STEP 1: what the semaglutide 2.4 mg obesity trial actually found
Weekly semaglutide cut body weight by 14.9% over 68 weeks against 2.4% on placebo. Most of that came back within a year of stopping.
In STEP 1, adults with obesity who injected semaglutide 2.4 mg once a week for 68 weeks lost an average of 14.9% of their body weight, against 2.4% for people on placebo injections who got the same diet and exercise counselling [1]. Half of the semaglutide group lost at least 15%. The catch showed up a year later: people who stopped regained about two-thirds of what they had lost [2].
Why this study matters
STEP 1 is the trial that moved semaglutide from a diabetes drug to a weight-loss drug. The US Food and Drug Administration approved semaglutide 2.4 mg as Wegovy on 4 June 2021 [3], a few months after the results appeared in the New England Journal of Medicine [1]. Nearly every “GLP-1 weight loss” figure you see quoted, including the famous 15%, traces back to this paper.
It's also a useful paper to read closely because the headline number depends on a statistical choice that's easy to miss, and because the follow-up tells you something the headline doesn't.
What they did
The trial randomised 1,306 people to semaglutide and 655 to placebo [1]. Everyone had counselling every four weeks aimed at a 500-kcal daily deficit and 150 minutes of activity a week. People with diabetes were excluded; so were people who'd had bariatric surgery or used a weight-loss drug in the previous 90 days [1].
The average participant was 46, weighed 105.3 kg and had a BMI of 37.9. Almost three-quarters (74.1%) were women, 75.1% were White, and 43.7% had prediabetes [1].
The two co-primary outcomes were the percentage change in weight at week 68 and the share of people who lost at least 5%. For reading the results, this matters: the main analysis counted everyone who was randomised, including people who stopped their injections partway through. The trial calls this the treatment policy estimand; in plain terms, it's closer to “what happens when you prescribe this” than “what happens if everyone takes it perfectly” [1].
What they found
| Outcome at week 68 | Semaglutide | Placebo |
|---|---|---|
| Mean weight change | −14.9% (−15.3 kg) | −2.4% (−2.6 kg) |
| Lost 5% or more | 86.4% | 31.5% |
| Lost 10% or more | 69.1% | 12.0% |
| Lost 15% or more | 50.5% | 4.9% |
| Waist change | −13.5 cm | −4.1 cm |
The treatment difference was 12.4 percentage points (95% CI −13.4 to −11.5), with p below 0.001 [1]. Blood pressure, HbA1c, fasting glucose, C-reactive protein and blood lipids all moved more in the semaglutide group, and self-rated physical functioning improved more too [1]. Among people who started with prediabetes, 84.1% on semaglutide had normal blood sugar by week 68, compared with 47.8% on placebo; that was an exploratory outcome, so treat it as a signal rather than a proof [1].
A subgroup of 140 people had DXA body-composition scans. Fat mass and visceral fat fell. Lean mass also fell in kilograms, though it rose as a proportion of body weight [1]. The paper doesn't settle how much of the weight lost was muscle, and 140 people isn't many.
Side effects
Adverse events of any kind were common in both arms (89.7% on semaglutide, 86.4% on placebo), which is normal for a 68-week trial where every headache gets logged [1]. The difference was in the gut: 74.2% of semaglutide users reported gastrointestinal events against 47.9% on placebo, mostly nausea, diarrhoea, vomiting and constipation. The authors describe these as mostly mild to moderate and transient [1].
Serious adverse events were reported in 9.8% versus 6.4%, a gap driven mainly by serious gastrointestinal problems (1.4% vs 0%) and gallbladder and liver problems (1.3% vs 0.2%) [1]. Gallbladder disorders, mostly gallstones, affected 2.6% versus 1.2%. Three people on semaglutide developed mild acute pancreatitis; all recovered [1]. Some 7.0% stopped semaglutide because of side effects, against 3.1% on placebo [1].
Caveats
- Who paid. Novo Nordisk, which makes semaglutide, designed the trial, monitored the sites, collected the data and ran the analysis. A sponsor-funded medical writer helped draft the paper [1]. That's standard for a licensing trial, and the NEJM peer review is serious, but it is not independent research.
- Who took part. Mostly White women in their mid-40s, with no diabetes. The authors themselves list the preponderance of women and White participants as a limitation, and add that volunteers for a weight-loss trial may be more committed than the average patient [1].
- Retention was good. 94.3% completed the trial and 81.1% stuck to treatment [1], so dropouts are unlikely to explain the result.
- Sixty-eight weeks. That's long for a weight-loss trial and short for a condition people live with for decades.
What happens when you stop
After week 68, everyone stopped the injections and the lifestyle programme. A subset of 327 people from selected sites was followed for another year [2]. In this group, the semaglutide arm had lost 17.3% by week 68. By week 120 they had regained 11.6 percentage points of it, leaving a net loss of 5.6%. Blood pressure, blood sugar and lipid improvements also drifted back towards baseline [2].
participants regained two-thirds of their prior weight loss, with similar changes in cardiometabolic variables
The extension analyses were exploratory and covered only a sixth of the original trial [2], so the exact figure is soft. The direction isn't.
What it means in practice
STEP 1 shows that semaglutide 2.4 mg, alongside diet and activity support, produces weight loss well beyond what counselling alone achieved in this trial, and that the benefit holds for as long as people keep taking it. It also shows the effect behaves like a treatment that works while you're on it, not a cure. Anyone quoting “15% weight loss” without the second half of that sentence is telling you half the story.
What we still don’t know
- How the results translate to people with type 2 diabetes, older adults and more ethnically varied groups, who were under-represented here.
- Whether the lean mass lost matters for strength or function over years, given DXA covered only 140 people.
- The best way to stop, taper or maintain, since the extension tested only abrupt withdrawal of both drug and lifestyle support.
- Whether weight loss of this size translates into fewer heart attacks and strokes; STEP 1 wasn't designed to answer that.
Educational content only — not medical advice. Many peptides discussed on HPR are not approved for human use. Talk to a qualified clinician before making any decision about your health.
Join the next webinar: Introduction to Peptides
with Mitch O’Callaghan, ISSCA Peptide Therapist · Founder, Proper Protocols
References
- [1]Wilding JPH, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, et al.. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med 2021. doi:10.1056/NEJMoa2032183
- [2]Wilding JPH, Batterham RL, Davies M, Van Gaal LF, Kandler K, Konakli K, et al.. Weight regain and cardiometabolic effects after withdrawal of semaglutide: the STEP 1 trial extension. Diabetes Obes Metab 2022. doi:10.1111/dom.14725
- [3]US Food and Drug Administration. Drugs@FDA: Wegovy (semaglutide), NDA 215256. Drugs@FDA database 2021. www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=215256
Keep reading
Retatrutide: what the trials show so far, and what is still a press release
Peer-reviewed trials show 24% weight loss at 48 weeks and large falls in liver fat; the headline 28% phase 3 figure is still company-reported.
Cagrilintide and CagriSema: what the amylin trials found
Alone, cagrilintide cut weight by about 11% in 26 weeks; paired with semaglutide it reached 20% at 68 weeks, but lost a head-to-head against tirzepatide.
SELECT: semaglutide cut major heart events by 20% in people who already had heart disease
In 17,604 adults with obesity and existing cardiovascular disease but no diabetes, semaglutide lowered major cardiac events from 8.0% to 6.5% over about three years.