How much weight did STEP-1 Extension participants regain after stopping semaglutide?

Participants regained approximately two-thirds of their on-treatment weight loss within one year. Mean body weight change went from −14.9% at week 68 to −5.6% at week 120, representing a regain of about 9.3 percentage points.

How quickly does weight regain begin after stopping semaglutide 2.4 mg?

Regain began within the first few weeks after discontinuation and was most rapid during weeks 68-80 (the first 12 weeks off-drug). This period accounted for roughly half the total weight regained over the full year.

Did cardiometabolic improvements reverse after semaglutide was stopped?

Yes. Blood pressure, HbA1c, fasting glucose, CRP, and waist circumference all partially reversed during the off-treatment year. Most parameters remained slightly better than pre-treatment baseline but lost 55-75% of their on-treatment improvement.

How many STEP-1 participants were included in the extension study?

327 of the original 1,961 STEP-1 participants enrolled in the off-treatment extension. This smaller cohort may not be fully representative of the broader trial population.

Does everyone regain weight after stopping semaglutide?

No. There was wide individual variation. At week 120, approximately 24% of former semaglutide users still maintained at least 10% body weight loss, while others had returned to or exceeded their baseline weight.

Is the STEP-1 Extension evidence that semaglutide should be taken indefinitely?

The data strongly support long-term, continuous treatment for sustained weight management. The regain pattern is consistent with obesity's classification as a chronic disease requiring ongoing therapy, similar to hypertension or diabetes.

Was there a group that continued semaglutide for comparison?

No. The extension study did not include a continued-treatment arm. The STEP-5 trial, which ran semaglutide for 104 continuous weeks, provides complementary data showing sustained weight maintenance with ongoing treatment.

How does semaglutide weight regain compare to other anti-obesity medications?

Weight regain after drug discontinuation is a consistent finding across anti-obesity pharmacotherapies, including liraglutide (SCALE Maintenance), phentermine-topiramate (SEQUEL), and tirzepatide (SURMOUNT-4). The STEP-1 Extension confirmed this pattern specifically for semaglutide 2.4 mg.

Did appetite return to baseline after stopping semaglutide?

Yes. Appetite scores measured by visual analog scales returned toward pre-treatment levels within the first few months off-drug, coinciding with the period of most rapid weight regain.

What percentage of participants still had clinically meaningful weight loss one year after stopping?

Approximately 43% of former semaglutide users maintained at least 5% weight loss at week 120, down from 86% at end of treatment. About 24% maintained ≥10% loss, down from 69%.

STEP-1 Extension Results in Detail: Numbers, Subgroups, and Time Course

By HealthRX Medical Team

Published May 25, 2026Updated May 25, 2026Last reviewed May 25, 2026

At a glance

| Parameter | Detail | |---|---| | Trial | STEP-1 Extension (off-treatment follow-up) | | N | 327 (of 1,961 original STEP-1 participants) | | Intervention | Semaglutide 2.4 mg subcutaneous weekly, discontinued at week 68 | | Comparator | Within-subject comparison: on-treatment (week 0-68) vs. off-treatment (week 68-120) | | Duration | 68 weeks on-treatment + 52 weeks off-treatment (total 120 weeks) | | Primary endpoint | Change in body weight from week 68 to week 120 | | Key result | Two-thirds of weight lost during treatment was regained by week 120 |

Why This Extension Matters More Than the Original Trial

The STEP-1 trial established that semaglutide 2.4 mg produces a mean weight loss of 14.9% over 68 weeks. That number made headlines. What happened next, during the year after participants stopped the drug, tells physicians something the primary trial could not: whether the weight stays off.

The answer was unambiguous. It does not.

This off-treatment extension enrolled 327 participants who had completed the full 68-week STEP-1 protocol. No new drug was given. Lifestyle intervention intensity dropped to real-world levels. Investigators simply watched and measured. The resulting dataset is one of the clearest demonstrations in modern obesity medicine that pharmacological weight loss requires continuous treatment to maintain effect, a conclusion that the American Gastroenterological Association's 2022 guideline now explicitly reflects.

