Inclusion Criteria:

• Adults (18-75 years) who have BMI >30kg/m²

• Able to reside within 50 miles of Mayo Clinic for the duration of the study

• Not currently on treatment (exceptions below) for cardiac, pulmonary, GI, hepatic, renal, hematological, neurological, or endocrine disorders.

• Biological sex: men or women. We shall attempt to recruit equal proportions of men and women. Women of childbearing potential will be using an effective form of contraception and have negative pregnancy tests within 48 hours of enrollment and before each isotope-based radiation exposure as part of the tests for gastric emptying or fluoroscopy required for the antroduodenal manometric tube placement.

Exclusion Criteria:

• Weight exceeding 137kg (safety limit of camera for measuring gastric emptying)

• Abdominal surgery other than appendectomy, Caesarian section or tubal ligation, cholecystectomy

• Chronic GI diseases, systemic disease or medications that could affect GI motility, appetite or absorption

• Patients with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia II

• Patients with diabetes, including T2DM on GLP-1RAs, amylin agonists/analogs (e.g. pramlintide), insulin, sulfonylureas (all due to risk of hypoglycemia with semaglutide or tirzepatide treatment); or on metformin, acarbose or DPP-4 inhibitors (e.g. sitagliptin and vildagliptin).

• Past or current history of pancreatitis, gallstones, history of alcoholism, blood triglyceride levels > 500mg/dL

• Intake of any medication (except multivitamins) within 7 days of the study.

• Exceptions are birth control pill, estrogen and thyroxine replacement, and medication administered for co-morbidities as long as they do not alter gastric functions. Thus, statins for hyperlipidemia, diuretics, β-adrenergic blockers, ACE inhibitors and angiotensin antagonists for hypertension are permissible. In contrast, resin sequestrants for hyperlipidemia (Psichas et al 2012), α2-adrenergic agonists for hypertension, are not permissible due to effects on stomach motor function or appetite.

• Hypersensitivity to semaglutide or tirzepatide

• Documented delayed gastric emptying: gastric emptying T_1/2 >174 min or gastric retention at 4 hours >25% based on 5-95%ile of 319 controls' GES of the same meal (320kcal, 30% fat)

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 05/09/2025. Questions regarding updates should be directed to the study team contact.