Diabetes Mellitus Type 2VagusSxNCT07278115
Effects on Remission of Type 2 Diabetes Mellitus Following Gastric Bypass Alone vs Gastric Bypass Combined With Truncal Vagotomy
A study testing Roux-en-Y Gastric Bypass plus Truncal Vagotomy and Roux-en-Y Gastric Bypass in people with Diabetes Mellitus Type 2, run by University Research Institute for the Study of Genetic & Malignant Disorders in Childhood at 2 sites in Greece.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 to 68 years
- Conditions the study is for
- Diabetes Mellitus Type 2
- What is being tested?
- Roux-en-Y Gastric Bypass plus Truncal Vagotomy and Roux-en-Y Gastric Bypass
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 40 participants
- Where
- 2 sitesGreece
- Study dates
- 24 Apr 2026to Dec 2028
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 68 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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
Trial locations and contacts
2 sites in 1 country. Contact the study team or a site near you to ask about taking part.
Greece2 sites, 2 recruiting
- Recruiting
Diabetes Surgery
Athens, Attica, 11527
Athena N Kapralou, MD, PhD, +306945750599, athinakapralou@gmail.com
- Not yet recruiting
Diabetes Surgery
Athens, Attica, 11527
Athena Kapralou, MD, PhD, +30 6945750599, athinakapralou@gmail.com
About this study
Official title: Effects on Remission of Type 2 Diabetes Mellitus Following Roux-en-Y Gastric Bypass Alone vs Roux-en-Y Gastric Bypass Combined With Truncal Vagotomy: A Triple-Blind Randomized Controlled Trial.
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:
Read more
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.
Read the detailed 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.
- Conditions
- Diabetes Mellitus Type 2
- Being tested
- Roux-en-Y Gastric Bypass plus Truncal Vagotomy, Roux-en-Y Gastric Bypass
- Keywords
- Type 2 diabetes mellitus, Insulin Resistance, Hyperglycemia, Obesity, Bariatric Surgery, Gastric Bypass, Vagotomy, Diabetes Surgery, Gut Hormones, GLP-1
- Medical subject headings
- Diabetes Mellitus, Type 2, Insulin Resistance, Hyperglycemia, Obesity
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Roux-en-Y Gastric Bypass plus Truncal VagotomyProcedure or surgery
Laparoscopic Roux-en-Y gastric bypass performed according to protocol, including creation of a small gastric pouch, gastrojejunostomy, and jejunojejunostomy. In addition, bilateral truncal vagotomy is performed at the distal esophagus, dividing both anterior and posterior vagal trunks to reduce vagal stimulation of the gastrointestinal tract. The combined procedure aims to assess whether vagotomy enhances type 2 diabetes mellitus remission beyond the effect of gastric bypass alone.
Roux-en-Y Gastric BypassProcedure or surgery
Laparoscopic Roux-en-Y gastric bypass performed according to protocol, including creation of a small gastric pouch, gastrojejunostomy, and jejunojejunostomy. No vagotomy is performed. This serves as the active comparator to evaluate the independent effect of adding truncal vagotomy on type 2 diabetes mellitus remission.
