Age 18 to 75 years
Sex: men and women; recruitment targets approximately balanced sexes
Obesity/overweight per FDA weight-management indication for tirzepatide (Zepbound): BMI ≥30 kg/m², or BMI ≥27 kg/m² with ≥1 weight-related comorbidity (e.g., hypertension, dyslipidemia, OSA, CVD).(Abbasi 2023)
No clinically meaningful weight change in the prior 3 months (<5% body weight change)
Able to reside within 50 miles of Mayo Clinic for the full study period (baseline visit, dosing, 48-hour physiologic testing, and Bravo monitoring logistics)
Medication washout feasible and willing to comply:
No medications (except multivitamins) within 7 days of study procedures
Allowed exceptions if stable and judged not to affect gastric function/appetite: birth control pill, estrogen replacement, thyroxine replacement, statins diuretics, beta-blockers, ACE inhibitors, ARBs (for hypertension)
Medically fit to undergo EGD with sedation/anesthesia, ability to tolerate transnasal catheter placement, and prolonged pH monitoring
Women of childbearing potential: effective contraception, and negative pregnancy test within 48 hours of enrollment.
Diabetes of any type, or use of diabetes/anti-obesity drugs affecting incretin pathways, including: GLP-1 receptor agonists or other tirzepatide-containing products amylin agonists/analogs (e.g., pramlintide), insulin, sulfonylureas, metformin, acarbose, DPP-4 inhibitors (e.g., sitagliptin, vildagliptin)
Personal or family history of medullary thyroid carcinoma or MEN2
Known serious hypersensitivity to tirzepatide or excipients
Prior abdominal/foregut surgery other than: appendectomy, C-section/tubal ligation, cholecystectomy. Specifically excludes bariatric surgery and anti-reflux surgery (e.g., fundoplication, LINX)
Structural esophageal disease prior to randomization, including hiatal hernia >3 cm, esophageal stricture, prior LA Grade B–D erosive esophagitis, or biopsy-proven Barrett’s esophagus, given their potential to independently alter reflux physiology and acid exposure.
Known esophageal motility disorder as defined by Chicago Classification v4.0 (e.g., achalasia, esophagogastric junction outflow obstruction, absent contractility, or hypercontractile esophagus).
Mechanical obstruction or anatomic abnormality that would preclude safe placement of study devices, including esophageal catheter placement for manometry or attachment of the Bravo pH capsule.
Documented delayed gastric emptying at baseline: gastric emptying T1/2 >174 min or gastric retention at 4 hours >25% (based on local normative dataset for the standard 320 kcal, 30% fat meal; protocol-defined)
Chronic GI diseases or systemic diseases that could affect motility, appetite, or absorption (e.g., IBD, significant neurologic disease, advanced renal/hepatic/cardiopulmonary disease), or active peptic ulcer disease
History of pancreatitis, gallstones, alcoholism/alcohol use disorder, or triglycerides >500 mg/dL
Medication exposures that confound motility/reflux and cannot be safely stopped: prokinetics (metoclopramide, erythromycin), anticholinergics; opioids for 3 months; appetite suppressants/stimulants; acid suppression that cannot be washed out (PPI/H2RA; washout window per protocol, e.g., PPIs 7-14 days)
Pregnancy or breastfeeding.