STEP-4: What Happens When You Stop
Last verified May 2026 · Phase 3a · Finished; published April 2021 · NCT03548987 ↗
Most drug trials compare treatment against placebo from the start. STEP-4 did something more pointed: it took people who had already responded, and removed the drug from half of them. That design isolates the question every patient eventually asks — is this permanent? — and answers it without the confounding that makes observational follow-up hard to read. The regain was not total within the trial window, and the divergence between the arms was steady rather than sudden. But the direction was unambiguous, and it has held up in the longer STEP-1 extension data since.
- Enrollment
- 803
- Duration
- 68 weeks in all: everyone spent 20 weeks getting up to 2.4 mg, then 48 weeks either continuing or on placebo, with observation running to week 75
- Drug
- Semaglutide 2.4 mg (Wegovy)
- Population
- Adults 18 and over with a BMI of 30 or more — or 27 or more if a weight-related condition came with it, meaning high blood pressure, abnormal cholesterol, sleep apnea or heart disease — and no diabetes. Of the 803 who reached randomization: average age 46, 79% women, average weight at that point 107.2 kg, 84% white. The run-in had already taken a mean 10.6% off them. Run across 73 sites in 10 countries between June 2018 and March 2020.
Primary endpoint
What happened to body weight over the 48 weeks after half the group lost the drug
Treatment arm
−7.9%
Comparator
+6.9%
Treatment difference: Estimated treatment difference −14.8 percentage points (95% CI −16.0 to −13.5; P<0.001)
★ This is the cleanest number on the site for the stopping question. Same people, same starting point, one variable changed: those who kept taking it lost another 7.9%, those switched to placebo put 6.9% back on. The gap between staying and stopping is nearly 15 percentage points inside a single year.
Secondary endpoints
| Endpoint | Treatment | Comparator | Difference |
|---|---|---|---|
| The same thing measured in kilograms About 13 kg — 29 pounds — separating the two groups after 48 weeks. The lines start pulling apart within weeks of the switch and never reconverge. | −7.5 kg | +5.7 kg | Net difference of roughly −13 kg between arms over 48 weeks of maintenance |
| Waist measurement Held on the drug, partly rebuilt off it. Belly fat follows total weight in both directions. | −6.9 cm | +3.2 cm | Estimated treatment difference −9.7 cm (95% CI −10.9 to −8.5; P<0.001) |
| Top blood-pressure number ⚠ Unchanged on the drug and up 5 points off it. The blood-pressure benefit from the run-in was gone within 48 weeks of stopping — worth knowing if a prescription was adjusted while you were losing weight. | 0 mmHg | +5 mmHg | Estimated treatment difference −3.9 mmHg (95% CI −5.8 to −2.0; P<0.001) |
| How people rated their own physical functioning Still improving on the drug, going backwards off it. Whatever was gained in day-to-day capability tracked the weight. | +1.0 point | −1.2 points | Estimated treatment difference +2.5 points (95% CI 1.6 to 3.3; P<0.001) |
| Still at least 5% below their original starting weight at the end ★ Nearly half the people who stopped were still below where they started, which is the honest counterweight to the headline. But the proportion holding any meaningful loss collapsed against those who continued. | 88.7% (461/520) | 47.6% (119/250) | Stark divergence in who held the run-in result through 48 weeks of maintenance. |
| Still at least 10% below their original starting weight Four times as many held a 10% loss by continuing — 79.0% against 20.4%. | 79.0% (411/520) | 20.4% (51/250) | Roughly 4× more participants on continued semaglutide held a clinically meaningful weight loss through trial end. |
| Still at least 15% below their original starting weight ⛔ Seven times as many. The threshold people reach for when comparing these drugs to surgery essentially disappeared in the group that stopped. | 63.7% (331/520) | 9.2% (23/250) | Roughly 7× more participants on continued semaglutide held a ≥15% loss through trial end. |
| Three-month average blood sugar ⚠ Nobody here had diabetes, so this moves inside the normal-to-prediabetic band. The direction matches everything else: preserved on the drug, slipping off it. | −0.2 | +0.1 | Glycemic gains from run-in preserved on continued semaglutide; small reversal on placebo. |