| Study group | Role | What they receive |
|---|---|---|
| Roux-en-Y Gastric Bypass with Truncal Vagotomy | Experimental | Participants in this arm will undergo a standard laparoscopic Roux-en-Y gastric bypass (RYGB) procedure combined with bilateral truncal vagotomy. The operation includes creation of a small gastric pouch completely separated from the remnant stomach, gastrojejunostomy to the alimentary limb, and a jejunojejunostomy to restore intestinal continuity, resulting in proximal intestinal bypass of the duodenum and proximal jejunum. Truncal vagotomy is performed by dividing both anterior and posterior vagal trunks at the lower esophagus to reduce vagally mediated biliopancreatic secretion and neurohormonal stimulation of digestion. This combined procedure aims to assess whether dual interruption of vagal and duodenal signaling enhances the metabolic and glycemic benefits of gastric bypass, promoting durable remission of type 2 diabetes mellitus. Receives: Procedure: Roux-en-Y Gastric Bypass plus Truncal Vagotomy |
| Roux-en-Y Gastric Bypass Alone | Active comparator | Participants in this arm will undergo a standard laparoscopic Roux-en-Y gastric bypass (RYGB) procedure without vagotomy. The surgery includes creation of a small, completely separated gastric pouch, a gastrojejunostomy to the alimentary limb, and a jejunojejunostomy approximately 100-150 cm distal to the ligament of Treitz, resulting in a proximal intestinal bypass of the duodenum and proximal jejunum. This configuration limits nutrient exposure to the upper gut, thereby inducing metabolic changes known to improve glycemic control and weight reduction. The procedure follows established bariatric surgical principles and serves as the control arm to evaluate the additive effect of truncal vagotomy on glucose homeostasis, gut hormone secretion, and remission of type 2 diabetes mellitus. Receives: Procedure: Roux-en-Y Gastric Bypass |
What is being measured
The primary outcome is the main question the study is designed to answer.
Complete remission of Type 2 Diabetes Mellitus at 12 Months Post-Surgery
Complete remission of type 2 diabetes will be defined as fasting plasma glucose <100 mg/dL and HbA1c <6.0%, maintained without the use of any antidiabetic medications for at least one year following surgery.
Measured: 12 months postoperatively
Secondary outcomes (26)
Partial remission of type 2 diabetes
Partial remission will be defined as HbA1c < 6.5% and fasting plasma glucose between 100-125 mg/dL, maintained without the use of any antidiabetic medications for at least one year following surgery.
Measured: 12 months postoperatively
Fasting Plasma Glucose
Change in fasting plasma glucose levels will be measured at each follow-up visit (1, 3, 6, and 12 months).
Measured: Baseline and up to 12 months postoperatively
Fasting Insulin
Change in fasting insulin levels will be assessed at baseline (pre-surgery) and at 12 months after surgery.
Measured: Baseline and 12 months postoperatively
Fasting C-Peptide levels
Change in fasting C-peptide levels will be assessed at baseline (pre-surgery) and at 12 months postoperatively.
Measured: Baseline and 12 months postoperatively
HbA1c
Change in HbA1c (%) from baseline across follow-up visits.
Measured: Baseline, 1, 3, 6, and 12 months postoperatively
Oral Glucose Tolerance Test (OGTT) Indices-plasma glucose measurement
After an overnight fast, participants will ingest 75 g of glucose orally. Blood samples will be collected at baseline (fasting) and at regular time intervals over a two-hour period, post-pradially to measure plasma glucose, insulin, and C-peptide.
Measured: Baseline and 12 months postoperatively
HOMA-IR (Insulin Resistance Index)
The Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) will be calculated using fasting plasma glucose and fasting insulin levels, according to the following formula:
HOMA-IR=Fasting glucose (mg/dL)×0.0555×Fasting insulin (mU/L)/22.5
Measured: Baseline and 12 months postoperatively
Use of Antidiabetic Medications
Change in the number of antidiabetic medications prescribed per patient compared with baseline. Each active oral or injectable non-insulin agent will be counted as one medication. A decrease in the number of medications will be considered an indicator of improved glycemic control.
Unit of Measure: Number of medications per participant
Measured: Baseline, 1, 3, 6, and 12 months postoperatively
Use of Insulin Therapy
Change in insulin therapy status at each follow-up visit, expressed as the proportion of participants achieving:
Complete discontinuation of insulin therapy,
≥50% reduction in daily insulin dose, or No change / continued insulin requirement. The primary reported measure will be the percentage of participants discontinuing insulin therapy, with additional categorical data on dose reduction and continuation summarized descriptively.
