Research

Long-term GLP-1 discontinuation and rebound: what the data show

STEP-1 Extension and SURMOUNT-4 are the most-cited evidence on weight regain after GLP-1 discontinuation. What the trials show and what the clinical implications are.

The most-cited clinical question alongside “does GLP-1 work for weight loss?” is “what happens when I stop?” The published evidence — STEP-1 Extension trial and SURMOUNT-4 — addresses this directly. This article summarizes the findings and the clinical implications.

STEP-1 Extension (Wilding et al., 2022)

The STEP-1 Extension trial followed STEP-1 participants for an additional year after discontinuation of randomized treatment. Patients in the semaglutide group during the original 68-week trial regained substantial weight after discontinuation. By 1 year post-discontinuation, the semaglutide group had regained approximately two-thirds of the weight initially lost; the placebo group had largely maintained their (smaller) initial losses.

The findings established that the appetite-suppression and weight-loss effect of semaglutide is largely contingent on continued exposure. Discontinuation produces gradual return toward pre-treatment intake patterns and toward pre-treatment weight.

SURMOUNT-4 (Aronne et al., JAMA 2024)

SURMOUNT-4 examined withdrawal versus continuation of tirzepatide after 36 weeks of open-label active treatment. Participants who had achieved substantial weight loss on tirzepatide during the open-label phase were randomized to continued tirzepatide or to placebo for an additional 52 weeks.

The continuation group maintained losses; the withdrawal group regained substantial weight (approximately 14% of body weight regained over the 52-week withdrawal phase, on average). The findings parallel the STEP-1 Extension findings for semaglutide and establish that weight maintenance after substantial GLP-1-induced weight loss generally requires continued therapy.

Clinical framing: GLP-1 as long-term therapy

The discontinuation findings support a clinical framing of GLP-1 receptor agonist therapy for chronic weight management as long-term therapy, analogous to long-term therapy for hypertension, lipid disorders, or diabetes. Discontinuation of effective therapy is followed by recurrence of the underlying condition (in this case, the appetite and metabolic patterns that produced the weight in the first place).

This framing informs counseling at GLP-1 initiation: patients should typically be planning for long-term therapy, not a brief course followed by indefinite weight maintenance.

Why discontinuation happens in real-world practice

Despite the long-term-therapy framing, discontinuation is common in real-world practice. Reasons include:

• Cost (insurance coverage, out-of-pocket).
• Supply shortages (some periods over 2022-2024 had constrained supply).
• Side-effect intolerance.
• Pregnancy or planning pregnancy.
• Specific clinical contraindications that emerge.
• Patient preference.

Discontinuation is sometimes a clinician decision, sometimes a patient decision, sometimes circumstance-driven. The nutritional implications apply regardless of why.

Nutritional implications during discontinuation

Discontinuation of GLP-1 therapy is typically followed by:

• Gradual return of pre-treatment appetite patterns over weeks to months (the medication’s pharmacological half-life and the rate of receptor downregulation reversal both contribute).
• Gradual increase in caloric intake.
• Gradual weight regain.

For patients planning a discontinuation (or experiencing one due to circumstance), the practical considerations:

• Maintain the protein-and-resistance-training framework. The lean-mass-preservation case actually intensifies during regain, because the body is in an anabolic state with abundant energy availability and resistance-training response is typically robust in this state.
• Maintain tracking habits. Patients who continue tracking through discontinuation often have more controlled regain trajectories than patients who stop tracking concurrently.
• Discuss with clinician. Discontinuation, whether planned or circumstance-driven, is appropriate to discuss with the clinician; some patients benefit from alternative pharmacotherapy or from intensified lifestyle intervention during the discontinuation phase.

Weight regain and body composition

A specific concern raised in the body-composition literature: weight regain after GLP-1 discontinuation may be disproportionately fat-mass regain, with limited recovery of the lean mass lost during the active weight-loss phase. The result is a body composition that is fatter (proportionally) than at the start of the original weight-loss phase, even if the absolute weight is similar.

This finding (still being characterized in long-term real-world cohorts) emphasizes the importance of resistance-training engagement during the active weight-loss phase, when the lean-mass-preservation case is most easily addressed.

Implications for the patient

For a patient on GLP-1 therapy considering or facing discontinuation:

• The expectation should be partial-to-substantial weight regain on discontinuation.
• The expectation should be greater regain in patients with shorter active-treatment durations.
• Lean-mass preservation during the active phase pays forward into a better body-composition outcome if/when discontinuation occurs.
• Re-initiation of therapy is possible if circumstances change.
• Discontinuation is a clinical conversation, not a unilateral decision.

Implications for the clinician

For the clinician:

• Set the long-term-therapy expectation at initiation.
• Counsel on the regain-on-discontinuation evidence.
• Plan for continuation (insurance navigation, alternative formulations during shortages, side-effect management) as part of the active-treatment phase.
• For discontinuation that does occur, consider intensified lifestyle intervention or alternative pharmacotherapy during the regain phase.

References

1. Wilding JPH, Batterham RL, Davies M, et al. Weight regain and cardiometabolic effects after withdrawal of semaglutide: the STEP 1 trial extension. Diabetes, Obesity and Metabolism. 2022;24(8):1553-1564.
2. Aronne LJ, Sattar N, Horn DB, et al. Continued treatment with tirzepatide for maintenance of weight reduction in adults with obesity: the SURMOUNT-4 randomized clinical trial. JAMA. 2024;331(1):38-48.
3. Bays HE, McCarthy W, Christensen S, et al. Obesity Algorithm — Obesity Medicine Association Practice Guidance. Obesity Pillars. 2024;9:100100.
4. American Diabetes Association. Standards of Care in Diabetes — 2025: Section 8, Obesity and weight management. Diabetes Care. 2025;48(Suppl 1):S145-S157.
5. Holmstrup ME, Fairman CM, Calanna S, et al. Body composition during pharmacologic weight loss with GLP-1 receptor agonists. Obesity Reviews. 2025;26(4):e13721.