Transcutaneous auricular vagus nerve stimulation to alleviate metformin-associated gastrointestinal adverse events and optimize glycaemic control: a randomized, sham-controlled pilot trial protocol

Background: Gastrointestinal adverse events (GI AEs) are the main dose-limiting side effects of metformin in type 2 diabetes mellitus (T2DM), reducing adherence and compromising long-term glycaemic control. Current strategies (dose adjustment or combination therapy) seldom address both tolerability and sustained metabolic efficacy. Transcutaneous auricular vagus nerve stimulation (taVNS) is a non-invasive neuromodulation technique that may modulate gut-brain-metabolic pathways-vagal reflexes, inflammation, intestinal barrier function, and enteroendocrine signaling-and thus improve drug tolerance while preserving glycaemic control. Methods: This single-center, randomized, sham-controlled pilot trial will enroll 60 T2DM patients with metformin-associated GI AEs, randomized 1:1 to either the taVNS group or the sham control group. The intervention lasts 2 weeks with a follow-up at week 4. Assessments at baseline and follow-up include a validated Metformin Symptom Severity Score (total score 0-50; primary outcome), Bristol Stool Form Scale, bowel urgency, glycaemic/metabolic indices [fasting blood glucose (FBG), 2-h postprandial glucose (PG2h), glycated albumin (GA), fasting C-peptide, fasting insulin, HOMA-IR, ISI], and mechanistic biomarkers (GLP-1, 5-HT, IL-6, IL-10, TNF-α, D-lactate, DAO, bile acids). Safety monitoring includes routine hematology, liver and renal function tests. Discussion: By combining clinical outcomes with targeted biomarker analyses in a randomized design, this pilot study will assess whether taVNS alleviates metformin-associated GI intolerance without impairing glycaemic efficacy, and will provide feasibility data, effect-size estimates, and biomarker selection for future confirmatory trials. Clinical trial registration: Trial registration International Traditional Medicine Clinical Trial Registry (ITMCTR) http://itmctr.ccebtcm.org.cn/, Identifier: ITMCTR2025001086.