Unit of Measure:
Percentage of participants (%)
Measured: Baseline, 1, 3, 6, and 12 months postoperatively
Body Weight
Change in body weight (kg) from baseline at each follow-up visit, measured under standardized conditions.
Measured: Baseline, 1, 3, 6, and 12 months postoperatively
Body Mass Index (BMI)
Change in BMI (kg/m²) calculated from measured weight and height at each visit.
Measured: Baseline, 1, 3, 6, and 12 months postoperatively
Waist and Hip Circumference
Change in waist and hip circumference (cm) measured with a flexible tape at standardized anatomical landmarks; waist-to-hip ratio will also be derived.
Measured: Baseline, 1, 3, 6, and 12 months postoperatively
Body Composition
Change in body fat percentage (% body fat) from baseline to 12 months postoperatively.
Measured: Baseline and 12 months postoperatively
Total Cholesterol
Change in fasting total cholesterol (mg/dL) measured by standard enzymatic methods.
Measured: Baseline, 1, 3, 6, and 12 months postoperatively
HDL Cholesterol
Change in fasting high-density lipoprotein cholesterol (mg/dL).
Measured: Baseline, 1, 3, 6, and 12 months postoperatively
LDL Cholesterol
Change in fasting low-density lipoprotein cholesterol (mg/dL).
Measured: Baseline, 1, 3, 6, and 12 months postoperatively
Triglycerides
Change in fasting triglyceride levels (mg/dL).
Measured: Baseline, 1, 3, 6, and 12 months postoperatively
C-Reactive Protein (CRP)
Change in high-sensitivity C-reactive protein (mg/L) as a marker of systemic inflammation.
Measured: Baseline, 1, 3, 6, and 12 months postoperatively
Blood Pressure
Change in systolic and diastolic blood pressure (mmHg).
Measured: Baseline, 1, 3, 6, and 12 months postoperatively
Change in Use of Lipid-Lowering Medications
Change in the proportion of participants using lipid-lowering medications compared to baseline. Medication use status (continued, reduced dose, or discontinued) will be assessed at each postoperative visit.
Measured: Baseline, 1, 3, 6, and 12 months postoperatively
Use of Antihypertensive Medications
Change in the number and classes of antihypertensive drugs prescribed.
Measured: Baseline, 1, 3, 6, and 12 months postoperatively.
Cardiovascular Risk Index (Obesity-Related)
Change in obesity-related cardiovascular risk, assessed using the ASCVD (Atherosclerotic Cardiovascular Disease) Risk Score developed by the American College of Cardiology. Calculation will be performed using the official online tool: https://tools.acc.org/ascvd-risk-estimator-plus/#!/calculate/estimate/.
Measured: Baseline and 12 months postoperatively
Cardiovascular Risk Index (Diabetes-Related)
Change in cardiovascular risk related to diabetes, assessed using the SCORE2-Diabetes risk prediction model, developed, calibrated, and validated by the European Society of Cardiology (ESC). Calculation will be performed through the ESC online tool: https://www.escardio.org/Education/ESC-Prevention-of-CVD-Programme/Risk-assessment/esc-cvd-risk-calculation-app.
Measured: Baseline and 12 months postoperatively
Oral Glucose Tolerance Test (OGTT) Indices-plasma insulin measurement
After an overnight fast, participants will ingest 75 g of glucose orally. Blood samples will be collected at baseline (fasting) and at regular time intervals over a two-hour period, post-pradially to measure plasma insulin.
Measured: Baseline and 12 months postoperatively
Oral Glucose Tolerance Test (OGTT) Indices-plasma C-peptide levels
After an overnight fast, participants will ingest 75 g of glucose orally. Blood samples will be collected at baseline (fasting) and at regular time intervals over a two-hour period, post-pradially to measure plasma C-peptide.
Measured: Baseline and 12 months postoperatively
Discontinuation of Antidiabetic Medications
Proportion of participants who discontinue all antidiabetic medications (excluding insulin) following surgery while maintaining normoglycemia.
