the effectiveness of the two most widely performed bariatric surgeries, RYGB and sleeve gastrectomy (SG), on T2D management with more success seen with RYGB. RYGB typically results in 23%–35% total body weight loss, with 72%–90% of patients with T2D achieving long‐term euglycemia without the need for oral hypoglycemic medications. ⁸ , ⁹ By bypassing the duodenum and proximal jejunum along with altering bile flow, RYGB transforms the normal nutrient signaling pathways, leading to significant changes in incretin hormone secretion, including an increase in GLP‐1 and a reduction in GIP. In doing so, it enhances insulin secretion, suppresses glucagon levels, and improves postprandial glucose control, often resulting in T2D remission independent of weight loss. ⁷ , ¹⁰ In contrast, SG is a restrictive procedure that reduces stomach volume without rerouting the small intestine. Although SG effectively promotes weight loss and offers some metabolic benefits, it lacks the profound effects on insulin sensitivity and glucose metabolism observed with RYGB due to the absence of the duodenal bypass. ¹¹ The effectiveness of RYGB compared with SG on T2D underscores the duodenum's role in obesity‐related T2D pathogenesis. In turn, new therapies have emerged to modulate duodenal pathophysiology in the management of T2D.

Currently, bariatric surgery offers the most reliable and sustainable results for treating obesity and its associated conditions. ¹² However, it is not a broadly scalable solution to the escalating T2D epidemic, as most procedures are invasive, irreversible, and carry a risk of morbidity. ¹³ Given the duodenum's accessibility via endoscopy, promising minimally invasive endoscopic techniques have been introduced as alternatives to traditional bariatric surgery. These procedures are collectively referred to as endoscopic bariatric and metabolic therapies (EBMTs). EBMTs serve as a viable treatment option for individuals with mild‐to‐moderate obesity who have not achieved weight loss through nonsurgical methods and are ineligible for or unwilling to undergo bariatric surgery.

Ablative therapies

Duodenal mucosal ablation (DMA) is a minimally invasive endoscopic procedure that uses hydrothermal ablation to treat the duodenal mucosa. Abnormal diabetic duodenal mucosa is replaced by healthy mucosa after treatment. Three types of DMA include duodenal mucosal resurfacing (DMR), recellularization via electroporation therapy (ReCET), and aqua therapy.

DMR

DMR is performed using specialized single‐use polyethylene terephthalate balloon catheters developed by Fractyl Laboratories (Fractyl, Lexington, MA, USA). These catheters are advanced into the duodenum alongside the endoscope over a guidewire. The technique involves circumferential hydrothermal ablation of the superficial duodenal mucosa at a temperature of 90°C applied for 10 s, over a 9–10 cm segment of the postpapillary duodenum. This ablation is followed by mucosal regeneration. To safeguard the deeper layers of the duodenum, the mucosa is first lifted with a saline injection for submucosal expansion before ablation. The lifting and ablation steps can be repeated multiple times within a single treatment session until the targeted duodenal area has been fully treated. Fluoroscopic imaging is employed during the procedure to confirm accurate placement of the guidewire and catheters. The rationale of the procedure is to re‐establish more normal enteroendocrine signals by the formation of new enterocytes and restoring incretin hormone modulation (especially regeneration of L cells, which produce GLP‐1), all of which lead to improved insulin sensitivity. ¹⁴ , ¹⁵ , ¹⁶

Early clinical evidence supporting DMR emerged from a first‐in‐human study evaluating variable ablation lengths, which demonstrated favorable short‐term metabolic outcomes with acceptable tolerability. ¹⁷ Both long‐segment (≥9 cm) and short‐segment (<6 cm) DMR significantly improved glycemic control in patients with T2D over a 6‐month follow‐up, with a mean ± SD HgbA1C reduction of 1.2% ± 0.3%. Notably, greater glycemic improvements were observed in patients undergoing long‐segment ablation, suggesting a potential dose‐response relationship between treated duodenal length and metabolic benefit. Weight loss during the study period was modest, suggesting that the glycemic benefits were largely independent of weight reduction. The most frequently reported adverse effect was transient abdominal pain. Duodenal stenosis occurred in 3 of 39 (7.7%) of the patients within 2–6 weeks postprocedure and was successfully managed with endoscopic balloon dilation. Interpretation of these early findings, however, was limited by variability in ablation length and the lack of anonymization with respect to background glucose‐lowering medications.

