Every course of obesity pharmacotherapy ends. Cost, supply, pregnancy plans, side effects, or the patient's own wish. In Egypt, cost alone makes discontinuation the rule, not the exception. Yet the entire evidence base describes what happens when the drug stops, and none of it tests how to stop.
Abrupt withdrawal fails predictably. One year after stopping semaglutide, STEP 1 extension participants had regained two thirds of their lost weight. SURMOUNT-4 showed the same pattern after tirzepatide withdrawal, and meta-analysis confirms it across agents. After MBS specifically, stopping GLP-1 therapy is likewise followed by regain.
The guidelines say: do not stop at all. The 2026 ADA and Obesity Association Standards strongly recommend continuing medication through maintenance, and the 2024 IFSO consensus agrees that when medication is needed to hold the benefit after MBS, ongoing treatment is probably necessary, while stating, at 94% agreement, that intermittent therapy and dose-reduction strategies require research. Our patients cannot follow the first recommendation. Cost decides for them. This trial is the research the second sentence asks for: the evidence for the moment when continuing is not an option.
Clinicians already taper, on no evidence. A 2025 expert commentary describes 8-to-12-week dose reductions in routine practice and states plainly that the approach is anecdotal and untested (Obesity and Endocrinology 2025). Practice has run ahead of the trial.
The general-population trial now exists, and we cite it rather than duplicate it. The REST trial has registered exactly this comparison, gradual 16-week dose reduction versus abrupt cessation, in non-surgical patients with obesity. No such trial exists after MBS.
Previous MBS of any type
On semaglutide 2.4 mg (or maximum tolerated dose of at least 1.7 mg) for at least 6 months
prescribed for recurrent weight gain or suboptimal response
Weight stable within 3% over the last 12 weeks
Type 2 diabetes requiring continued GLP-1 therapy
Planned revisional surgery within the study period
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, and such patients follow that pathway, not this protocol
Concurrent use of any other obesity medication
Parallel
Semaglutide weekly injection
DrugActive pens at 1.7 mg for 4 weeks, then 1.0, 0.5, and 0.25 mg for 4 weeks each; injections stop at week 16. Maintenance program throughout: dietitian visits at months 0, 1, 2, 4, and then every 2 months; protein maintained at 60-80 g/day (1.0-1.5 g/kg ideal body weight, ERAS guidance); 150 minutes of weekly activity plus resistance training twice weekly; wrist accelerometer worn continuously. Restart rule: after month 6, open-label pharmacotherapy may be restarted only if the Delphi recurrence criteria are met; every restart is recorded and the patient stays in follow-up. The primary analysis is treatment-policy; a hypothetical estimand ignoring restart is a supporting analysis.
Placebo
DrugMatched placebo pens on the identical schedule from week 0; injections stop at week 16. Maintenance program throughout: dietitian visits at months 0, 1, 2, 4, and then every 2 months; protein maintained at 60-80 g/day (1.0-1.5 g/kg ideal body weight, ERAS guidance); 150 minutes of weekly activity plus resistance training twice weekly; wrist accelerometer worn continuously. Restart rule: after month 6, open-label pharmacotherapy may be restarted only if the Delphi recurrence criteria are met; every restart is recorded and the patient stays in follow-up. The primary analysis is treatment-policy; a hypothetical estimand ignoring restart is a supporting analysis.
Percentage change in body weight
Measured in kilograms from randomization to month 12, measured on the same calibrated scale, morning, light clothing.
Weight change
measured in kilograms
Proportion weight
regaining more than 25% and more than 50% of the weight lost during treatment.
Recurrent weight gain
Recurrent weight gain (RWG) is defined by the July 2026 international Delphi consensus as gaining more than 25% of the weight that was initially lost from the post-surgical nadir (the lowest weight point achieved after metabolic and bariatric surgery) Panel and Scope: A two-round modified Delphi study published in mid-2026 involved 66 international experts across five medical specialties to standardize definitions following metabolic and bariatric surgery (MBS) Preferred Terminology: The panel established "suboptimal" as the preferred overarching term (89.5% consensus) Optimal Measurement Metric: Percentage of Total Weight Loss (%TWL) was voted the optimal measurement approach (94.6% consensus) Related Thresholds: * Surgical nonresponse: Less than 10% TWL at 12 months (73.0% consensus). * Normal physiologic response: A 10% fluctuation in percentage of excess weight loss (%EWL) from the nadir (83.8% consensus).
Time to pharmacotherapy restart
Restart rule: after month 6, open-label pharmacotherapy may be restarted only if the Delphi recurrence criteria are met; every restart is recorded and the patient stays in follow-up. The primary analysis is treatment-policy; a hypothetical estimand ignoring restart is a supporting analysis.
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