Unit of Measure: Percentage of participants (%)
Measured: Baseline, 1, 3, 6, and 12 months postoperatively
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Dec 2025
- Study start24 Apr 2026
- Primary completionDec 2028 (estimated)
- Study completionDec 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Diabetes Mellitus Type 2Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Outcomes assessor
- Enrolment
- 40 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University Research Institute for the Study of Genetic & Malignant Disorders in Childhood
- Sponsor type
- University, hospital or other
- Collaborators
- National and Kapodistrian University of Athens
- Responsible party
- Principal investigator, Athena Kapralou, University Research Institute for the Study of Genetic & Malignant Disorders in Childhood
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07278115
- Sponsor's protocol ID
- HippokrationHosp89/14-07-2025
- Acronym
- VagusSx
- Status last verified
- Apr 2026
- First submitted
- 28 Sep 2025
- Last updated
- 30 Apr 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: Yes. Individual participant data (IPD) that underlie the results reported in future publications will be shared, including de-identified datasets of baseline characteristics, perioperative data, and postoperative outcomes (glycemic indices, weight, laboratory results, complications, and follow-up measures). A data dictionary describing all variables will also be provided to allow full interpretation. Data will be available to qualified researchers upon reasonable request and with approval from the coordinating center at Hippokration University Hospital.
Publications
Kapralou AN, Yapijakis C, Chrousos GP. The Duodenum-Centered Neurohormonal Hypothesis of Type 2 Diabetes: A Mechanistic Review and Therapeutic Perspective. Curr Issues Mol Biol. 2025 Aug 14;47(8):657. doi: 10.3390/cimb47080657.
PubMed 40864811Kapralou AN, Chrousos GP. Metabolic effects of truncal vagotomy when combined with bariatric-metabolic surgery. Metabolism. 2022 Oct;135:155263. doi: 10.1016/j.metabol.2022.155263. Epub 2022 Jul 11.
PubMed 35835160
Study at a glance
From the registry record, last updated by the sponsor on 30 Apr 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effects on Remission of Type 2 Diabetes Mellitus Following Roux-en-Y Gastric Bypass Alone vs Roux-en-Y Gastric Bypass Combined With Truncal Vagotomy: A Triple-Blind Randomized Controlled Trial.
- ClinicalTrials.gov ID
- NCT07278115
- Acronym / sponsor ID
- VagusSx / HippokrationHosp89/14-07-2025
- Conditions
- Diabetes Mellitus Type 2
- Keywords
- Type 2 diabetes mellitus, Insulin Resistance, Hyperglycemia, Obesity, Bariatric Surgery, Gastric Bypass, Vagotomy, Diabetes Surgery
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 40 participants (estimated)
- Lead sponsor
- University Research Institute for the Study of Genetic & Malignant Disorders in ChildhoodUniversity, hospital or other
- Collaborators
- National and Kapodistrian University of Athens
- Study start
- 24 Apr 2026 (actual)
- Primary completion
- Dec 2028 (estimated)
- Study completion
- Dec 2028 (estimated)
- First posted
- 11 Dec 2025 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Roux-en-Y Gastric Bypass with Truncal Vagotomy | Experimental | Procedure: Roux-en-Y Gastric Bypass plus Truncal VagotomyParticipants in this arm will undergo a standard laparoscopic Roux-en-Y gastric bypass (RYGB) procedure combined with bilateral truncal vagotomy. The operation includes creation of a small gastric pouch completely separated from the remnant stomach, gastrojejunostomy to the alimentary limb, and a jejunojejunostomy to restore intestinal continuity, resulting in proximal intestinal bypass of the duodenum and proximal jejunum. Truncal vagotomy is performed by dividing both anterior and posterior vagal trunks at the lower esophagus to reduce vagally mediated biliopancreatic secretion and neurohormonal stimulation of digestion. This combined procedure aims to assess whether dual interruption of vagal and duodenal signaling enhances the metabolic and glycemic benefits of gastric bypass, promoting durable remission of type 2 diabetes mellitus. |