Subsequent studies have provided consistent evidence supporting the durability of DMR‐induced glycemic improvements. In a multicenter prospective open‐label study of 36 patients with T2D (body mass index [BMI], 24–40 kg/m²; HgbA1C, 7.5%–10%) on stable oral antidiabetic therapy, DMR resulted in a mean absolute HgbA1C reduction of 0.9% and a concomitant decrease in fasting plasma glucose of approximately 1.7 mmol/L at 24 weeks. These improvements were sustained for up to 12 months and occurred independently of weight loss, reinforcing the concept of a weight‐independent metabolic mechanism. ¹⁴ Similarly, in the randomized, sham‐controlled REVITA‐2 trial, DMR achieved a median absolute HgbA1C reduction of 0.95% at 24 weeks, compared with 0.65% in the sham group (P = 0.147). Although no statistically significant difference was observed in the overall analysis, stratified analyses by geographical locations (Europe vs Brazil) demonstrated a significant reduction in HgbA1C, highlighting potential heterogeneity in treatment response. ¹⁶

These findings are further supported by a systematic review and meta‐analysis of four studies, which demonstrated significant reductions in HgbA1C of 1.72% at 3 months and 0.94% at 6 months following DMR, with sustained benefits observed up to 1 year in longitudinal follow‐up studies. ¹⁴ , ¹⁵ Importantly, the magnitude of HgbA1C reduction observed with this single endoscopic intervention exceeds that typically achieved with most oral antidiabetic agents, which generally lower HgbA1C by approximately 0.5% to 1.25%. ¹⁸

The American Association of Clinical Endocrinologists has recognized that DMR has been granted US Food and Drug Administration (FDA) Breakthrough Device designation, a status that may expedite its development and regulatory review for the treatment of T2D, and has highlighted its potential role as a therapeutic option and adjunct to oral medications in individuals with T2D. ¹⁹ Additionally, the procedure has demonstrated promise in improving liver‐related outcomes, including reductions in liver fat content among patients with metabolic dysfunction‐associated steatotic liver disease (MASLD). ²⁰

Regarding the side effect profile, procedure‐related self‐limiting gastrointestinal symptoms, such as abdominal pain, are common. ¹⁴ Hypoglycemia is an infrequent adverse event, occurring in 7.7% of patients in the REVITA‐2 randomized trial. ¹⁶ Given the potential for serious but rare complications, such as duodenal stenosis and jejunal perforation, careful patient selection is essential, and the risks and benefits of DMR should be individually assessed before treatment.

ReCET

Pulsed electric fields represent an emerging ablation technique that induces electroporation by applying electrical currents to the phospholipid cell membrane, creating pores that increase its permeability. When cells are subjected to high‐voltage electric pulses, irreversible electroporation (IRE) occurs, leading to various forms of cell death, including apoptosis, necrosis, and immunogenic cell death. ²¹ IRE has been employed to ablate arrhythmogenic cardiac tissue, localized tumors, and malignancies in anatomically complex regions, such as locally advanced pancreatic cancer. ²² , ²³ As a nonthermal ablation method, IRE avoids heat‐related tissue damage, making it especially promising. ²³ ReCET is a single‐session endoscopic procedure that delivers IRE to the duodenal mucosa via gastroduodenoscopy using the Endogenex catheter (Plymouth, MN, USA). Under direct endoscopic visualization, the catheter's flexible circuit is deployed, and pulsed electric field ablation is applied to two‐thirds of the duodenal circumference after ampulla. This step is repeated distally in a sequential fashion until approximately 10 cm of duodenal mucosa is treated. These pulsed electric fields initiate apoptosis and promote regeneration of the duodenal mucosa in patients. This approach may result in reduced inflammation and fewer gastrointestinal side effects compared with DMR and, importantly, does not require submucosal lifting before ablation. ²⁴

