The goal of this pilot clinical trial is to determine the effectiveness of Tirzepatide in patients with persistent obesity (BMI > 30) 12 months after bariatric surgery (Roux-en-Y Gastric Bypass). The investigators also aim to determine the frequency of side effects with Tirzepatide in this patient population. Patients who take tirzepatide 12 months after bariatric surgery will be compared to patients who continue with the current standard of care for patients who have previously undergone Gastric Bypass Surgery.

Obesity affects nearly half of the U.S. population, impacting health outcomes including diabetes, cardiovascular risk, longevity, and quality of life. While bariatric surgery such as gastric bypass stands as the most effective intervention, 65% of individuals experience persistent obesity when undergoing surgical weight loss alone. Given the wide-ranging impact of obesity on health outcomes, a critical need exists to explore the efficacy of adjuvant weight loss therapies after gastric bypass surgery. Tirzepatide (TRZ), a type of glucagon-like peptide-1 receptor agonist, shows remarkable effectiveness in medical obesity with 25% weight loss after sustained therapy. However, nearly two-thirds of patients taking medications like TRZ have mild to moderate gastrointestinal (GI) symptoms, including nausea, vomiting, and abdominal pain. These medication side-effects could be a consequence of gastroparesis via vagal stimulation of the stomach, and may represent a major driver of weight loss. Limited data exist regarding use of these newer agents, such as TRZ, in patients who have undergone gastric bypass, which disrupts vagal nerves responsible for managing food transit and gastric emptying. This is a major and timely scientific gap in understanding whether gastric bypass surgery might mitigate these GI symptoms while allowing for enhanced weight loss with adjuvant TRZ use in the post-operative period. The investigators propose a pilot, phase II, open-label trial enrolling patients twelve months after gastric bypass with a nadir Body Mass Index ≥ 30 kg/m2. Study subjects will be randomized to either 24 weeks of TRZ or post-surgery standard of care. Subjects randomized to the standard of care arm will crossover to receive the intervention drug after 24 weeks of observation. Our proposal consists of two aims. First, the investigators will determine the impact of adjuvant TRZ administration on weight, total fat mass, and lean body mass in patients with a history of gastric bypass (Aim 1). Second, the investigators aim to investigate the frequency and severity of GI discomfort associated with TRZ utilizing a validated patient reported outcome questionnaire, and they will investigate the impact of TRZ on GI motility in patients with prior Gastric Bypass (Aim 2).

Inclusion Criteria:

1. Subject must be able to understand and provide informed consent.
2. BMI > 30 12 months after bariatric surgery.
3. Age > 25 and < 65
4. Patients undergoing primary Roux-en-Y Gastric Bypass

Exclusion Criteria:

1. Inability or unwillingness of a subject to give written informed consent or comply with the study protocol.
2. Diagnosis of type I Diabetes
3. Revisional bariatric surgery (prior adjustable gastric band, sleeve gastric, vertical banded gastroplasty).
4. Use of medications for type 2 di
5. Hemoglobin A1c > 8.5 in last 3 months.
6. Patient-reported Tobacco, e-cigarette, or smoked marijuana use within 12 months As this would preclude patients from undergoing bariatric surgery.
7. Personal history of pancreatitis as determined by history.
8. Personal or family history of medullary thyroid cancer by history or multiple endocrine neoplasia syndrome type 2
9. Pregnancy by urine testing, current lactation, or plans to become pregnant during the study period.
10. Use of systemic glucocorticoids in the past 28 days
11. Myocardial infarction, unstable angina, stroke, or heart failure (NYHA class II) within 1 year by history.
12. History of solid organ transplant.
13. History of physician-diagnosed malignancy (other than excised non-melanoma skin cancer) in the past 5 years.
14. Current uncontrolled hypertension (systolic >150, diastolic >90) or untreated hyperthyroidism.
15. Current, diagnosed, or self-reported drug or alcohol abuse that, in the opinion of the investigator, would interfere with the subject's ability to comply with study requirements.
16. Screening creatinine elevation with EGFR < 60 at time of randomization.
17. Tobacco use in last 12 months
18. Pregnancy
19. Prisoners
20. Unable or unwilling to follow-up
21. Unable to understand English/Spanish

All participant-level data will be preserved and shared. Shared data will be deidentified prior to sharing. Clinicaltrials.gov will document recruitment progress and final results. Study protocols will be shared with publications as supplementary data and made available upon request. All participant consent document will be collected and stored electronically utilizing the REDCap study data repository. The REDCap data warehouse will also contain the study data dictionary. Study protocols have also been published on the ClinicalTrials.gov and any protocol amendments will be reflected on the ClinicalTrials.gov study page. The investigators will utilize the Research Electronic Data Capture (REDCap) data warehouse maintained locally at Vanderbilt for all data collection. Upon study completion and prior to closing the REDCap data warehouse for this study, the investigators will archive all data after removing patient identifiers in the Open Science Framework data repository.

Per institutional policy, data will be maintained in the local REDCap data repository for 6 years after closure of the study. Following this period, data will be deidentified and uploaded to the OSF repository, which has funding for at least 50 years of data storage.