Transcutaneous Auricular Vagus Nerve Stimulation for Poor Weight-Loss Response to Incretin Receptor Agonists

Adjunctive Transcutaneous Auricular Vagus Nerve Stimulation in Overweight or Obese Patients With a Suboptimal Weight-Loss Response to Incretin Receptor Agonists: A Single-Center, Randomized, Sham-Controlled Pilot Study

This is a single-center, randomized, participant-blinded, sham-controlled pilot trial designed to evaluate the adjunctive effect of transcutaneous auricular vagus nerve stimulation (taVNS) in overweight or obese patients who show a suboptimal weight-loss response to incretin receptor agonist therapy. A total of 24 participants will be randomly assigned to receive either taVNS plus tirzepatide 5 mg or sham stimulation plus tirzepatide 5 mg for 12 weeks. The primary objective is to compare the percent change in body weight from baseline to week 12 between the two groups.

Study Overview

• Status: Recruiting
• Conditions: Obesity & Overweight
• Intervention / Treatment: Device: transcutaneous auricular vagus nerve stimulation; Device: Sham

Detailed Description

This is a prospective, single-center, randomized, participant-blinded, sham-controlled, parallel-group pilot study conducted at the Department of Endocrinology, Nanjing Drum Tower Hospital. The study will enroll 24 overweight or obese participants with a suboptimal weight-loss response, defined as a body weight reduction of no more than 10% after at least 24 weeks of incretin receptor agonist treatment. Eligible participants will be randomized in a 1:1 ratio to the taVNS plus tirzepatide 5 mg group or the sham stimulation plus tirzepatide 5 mg group for 12 weeks.

Before and after intervention, all participants will undergo standardized assessments, including lifestyle questionnaires, anthropometric measurements, body composition analysis, autonomic function evaluation, laboratory testing, and assessment of hepatic steatosis and fibrosis. Autonomic function assessment will include heart rate variability, cardiovascular autonomic reflex tests, sudomotor function, and brain MRI. Liver-related assessments will include FibroTouch and liver MRI. During follow-up, body weight will be monitored weekly by telephone or WeChat, waist circumference, hip circumference, and body composition will be reassessed every 4 weeks, and device use will be monitored through an app to ensure adherence and protocol consistency.

The primary endpoint is the between-group difference in percent change in body weight from baseline to week 12. Secondary endpoints include changes in body composition and fat distribution, glucose- and lipid-related metabolic parameters, liver function and hepatic steatosis/fibrosis-related parameters, and autonomic function measures. Exploratory analyses will evaluate changes in brain imaging phenotypes after 12 weeks of intervention.

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Yan Bi, MD, PhD; Phone Number: 6-25-83-105302; Email: biyan@nju.edu.cn
• Study Contact Backup: Name: Tian Wei Gu, MD, PhD; Phone Number: (86) 25-831066 (86) 25-83106666; Email: gtw0235@163.com

Study Locations

• China
  • Jiangsu
    • Nanjing, Jiangsu, China, 210008
      • Recruiting
      • Department of Endocrinology, the Affiliated Drum Tower Hospital of Nanjing University Medical School
      • Contact: Tian Wei Gu, MD, PhD; Phone Number: (86) 25-831066 (86) 25-83106666; Email: gtw0235@163.com
      • Contact: Yan Bi, MD,PhD; Phone Number: 6-25-83-105302; Email: biyan@nju.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Individuals with obesity, or overweight accompanied by at least one weight-related comorbidity (e.g., hypertension or fatty liver disease), who have been receiving incretin receptor agonist therapy for at least 6 months and have achieved ≤10% weight loss during treatment;
2. Willingness to provide written informed consent.

Exclusion Criteria:

