Abbreviations: AACE (American Association of Clinical Endocrinologists), ADA (American Diabetes Association), DMR (duodenal mucosal resurfacing), GLP-1RA (glucagon-like-peptide-1 receptor agonist), RYGB (Roux-en-Y gastric bypass), T2DM (type 2 diabetes mellitus)

Type 2 diabetes mellitus (T2DM) is a chronic disease that requires lifelong management and is associated with significant morbidity and mortality when left untreated or suboptimally treated. Thus, there is a desperate need for innovative therapies aimed at improving insulin resistance. Newer pharmacotherapeutic agents appear to show promise but are expensive and require lifelong therapy that often involves uncomfortable subcutaneous injections that result in poor tolerability. In patients who undergo Roux-en-Y gastric bypass (RYGB) surgery for weight loss, the duodenum is excluded from receiving nutrients, resulting in a dramatic improvement in glycemic control immediately after surgery. Bariatric surgery is slowly gaining acceptance but is still severely underused and limited to a selected group of patients. Thus, in reality, many patients with T2DM will never have their disease reversed and will likely require exogenous insulin indefinitely, despite the fact that treating an insulin-resistant state with more insulin further perpetuates the disease. Consequently, any novel therapy proposed as an alternative to insulin deserves consideration.

The field of endoscopic and metabolic bariatric therapies is garnering interest worldwide. Newer therapies have come into fruition to target the duodenum to simulate an aspect of RYGB, ie, bypassing the duodenum and improving glycemic control via an insulin-sensitizing effect irrespective of changes in body mass index. Duodenal mucosal resurfacing (DMR) is an endoscopic procedure that ablates the duodenal mucosa distal to the major papilla through the application of hydrothermal energy. The results from the first international, open-label, prospective multicenter study demonstrated that a single session of DMR in patients with T2DM taking oral glucose-lowering medications resulted in a significant improvement in glycemic control at 6 months, and the results were sustained at 12 months, with a low risk of postprocedural adverse events.1van Baar A.C.G. Holleman F. Crenier L. Endoscopic duodenal mucosal resurfacing for the treatment of type 2 diabetes mellitus: one year results from the first international, open-label, prospective, multicentre study.Glucagon-like-peptide-1 receptor agonist (GLP-1RA) therapy is an established treatment for T2DM as either a first-line or a second-line treatment in patients with sufficient β-cell reserve. These medications stimulate production of endogenous insulin and thus are favored over administration of exogenous insulin. Van Baar et al2van Baar A.C.G. Meiring S. Smeele P. Duodenal mucosal resurfacing combined with glucagon-like peptide-1 receptor agonism to discontinue insulin in type 2 diabetes: a feasibility study. combined application of DMR and administration of GLP-1RA therapy in patients with T2DM using insulin therapy, with the hypothesis that this combined strategy would eliminate the need to continue exogenous insulin. In this pilot study, 16 patients with T2DM with adequate β-cell reserve and with an HbA1c ≤8.0% who were using long-acting insulin therapy were treated with a single session of DMR. Insulin was discontinued immediately after the procedure, whereas all oral glucose-lowering medications were continued throughout the study. Two weeks after DMR, self-administration of a subcutaneous GLP-1RA, liraglutide, once daily was initiated and titrated upward at dosages indicated for the treatment of T2DM. The primary endpoint of the study was the percentage of patients who were able to successfully discontinue insulin therapy with appropriate glycemic control, defined as an HbA1c ≤7.5% at the 6-month follow-up period, whereas secondary endpoints included long-term follow-up of the cohort and changes in both glycemic and metabolic parameters. At the 6-month follow-up visit, 69% (n = 11) of the patients were not taking insulin therapy and had an HbA1c ≤7.5%, and at 12 and 18 months after DMR, 56% (n = 9) and 53% (8/15) of patients, respectively, continued not to use insulin therapy. Furthermore, improvements in glycemic and metabolic parameters were observed.The authors present a novel and intriguing study that aimed to treat T2DM by nonsurgical methods, using combination endoscopic and incretin-analogue therapy to eliminate the use of insulin, a hormone that, although necessary, promotes weight gain, is expensive, and can be exhausting. To date, most studies of endoscopic and metabolic bariatric therapies have focused on weight loss as a primary endpoint as opposed to improvement of metabolic parameters, even though it is the metabolic component of disorders such as T2DM that contribute to long-lasting and devastating effects, including cardiovascular disease and death. Hence, we commend the authors on their well-designed prospective interventional study, with low attrition rates despite the relatively longer follow-up times and evaluation of numerous glycemic parameters and metabolic parameters. Even though the outcomes in this article differ from the recommended outcomes of the decade-old ASGE white paper on EBTs, we believe the field needs more well-designed studies such as this, in addition to shifting the focus of treatment to “comorbidities associated with obesity” as opposed to treating excess weight alone.3ASGE/ASMBS Task Force on Endoscopic Bariatric Therapy
A pathway to endoscopic bariatric therapies.This study raises a very important question in regard to HbA1c goals after EBMT interventions. The authors defined adequate glycemic control as an HbA1c ≤7.5% without insulin at the 6-month follow-up visit, which is arguably not a clinically meaningful outcome because only patients with HbA1c ≤8.0% were included in the study. HbA1c targets should probably be more stringent in line with the American Diabetes Association (ADA) of 1van Baar A.C.G. Holleman F. Crenier L. Endoscopic duodenal mucosal resurfacing for the treatment of type 2 diabetes mellitus: one year results from the first international, open-label, prospective, multicentre study.