| Roux-en-Y Gastric Bypass Alone | Active comparator | Procedure: Roux-en-Y Gastric BypassParticipants in this arm will undergo a standard laparoscopic Roux-en-Y gastric bypass (RYGB) procedure without vagotomy. The surgery includes creation of a small, completely separated gastric pouch, a gastrojejunostomy to the alimentary limb, and a jejunojejunostomy approximately 100-150 cm distal to the ligament of Treitz, resulting in a proximal intestinal bypass of the duodenum and proximal jejunum. This configuration limits nutrient exposure to the upper gut, thereby inducing metabolic changes known to improve glycemic control and weight reduction. The procedure follows established bariatric surgical principles and serves as the control arm to evaluate the additive effect of truncal vagotomy on glucose homeostasis, gut hormone secretion, and remission of type 2 diabetes mellitus. |
Who may qualify
- Ages
- 18 to 68 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- BMI ≥ 30 kg/m²
- Age: 18-68 years
- Confirmed type 2 diabetes mellitus with:
- Advanced-DiaRem Score > 5* * Advanced-DiaRem Score: a validated scoring system predicting diabetes remission after bariatric surgery.
Key exclusion criteria (7 listed)
- 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):
- Type 1 diabetes mellitus
- Alcohol or drug addiction
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Roux-en-Y Gastric Bypass plus Truncal VagotomyLaparoscopic Roux-en-Y gastric bypass performed according to protocol, including creation of a small gastric pouch, gastrojejunostomy, and jejunojejunostomy. In addition, bilateral truncal vagotomy is performed at the distal esophagus, dividing both anterior and posterior vagal trunks to reduce vagal stimulation of the gastrointestinal tract. The combined procedure aims to assess whether vagotomy enhances type 2 diabetes mellitus remission beyond the effect of gastric bypass alone. | Procedure or surgery | Roux-en-Y Gastric Bypass with Truncal Vagotomy |
| Roux-en-Y Gastric BypassLaparoscopic Roux-en-Y gastric bypass performed according to protocol, including creation of a small gastric pouch, gastrojejunostomy, and jejunojejunostomy. No vagotomy is performed. This serves as the active comparator to evaluate the independent effect of adding truncal vagotomy on type 2 diabetes mellitus remission. | Procedure or surgery | Roux-en-Y Gastric Bypass Alone |
Primary outcome
Complete remission of Type 2 Diabetes Mellitus at 12 Months Post-Surgery
Time frame: 12 months postoperatively
Complete remission of type 2 diabetes will be defined as fasting plasma glucose <100 mg/dL and HbA1c <6.0%, maintained without the use of any antidiabetic medications for at least one year following surgery.
26 secondary outcomes
Partial remission of type 2 diabetes
Time frame: 12 months postoperatively
Fasting Plasma Glucose
Time frame: Baseline and up to 12 months postoperatively
Fasting Insulin
Time frame: Baseline and 12 months postoperatively
Fasting C-Peptide levels
Time frame: Baseline and 12 months postoperatively
HbA1c
Time frame: Baseline, 1, 3, 6, and 12 months postoperatively
Oral Glucose Tolerance Test (OGTT) Indices-plasma glucose measurement
Time frame: Baseline and 12 months postoperatively
HOMA-IR (Insulin Resistance Index)
Time frame: Baseline and 12 months postoperatively
Use of Antidiabetic Medications
Time frame: Baseline, 1, 3, 6, and 12 months postoperatively
Use of Insulin Therapy
Time frame: Baseline, 1, 3, 6, and 12 months postoperatively
Body Weight
Time frame: Baseline, 1, 3, 6, and 12 months postoperatively
Body Mass Index (BMI)
Time frame: Baseline, 1, 3, 6, and 12 months postoperatively
Waist and Hip Circumference
Time frame: Baseline, 1, 3, 6, and 12 months postoperatively
Body Composition
Time frame: Baseline and 12 months postoperatively
Total Cholesterol
Time frame: Baseline, 1, 3, 6, and 12 months postoperatively
HDL Cholesterol
Time frame: Baseline, 1, 3, 6, and 12 months postoperatively
LDL Cholesterol
Time frame: Baseline, 1, 3, 6, and 12 months postoperatively
Triglycerides
Time frame: Baseline, 1, 3, 6, and 12 months postoperatively
C-Reactive Protein (CRP)
Time frame: Baseline, 1, 3, 6, and 12 months postoperatively
Blood Pressure
Time frame: Baseline, 1, 3, 6, and 12 months postoperatively
Change in Use of Lipid-Lowering Medications
Time frame: Baseline, 1, 3, 6, and 12 months postoperatively
Use of Antihypertensive Medications
Time frame: Baseline, 1, 3, 6, and 12 months postoperatively.
