STEP-8 Extension Data: What Happened After the Trial Ended

At a glance

Detail	Value
Trial	STEP-8 (NCT04074161)
N	338 adults with obesity (BMI ≥30) or overweight (BMI ≥27) with ≥1 comorbidity
Intervention	Semaglutide 2.4 mg SC once weekly
Active comparator	Liraglutide 3.0 mg SC once daily
Additional comparator	Placebo (matched to each active arm)
Treatment duration	68 weeks
Off-treatment follow-up	7 weeks (weeks 68 to 75)
Primary endpoint	Percentage change in body weight at week 68
Key result	Semaglutide: -15.8% vs liraglutide: -6.4% (estimated treatment difference: -9.4 percentage points, P<0.001)

Why Off-Treatment Data Matters More Than the Headline Number

The STEP-8 primary publication confirmed what many expected: once-weekly semaglutide 2.4 mg produced roughly 2.5 times more weight loss than once-daily liraglutide 3.0 mg over 68 weeks. That finding settled a clinical question about which injectable GLP-1 receptor agonist delivers greater efficacy for weight management.

But it also opened a different question. If semaglutide causes substantially more weight loss, does stopping it trigger proportionally more regain? The 7-week off-treatment observation period in STEP-8 was short, too short on its own to answer that question fully. It did, however, show an immediate and consistent upward weight trajectory in both arms once injections ceased. Longer follow-up data from sister trials in the STEP program fill in the picture.

The 7-Week Off-Treatment Window in STEP-8

STEP-8 included a protocol-specified 7-week follow-up after the 68-week treatment period. During this window, all participants discontinued their assigned medication while continuing the background lifestyle intervention (reduced-calorie diet plus 150 minutes per week of physical activity).

Even in just 7 weeks, measurable weight regain appeared in both groups. Participants who had been on semaglutide showed a steeper absolute rebound, consistent with their deeper nadir. Those on liraglutide also regained, though from a higher post-treatment weight. The trial's supplementary data document this trajectory in weekly weight measurements through week 75.

The clinical implication is direct. Neither drug produces durable weight loss after withdrawal. The biological set point, driven by persistent changes in appetite-regulating hormones like ghrelin, GLP-1, and peptide YY, reasserts itself within weeks of stopping therapy.

What the STEP-1 Extension Told Us About Semaglutide Withdrawal

STEP-8 itself was not designed with a long off-treatment extension. The most informative data on semaglutide 2.4 mg durability comes from the STEP-1 trial extension, published in Diabetes, Obesity and Metabolism in 2022. In that study, participants who had lost an average of 17.3% of body weight over 68 weeks of semaglutide treatment were followed for an additional year without the drug.

Results from the STEP-1 extension at one year off-treatment:

Two-thirds of the weight lost came back. Waist circumference followed the same pattern. Cardiometabolic improvements in blood pressure, lipids, and HbA1c also eroded, though not always to baseline levels. These data carry direct relevance for STEP-8 participants on semaglutide because the populations, dosing, and treatment durations were comparable.

Liraglutide Withdrawal: The SCALE Maintenance and Extension Data

For the liraglutide 3.0 mg arm, the closest long-term discontinuation data comes from the SCALE Obesity and Prediabetes trial extension. In that 3-year study, participants who stopped liraglutide after 56 weeks regained the majority of weight lost, while those who continued therapy maintained their losses.

A separate SCALE Maintenance trial examined what happened after an initial low-calorie diet run-in. Participants randomized to liraglutide after the run-in kept weight off; those on placebo regained it. The pattern is the same: liraglutide works while you take it, and weight returns when you stop.

Comparing the withdrawal curves across both drugs reveals a consistent biological signal. GLP-1 receptor agonists suppress appetite and reduce caloric intake through central mechanisms that reverse when the drug clears. The half-life difference (roughly one week for semaglutide vs 13 hours for liraglutide) means the withdrawal curve starts sooner with liraglutide, but the destination is similar.

Did the Semaglutide Advantage Persist Off-Treatment?

This is the question the field has not fully answered for STEP-8 specifically, because the off-treatment follow-up was only 7 weeks. But the available data from STEP-1 extension and SCALE extension suggest that the proportional regain is comparable across both drugs: roughly 60% to 70% of lost weight returns within 12 months of stopping.

