The purpose of this study is to assess the effect of gastric fundal mucosal ablation (GFMA) on weight trajectory following discontinuation of once-weekly semaglutide or tirzepatide in adults with obesity. In this study, GFMA will be performed on patients who have experienced > 10% weight loss with GLP-1 therapy and who plan to discontinue use of GLP-1 medications for the duration of the study.

Obesity is a multifactorial, chronic, and progressive disease of pandemic proportions. Incretin mimetics , such as semaglutide and tirzepatide, induce weight loss in adults with obesity, while also improving weight-related medical conditions, such as cardiac and renal disease. The beneficial effects on weight and metabolism require the continued presence of these medications, which have a half-life of approximately five to seven days. This concept was substantially illustrated in the STEP4 and SURMOUNT4 randomized controlled trials. In the STEP4 trial, adults with obesity were treated with semaglutide for a 20-week run-in, losing 10.6% of body weight, thereafter randomized 2:1 to continued semaglutide use vs placebo. Over the subsequent 48 weeks, the semaglutide arm lost an additional 7.9% of original body weight, whereas the placebo arm saw two-thirds the lost weight return. In the SURMOUNT-4 trial, adults with obesity were treated with tirzepatide for a 36-week run-in period, losing 20.9% of body weight, thereafter, randomized 1:1 for continued treatment or placebo. Over the subsequent 52 weeks, the treatment arm lost an additional 5.5% of body weight, whereas the placebo arm saw a return of approximately half the weight that had been lost. These observations present challenges for long-term obesity management when confronted by multiple reports showing high rates of discontinuation of incretin mimetics soon after initiation. These observations present challenges for long-term obesity management when confronted by multiple reports showing high rates of discontinuation of incretin mimetics soon after initiation. Gastric fundal mucosal ablation (GFMA) is a novel endoscopic approach to control appetite which uses hybrid argon plasma coagulation (HybridAPC) to ablate the superficial tissue of the gastric fundus to induce cell death and fibrotic remodeling. In an early safety and feasibility study of ten adults with obesity, GFMA reduced circulating levels of the only known hunger hormone in humans, ghrelin. This led to a measured suppression of inter-meal hunger and cravings, as well as improved confidence in the ability to resist cravings. In addition to reducing ghrelin-producing cell population within the fundus, GFMA induced significant fundal fibrin deposition. This resulted in a stiffer, less compliant fundus, reducing maximum tolerated volume of a standardized nutrient drink test, enhancing intra-meal satiation. Given that GFMA induces appetite control through both visceroceptive and hormonal mechanism, much like incretin mimetics, we hypothesize that GFMA can prevent or limit weight recurrence in adults who have stopped these medications after successful obesity treatment.

Inclusion Criteria:

1. Subjects aged 21-65
2. Body mass Index (BMI) ≥30 kilograms per square meter (kg/m²), or ≤45 kg/m²
3. Observed ≥ 10% TBWL with semaglutide or tirzepatide use for primary obesity therapy
4. Subject did not experience >50% weight recurrence since discontinuation of semaglutide or tirzepatide
5. Maintained a stable dose of semaglutide or tirzepatide for a minimum of 12 weeks
6. Have recently discontinued or are planning to discontinue semaglutide or tirzepatide (≤ 24 weeks from last dose to time of study procedure)
7. No previous medical history of diabetes mellitus
8. Willing and able to participate in the study procedures
9. Understand and voluntarily sign the informed consent

Exclusion Criteria:

1. Known diagnosis of type I or type II diabetes or a Hemoglobin A1c > 6.5% at time of screening
2. Use of GLP-1 or GLP-1/GIP medication for the treatment of diabetes, rather than obesity.
3. Use of anticoagulation, antithrombotic agents, and/or NSAIDs that cannot be discontinued for a minimum of 12 weeks
4. Known bleeding diathesis that cannot be corrected through medical means.
5. History of decompensated end-organ disease
6. Unwillingness to abstain from the use of incretin mimetics during the study duration.
7. Unwillingness to abstain from the use of tobacco during the study duration
8. Patients on any medications or supplements including those that may influence cholecystokinin (CCK), glucose, growth hormone, insulin and/or somatostatin levels
9. History of any stomach manipulation (including repair of hiatal hernia or fundoplication) deemed unsafe by PI for GFMA
10. Active disordered eating
11. Patients who do not give their consent to the enrollment in the study or are incompetent, unconscious or unable to express their consent for any reason
12. Known diagnosis of gastroparesis or functional dyspepsia
13. Patients who are pregnant, who plan to become pregnant during study duration, or patients of child-bearing potential who refuse effective birth control methods (as approved by PI)
14. Active H. pylori infection or history of H pylori without treatment and confirmation of eradication
15. Active gastric ulceration.
16. Use of concomitant medications known to induce weight loss (including but not limited to liraglutide, phentermine, phentermine/topiramate, bupropion/naltrexone, metformin)