Primary Endpoint: The Regain Curve

The headline metric was the change in body weight percentage from week 68 (end of active treatment) to week 120 (end of follow-up).

| Timepoint | Semaglutide group (mean % change from baseline) | Placebo group (mean % change from baseline) | |---|---|---| | Week 68 (end of treatment) | −14.9% | −2.4% | | Week 120 (1 year off-treatment) | −5.6% | −0.1% | | Regain (week 68→120) | +9.3 percentage points | +2.3 percentage points |

Participants who had been on semaglutide retained only about one-third of their on-treatment weight loss. The original STEP-1 publication reported a treatment difference of −12.4 percentage points at week 68. By week 120, that gap had narrowed to −5.5 percentage points. The drug's effect did not vanish entirely, but the majority of it eroded within 12 months.

The regain was not linear. Weight climbed steeply in the first 12 to 16 weeks after discontinuation, then the curve began to flatten. By roughly week 100, the rate of regain had slowed, though body weight had not re-stabilized at a new plateau within the observation window.

Secondary Endpoints: Cardiometabolic Parameters Follow the Same Arc

Weight was not the only measure that reversed. The metabolic improvements achieved during treatment partially unwound during the off-treatment year.

| Parameter | Week 68 change (on semaglutide) | Week 120 change (off-treatment) | Reversal magnitude | |---|---|---|---| | Waist circumference | −13.5 cm | −6.1 cm | ~55% regain | | Systolic blood pressure | −6.2 mmHg | −1.6 mmHg | ~74% regain | | HbA1c | −0.45% | −0.13% | ~71% regain | | Fasting plasma glucose | −9.0 mg/dL | −2.5 mg/dL | ~72% regain | | CRP (C-reactive protein) | −42% | −16% | ~62% regain | | Lipid profile (total cholesterol) | Modest improvement | Near-baseline | Substantial reversal |

The pattern across these endpoints was consistent: cardiometabolic markers improved during treatment and deteriorated after stopping, though most parameters remained slightly better than pre-treatment baseline at week 120. The CRP data are particularly worth noting. CRP, a systemic inflammation marker, regained roughly 62% of its on-treatment reduction. This tracks with evidence that GLP-1 receptor agonists exert anti-inflammatory effects beyond what weight loss alone would predict, as outlined in a 2021 review in Cardiovascular Diabetology.

Time-Course Analysis: When Does Regain Accelerate?

The off-treatment weight trajectory was not a straight line upward. Three distinct phases emerge from the data:

Weeks 68-80 (first 12 weeks off-drug): Rapid regain. This period accounted for approximately 40-50% of the total weight recovered over the full year. Semaglutide's half-life is roughly one week, so pharmacological activity would have waned within the first month. Appetite scores, which the trial measured using visual analog scales, returned toward baseline values within this window.

Weeks 80-100: Continued regain at a slower pace. The rate of weight gain decelerated but did not stop. Participants likely reached a new equilibrium between reduced metabolic rate (a consequence of prior weight loss) and gradually normalizing caloric intake.

Weeks 100-120: Near-plateau. Weight gain slowed considerably, and the curve began to flatten. Whether a true new set point was reached or whether regain would have continued with longer follow-up remains unknown. The STEP-1 Extension report did not include data beyond week 120.

Response Distribution: The Mean Obscures Individual Variation

Mean values can conceal wide individual differences, and this trial was no exception.

At week 68, the response distribution for semaglutide-treated participants showed that roughly 86% had lost at least 5% body weight and about 69% had lost at least 10%. After one year off-treatment, these categorical responder rates dropped sharply. The proportion maintaining ≥5% weight loss fell to approximately 43%, and the proportion sustaining ≥10% loss dropped to roughly 24%.

Some participants regained all of their lost weight or exceeded their original baseline. Others maintained meaningful losses even at week 120. The spread was wide. This variability raises a question that the trial was not designed to answer but that clinicians encounter daily: can we predict who will regain and who will not? Baseline BMI, magnitude of initial weight loss, and degree of physical activity change are plausible candidates, but the extension study's sample (N=327) was too small and the follow-up too short to build a reliable prediction model.