ReCET is designed as a single endoscopic intervention that induces superficial cellular apoptosis followed by re‐epithelialization with regenerated, metabolically active mucosa. Consistent with this proposed mechanism, early clinical experience has evaluated ReCET as a one‐time procedure. A study on the safety, feasibility, and therapeutic efficacy of ReCET in the management of T2D, followed by the initiation of semaglutide, in a cohort of 14 patients with long‐term insulin dependence was performed in Amsterdam. At the 1‐year follow‐up, 86% of patients remained off insulin therapy, and HgbA1C levels had decreased by approximately 1.3%. ²⁴ An ongoing double‐blind, randomized, sham‐controlled trial is currently underway at Cedars Sinai Hospital investigating how the current combination therapy compares with a sham procedure paired with GLP‐1 receptor agonist (GLP‐1RA) therapy. ²⁵

In the study by Busch et al, no participants experienced any serious adverse events. ²⁴ However, mild and self‐limiting side effects, such as sore throat, diarrhea, obstipation, and black stools, were commonly reported. Longer follow‐up suggests durability may extend further (reported up to 24 months), supporting the rationale that repeated procedures are not routinely required within the first 1–2 years for responders. ²⁴

However, the need for retreatment and the limits of repeating ReCET remain incompletely defined, because published studies to date primarily evaluate outcomes after a single treatment, and systematic data on planned “re‐dosing,” optimal intervals, or maximum number of repeat procedures are not yet established. If clinical benefit diminishes over time, retreatment may be biologically plausible given the mucosal‐regeneration premise; however, future trials will need to quantify to define safe repeatability thresholds.

AQUA THERAPY

Aqua Medical (Pleasanton, CA, USA) has created a disruptive endoscopic vapor‐based ablation system designed to treat T2D by performing duodenal ablation through a minimally invasive, transoral endoscopic procedure. ²⁶ This procedure uses radiofrequency vapor ablation (RFVA), which is administered via an endoscope. The ablation process leads to the regeneration of the duodenal mucosa, restoring it from a diseased to a healthy state.

Papaefthymiou et al have published a case series of 27 patients at Cleveland Clinic London who underwent therapy in 2024 with 6‐month results showing 100% technical success and 1.2% HgbA1C drop at 12 weeks and 0.8% drop at 24 weeks. ²⁷

The company will be launching a pilot study in the US in 2026 through four centers including the University of North Carolina, Mayo Clinic, Hoag Hospital, and Honor Health.

LINERS

Two main hypotheses have been proposed to explain how endoluminal sleeves impact T2D. The “foregut hypothesis” suggests that the duodenum plays a central role in the development of obesity and associated metabolic disorders and that T2D arises from the excessive production of an anti‐incretin factor that inhibits normal metabolic function. Therefore, bypassing the upper small intestine, specifically the duodenum and proximal jejunum, and delivering partially digested nutrients more rapidly to the distal gut may block the signals that promote insulin resistance and the development of T2D. ²⁸ , ²⁹ In contrast, the “hindgut hypothesis” posits that improved diabetes control is because of the faster transit of nutrients to the distal intestine, which stimulates physiological signals that enhance glucose metabolism and support weight loss, primarily through activation of the so‐called physiological “ileal brake” mechanism. ³⁰ , ³¹ The ileal brake is a natural feedback mechanism that delays gastric emptying and intestinal transit when nutrients, especially fats, arrive in the ileum. This response is driven by gut hormones like peptide YY and GLP‐1, which promote satiety and suppress appetite.

