STEP 1: what the semaglutide 2.4 mg obesity trial actually found

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

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 [1]. That prediabetes result was an exploratory outcome, and its direction lines up with the trial's primary findings.

A subgroup of 140 people had DXA body-composition scans. Fat mass and visceral fat fell, and lean mass fell in kilograms while rising as a proportion of body weight [1]. That scan group is small, so read the fat-versus-lean split as a pointer rather than a breakdown.

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].

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 is still open

• 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.

What this means

HPR's position is that semaglutide 2.4 mg is a treatment you stay on, not a course you finish, and it should be prescribed, explained and paid for on that basis. In STEP 1 the drug did its job for as long as people kept injecting it: 14.9% average weight loss at 68 weeks, with the benefits tracking the injections [1]. When the injections stopped, about two-thirds of the loss came back within a year [2]. Read together, those two facts describe a maintenance therapy. We think that changes the question a patient should be asked before starting — not whether they can lose the weight, but whether they can keep taking this, and affording it, for years.

We would push back on two habits in how this trial gets quoted. The first is the bare "15%". Half of the semaglutide group lost at least 15%, and half did not [1]; the average was 14.9%. The second is treating the regain data as a verdict on the drug. It isn't — it is what stopping a maintenance treatment looks like, and the extension's own numbers show it [1][2].

Where we land: the case for semaglutide 2.4 mg in obesity is strong, and it is a long-term commitment, and we think those are the same statement rather than two competing ones. To disagree, a reader has to argue that a treatment whose effect reverses on withdrawal should still be sold and framed as a finite cure. We don't think the STEP 1 data carry that argument, and we would rather the conversation start from what is known: it works while you take it, in people without diabetes who largely stuck with it, and it stops working when you stop.

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.