Immediate Versus Criterion-triggered Semaglutide for Suboptimal Clinical Response One Year After Primary Metabolic and Bariatric Surgery

Roughly one patient in five never reaches the expected weight loss after MBS, and long-term regain after SG is well documented. These patients are identifiable at the 12-month visit. Today they are watched, coached, and treated only when failure is established. Whether the drug works in this group is no longer the question. BARI-STEP, published this year, randomized 70 patients with less than 20% weight loss after gastric bypass (including one-anastomosis) or sleeve gastrectomy, a mean of seven years after surgery, to semaglutide 2.4 mg or placebo: 18.0% loss versus 0.4% gain at 68 weeks, an adjusted difference of 19.1 percentage points. Its population was mixed, 55.7% with recurrent weight gain and 44.3% with suboptimal initial response, and its exploratory comparison found no difference in drug response between the two presentations. BARI-OPTIMISE showed the same direction with liraglutide, as did a randomized trial after gastric banding. Efficacy is settled. Timing is not. BARI-STEP recruited patients a mean of seven years past surgery, after failure had hardened. No trial has tested treating at first recognition, the 12-month visit, against the current standard of structured waiting. The field's own reviews name timing and duration as the open questions. The 2024 IFSO international consensus reached 100% agreement that medication after MBS should generally be withheld until the weight plateau, and 100% agreement that adding it for a suboptimal response can then improve outcomes. That is exactly our immediate arm: treat at the plateau, at first recognition. The triggered arm is what clinics actually do: wait for established failure. Both positions rest on expert agreement, not on a trial. This is the randomized test of the consensus pathway. A registered open-label pilot starts tirzepatide at 12 or 18 months but is small, unblinded, and not a strategy comparison. The 2026 consensus draws the line for us, and this protocol respects it. The Delphi panel defined surgical nonresponse as less than 10% TWL at 12 months, defined recurrent weight gain as regain of more than 25% of lost weight from nadir, and treated a 10% swing in %EWL from nadir as normal physiologic fluctuation. It gave no 12-month label at all to the patient with 10 to 19.9% TWL, and the IFSO Delphi consensus expects the weight nadir up to 2 years after surgery (Obes Surg 2023). So a patient at 14% TWL at one year may still be on the way down, and calling that failure would be wrong. The protocol therefore splits eligibility into two tiers. Below 10% TWL at 12 months: consensus-defined nonresponse, randomized at once, waiting adds nothing. 10 to below 20% TWL: randomized only after a documented plateau, defined in Section 4, with a hard cap at month 18 so waiting cannot drift into neglect. Randomization is stratified by tier, and results are reported by tier.

Inclusion Criteria: * Primary laparoscopic SG or RYGB at our unit or a participating unit * %TWL less than 20% from the day of surgery, in one of two tiers. Tier A, surgical nonresponse: below 10% TWL at the 12-month visit; eligible immediately, randomization between months 12 and 14. Tier B, suboptimal response: 10 to below 20% TWL at the 12-month visit; eligible only after a documented plateau, randomization between months 12 and 18 (Plateau, defined. Two clinic weights at least 12 weeks apart differing by less than 2% of body weight, on the trial scale, with no change in treatment between them. This sits inside the swing the consensus panel itself called normal physiologic fluctuation. A Tier B patient still losing at month 12 is re-weighed at months 15 and 18. Reaching 20% TWL at any point means a good response and no enrollment. Still below 20% at month 18 means eligible regardless of plateau; the cap stops watchful waiting from becoming neglect.) * Anatomy assessed as normal in all: upper endoscopy for every patient, contrast study when symptoms suggest it * Able to self-inject and consent. Exclusion Criteria: * Any GLP-1-based therapy since surgery * Recurrent weight gain by the consensus definition, regain of more than 25% of the weight lost from nadir; these patients belong to RESURGE, not here * Anatomical abnormality explaining the poor response (these patients go to the revision pathway, not this trial) * Pregnancy or conception planned within the study (obesity pharmacotherapy is stopped at least 2 months before any planned conception, per current labeling and the 2026 Standards) * type 1 diabetes * medullary thyroid carcinoma or MEN2 history * pancreatitis history * untreated severe depression or active eating disorder on psychological review