Duodenojejunal bypass liner (DJBL)/Sleeve/Endobarrier

The DJBL is a minimally invasive and removable endoscopic device that mimics the metabolic effects of RYGB and surgical duodenojejunal exclusion. It achieves this by preventing contact between partially digested nutrients and the proximal segments of the small intestine, specifically the duodenum and proximal jejunum. ³² This triggers an anti‐incretin effect that slows gastric emptying and induces malabsorption within the foregut. These physiological mechanisms contribute to substantial weight loss and improve metabolic outcomes, including better glycemic control, reduced risk of dyslipidemia and MASLD, and decreased cardiovascular risk. ³³

The DJBL device is manufactured by GI Dynamics (Endobarrier; Lexington, MA, USA). It consists of a single‐use 60‐ to 120‐cm long, flexible, impermeable, Teflon fluoropolymer liner secured in the duodenal bulb by a self‐expanding nitinol anchor. ³⁴ The liner extends into the proximal jejunum, preventing the mixing of chyme with bile and pancreatic enzymes until the contents reach the distal jejunum. The DJBL is endoscopically implanted under general anesthesia. The procedure begins with the placement of a guidewire into the jejunum, as distally as possible. Using both fluoroscopic and endoscopic guidance, the device is then advanced over the guidewire. The fluoropolymer liner is positioned to cover the duodenum and proximal jejunum. Once proper placement is confirmed via fluoroscopy, the anchoring mechanism is deployed and secured at the duodenal bulb. To finalize the procedure, a water‐soluble contrast agent is injected through the endoscope's working channel to verify correct positioning and confirm that there are no obstructions or kinks in the liner. ³⁵

DJBL removal is carried out endoscopically under general anesthesia with fluoroscopic guidance, using a dedicated grasping tool designed for the device. This is performed within a suitable foreign body retrieval hood, similar in design to a large endoscopic cap, attached to the distal end of the gastroscope. ³⁶ Ideally, the device should be explanted within 12 months unless earlier removal is necessitated by adverse events. Previous studies have shown that extending DJBL use beyond 12 months, up to 24 months, increases the risk of complications without offering additional clinical benefit. ³⁶

The efficacy and safety of DJBL in the context of T2D have been evaluated across multiple studies. Multiple pilot studies and randomized controlled trials on obese and morbidly obese patients with T2D have demonstrated that DJBL leads to significant weight loss and reductions in HgbA1C after the procedure compared with standard medical therapy. ³⁷ , ³⁸ , ³⁹ After 6 months of intervention in a randomized controlled trial of DJBL vs conventional medical therapy for T2D, the DJBL group showed a marked HgbA1C reduction from 8.3% to 7%, whereas the control group reached only 7.9%, with comparable findings sustained at 1 year. ³⁶ Moreover, many DJBL patients were able to either taper down or completely discontinue insulin and oral glucose‐lowering agents. Similarly, significant reductions in fasting plasma glucose were observed as early as 1 week following DJBL implantation, with these improvements sustained through 24 and 52 weeks, indicating the device's potential efficacy in managing T2D. ³⁷ , ³⁹ , ⁴⁰

A meta‐analysis evaluating the impact of DJBL on glycemic control in individuals with obesity and T2D found that the device was linked to a reduction in HgbA1C levels by 1.3% (95% CI, 1.0%–1.6%) compared with control groups. The study went on to show 0.9% reduction in HgbA1C compared with baseline 6 months after explant. ⁴¹ DJBL has also been compared with standard pharmacological treatments in metabolic syndrome (ENDOMETAB trial), nearly 10% total body weight vs 2% in controls after 12 months, along with a significant 0.5% reduction in HgbA1C. The ENDOMETAB trial demonstrated that DJBL therapy, when compared with the standard pharmacological management of metabolic syndrome, achieved markedly greater weight loss at 12 months (~10% vs 2% in controls) and was associated with a significant 0.5% decrease in HgbA1C. Although significant improvements in weight loss and glycemic control are observed during the 12‐month implantation period, some studies have demonstrated attenuation or loss of these effects following explantation, with outcomes converging toward those of control groups receiving standard medical therapy. ⁴² Because of conflicting durability outcomes, repeat DJBL implantation may theoretically be required to maintain long‐term metabolic benefit; however, the feasibility of repeated use is constrained by safety considerations. Prolonged or repeated implantation beyond 12 months has been associated with higher rates of adverse events without additional clinical benefit, and current recommendations advise explanation within 1 year.

