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

This is a prospective, single-center, randomized, participant-blinded, sham-controlled, parallel-group 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 12 weeks of tirzepatide 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.

• transcutaneous auricular vagus nerve stimulation (Device), also known as 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.
• Sham (Device), also known as 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.

Primary outcomes

• Percent Change in Body Weight From Baseline [Baseline, 4 weeks, 8 weeks, 12 weeks]: 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.

Secondary outcomes

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

Other outcomes

• Change in Brain Biotype [Baseline, Week 12]: 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.

Sex: All, ages: 18 Years to 50 Years

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 tirzepatide therapy for at least 12 weeks 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.

• Yan Bi, MD, PhD, Study director, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University