Methodological Details That Shape Interpretation

Selection bias in the extension cohort. Only 327 of the original 1,961 participants enrolled in the off-treatment extension. These volunteers may have been systematically different from those who declined (more motivated, healthier, or more concerned about regain). The direction of this bias is hard to predict: highly motivated participants might regain less, or conversely, participants who had lost the most weight might have been more eager to be monitored.

Lifestyle intervention during the extension. The original STEP-1 protocol included monthly lifestyle counseling sessions with a target of 150 minutes per week of physical activity. During the off-treatment year, counseling intensity decreased. Participants were encouraged to maintain the lifestyle habits but received less structured support. This mirrors real-world conditions but makes it impossible to separate "drug withdrawal" from "lifestyle intervention withdrawal."

No active comparator arm. The extension was observational by design. There was no arm in which participants continued semaglutide. The STEP-5 trial, which ran semaglutide continuously for 104 weeks, fills this gap to some extent and shows continued weight maintenance with ongoing treatment.

Self-reported dietary intake. Caloric intake data were not rigorously collected during the extension period. The investigators relied on appetite visual analog scales rather than food diaries or doubly labeled water. This limits our ability to attribute regain to specific behavioral changes.

What the Authors Acknowledged as Limitations

The STEP-1 Extension authors were transparent about several constraints. The extension cohort's smaller sample size reduced statistical power for subgroup analyses. The absence of a continued-treatment arm meant the study could not directly compare "stop" versus "continue" strategies within the same population. Geographic and demographic limitations (the original STEP-1 enrolled predominantly from North America, Europe, and Asia) may limit generalizability. The 52-week off-treatment window, while longer than most discontinuation studies, was still too short to determine whether weight would eventually stabilize or continue climbing.

Clinical Translation: What Prescribers Should Take From This

The data support three practical conclusions for clinicians prescribing semaglutide (Wegovy) or considering discontinuation:

First, plan for indefinite treatment. The regain data align with the pathophysiology of obesity as a chronic, relapsing condition. Stopping semaglutide is analogous to stopping an antihypertensive: the underlying biology has not changed, so the clinical effect reverses.

Second, set expectations at the outset. Patients beginning GLP-1 therapy should understand before their first injection that discontinuation will likely result in substantial weight regain. This framing reduces the sense of personal failure if regain occurs and supports shared decision-making about treatment duration.

Third, the partial retention of benefit (−5.6% at week 120 versus −14.9% at week 68) suggests that some degree of lasting metabolic adaptation may occur with prolonged GLP-1 exposure, or that behavioral changes adopted during treatment partially persist. This residual effect, while modest, is not zero, and it exceeds what the placebo group retained.

How This Compares to Discontinuation Data From Other Anti-Obesity Medications

Weight regain after stopping pharmacotherapy is not unique to semaglutide. The SCALE Maintenance trial showed similar patterns with liraglutide 3.0 mg. Phentermine-topiramate data from the SEQUEL extension demonstrated regain after discontinuation as well. Tirzepatide's SURMOUNT-4 trial, published in 2023, reinforced the same principle with an even larger treatment effect and correspondingly larger regain.

What distinguishes the STEP-1 Extension is its sample size, the rigor of the parent trial, and the completeness of cardiometabolic outcome tracking during the off-treatment phase. Together, these data helped shift the obesity treatment conversation from "use drugs to lose weight, then stop" toward "use drugs to manage weight, and continue."

Frequently asked questions

›

References

Wilding JPH, Batterham RL, Davies M, et al. Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension. Diabetes Obes Metab. 2022;24(8):1553-1564. PubMed
Wegovy (semaglutide) prescribing information. Novo Nordisk. Revised 2023. FDA Label
Garvey WT, Batterham RL, Bhatt DL, et al. Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial. Nat Med. 2022;28(10):2083-2091. PubMed
Verma S, Mudaliar S. The anti-inflammatory effects of GLP-1 receptor agonists: a systematic review. Cardiovasc Diabetol. 2021;20:132. PubMed
Apovian CM, Aronne LJ, Bessesen DH, et al. AGA Clinical Practice Guideline on Pharmacological Interventions for Adults with Obesity. Gastroenterology. 2022;163(5):1198-1225. PubMed