DJBL is generally associated with mild‐to‐moderate adverse events such as abdominal pain, nausea, and vomiting, which are typically manageable with conservative care. ⁴³ However, serious complications have been reported, including sleeve migration (4.9%), gastrointestinal bleeding (3.9%), obstruction (3.4%), and rare events like liver abscess, cholangitis, cholecystitis, and esophageal perforation (each ~0.1%–1%). ⁴⁴ , ⁴⁵ Up to 38% of patients have required early device removal because of these complications. ³² , ³⁷ , ³⁸ Although no procedure‐related deaths have been reported, the risk‐benefit profile of DJBL should be carefully considered in clinical decision‐making. Vitamin and mineral malabsorption is a relatively underexplored complication of DJBL therapy. A 12‐month analysis of 19 insulin‐dependent patients with T2D revealed significant declines in hemoglobin, hematocrit, iron, ferritin, vitamin B₁₂, serum albumin, and serum prealbumin. Bone mineral density remained stable; however, further investigation is necessary to guide nutrition management. ⁴⁶

Currently, the American Society for Gastrointestinal Endoscopy and European Society for Gynaecological Endoscopy suggest DJBL therapy combined with lifestyle modification over lifestyle modification alone for the treatment of obesity and T2D, reflecting moderate‐quality evidence and uncertainty regarding long‐term durability and safety. Therefore, further studies are needed to determine whether staged or repeat implantation strategies could be safely implemented and whether adjunctive therapies could help sustain metabolic improvements after device removal.

Gastroduodenojejunal bypass liner

The ValenTx gastroduodenojejunal bypass sleeve (ValenTx Endoluminal Bypass, Hopkins, MN, USA) is a 120‐cm fluoropolymer sleeve designed to be anchored at the gastroesophageal junction. Its placement involves a combined endoscopic and laparoscopic approach, with laparoscopy facilitating external visualization to ensure accurate transmural anchoring. The sleeve extends from the stomach to the jejunum, allowing ingested nutrients to bypass the stomach, duodenum, and proximal jejunum. The device can be removed endoscopically by severing the anchoring sutures.

Early clinical trials in patients with morbid obesity have demonstrated notable weight loss and metabolic benefits. ⁴⁷ In one study, successful implantation was achieved in 92% (22 of 24) of patients, although five patients (23%) required early device removal because of odynophagia. ⁴⁷ At 12 months, the remaining 10 patients had average percentage excess weight loss of 35.9%. ⁴⁷

Among the six patients who retained a fully attached sleeve throughout 12 months, the mean excess weight loss reached 54%. In contrast, the remaining four patients with partial sleeve detachment had lower weight loss outcomes. Additionally, all four patients with T2D in this study showed improvements in HgbA1C and fasting glucose levels. No major postexplanation adverse events were reported. ⁴⁷

ANASTOMOSES

Magnets

Enteral magnet‐based anastomoses have gone through multiple evolutions. There have been two major approaches to the placement of these magnets: either with enteroscopy or laparoscopic‐assisted endoscopy.

The MagDI system by GT Metabolic (San Jose, CA, USA) requires the patient to swallow the first magnet. Then the magnet is visualized with fluoroscopy and found within the lumen via laparoscopy and the magnet is taken to the distal small bowel with an extraluminal magnetic device introduced laparoscopically into the peritoneal cavity. Meanwhile, an endoscopy is performed, and a second magnet is placed in the duodenum 20 cm distal to the pylorus. The two magnets are then brought together, and the duodenoileal anastomosis is formed over the following 2–3 weeks with the magnet passing through the bowel within approximately 24 h. The patent duodenoileal anastomosis allows alimentary contents to pass through both the native duodenojejunal pathway and the newly created duodenoileal conduit. ⁴⁸

The Incisionless Magnetic Anastomosis System by GI Windows (Westwood, MA, USA) creates a jejunoileal anastomosis. The procedure involves the simultaneous use of an enteroscopy and a colonoscopy, with magnets deployed in the proximal jejunum and the ileum through the working channels of each scope. Once positioned and coupled, the octagonal magnets cause necrosis and form a wide‐bore compression anastomosis, enabling partially digested food to bypass a portion of the small intestine and rapidly reach the distal ileum. Similar to MagDI, the magnets are naturally expelled via stool, eliminating the need for additional procedures to remove the device.

