Overview
This randomized, triple-blind clinical trial investigates whether adding truncal vagotomy to Roux-en-Y gastric bypass (RYGB) enhances remission of type 2 diabetes mellitus (T2DM) in patients with obesity. The study explores whether modulation of vagal signaling provides superior metabolic outcomes compared to standard RYGB alone.
- Background
RYGB is a proven metabolic procedure capable of inducing diabetes remission; however, the mechanisms remain incompletely defined. Emerging evidence supports a duodenum-centered neurohormonal model suggesting that amplified digestion-driven by vagal and hormonal hyperstimulation-plays a key role in the development of insulin resistance. The vagus nerve regulates pancreatic and biliary secretion, as well as gut hormone release. By combining truncal vagotomy with RYGB, the study aims to attenuate vagal overactivation and evaluate its impact on glucose homeostasis and hormonal adaptation.
- Design
Eligible adults (18-65 years) with BMI ≥30 kg/m² and confirmed T2DM (HbA1c ≥6.5%, or on antidiabetic therapy with HbA1c ≥6.1%) will be randomized to:
- RYGB alone, or
- RYGB with truncal vagotomy. Participants, postoperative staff, and assessors will remain blinded to allocation.
Primary Outcome:
Remission of T2DM at 12 months postoperatively, defined as fasting plasma glucose \<100 mg/dL and HbA1c \<6.0% without antidiabetic medication for at least one year.
Secondary Outcomes:
Changes in HbA1c, fasting glucose, insulin, C-peptide, OGTT-derived indices, GLP-1, CCK, PYY, GLP-2, oxyntomodulin responses, HOMA-IR, body composition, cardiovascular risk markers, medication use, and quality-of-life parameters. Surgical metrics include hospital stay, readmissions, complications, gastrointestinal symptoms, nutritional deficiencies, and bone density changes.
Follow-Up:
Assessments occur preoperatively and at 1, 3, 6, and 12 months after surgery.
- Significance
The VagusSx Trial tests whether targeted vagal and duodenal pathway interruption can improve glycemic control beyond weight loss alone, offering a novel, physiology-based strategy for durable diabetes remission.
Description
Detailed Description
This randomized, triple-blind, controlled clinical trial evaluates the metabolic impact of adding truncal vagotomy to standard Roux-en-Y gastric bypass (RYGB) in adults with obesity and type 2 diabetes mellitus (T2DM). The trial, titled VagusSx, investigates whether targeted interruption of vagal signaling augments diabetes remission beyond the effects of caloric restriction and weight loss alone.
Scientific Background and Rationale
RYGB has been established as an effective metabolic surgery leading to remission of T2DM in a significant proportion of patients. However, the exact mechanisms remain incompletely understood. Increasing evidence supports a duodenum-centered neurohormonal model in which amplified digestion-driven by chronic vagal and enteroendocrine hyperstimulation-promotes insulin resistance. The vagus nerve regulates biliopancreatic secretion, gastric motility, and the release of hormones such as cholecystokinin (CCK) and secretin. Continuous exposure to high-fat, high-glycemic diets may cause persistent vagal activation, exaggerated hormonal secretion, and enhanced nutrient absorption, ultimately contributing to β-cell stress and insulin resistance.
Truncal vagotomy is hypothesized to attenuate this hyperactivation, reducing biliopancreatic output and digestive efficiency, thereby improving glucose homeostasis and insulin sensitivity. When combined with RYGB-which excludes the duodenal mucosa from nutrient contact and enhances distal gut hormone signaling-the dual intervention may provide synergistic effects through both neural and hormonal pathways.
Study Design
This is a prospective, randomized (1:1), triple-blind clinical trial with two parallel arms:
Standard RYGB (control group)
RYGB plus truncal vagotomy (intervention group)
Participants, postoperative care staff, and assessors remain blinded to allocation. Randomization is performed via concealed envelopes using computer-generated sequences.
Eligibility
Inclusion criteria: adults aged 18-65 years, BMI ≥30 kg/m², confirmed T2DM with HbA1c ≥ 6.5% or use of antidiabetic medication with HbA1c ≥ 6.1%, and Advanced DiaRem Score \> 5.
