Effects of Tirzepatide on Esophagogastric Junction Mechanics, Reflux Burden, and Gastric Physiology in Adults With Obesity

This study will assess whether a single subcutaneous dose of tirzepatide 7.5 mg , compared with saline placebo, increases total esophageal acid exposure time during a 96-hour wireless pH recording beginning about 48 hours after study medication.

Inclusion Criteria: 1. Signed and dated informed consent form with HIPAA authorization 2. Male or female, ages 18-75 inclusive. 3. Obesity/overweight as per FDA weight-management indication for tirzepatide (Zepbound®): defined as BMI ≥ 30 kg/m² or BMI ≥ 27 kg/m² with ≥ 1 weight-related comorbidity such as hypertension, dyslipidemia, OSA or CVD and \< 45 kg/m2. 4. Able to travel to Mayo Clinic for all required in-person study visits.. 5. In good general health with no untreated, clinically significant cardiac, pulmonary, gastrointestinal, hepatic renal, hematologic, neurologic, psychiatric or endocrine disorder. 6. Women of childbearing potential must have a negative pregnancy test result within 48 hours of administration of study medication. They must agree to use a highly effective method of contraception through 4 weeks after the single dose of study medication. Because tirzepatide may reduce the bioavailability of oral hormonal contraceptives, women who are using oral hormonal contraceptives must also use an additional barrier method of contraception during this time. Women who are postmenopausal times 1 year, post tubal ligation or post hysterectomy are exempt from pregnancy tests. 7. No increase or decrease in body weight \> 5% during the 3 months before study entry. 8. No GLP-1 receptor agonist or dual incretin medication during the 3 months before study entry. 9. Agree to adhere to diet instructions prior to EGD and manometry. Exclusion Criteria: 1. Pregnancy or breastfeeding. A point of care urine pregnancy test will be performed within 48 hours of receipt of the study medication for all women of childbearing potential. Women who are postmenopausal times 1 year, post tubal ligation or post hysterectomy are exempt from pregnancy tests. 2. Diagnosis of type 1 or type 2 diabetes regardless of current treatment, because diabetes and its therapies may affect gastrointestinal physiology and may alter the safety profile of tirzepatide in this acute mechanistic study. 3. Personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type II. 4. Known serious allergic reaction to components of tirzepatide, midazolam or topical lidocaine. 5. Treatment with an investigational drug/intervention within 30 days or five half-lives of the study medication, whichever is longer. 6. History of abdominal surgery other than appendectomy, cholecystectomy, tubal ligation or cesarian section. Bariatric surgery and anti-reflux surgery including fundoplication or LINX are exclusions. 7. Chronic systemic or GI diseases that could affect GI motility, appetite or absorption (e.g., IBD, significant neurologic disease, advanced renal/hepatic/cardiopulmonary disease), or active peptic ulcer disease 8. Previously documented structural esophageal disease including hiatal hernia \>3 cm, esophageal stricture, prior LA Grade B-D erosive esophagitis, or biopsy-proven Barrett's esophagus. 9. Previously diagnosed major esophageal motility disorder based on Chicago Classification v4.0 including achalasia, esophagogastric junction outflow obstruction, absent contractility, distal esophageal spasm or hypercontractile esophagus. 10. Mechanical obstruction, bleeding diathesis, esophageal varices, severe esophagitis, or another anatomic or clinical condition that would preclude safe placement of study devices, including the manometry catheter, Endo FLIP catheter, or Bravo pH capsule. 11. Pacemaker or implanted cardiac defibrillator. Other implanted electronic devices will be reviewed by the study physician for compatibility with the Bravo system. 