A multicenter study evaluating MagDI has shown an HgbA1C reduction from 7.5% to 6.4% 1 year after placement. There were some complications, including general gastrointestinal symptoms and nutrition deficiencies. There was one serious adverse event concerning for duodenitis after magnet deployment that was empirically treated with antibiotics with resolution. ⁴⁹

A feasibility pilot study of 10 patients was completed using the Incisionless Magnetic Anastomosis System for those with morbid obesity. At 12 months, patients experienced an average total body weight loss of 14.6% and excess weight loss of 40.2%, along with significant improvements in HgbA1C and fasting glucose levels among those all patients with prediabetes or T2D. ⁵⁰ No serious adverse events were reported, although most patients experienced temporary nausea and diarrhea that resolved. Similarly, an open‐label, prospective, single‐arm study evaluating the safety and feasibility of self‐assembling magnets in eight patients with obesity and T2D (median BMI, 38.8 kg/m²) reported promising outcomes. At 12 months postprocedure, HgbA1C levels dropped below 7.0% in 75% of patients, and 87.5% achieved a total body weight loss exceeding 5%. ⁵¹

Endoscopic ultrasound (EUS)–guided lumen‐apposing metal stents (LAMS)

EUS‐guided drainage with LAMS is an established treatment option to efficiently drain pancreatic fluid, gallbladder, and biliary obstructions. ⁵² , ⁵³ It allows for precise, real‐time imaging and access to organs while minimizing complications. The introduction of electrocautery‐tipped LAMS (EC‐LAMS) has further simplified the procedure by enabling one‐step transmural drainage, reducing the need for multiple interventions. Compared with plastic stents, LAMS provide better clinical success with similar safety profiles.

The procedure is performed endoscopically under general anesthesia with EUS guidance. An appropriate jejunal loop in close apposition to the stomach is identified, and an EC‐LAMS is deployed to establish a gastrojejunal anastomosis, thereby permitting direct transit of gastric contents into the jejunum. ⁵⁴ To ensure effective exclusion of the duodenum and minimize nutrient passage through the native gastroduodenal pathway, the pylorus may be temporarily occluded using endoscopic suturing or clipping techniques. Stent position and luminal patency are confirmed endoscopically and, when indicated, with fluoroscopic imaging. This approach results in a fully endoscopic, potentially reversible gastrojejunal bypass that diverts nutrient flow away from the duodenum and proximal small intestine.

A feasibility study was done with pigs that showed clinical success for the intended purpose of weight loss. ⁵⁵ However, the use of gastrojejunal LAMS has shown clinical success for managing pathology such as duodenal malignancy or inflammatory duodenal strictures. Although gastrojejunal LAMS procedures have not been performed to manage T2D, based on the new information about duodenal physiology in T2D, it can be hypothesized that there would likely be improvement in HgbA1C. ⁵⁶

NEW TECHNOLOGY

EUS‐guided injection of stimulant for GLP‐1 production

Endoscopic injection of GLP‐1 stimulants is a minimally invasive technique designed to enhance endogenous incretin secretion by directly targeting enteroendocrine L cells within the intestinal mucosa. This procedure involves the use of EUS‐guided injection to deliver bioactive agents such as bile acids, nutrient mimetics, or cellular activators into the submucosal layer of the duodenum in patients who are trying to experience weight loss. This is an emerging treatment for individuals with T2D and obesity. By stimulating local GLP‐1 production, this approach aims to improve glycemic control, insulin sensitivity, and appetite regulation without the need for chronic systemic administration of GLP‐1RAs. Although EUS‐guided injection approaches may promote a physiologically regulated incretin response, existing data are limited to short‐term outcomes, and the longevity of these effects relative to chronic GLP‐1RA therapy is not yet established.

