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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.
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 al
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.
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 <7% or even <6.5% according to the American Association of Clinical Endocrinologists (AACE). It is also important to keep in mind that the addition of GLP-1RAs is recommended in patients with cardiovascular disease, overweight, or obesity independent of their current HbA1C or HbA1C goal. In this study, reductions in HbA1c were mild to modest at most with DMR, although this may have been secondary to discontinuation of insulin. A mean reduction of 0.5% was seen at the 18-month follow-up visit in responders, which was not statistically significant. Similarly, in the results from the first international, open-label, prospective, multicenter study, HbA1c was reduced by 0.9% at 6 months in comparison with baseline.
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.
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.
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).
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!
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.
van Baar A.C.G.
Endoscopic duodenal mucosal resurfacing for the treatment of type 2 diabetes mellitus: one year results from the first international, open-label, prospective, multicentre study.
Duodenal mucosal resurfacing (DMR) is an endoscopic intervention in which the duodenal mucosa is ablated by hydrothermal energy. DMR improves glycemic control in patients with type 2 diabetes (T2D), most likely by altered duodenal signaling leading to insulin sensitization. We studied whether we could discontinue insulin use in T2D patients by combining DMR with glucagon-like peptide-1 receptor agonist (GLP-1RA) and lifestyle counseling.