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:

| Metric | End of treatment (week 68) | One year off-treatment (week 120) | |---|---|---| | Mean weight change from baseline | -17.3% | -5.6% | | Weight regained (of amount lost) | -- | ~68% | | Waist circumference change from baseline | -13.5 cm | -5.1 cm | | Participants who maintained ≥10% weight loss | ~69% | ~19% | | Participants who returned to within 5% of baseline weight | ~10% | ~44% |

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:

| Safety concern | Evidence status | |---|---| | Pancreatitis | Rare; rates consistent across GLP-1 class. No signal of increased risk vs background | | Gallbladder events (cholelithiasis, cholecystitis) | Dose-dependent increase observed. Rapid weight loss is a known risk factor | | Thyroid C-cell tumors | Rodent signal (not replicated in primates). Contraindicated in patients with personal/family history of medullary thyroid carcinoma or MEN2 | | Suicidal ideation | EMA and FDA reviews found no causal signal as of 2024. Monitoring continues | | Muscle mass loss | 25% to 40% of total weight lost is lean mass. Not unique to GLP-1 agents; reflects caloric deficit physiology |

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

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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