A recent prospective randomized study compared EUS‐guided gastric botulinum toxin (BTX) injections with GLP‐1RA injections (subcutaneous) for weight loss, providing insight into the potential of EUS‐guided metabolic interventions. ⁵⁷ The study found that both approaches led to significant weight loss over a 12‐week period, with the BTX group experiencing a 10.5% reduction in body weight, compared with 9.4% in the GLP‐1RA group, with no statistically significant difference between the two. Importantly, the BTX group experienced fewer systemic side effects and increased satiety, possibly because of delayed gastric emptying, suggesting that EUS‐guided injection techniques may offer a safer and more tolerable alternative to systemically administered pharmacotherapy. The duration of metabolic benefit following EUS‐guided injection of agents intended to stimulate endogenous GLP‐1 production is not yet well defined, as clinical experience with this approach remains limited.

CONCLUSION

The expanding field of endoscopic metabolic therapies represents a significant evolution in the management of T2D, obesity, and related comorbidities, including MASLD. Foundational bariatric operations such as RYGB and SG have demonstrated that targeted modification of gastrointestinal anatomy can lead to durable metabolic improvements and, in some cases, remission of T2D through mechanisms extending beyond caloric restriction. These insights have underscored the central role of the duodenum in metabolic disease pathophysiology and have catalyzed the development of duodenum‐directed endoscopic interventions, including mucosal ablation therapies, duodenal liners, and endoscopic bypass techniques (Table 1).

Table 1.

Summary of duodenal‐based endoscopic therapies for the management of T2D.

Therapy/procedure	Mechanism of action	Advantages	Limitations/risks per type of therapy and therapy specific	A1C reduction	Status
Ablationa	Foregut pathway correction by replacing maladapted duodenal mucosa; shown improvements incretin signaling and insulin sensitivity		Transient abdominal pain
Duodenal mucosal resurfacing	Hydrothermal ablation of superficial duodenal mucosa to restore enterocyte signaling and incretin function	Minimally invasive; incretin‐based; weight‐independent glucose control	Hypoglycemia, nausea, diarrhea, and duodenal stenosis (7.7%); jejunal perforation	0.7%–1.2% at 24–52 weeks	Multiple prospective trials; FDA Breakthrough device Designation. recognized by AACE
Recellularization via electroporation therapy	Irreversible electroporation causes targeted mucosal apoptosis, promoting renewal and reducing inflammation	Nonthermal; no submucosal lifting; single session	Mild GI symptoms (eg, diarrhea and sore throat); no serious adverse events	1.3% at 12 months	First‐in‐human study completed; RCT ongoing
Aqua therapy (RFVA)	RFVA induces mucosal regeneration and GLP‐1 production	Minimally invasive; endoscopic	Limited published human outcome data	0.8%–1.2% at 12–24 weeks	Early‐stage, under evaluation
Linersa	Accelerated nutrient delivery to distal intestine with GLP‐1 increase; mimics RYGB anatomy without surgery		Abdominal pain, back pain, nausea, vomiting, device migration, and nutrient malabsorption
Duodenojejunal bypass liner (EndoBarrier)	Endoluminal sleeve bypasses duodenum and proximal jejunum; enhances distal gut hormone signaling	Reversible; nonsurgical; GLP‐1 and peptide YY mediated benefits	<0.1%–1% liver abscess, cholangitis, cholecystitis, and esophageal perforation; up to 38% early removal	1.3% at explant; 0.9% at 6 months postexplant	In ASGE and ESGE guidelines with conditional support with moderate evidence (meta‐analyses and RCTs that support efficacy)
Gastroduodenojejunal bypass liner	Endoluminal bypass of stomach, duodenum, and proximal jejunum via anchored sleeve	High weight/metabolic efficacy	Dysphagia and odynophagia	Reported improvement; need granular data	Pilot trials; feasibility confirmed
Anastomosis	Mechanical diversion of nutrient stream and duodenal exclusion with an accelerated distal nutrient delivery; recreates RYGB metabolic signature without surgical anastomosis		Abdominal pain, back pain, nausea, vomiting, device migration, and nutrient malabsorption
Magnetic anastomosis	Creates dual path jejunoileal bypass using self‐assembling magnets	Incisionless; magnets expelled naturally	Gastritis, diarrhea, vomiting, nausea, hair loss, abdominal pain, and duodenitis (2.6%)	MagDI: 1.1% at 12 months IMAS: 75% <7.0% HgbA1C at 12 months	Multicenter studies demonstrate feasibility and metabolic improvements
Gastrojejunal LAMS bypass	Endoscopic bypass via lumen‐apposing metal stents and pyloric closure	Precision placement; proven feasibility in benign GI disease	Stent migration	No T2D‐specific outcome data	Preclinical and feasibility studies support concept
New technology
EUS‐guided GLP‐1 stimulation	Submucosal injection of GLP‐1 stimulants into duodenum via EUS	Minimally invasive; fewer systemic side effects	Not studied yet	No T2D‐specific outcome data	Early animal trials suggest noninferiority to GLP‐1 agonists

