GLP-1 Receptor Agonists Post-Bariatric Surgery (GRABS) Pilot Trial

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).

Participants in the TRZ cohort will initiate a standardized dose titration as described in the package insert. Participants will begin TRZ at 2.5 mg for four weeks and then increase by 2.5 mg every 4 weeks to a maximum dose of 15 mg. If subjects experience intolerable GI symptoms, they will be allowed to decrease to a lower dose by 2.5 mg for 2 weeks, at which point another attempt at an increased dose will be trialed. Should patients not tolerate a higher dose a second time, they will have the dose again lowered by 2.5 mg and kept at the lower dose for the remainder of the study, except for patients who do not tolerate two attempts at 5 mg. For patients who fail to titrate to at least 5 mg TRZ, a third attempt at an increased dose will be attempted 4 weeks after the second decrease in dose. These patients will then remain on 5 mg for the remainder of the intervention period. All participants receiving TRZ will be pooled in terms of outcomes measures.

Drug: Tirzepatide

Patients randomized to the control arm will receive the standard of care for weight maintenance after gastric bypass including dietary guidance provided by the Vanderbilt Surgical Weight Loss handbook for 24 weeks. After 24 weeks, particiapnts in the control arm will crossover to the Tirzepatide arm and receive 24 weeks of TRZ following the same titration.

Other: Standard of Care post-gastric bypass

Tirzepatide will be initiated 12 or 18 months (12 months + 24 weeks) after patients undergo Roux-en-Y Gastric Bypass. Patients will be started on the lowest dose of 2.5 mg and the dose increased every 6 weeks following an adaptive maximum dose titration protocol. Patients will then complete a final 4 weeks of the study drug.

Patients randomized to the control arm will receive the standard of care for weight maintenance after gastric bypass including dietary guidance provided by the Vanderbilt Surgical Weight Loss handbook. This includes recommendations for 64 oz of fluids per day, ≥60 grams of protein/day, and daily bariatric multivitamins. Patients will continue to have access to dedicated bariatric dietitians, advanced practice providers, and surgeons on an ad hoc basis per patients' request.

Plazo: baseline to 24 weeks

Percent total weight change baseline to 24 weeks

Plazo: baseline to 24 weeks

Mixed-model adjusted mean difference at Week 24

Plazo: baseline to 24 weeks

Changes in fat mass

Plazo: baseline to 24 weeks

Changes in acetaminophen area under the curve in the intervention arm

Plazo: baseline to 24 weeks

Utilizing DXA, we will determine changes in lean body mass in both arms

Plazo: weeks 24 to 48

Degree of weight regain in intervention arm after discontinuation of TRZ

Plazo: baseline to 24 weeks

incidence of obesity remission (BMI \< 30)

Plazo: baseline to 24 weeks.

Incidence of remission of Type 2 Diabetes, Hyperlipidemia, Hypertension

Plazo: baseline to 24 weeks

Changes in clinical obtained anthropometric measurements including waist circumference and waist-to-hip ratio

Plazo: baseline to 24 weeks.

Changes in DXA-proven body composition including lean body mass and ratio of lean body mass to fat mass

Plazo: baseline to 24 weeks

1\. heartburn/regurgitation, 2. nausea/vomiting, 3. postprandial fullness, 4. bloating, 5. upper and lower abdominal pain

Plazo: baseline to week 24 and week 24 to week 28 (after TRZ discontinuation)

Determining evolution of PAGI-SYM scores across treatment in both arms and after discontinuation of TRZ in the intervetion arm.

Plazo: baseline to 24 weeks

difference in acetaminophen AUC between Intervention and control groups

Plazo: baseline to 24 weeks

change in intervention arm mixed meal AUC for Glucose, Insulin, and GLP-1

Plazo: baseline to 24 weeks

Incidence of missed doses, patient-driven drug discontinuation, patient withdrawal in intervention arm

Plazo: baseline to 48 weeks

Incidence of adverse events including emergency department visits, hospitalizations, and reoperations

GLP-1 Receptor Agonists Post-Bariatric Surgery (GRABS) Pilot Trial