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.
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.
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)
Parallel
Semaglutide weekly injection
Drugsemaglutide escalated to 2.4 mg weekly, continued for 12 months.
Placebo
DrugCriterion-triggered strategy: matched placebo with identical lifestyle support; guaranteed open-label semaglutide the moment consensus recurrence criteria are met, and in any case 12 months after randomization if response remains suboptimal.
Percentage total weight loss
Measured in kilograms from pre-surgery weight at 12 months after randomization, same calibrated scale, morning, light clothing.
Percentage total weight loss
Measured in kilograms at 6 and 24 months after randomization
change in HbA1c
An HbA1c level reflects your average blood sugar over the past two to three months, and any meaningful change typically takes at least 6 weeks to show because red blood cells live for about 3 months. Normal: Below 5.7% Prediabetes: 5.7% to 6.4% Diabetes: 6.5% or higher
systolic and diastolic blood pressure
Normal blood pressure is less than 120 mm Hg systolic and less than 80 mm Hg diastolic. Systolic (Top Number): Measures the pressure in your arteries when your heart beats and contracts. Diastolic (Bottom Number): Measures the pressure in your arteries when your heart rests between beats. • Normal: Less than 120 mm Hg systolic and less than 80 mm Hg diastolic. • Elevated: 120-129 mm Hg systolic and less than 80 mm Hg diastolic. • Stage 1 Hypertension (High Blood Pressure): 130-139 mm Hg systolic or 80-89 mm Hg diastolic. • Stage 2 Hypertension: 140 mm Hg or higher systolic, or 90 mm Hg or higher diastolic. • Hypertensive Crisis: Higher than 180 mm Hg systolic and/or higher than 120 mm Hg diastolic. This requires immediate emergency medical care
total cholesterol, LDL, HDL, and triglycerides
Normal adult values for a lipid panel are measured in milligrams per deciliter (mg/dL): • Total Cholesterol: Below 200 mg/dL is desirable. (Borderline high is 200-239 mg/dL, and high is 240 mg/dL and above.) • LDL ("Bad") Cholesterol: Below 100 mg/dL is optimal. (130-159 mg/dL is borderline high, and 160-189 mg/dL or higher is high.) • HDL ("Good") Cholesterol: 60 mg/dL and higher is protective. Levels below 40 mg/dL for men or below 50 mg/dL for women are considered low. • Triglycerides: Below 150 mg/dL is normal. (Borderline high is 150-199 mg/dL, and high is 200-499 mg/dL.)
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