Key exclusion criteria: prior bariatric or major abdominal surgery, type 1 diabetes, chronic corticosteroid use, major psychiatric or systemic disease, or substance abuse.
Interventions
All surgeries are performed laparoscopically by the same surgical team.
Roux-en-Y gastric bypass (RYGB): creation of a small gastric pouch, gastrojejunostomy, and jejunojejunostomy (proximal intestinal bypass).
Truncal vagotomy: complete division of anterior and posterior vagal trunks at the distal esophagus prior to gastric pouch creation.
Standardized perioperative and nutritional management is applied to both groups.
Assessments and Follow-Up
Participants are evaluated at baseline (preoperative), and at 1, 3, 6, and 12 months postoperatively.
Data are collected by a multidisciplinary team (surgery, endocrinology, dietetics, psychology) using standardized laboratory, imaging, and validated questionnaires.
Primary Outcome
Remission of T2DM at 12 months, defined as fasting plasma glucose \< 100 mg/dL and HbA1c \< 6.0% without antidiabetic therapy for ≥12 months.
Key Secondary Outcomes
Glycemic and hormonal parameters: HbA1c, fasting glucose, insulin, C-peptide, OGTT-derived indices (insulin sensitivity, β-cell responsiveness, disposition index), and hormonal responses (GLP-1, CCK, PYY, GLP-2, oxyntomodulin).
Body composition and anthropometry: weight, BMI, waist/hip ratio, fat mass, lean mass.
Cardiometabolic risk markers: lipid profile, blood pressure, CRP, ASCVD and SCORE2-Diabetes risk indices.
Bone status: bone mineral density by DEXA.
Nutritional status: micronutrient levels (vitamins A, D, E, K, B1, B12, folate, iron, zinc, copper, calcium, magnesium, phosphorus) and prevalence of deficiencies.
Medication use: discontinuation or reduction of antidiabetic, antihypertensive, and lipid-lowering therapies.
Surgical metrics: length of stay, readmissions, early and late complications (graded by Dindo classification), gastrointestinal symptoms, dumping syndrome, and hypoglycemia episodes.
Dietary behavior: changes in food frequency, tolerance, craving, and binge-eating scales.
Physical activity: objectively measured and self-reported activity (IPAQ).
Psychosocial outcomes: treatment satisfaction, diabetes-related symptoms, and psychological well-being.
Data Management and Analysis
All data are recorded in electronic case-report forms and stored in a secure database. Continuous variables will be analyzed using repeated-measures ANOVA or mixed models. Categorical data will be compared with χ² or Fisher's exact tests. Statistical significance is set at p \< 0.05. Intention-to-treat and per-protocol analyses will be performed.
Ethical Considerations
The trial adheres to the Declaration of Helsinki, Good Clinical Practice (GCP) standards, and COPE ethical guidelines. Written informed consent is obtained from all participants. The study protocol has received institutional ethics approval and is registered at ClinicalTrials.gov.
Significance
The VagusSx trial introduces a novel physiologic concept: neural-hormonal modulation of digestion as a therapeutic target in diabetes surgery. By interrupting vagal and proximal intestinal signaling, the study aims to test whether this combined intervention promotes durable diabetes remission beyond the effects of caloric restriction, potentially reshaping the mechanistic understanding and future direction of metabolic surgery.
Eligibility
Inclusion Criteria:
- BMI ≥ 30 kg/m²
- Age: 18-68 years
- Confirmed type 2 diabetes mellitus with:
- HbA1c ≥ 6.5%, or
- HbA1c ≥ 6.1% and the use of antidiabetic medication
- Advanced-DiaRem Score \> 5\ \ Advanced-DiaRem Score: a validated scoring system predicting diabetes remission after bariatric surgery.
Exclusion Criteria:
- Previous bariatric surgery or major abdominal surgery (e.g., enterectomy, gastrectomy, colectomy, hepatectomy, partial or total pancreatectomy)
- Major, uncompensated health problems (major psychiatric, endocrine, cardiac, pulmonary, hepatic, or renal disorder; cancer; or other conditions with increased risk of complications)
- Use of corticosteroids (glucocorticoids):
- Chronic corticosteroid use for \> 3 months within the last year, or
- Corticosteroid therapy within the last 3 months
- Type 1 diabetes mellitus
- Alcohol or drug addiction