| Blood sugar after an overnight fast About 9 mg/dL apart between the groups — flat on the drug, rising off it. | −1.1 mg/dL | +7.6 mg/dL | Net difference of about 9 mg/dL between arms. |
| How many simply gained weight over those 48 weeks ⛔ The plainest row in the table: more than four in five of the people who stopped gained weight, against roughly one in six of those who continued. Stopping does not mean holding steady — for most people it means going back up. | 15.2% (79/520) | 82.4% (206/250) | Direction of weight change reverses cleanly when treatment is withdrawn. |
Adverse events
| Event | Treatment rate | Comparator rate |
|---|---|---|
| Any stomach or bowel problem, during the 48 weeks after randomization Most were mild to moderate, and they faded in the group whose drug was withdrawn as it cleared their system. | 49.1% (continued semaglutide) | 26.1% (switched to placebo) |
| Nausea, during the 48 weeks after randomization ★ Compare against the run-in: 46.8% of the full starting cohort felt nauseated while the dose was being raised. Once people are settled at the maintenance dose the rate is a third of that. Side effects front-load. | 14.0% (75/535) | 4.9% (13/268) |
| Diarrhea, during the 48 weeks after randomization Twice the placebo rate, and far below what the same people reported during titration. | 14.4% (77/535) | 7.1% (19/268) |
| Vomiting, during the 48 weeks after randomization About one in ten on the drug against 3% off it. | 10.1% (54/535) | 3.0% (8/268) |
| Constipation, during the 48 weeks after randomization Roughly twice the placebo rate. | 11.6% (62/535) | 6.0% (16/268) |
| Headache, during the 48 weeks after randomization Uncommon, and about double the placebo rate. | 7.7% (41/535) | 3.7% (10/268) |
| Gallstones, counted as a serious event Gallstones are a known consequence of losing weight quickly however it happens. The numbers here were small in both groups. | 0.9% (5/535) | 0.7% (2/268) |
| Quit the drug for good over a side effect ★ Effectively identical in both arms, and the reason is a design artifact worth understanding: anyone who could not tolerate the drug had already dropped out during the 20-week run-in, before randomization. This trial's tolerability figures describe people already known to tolerate it. | 2.4% | 2.2% |
| Any serious adverse event, during the 48 weeks after randomization Slightly lower on the drug than off it, with nothing clustering in one body system. One death occurred in the continuing group and was independently judged unrelated to the drug. | 5.2% (28/535) | 5.6% (15/268) |
Clinical significance
This is the trial with the most direct bearing on money. If treatment is indefinite, then the number that matters is not the first month's promotional rate but the standing monthly price multiplied by years, and a seller's billing cycle and cancellation terms become part of the clinical picture rather than fine print. ⛔ It also reframes the marketing language you will encounter: a 'program' with an end date is describing a commercial arrangement, not a treatment plan. Nothing here says stopping is wrong — plenty of people stop for good reasons — but it does mean stopping should be a decision rather than a surprise.
Who sells semaglutide, and for how much
This trial tested Semaglutide 2.4 mg (Wegovy). Across the 556 sellers on this register, 283 publish a standing monthly cash price for compounded semaglutide, from $79 a month, with a median of $174.
⛔ None of those sellers was in this trial. A compounded preparation is not the product studied here: no agency has reviewed that specific preparation for safety, effectiveness or manufacturing quality, and its concentration is set by whichever pharmacy filled it. The result above is the strongest evidence available for semaglutide and it was generated on something else. Every seller, with its price record.
Frequently Asked Questions
References
- 1.Rubino D, Abrahamsson N, Davies M, et al.; STEP 4 Investigators. 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. PMID: 33755728.
- 2.Novo Nordisk A/S. Study Results: Effect and Safety of Semaglutide 2.4 mg Once-weekly in Subjects With Overweight or Obesity Who Have Reached Target Dose During Run-in Period (STEP 4, NCT03548987). ClinicalTrials.gov. 2022. https://clinicaltrials.gov/study/NCT03548987?tab=results
- 3.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. PMID: 35441470.
- 4.Aronne LJ, Sattar N, Horn DB, et al.; SURMOUNT-4 Investigators. Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial. JAMA. 2024. PMID: 38078870.