12. Known clinically significant or severe hypersensitivity to stainless steel or metals in the Bravo capsule delivery system, including nickel, chromium, copper, cobalt, or iron, when the study physician determines that the capsule placement would pose an unacceptable risk. A history of a nonspecific or mild metal sensitivity is not an exclusion. 13. Planned or reasonably anticipated MRI within 30 days after Bravo capsule placement, or inability to comply with the 30-day MRI restriction. 14. Known gastroparesis or previously documented delayed gastric emptying based on a clinically indicated gastric emptying test. 15. History of pancreatitis, active or recent symptomatic gallbladder disease, including symptomatic cholelithiasis or cholecystitis, alcohol use disorder, or triglycerides \>500 mg/dL 16. Significant untreated GERD based on screening with the GERD HRQL questionnaire. If participant has any total score ≥ 20 on questions 1-10, the participant will be interviewed by a study physician. If participant is excluded from the study, s/he will be referred to their primary care physician. 17. Use of acid-suppressive medication that cannot be discontinued for at least 14 days before Bravo capsule placement and withheld through completion of the 96-hour recording, unless resumed for clinical necessity. 18. Disallowed concomitant medications due to effects on stomach or appetite: 1. Resin sequestrants for hyperlipidemia * Cholestyramine (Questran®) * Colesevelam (WelChol®) * Colestipol (Colestid®) 2. α2-agonists for hypertension * Clonidine (Catapres®) * Methyldopa * Guanfacine (Intuniv®) 3. 5HT3 receptor antagonists * Ondansetron (Zofran®) * Granisetron (Kytril®) * Palonosetron (Posfrea®) 4. NK-1 receptor antagonists * Aprepitant (Emend®) * Fosaprepitant (Focinvez®) * Rolapitant (Varubi®) 5. Dopamine receptor antagonists / prokinetics * Metoclopramide (Reglan®) * Domperidone (Motilium®) * Prochlorperazine (Compazine®) * Haloperidol (Haldol®) 6. Anticholinergics * Scopolamine (Transderm Scop®) * Dicyclomine (Bentyl®) * Hyoscyamine (Levsin®) 7. Corticosteroids * Dexamethasone (Decadron®) * Methylprednisolone (Medrol®) 8. Antipsychotics * Olanzapine (Zyprexa®) * Quetiapine (Seroquel®) 9. Opioids * Tramadol (Ultram®) * Morphine (MS Contin®) * Oxycodone (OxyContin®) * Fentanyl * Hydromorphone (Dilaudid®) * Codeine * Methadone 10. Cannabinoids and cannabinoid products * THC * CBD * Dronabinol * Nabilone 11. Tricyclic antidepressants * Nortriptyline (Pamelor®) * Amitriptyline (Elavil®) * Doxepin (Silenor®) * Desipramine (Norpramin®) * Imipramine (Tofranil®) 12. Prokinetics * Tegaserod (Zelnorm®) * Pyridostigmine (Regonol®) Prucalopride (Motegrity®) 13. Selective serotonin and norepinephrine reuptake inhibitors * Venlafaxine (Effexor®) * Duloxetine (Cymbalta®) * Desvenlafaxine (Pristiq®) Note: Selective serotonin reuptake inhibitors are acceptable provided that the dose has been stable prior to study for 30 days. * Fluoxetine (Prozac®) * Citalopram (Celexa®) * Escitalopram (Lexapro®) * Paroxetine (Paxil®) * Sertraline (Zoloft®) 14. Selective norepinephrine reuptake inhibitors * Atomoxetine (Strattera®) * Viloxazine (Qelbree®) Note: Bupropion (Wellbutrin®)is acceptable provided that the dose has been stable prior to study for 30 days. 15. Other weight loss medications * Bupropion with naltrexone * Phentermine with or without topiramate 16. ADHD medications * Methylphenidate (Ritalin® or Concerta®) * Dextroamphetamine (Adderall®) * Lisdexamfetamine (Vyvanse®) 17. Mirtazapine and buspirone (Buspar®) 18. Sulfonylureas * Glimepiride (Amaryl®) * Glipizide (Glucatrol®) * Glyburide (Diabeta®) 19. DPP-4 inhibitors * Sitagliptin (Januvia * Vildagliptin (Galvus®) * Linagliptin (Tradjenta®) * Alogliptin (Nesina®) 20. Metformin, acarbose and insulin 21. Amylin agonists/analogs • Pramlintide (Symlin®) 22. Cyclobenzaprine (Flexeril®)