GLP-1RAs for treatment of T2DM is well recognized as a first-line or second-line therapy per the ADA, the AACE, and the European Association for the Study of Diabetes. It clearly has an important role earlier, before insulin therapy is begun. In lieu of this recommendation, would it not be more prudent to study DMR therapy in patients using GLP-1RA therapy, with the goal of maximizing HbA1c targets and/or preventing progression to insulin therapy? Furthermore, the dose of liraglutide used was that of diabetic therapy (1.8 mg), not weight loss (3 mg), and we cogitate whether use of a higher dose would have resulted in a larger percentage of patients reaching the primary endpoint.

The results of the primary outcome of the study should be interpreted with some caution. Although 11 out of 16 patients were not using insulin therapy at the 6-month mark, the cohort of responders was reduced to 56% (9/16)/15) at 12 and 18 months, respectively, which questions the long-term durability of the treatment. In addition, some may not consider exchanging insulin for a GLP-1RA a success in terms of treatment. Furthermore, the selection criteria for this study were stringent, and the results may not translate to the general population, where the prevalence of obesity with T2DM may be higher and associated with higher baseline levels of HbA1c.

Bypassing absorption in the duodenum by surgical (ie, RYGB surgery) or endoscopic methods has demonstrated improvement in glycemic control and insulin sensitization.4Machytka E. Bužga M. Zonca P. et al.Partial jejunal diversion using an incisionless magnetic anastomosis system: 1-year interim results in patients with obesity and diabetes. However, the exact mechanisms have not been completely elucidated. At the enterocyte level, significant changes in the expression and activity of major dietary sugar transporters and gluconeogenic enzyme have been identified in certain patients with obesity—changes that can lead to significant increases in glucose absorption.5Hasan N.M. Johnson K.F. Yin J. et al.Intestinal stem cell-derived enteroids from morbidly obese patients preserve obesity-related phenotypes: elevated glucose absorption and gluconeogenesis. Thus, bypassing this system by RYGB surgery would logically result in reduced glucose uptake and transport. With DMR, ablating the mucosal layer of duodenal enterocytes may rejuvenate and repopulate the duodenal mucosa with “healthier” enterocytes, resulting in better regulation of glucose uptake and transportation. These cellular changes and alterations in glucose homeostasis that occur with these therapies need better clarification to ultimately provide personalized, targeted therapies in patients with obesity- and metabolic-related diseases.Similar to bariatric surgery, evolving endoscopic therapies are focusing more on metabolic outcomes in comparison with weight loss alone (Fig. 1).6Kumbhari V. Lehmann S. Schlichting N. Gastric mucosal devitalization is safe and effective in reducing body weight and visceral adiposity in a porcine model.,7Oberbach A. Schlichting N. Heinrich M. Gastric mucosal devitalization reduces adiposity and improves lipid and glucose metabolism in obese rats. EBMTs offer an innovative incisionless solution for the treatment of metabolic disease. As demonstrated in this study and other EBMT and GLP-1RA combination studies,8

Badurdeen D, Hoff AC, Barrichello S. Efficacy of liraglutide to prevent weight regain after retrieval of an adjustable intra-gastric balloon: a case-matched study. Obes Surg. Epub 2020 Nov 19.

,9

Badurdeen D, Hoff AC, Hedjoudje A. Endoscopic sleeve gastroplasty plus liraglutide versus endoscopic sleeve gastroplasty alone for weight loss. Gastrointest Endosc 2021;93:1316-24.e1.

personalized, precision therapies10Ghoz H. Jaruvongvanich V. Matar R. A preclinical animal study of combined intragastric balloon and duodenal-jejunal bypass liner for obesity and metabolic disease. will likely be a part of the solution for obesity and metabolic disease. Given that obesity and metabolic disorders coexist in many if not most patients with overweight and obesity, the time has come to start combatting both weight and metabolic parameters with endoscopic therapies that target both issues in a safe and effective manner. It’s time to say goodbye to the old duodenal mucosa and in with the new—rejuvenate and repopulate!

Figure 1Small-bowel interventions. Used with permission of Mayo Foundation for Medical Education and Research; all rights reserved.

Disclosure

Dr Gomez is a consultant for Olympus. Dr Kumbhari is a consultant for Apollo Endosurgery, Boston Scientific, Medtronic, Pentax Medical, and Fujifilm and the recipient of research support from Erbe and Fujifilm. The other author disclosed no financial relationships.

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Partial jejunal diversion using an incisionless magnetic anastomosis system: 1-year interim results in patients with obesity and diabetes.

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Intestinal stem cell-derived enteroids from morbidly obese patients preserve obesity-related phenotypes: elevated glucose absorption and gluconeogenesis.

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Badurdeen D, Hoff AC, Barrichello S. Efficacy of liraglutide to prevent weight regain after retrieval of an adjustable intra-gastric balloon: a case-matched study. Obes Surg. Epub 2020 Nov 19.

Badurdeen D, Hoff AC, Hedjoudje A. Endoscopic sleeve gastroplasty plus liraglutide versus endoscopic sleeve gastroplasty alone for weight loss. Gastrointest Endosc 2021;93:1316-24.e1.

Ghoz H. Jaruvongvanich V. Matar R.

A preclinical animal study of combined intragastric balloon and duodenal-jejunal bypass liner for obesity and metabolic disease.

Clin Transl Gastroenterol. 11: e00234Article InfoIdentification

DOI: https://doi.org/10.1016/j.gie.2021.01.039

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© 2021 by the American Society for Gastrointestinal Endoscopy

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