Endoscopic Duodenal Mucosal Resurfacing for the Treatment of Type 2 Diabetes: 6-Month Interim Analysis From the First-in-Human Proof-of-Concept Study

Abstract

OBJECTIVETo assess procedural safety and glycemic indices at 6 months in a first-in-human study of duodenal mucosal resurfacing (DMR), a novel, minimally invasive, upper endoscopic procedure involving hydrothermal ablation of the duodenal mucosa, in patients with type 2 diabetes and HbA 1c ‡7.5% (58 mmol/mol) on one or more oral antidiabetic agents. RESEARCH DESIGN AND METHODSUsing novel balloon catheters, DMR was conducted on varying lengths of duodenum in anesthetized patients at a single medical center. RESULTSA total of 39 patients with type 2 diabetes (screening HbA 1c 9.5% [80 mmol/mol]; BMI 31 kg/m 2 ) were treated and included in the interim efficacy analysis: 28 had a long duodenal segment ablated (LS; ∼9.3 cm treated) and 11 had a short segment ablated (SS; ∼3.4 cm treated). Overall, DMR was well tolerated with minimal gastrointestinal symptoms postprocedure. Three patients experienced duodenal stenosis treated successfully by balloon dilation. HbA 1c was reduced by 1.2% at 6 months in the full cohort (P < 0.001). More potent glycemic effects were observed among the LS cohort, who experienced a 2.5% reduction in mean HbA 1c at 3 months postprocedure vs. 1.2% in the SS group (P < 0.05) and a 1.4% reduction at 6 months vs. 0.7% in the SS group (P = 0.3). This occurred despite net medication reductions in the LS cohort between 0 and 6 months. Among LS patients with a screening HbA 1c of 7.5-10% (58-86 mmol/mol) and on stable antidiabetic medications postprocedure, HbA 1c was reduced by 1.8% at 6 months (P < 0.01). CONCLUSIONSSingle-procedure DMR elicits a clinically significant improvement in hyperglycemia in patients with type 2 diabetes in the short-term, with acceptable safety and tolerability. Long-term safety, efficacy, and durability and possible mechanisms of action require further investigation.

The Importance of the Gastrointestinal Tract in Controlling Food Intake and Regulating Energy Balance

“…Indeed, evidence suggests that altered EEC secretion as a consequence of altered nutrient stimulation contributes to the weight-loss and metabolic benefits of bariatric surgery 85 . Similarly, preventing nutrient contact with the duodenal mucosa by placing an endoscopic liner known as Endobarrier 86 , or thermic ablation of the duodenal mucosa 87 , results in improved metabolic profiles hypothetically based on their impact upon EEC functioning. Given the rapid recent advancement in our understanding of EEC biology functional foods or designer drugs aimed at modulating EEC secretion will soon reach clinical practice.…”

Ablation of the Duodenal Mucosa as a Strategy for Glycemic Control in Type 2 Diabetes: Role of Nutrient Signaling or Simple Weight Loss

“…In this issue of Diabetes Care , Rajagopalan et al (1) present a new therapeutic strategy for treatment of T2D. The strong point of the study is that the authors have developed and studied a novel therapeutic approach in T2D that could elucidate new disease mechanisms involving the role of the duodenum in metabolic regulation.…”

“…Various authors have suggested that duodenal bypass 1 ) alters enteroendocrine cell secretion of factors such as glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide, and peptide YY; 2 ) mediates changes in the gastrointestinal microbiome; or 3 ) produces changes in bile acids that signal through intestinal membrane-bound G-protein–coupled receptors (e.g., TGR5) or hepatocellular farnesoid X receptors with downstream effects on GLP-1 production and secretion of fibroblast growth factors, respectively (5). In the study by Rajagopalan et al (1), DMR was used to prevent nutrient signaling from the duodenum in patients with T2D, and HbA 1c lowering constituted the primary outcome measure.…”

“…The weakness of the study by Rajagopalan et al (1) relates to effectiveness for HbA 1c lowering relative to less invasive approaches using lifestyle therapy and/or medications, as well as the unknown risks of repeated procedures that appear to be necessary to chronically sustain a glucose-lowering effect. A total of 39 patients with T2D were included in the study, with 11 receiving short-segment ablation (∼3.4 cm) and 28 long-segment ablation (∼9.3 cm) of duodenal mucosa (1).…”

Endoscopic Duodenal Mucosal Resurfacing for the Treatment of Type 2 Diabetes

“…DMR is a novel, minimally invasive, transoral procedure involving hydrothermal ablation to modify the lining of the duodenum. Recently, an initial study in patients with type 2 diabetes [7] assessed safety and glycaemic indices at 6 months; there was an HbA 1c improvement of 1.2% at the end of follow-up. Another recent publication showed that both glycaemic markers and transaminase levels were improved after this procedure, suggesting potential favourable effects on fatty liver disease as well [8].…”