That means the absolute gap narrows. If semaglutide patients lost 15.8% and regained ~67% of it, their net loss settles around 5.2% at one year. If liraglutide patients lost 6.4% and regained ~65%, their net loss settles around 2.2%. Semaglutide still wins on net retained weight loss, but the clinical difference shrinks from 9.4 percentage points on-treatment to roughly 3 percentage points off-treatment.

This arithmetic matters for cost-effectiveness analyses and for patients deciding whether to commit to indefinite therapy. The FDA label for semaglutide (Wegovy) does not specify a treatment duration, implicitly acknowledging that the drug is meant for chronic use.

Safety Signals That Emerged Over Time

The STEP-8 publication reported that gastrointestinal adverse events were more common with semaglutide (84.1% of participants reported at least one) than with liraglutide (72.3%). Nausea, diarrhea, constipation, and vomiting accounted for the majority. Most were mild to moderate and occurred during dose escalation.

Longer-term pharmacovigilance data from post-marketing surveillance and the broader STEP program have identified additional signals worth noting:

The lean mass loss finding is particularly relevant to the extension discussion. Participants who regain weight off-treatment tend to regain more fat than lean tissue, resulting in a less favorable body composition than at baseline. This "fat overshooting" phenomenon has been described in weight cycling literature for decades and applies regardless of the method used to lose weight initially.

STEP-4: The Continuation vs Withdrawal Experiment

The most elegant durability test in the STEP program came from STEP-4, published in JAMA in 2021. All participants received semaglutide 2.4 mg for 20 weeks, then were randomized to either continue or switch to placebo for another 48 weeks.

The results were stark. Continuers lost an additional 7.9% of body weight (total: -17.4% at week 68). Switchers regained 6.9% from their week-20 nadir, ending at -5.0% from baseline. The weight trajectories diverged within 4 weeks of randomization and continued separating through the end of the study.

STEP-4 provides the strongest within-trial evidence that semaglutide's benefits require ongoing treatment. It is the study clinicians most often cite when explaining to patients why this is not a "course of treatment" but an ongoing prescription, similar to statins for cholesterol or antihypertensives for blood pressure.

What This Means for Clinical Practice

Three practical takeaways emerge from the STEP-8 data and its surrounding evidence base.

First, the head-to-head superiority of semaglutide over liraglutide is real but contingent on continued treatment. Stopping either drug leads to substantial regain. The 2022 AGA clinical practice guideline on pharmacological interventions for obesity reflects this by recommending long-term pharmacotherapy for patients who respond, rather than time-limited courses.

Second, the 7-week off-treatment period in STEP-8 was too short to draw durable conclusions. It was designed as a washout for safety assessment, not as a maintenance study. Patients and clinicians should not interpret the week-75 data point as representing a stable post-treatment weight.

Third, the conversation about GLP-1 agonists for obesity needs to include the plan for discontinuation, or the plan not to discontinue. Patients who start semaglutide with the expectation of a finite treatment course should understand that the evidence strongly predicts regain. Those who commit to chronic therapy should understand the cost, injection burden, and gastrointestinal side effect profile over years, not months.

Limitations of the Available Follow-Up Evidence

STEP-8 was not powered or designed for long-term off-treatment outcomes. The 7-week washout captured the initial slope of regain but nothing about where weight stabilizes.

The STEP-1 extension cohort was a subset of the original trial population, introducing potential selection bias (participants willing to continue follow-up may differ systematically from those who dropped out). Weight was self-reported at some off-treatment visits, reducing measurement precision.

No head-to-head extension directly compared long-term outcomes of semaglutide withdrawal vs liraglutide withdrawal. The cross-trial comparisons presented here rely on similar but not identical populations, protocols, and measurement schedules.

Finally, the longest available off-treatment data for semaglutide 2.4 mg extends to roughly 52 weeks after cessation. Whether a new equilibrium is reached at that point or whether further regain continues beyond one year remains unknown.

Frequently asked questions

›How much weight did STEP-8 participants regain after stopping semaglutide?

