Weight Regain After Stopping GLP-1s: What the Data Actually Shows

The Primary Evidence: STEP 1 Extension

The most cited study on GLP-1 discontinuation is the STEP 1 trial extension, published in Diabetes, Obesity and Metabolism in August 2022. It followed 327 participants for one year after they stopped taking semaglutide 2.4 mg and discontinued the accompanying lifestyle intervention.

The findings were striking: after 68 weeks on semaglutide 2.4 mg, participants had lost an average of 17.3% of their body weight. One year after stopping both the medication and the lifestyle intervention, they had regained an average of 11.6 percentage points—leaving a net weight loss of just 5.6% from baseline.

Critically, the cardiometabolic improvements that came with weight loss also reversed. Blood pressure, lipid profiles, and glycemic markers that had improved during treatment returned toward baseline levels after stopping semaglutide.

Who Regained the Most?

The extension study found that participants who had achieved the greatest weight loss during treatment also experienced more rapid and substantial regain afterward. This pattern is consistent across weight loss methods—bariatric surgery, lifestyle intervention, and pharmacotherapy all show similar rebounds proportional to initial success.

SURMOUNT-4: Tirzepatide Discontinuation

The SURMOUNT-4 trial, published in JAMA in January 2024, examined what happens when tirzepatide is withdrawn after achieving substantial weight loss.

The trial design was elegant: 670 participants first received 36 weeks of open-label tirzepatide, losing an average of 20.9% of body weight. They were then randomized to either continue tirzepatide or switch to placebo for another 52 weeks.

The contrast was dramatic. Patients who continued tirzepatide not only maintained their weight loss but lost an additional 5.5%, ending up 25.3% lighter than when they started. Those who stopped regained an average of 14 percentage points, ending up only 9.9% lighter than baseline—still meaningful, but less than half the loss achieved by those who continued.

December 2025 Post-Hoc Analysis: Cardiometabolic Effects

A recent post-hoc analysis of SURMOUNT-4, published in JAMA Internal Medicine (November 2025), examined how weight regain affected cardiometabolic parameters:

Only 18% of participants who stopped tirzepatide maintained most of their weight loss (regaining less than 25%). The vast majority—82%—regained at least a quarter of what they had lost, with corresponding reversals in blood pressure, lipids, and insulin levels.

Real-World Data: A Different Picture?

Clinical trial results may not perfectly reflect what happens in everyday practice. Several real-world studies suggest weight regain patterns may differ outside the controlled trial environment.

Epic Research Analysis (January 2024)

An analysis of 20,274 patients who lost at least 5 pounds on semaglutide found:

• 55.7% either maintained their weight or continued losing after stopping
• 25.6% regained some weight but remained below their starting weight
• 17.7% regained all lost weight or more

This is notably more optimistic than clinical trial data. Researchers suggest two possible explanations: patients in real-world settings often lose less weight initially (and thus have less to regain), and real-world discontinuation may be more gradual.

Why the Discrepancy?

Dr. Hamlet Gasoyan, whose team studied GLP-1 discontinuation in Ohio and Florida, explained to AJMC:

Understanding Why Regain Happens

Weight regain after stopping GLP-1s isn't a mystery—it's the predictable result of removing treatment for an ongoing condition. The medications work through several mechanisms:

1. Appetite suppression: GLP-1s interact with brain regions that control hunger and satiety. When the drug is removed, appetite returns to baseline levels.
2. Slowed gastric emptying: Food moves more slowly through the stomach, creating longer-lasting fullness. This effect stops when the medication stops.
3. Reduced reward response: GLP-1s modulate how the brain responds to food as a reward. Without the medication, food cravings return.
4. Metabolic adaptation: The body's energy expenditure adjusts during weight loss. After stopping medication, metabolic rate may remain suppressed while appetite increases.

Evidence-Based Strategies to Minimize Regain

While no intervention fully replaces GLP-1 medications, research points to several strategies that may help:

1. Exercise During Treatment (Critical)

A 2024 randomized trial from Copenhagen found that patients who exercised while on liraglutide maintained their weight loss better after stopping than those on medication alone:

• Patients who only took medication regained most of their weight after stopping
• Patients who combined medication with supervised exercise maintained weight and body composition for at least one year after discontinuation
• The key appears to be establishing exercise habits while on medication, not trying to add them after stopping

2. Gradual Dose Tapering

Research presented at the 2024 European Congress on Obesity found that gradually reducing GLP-1 doses while maintaining lifestyle coaching may help:

• 353 patients who tapered semaglutide over ~9 weeks (vs. abrupt discontinuation) maintained weight loss better
• Continued lifestyle coaching during and after tapering appeared beneficial
• Standard practice is to stop abruptly; tapering over 2-8+ weeks may be worth discussing with your provider

3. Transition to Alternative Medications

A 2024 real-world study examined whether older, less expensive anti-obesity medications could help maintain weight after discontinuing GLP-1s:

• Patients who transitioned to medications like phentermine, topiramate, or metformin maintained weight better than those on no medication
• While less effective than GLP-1s, these generic options may serve as a "maintenance" strategy when cost or access prevents continued GLP-1 use

4. High-Protein Diet + Strength Training

Experts at Mass General Brigham recommend combining dietary and exercise strategies during treatment:

• Protein intake: Adequate protein helps preserve muscle mass during weight loss and may support satiety after stopping medication
• Resistance training: Building muscle during treatment may help maintain metabolic rate after discontinuation
• Both strategies should be established during GLP-1 treatment, not introduced afterward

5. Professional Support

A 2023 study found that patients who had ongoing support from dietitians, trainers, and mental health professionals regained less weight over 2 years than those without professional guidance. Obesity medicine specialists increasingly recommend comprehensive teams for long-term management.

Discontinuation Rates in Practice

Many patients don't stay on GLP-1s long-term, regardless of plans. A January 2025 JAMA Network Open study of 125,474 patients found:

Reasons for discontinuation included cost, side effects, weight plateau, and medication shortages. Weight regain was the most common factor associated with later reinitiation.

The Clinical Consensus

Medical organizations and researchers increasingly frame GLP-1s as long-term or indefinite therapy for obesity, similar to how statins are used for hyperlipidemia or antihypertensives for high blood pressure:

• The Endocrine Society's clinical practice guidelines recommend ongoing pharmacotherapy for patients who respond to treatment
• Novo Nordisk (Wegovy) and Eli Lilly (Zepbound) position their medications as long-term treatments, not short-term weight loss aids
• The SURMOUNT-MAINTAIN trial, currently ongoing, is specifically studying whether lower maintenance doses can preserve weight loss

Practical Recommendations

If You're Currently on a GLP-1

• Start exercise now—establishing habits during treatment leads to better maintenance
• Focus on high-protein foods and strength training to preserve muscle mass
• Discuss long-term plans with your prescriber; don't assume stopping is the goal

If You're Planning to Stop

• Talk to your provider about tapering vs. abrupt discontinuation
• Consider transitioning to alternative medications if cost is the barrier
• Intensify lifestyle interventions before stopping, not after
• Schedule close follow-up within the first month off medication

If You've Already Stopped and Regained

• Restarting GLP-1s is an option—the medications remain effective on subsequent courses
• Weight regain is not a personal failure; it's a biological response to stopping treatment
• Consult an obesity medicine specialist about comprehensive management options