Abbreviations: AACE, American Association of Clinical Endocrinologists; ASGE, American Society for Gastrointestinal Endoscopy; ESGE, European Society for Gynaecological Endoscopy; EUS, endoscopic ultrasound; FDA, US Food and Drug Administration; GI, gastrointestinal; GLP‐1, glucagon‐like peptide 1; HgbA1C, glycated hemoglobin; IMAS, Incisionless Magnetic Anastomosis System; LAMS, lumen‐apposing metal stents; RCT, randomized controlled trial; RFVA, radiofrequency vapor ablation; RYGB, Roux‐en‐Y gastric bypass; T2D, type 2 diabetes.

^a No final FDA approval for use at time of publication.

At present, only a subset of these therapies is clinically available, primarily within specialized centers of excellence in bariatric and metabolic endoscopy, where appropriate expertise, multidisciplinary support, and institutional oversight exist. These established interventions offer minimally invasive alternatives for carefully selected patients but remain limited by regulatory approval status, procedural complexity, operator training requirements, and reimbursement constraints. Newer approaches, such as EUS‐guided injection of agents designed to stimulate endogenous GLP‐1 production, are in the investigational stage and are not yet ready for widespread clinical adoption.

Although current duodenum‐targeted therapies have largely focused on glycemic control in T2D, growing clinical experience suggests broader systemic effects on obesity, liver disease, and other metabolic disorders. A similar trajectory has been observed in endobariatrics, where procedures initially developed for obesity management are increasingly recognized for their metabolic benefits as access expands. Looking forward, clinical trials, long‐term safety data, regulatory clarification, and scalable training pathways will be essential to determine which of these emerging therapies transition from experimental use to routine clinical practice. Together, these advances signal a rapidly evolving field in which endoscopic metabolic interventions may progressively complement pharmacologic and surgical approaches, increasing access for patients worldwide.

AUTHOR CONTRIBUTIONS

Roma Patel, Zehra Naseem, Prisha Gattu, Stephen Firkins, and Roberto Simons‐Linares equally contributed to the conception/design of the research. Roma Patel, Zehra Naseem, and Prisha Gattu contributed to the acquisition of the data. Roma Patel, Zehra Naseem, and Prisha Gattu contributed to the draft of the manuscript. Roma Patel, Zehra Naseem, Roberto Simons‐Linares, and Stephen Firkins critically revised the manuscript. Roma Patel, Zehra Naseem, Prisha Gattu, Stephen Firkins, and Roberto Simons‐Linares gave final approval. Roma Patel, Zehra Naseem, Prisha Gattu, Stephen Firkins, and Roberto Simons‐Linares agree to be accountable for all aspects of work, ensuring integrity and accuracy.

CONFLICT OF INTEREST STATEMENT

None declared.

Patel R, Naseem Z, Gattu P, Firkins S, Simons‐Linares R. Endoscopic small bowel therapies for type 2 diabetes. Nutr Clin Pract. 2026;41:1296‐1306. 10.1002/ncp.70111