During the 7-week off-treatment period, both semaglutide and liraglutide groups showed early weight regain. Longer data from the STEP-1 extension trial showed approximately 68% of lost weight returned within one year of stopping semaglutide 2.4 mg. No STEP-8-specific long-term off-treatment data has been published beyond week 75.

›Was STEP-8 designed to study long-term outcomes after treatment?

No. STEP-8 included a 7-week post-treatment observation mainly for safety washout purposes. It was not powered or structured to evaluate durable weight maintenance off-treatment. The STEP-1 extension and STEP-4 trials provide stronger evidence on durability.

›Does the semaglutide advantage over liraglutide last after both drugs are stopped?

The absolute gap narrows substantially. On-treatment, the difference was 9.4 percentage points of body weight. Based on cross-trial extension data, the net retained weight loss difference shrinks to roughly 3 percentage points after one year without either drug, since both groups regain 60% to 70% of what they lost.

›Is weight regain after GLP-1 agonists worse than weight regain after dieting?

The proportional regain (60% to 70% within a year) is comparable to what is seen after caloric-restriction-only approaches. The difference is that GLP-1 agonists produce deeper initial losses, so the absolute amount regained is larger. The underlying biology, including hormonal adaptation to reduced body weight, is the same.

›Do cardiometabolic improvements from semaglutide persist after stopping?

Partially. The STEP-1 extension showed that improvements in blood pressure, lipid levels, and HbA1c eroded during the off-treatment year, though some markers remained slightly better than baseline. The degree of erosion correlated with the amount of weight regained.

›Did STEP-4 prove semaglutide needs to be taken indefinitely?

STEP-4 showed that switching from semaglutide to placebo after 20 weeks led to significant weight regain, while continuing treatment produced additional loss. This is the strongest evidence that benefits require ongoing use, though "indefinitely" remains a policy and cost question, not a biological certainty.

›What happens to muscle mass when patients regain weight after stopping semaglutide?

Weight regained after stopping GLP-1 therapy is disproportionately fat rather than lean tissue. This "fat overshooting" results in a body composition that may be less favorable than before treatment. Resistance training during and after treatment may partially mitigate this, though no randomized trial has tested that specific intervention in the STEP population.

›Are there ongoing trials studying longer-term outcomes from STEP-8?

No STEP-8-specific extension trial has been registered or published. The SELECT cardiovascular outcomes trial (semaglutide 2.4 mg in patients with established cardiovascular disease and overweight/obesity) provides the longest-duration efficacy and safety data for this dose, with a median follow-up exceeding 3 years.

›Should patients plan to take semaglutide for life based on these results?

Current guidelines from the AGA and the Endocrine Society recommend long-term pharmacotherapy for patients who achieve clinically meaningful weight loss (≥5%). The decision to continue indefinitely involves weighing efficacy, cost, side effects, and individual patient values. Discontinuation should include a plan for close weight monitoring and intensified lifestyle support.

›How does the STEP-8 off-treatment data compare to tirzepatide withdrawal data?

The SURMOUNT-4 trial showed a similar pattern with tirzepatide: participants randomized to placebo after 36 weeks of treatment regained roughly 14 percentage points of body weight over the next 52 weeks. The proportional regain pattern appears to be a class-wide phenomenon for incretin-based therapies, not specific to any single agent.

References

1. Rubino DM, Greenway FL, Khalid U, et al. Effect of weekly subcutaneous semaglutide vs daily liraglutide on body weight in adults with overweight or obesity without diabetes: the STEP 8 randomized clinical trial. JAMA. 2022;327(2):138-150. PubMed
2. 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
3. Rubino D, Abrahamsson N, Davies M, et al. Effect of continued weekly subcutaneous semaglutide vs placebo on weight loss maintenance in adults with overweight or obesity: the STEP 4 randomized clinical trial. JAMA. 2021;325(14):1414-1425. PubMed
4. le Roux CW, Astrup A, Fujioka K, et al. 3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes (SCALE Obesity and Prediabetes). Lancet. 2017;389(10077):1399-1409. PubMed
5. Wegovy (semaglutide) prescribing information. U.S. Food and Drug Administration. FDA Label
6. Garvey WT, et al. AGA clinical practice guideline on pharmacological interventions for adults with obesity. Gastroenterology. 2022;163(5):1198-1225. PubMed