1. Presence of diseases that may substantially affect body weight homeostasis, including Cushing's syndrome, uncontrolled thyroid disease (thyroid-stimulating hormone >6.0 mIU/L or <0.4 mIU/L), malignancy, or similar conditions;
2. Use within the past 3 months of medications, other than incretin receptor agonists, that may significantly affect body weight, including glucocorticoids and antipsychotic agents;
3. Skin infection or damage involving the auricular area;
4. Women planning pregnancy in the near future;
5. Contraindications to MRI, such as metallic prostheses or claustrophobia;
6. Diagnosis of diabetes mellitus; Inability to complete the 12-week intervention period for practical reasons, such as frequent business travel or planned travel.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: taVNS Plus Tirzepatide 5 mg; Participants will receive active transcutaneous auricular vagus nerve stimulation plus tirzepatide 5 mg for 12 weeks. Active stimulation will be delivered to the bilateral cymba conchae, an auricular region innervated by the auricular branch of the vagus nerve. Stimulation will use an intermittent waveform of 15 seconds on and 5 seconds off at 20 Hz, with a pulse width of 0.2 ms. Stimulation intensity will be titrated from 0 mA to a level that produces mild tingling without obvious discomfort, usually 1.0-2.5 mA. Stimulation will be administered twice daily for 30 minutes per session, 5 days per week, for 12 weeks. Tirzepatide will be administered as a subcutaneous injection once weekly.	Device: transcutaneous auricular vagus nerve stimulation; Participants will receive active transcutaneous auricular vagus nerve stimulation plus tirzepatide 5 mg for 12 weeks. Active stimulation will be delivered to the bilateral cymba conchae, an auricular region innervated by the auricular branch of the vagus nerve. Stimulation will use an intermittent waveform of 15 seconds on and 5 seconds off at 20 Hz, with a pulse width of 0.2 ms. Stimulation intensity will be titrated from 0 mA to a level that produces mild tingling without obvious discomfort, usually 1.0-2.5 mA. Stimulation will be administered twice daily for 30 minutes per session, 5 days per week, for 12 weeks. Tirzepatide will be administered as a subcutaneous injection once weekly.; Other Names: tirzepatide 5 mg
Sham Comparator: Sham Stimulation Plus Tirzepatide 5 mg; Participants will receive sham stimulation in addition to tirzepatide 5 mg for 12 weeks. Sham stimulation will be applied to the bilateral tail of the helix, an auricular site without vagus nerve distribution, whereas active taVNS targets the cymba conchae, which is innervated by the auricular branch of the vagus nerve. The sham group will use the same waveform parameters, stimulation intensity titration, and treatment schedule as the active group, namely twice daily for 30 minutes per session, 5 days per week, for 12 weeks. Tirzepatide will be administered as a subcutaneous injection once weekly.	Device: Sham; Participants will receive sham stimulation in addition to tirzepatide 5 mg for 12 weeks. Sham stimulation will be applied to the bilateral tail of the helix, an auricular site without vagus nerve distribution, whereas active taVNS targets the cymba conchae, which is innervated by the auricular branch of the vagus nerve. The sham group will use the same waveform parameters, stimulation intensity titration, and treatment schedule as the active group, namely twice daily for 30 minutes per session, 5 days per week, for 12 weeks. Tirzepatide will be administered as a subcutaneous injection once weekly.; Other Names: tirzepatide 5 mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change in Body Weight From Baseline	Percent change in body weight from baseline to week 12 will be compared between the taVNS plus tirzepatide group and the sham stimulation plus tirzepatide group to evaluate the adjunctive effect of taVNS on weight reduction.	Baseline, 4 weeks, 8 weeks, 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Waist Circumference	Change in waist circumference from baseline to Week 4, Week 8, and Week 12 will be assessed using standardized anthropometric measurement.	Baseline, Week 4, Week 8, Week 12
Change in Body Composition and Fat Distribution	Changes in body composition and fat distribution will be assessed by body fat percentage using anthropometric measurements and body composition analysis.	Baseline, ,Week 4, Week 8, Week 12
Change in blood glucose	Change in fasting blood glucose from baseline to Week 12 will be assessed using laboratory testing.	Baseline, Week 12
Change in Hip Circumference	Change in hip circumference from baseline to Week 4, Week 8, and Week 12 will be assessed using standardized anthropometric measurement.	Baseline, Week 4, Week 8, Week 12
Change in Visceral Fat Area	Change in visceral fat area from baseline to Week 4, Week 8, and Week 12 will be assessed using body composition analysis.	Baseline, Week 4, Week 8, Week 12
Change in Glycated Hemoglobin	Change in glycated hemoglobin (HbA1c) from baseline to Week 12 will be assessed using laboratory testing.	Baseline, Week 12
Change in High-Density Lipoprotein Cholesterol	Change in high-density lipoprotein cholesterol (HDL-C) from baseline to Week 12 will be assessed using laboratory testing.	Baseline, Week 12
Change in Low-Density Lipoprotein Cholesterol	Change in low-density lipoprotein cholesterol (LDL-C) from baseline to Week 12 will be assessed using laboratory testing.	Baseline, Week 12
Change in Triglycerides	Change in triglycerides from baseline to Week 12 will be assessed using laboratory testing.	Baseline, Week 12
Change in Controlled Attenuation Parameter	Change in controlled attenuation parameter (CAP) from baseline to Week 12 will be assessed using transient elastography.	Baseline, Week 12
Change in Liver Stiffness Measurement	Change in liver stiffness measurement (LSM) from baseline to Week 12 will be assessed using transient elastography.	Baseline, Week 12
Change in Liver Function	Change in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) from baseline to Week 12 will be assessed using laboratory testing.	Baseline, Week 12
Change in Heart Rate Variability	Change in heart rate variability from baseline to Week 12 will be assessed using time-domain and/or frequency-domain heart rate variability analysis.	Baseline, Week 12
Change in Cardiovascular Autonomic Reflex Test Result	Change in cardiovascular autonomic reflex function from baseline to Week 12 will be assessed using standardized cardiovascular autonomic reflex testing.	Baseline, Week 12
Change in Central Autonomic Network Functional Connectivity	Change in central autonomic network features from baseline to Week 12 will be assessed using brain MRI-based functional connectivity analysis.	Baseline, Week 12

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Brain Biotype	Changes in brain biotype after 12 weeks of intervention will be explored using brain MRI-based analyses. Brain biotype will be assessed at baseline and Week 12 using brain MRI-based analyses. Brain biotype will be defined as an MRI-derived classification based on pre-specified brain imaging features, such as resting-state functional connectivity patterns. Participants will be assigned to a brain biotype category according to the pre-specified MRI analysis algorithm.	Baseline, Week 12

Collaborators and Investigators

• Sponsor: The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School
• Investigators: Study Director: Yan Bi, MD, PhD, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University

Study record dates

Study Major Dates

• Study Start (Actual): April 21, 2026
• Primary Completion (Estimated): July 14, 2026
• Study Completion (Estimated): July 21, 2026

Study Registration Dates

• First Submitted: May 18, 2026
• First Submitted That Met QC Criteria: May 28, 2026
• First Posted (Actual): June 2, 2026

Study Record Updates

• Last Update Posted (Actual): June 2, 2026
• Last Update Submitted That Met QC Criteria: May 28, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Non-responders; Transcutaneous Auricular Vagus Nerve Stimulation; Obesity & Overweight; Incretin Receptor Agonists
• Additional Relevant MeSH Terms: Nutrition Disorders; Overnutrition; Body Weight; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Signs and Symptoms; Overweight; Obesity
• Other Study ID Numbers: 2026-0518-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No