Clinical Research Studies

The Revita® System is an endoscopic treatment consisting of a single catheter and console designed to lift the duodenal mucosa with saline followed by controlled circumferential hydrothermal ablation of the mucosa. The exclusion of the duodenum from the passage of nutrients by surgical diversion appears to result in weight-independent improvements in glycemia associated with a reduction in insulin resistance. This effect is also notable in being almost immediate in its onset (within days) and durable over time (years). The gastrointestinal tract is now recognized to be the largest endocrine organ in the body. It releases gastrointestinal hormones in a finely tuned pattern to help the body achieve glucose homeostasis in the fasting and post-prandial states, with the gastro-intestinal mucosa playing the role as a critical sensing and secreting interface. Bypass of the proximal small bowel appears to modify the secretion of certain key gastrointestinal hormones that in turn lead to improvements in glucose homeostasis. This occurs without calorie malabsorption. Rather, these changes restore the ability of the liver to suppress endogenous glucose production in response to insulin, a physiologic process that is otherwise impaired in diabetes. There are two main theories on how the bypass of the proximal small bowel exerts such a strong anti-diabetic effect, both of which may explain the role of the small bowel in glucose homeostasis.29 First, some believe that the delivery of excess nutrients to the distal small bowel leads to enhanced secretion of GLP-1 (and perhaps additional related insulin-secreting hormones) from the GLP-1-rich entero-endocrine cells of the terminal ileum. Enhanced GLP-1 release into the bloodstream after an ingested meal has a number of beneficial effects on glucose homeostasis30. A second theory is that individuals with Type 2 Diabetes acquire mucosal alterations in their proximal small bowel that contribute to insulin resistance and glucose intolerance and that bypass of this segment is beneficial. Data from rats and humans suggest that prolonged exposure to a Western diet leads to an increase in enteroendocrine cell numbers and a subsequent gastric inhibitory peptide (GIP) after a meal.Other studies have demonstrated hypertrophy of the mucosa of the small bowel in subjects with diabetes.In this way, the insulin resistance of the body may arise from hormones produced by the proximal small bowel as a consequence of these mucosal alterations. The hypothesis is that bypass of the duodenum by nutrients prevents the release of these hormones and therefore immediately leads to an improvement in glucose tolerance after surgery. Moreover, it is now becoming increasingly recognized that the upstream surgical perturbation of the gastrointestinal tract, resulting in the exclusion of the duodenum, does indeed manifest a compelling anti-diabetic effect but the diabetes state of the patient is also a key determinant of outcome. Studies have now reported that the potency of the anti-diabetic effect manifested with metabolic surgery is contingent on or influenced by innate endogenous beta-cell reserve or insulin secretory capacity. In other words, surgery elicits powerful anti-diabetic effects but more notably in the presence of sufficient endogenous beta-cell secretory capacity. This raises important questions concerning a more targeted use of such interventions in individuals that have certain beta-cell reserve characteristics and/or certain companion pharmacological agents that augment beta-cell secretory function (e.g. GLP-1-receptor agonists) to best optimize outcome. A model of type 2 diabetes pathogenesis emerges from these observations. Namely, a life of excess fat and sugar ingestion in genetically prone individuals can lead to changes in the mucosa of the proximal small bowel. These mucosal changes, in turn, are associated with alterations in signals emanating from the proximal gut (including hormone secretion). This altered proximal gut signal exerts an effect that worsens insulin resistance, could negatively affect insulin secretion and may well drive the pathogenesis of T2D. In this context, duodenal exclusion through surgery or a medical device may reduce the abnormal signal emanating from the proximal gut, and thus improves glucose homeostasis. Duodenal mucosal resurfacing (DMR), using the Revita® System, is designed to mimic the metabolic benefit of the duodenal exclusion component of bariatric surgery, thereby eliciting an insulin-sensitizing effect. Duodenal Mucosal Resurfacing (DMR) consists of a highly controlled mucosal lift and ablation procedure of the post papillary duodenum using the Revita® System over the guided wire placed using a standard endoscope. The Revita® clinical data indicates that DMR exerts insulin-sensitizing like effects as evidenced by a lowering of HOMA-IR40, by an insulin-sensitizing metabolic signature by metabolomics testing (e.g., lowering of a-hydroxybutyrate, diacylglycerol, and peroxidase activity), and by other related insulin-sensitizing biomarker effects (including lowered hepatic transaminases and urinary microalbumin). Unlike bariatric surgery, which involves an anatomical bypass of the duodenum and therefore no exposure of ingested nutrients to the surface of that portion of the GI tract, DMR is designed to ablate and re-epithelialize the duodenal mucosal surface, thus allowing nutrients to be exposed to a newly regrown and normalized local mucosa. This infers that the duodenal mucosa surface is in some way abnormal in insulin resistant T2D subjects and is, therefore, emanating a potential ‘insulin resisting’ effect. This notion is supported by multiple lines of evidence: the duodenum undergoes a maladaptive hypertrophic response when exposed to unhealthy nutrients (i.e., fat, simple sugars); this change appears to be associated with an augmented insulin-resistant signal emanating from this portion of the bowel. This signal appears to be persistent and reversible in T2D, as revealed in post-bariatric surgery: in those individuals in whom metabolic improvement has been established after surgery, the acute re-exposure of the bypassed duodenum to nutrients quickly restores the insulin resistant, hyperglycemic, dysmetabolic condition that had existed pre-surgery ; and ablation technology applied to other tissue surfaces has shown that the natural tissue response to ablation is re-growth of a healthy tissue surface. Taken together, there is a strong rationale that the duodenal mucosa of T2D subjects is abnormal and that subjects would likely reap a metabolic benefit if the local duodenal mucosa is resurfaced through an ablation technique. In addition to the glycemic benefits previously seen, data has also indicated liver benefits after ablating abnormal duodenal mucosa in T2D. The C-20000 study, which did not require a NAFLD diagnosis at baseline, showed that approximately 85% of patients had fatty liver even in the presence of normal liver transaminases, confirming prior evidence of the growing epidemiologic overlap with T2D.Patients with NAFLD (liver MRI-PDFF > 5%)at baseline showed a large magnitude and a clinically meaningful reduction in liver fat content at week 12, confirming earlier findings of reductions in ALT through 2 years. These data provide insight into a potential therapeutic opportunity for DMR to favorably impact both T2D and NAFLD/NASH in a manner that can modify the natural history of these chronic and progressive diseases.