Cardiovascular Risk Index (Obesity-Related)
Time frame: Baseline and 12 months postoperatively
Cardiovascular Risk Index (Diabetes-Related)
Time frame: Baseline and 12 months postoperatively
Oral Glucose Tolerance Test (OGTT) Indices-plasma insulin measurement
Time frame: Baseline and 12 months postoperatively
Oral Glucose Tolerance Test (OGTT) Indices-plasma C-peptide levels
Time frame: Baseline and 12 months postoperatively
Discontinuation of Antidiabetic Medications
Time frame: Baseline, 1, 3, 6, and 12 months postoperatively
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Apr 2026.
- Background: PubMed 40864811Kapralou AN, Yapijakis C, Chrousos GP. The Duodenum-Centered Neurohormonal Hypothesis of Type 2 Diabetes: A Mechanistic Review and Therapeutic Perspective. Curr Issues Mol Biol. 2025 Aug 14;47(8):657. doi: 10.3390/cimb47080657.
- Background: PubMed 35835160Kapralou AN, Chrousos GP. Metabolic effects of truncal vagotomy when combined with bariatric-metabolic surgery. Metabolism. 2022 Oct;135:155263. doi: 10.1016/j.metabol.2022.155263. Epub 2022 Jul 11.
- Detailed information about the VagusSx Clinical Trial evaluating the effects of Roux-en-Y Gastric Bypass with or without Truncal Vagotomy on remission of Type 2 Diabetes Mellitus in patients with obesity.Link provided by the sponsor.
- Peer-reviewed article by our research team (who also registered this clinical trial) exploring the metabolic effects of truncal vagotomy when combined with gastric bypass, providing mechanistic support for this novel surgical strategy in type 2 diabetes.Link provided by the sponsor.
- Official website of the A' Department of Propaedeutic Surgery, School of Medicine, National and Kapodistrian University of Athens, based at Hippocration General Hospital of Athens - the site where the clinical trial will be conducted.Link provided by the sponsor.
- Individual participant dataSharing planned: Yes. Yes. Individual participant data (IPD) that underlie the results reported in future publications will be shared, including de-identified datasets of baseline characteristics, perioperative data, and postoperative outcomes (glycemic indices, weight, laboratory results, complications, and follow-up measures). A data dictionary describing all variables will also be provided to allow full interpretation. Data will be available to qualified researchers upon reasonable request and with approval from the coordinating center at Hippokration University Hospital.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Roux-en-Y Gastric Bypass plus Truncal Vagotomy and Roux-en-Y Gastric Bypass in people with Diabetes Mellitus Type 2, run by University Research Institute for the Study of Genetic & Malignant Disorders in Childhood at 2 sites in Greece.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 30 Apr 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Greece. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Athena N Kapralou, MD, PhD (+306945750599, athinakapralou@gmail.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Complete remission of Type 2 Diabetes Mellitus at 12 Months Post-Surgery (time frame: 12 months postoperatively). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT07278115, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Apr 2026.