Key facts
- Drug / target: semaglutide, a GLP-1 receptor agonist; administered as 2.4 mg once weekly by subcutaneous injection, versus placebo, both with lifestyle intervention.
- Sponsor: Novo Nordisk.
- Design: randomized, double-blind, placebo-controlled, phase 3 (randomized 2:1 to semaglutide or placebo).
- Population + n: 1,961 adults with overweight or obesity (BMI ≥ 30, or ≥ 27 with a weight-related condition) without diabetes.
- Duration: 68 weeks of treatment.
- Primary endpoint: percentage change in body weight from baseline to week 68 (co-primary: proportion reaching ≥ 5% loss).
- Headline result: −14.9% with semaglutide vs −2.4% with placebo (a 12.4-percentage-point difference).
- Registration: NCT03548935 (ClinicalTrials.gov).
- Publication: New England Journal of Medicine, 2021 — PubMed 33567185.
What was the STEP 1 trial?
STEP 1 was the pivotal phase 3 study of semaglutide for weight management — the trial that turned a diabetes drug into the reference standard for obesity pharmacotherapy.
Its full name is Semaglutide Treatment Effect in People with Obesity, and it was the first trial in the STEP program, sponsored by Novo Nordisk and registered as NCT03548935. The design was a randomized, double-blind, placebo-controlled phase 3 trial: participants were randomized in a 2:1 ratio to receive either semaglutide 2.4 mg once weekly or matching placebo, and neither participants nor investigators knew who was in which group. Both arms received the same lifestyle intervention, so the difference between them isolates the drug effect. The primary results were published in the New England Journal of Medicine in 2021 (PMID 33567185).
Who was in it?
STEP 1 enrolled 1,961 adults with overweight or obesity. Eligibility required a body-mass index of 30 or higher, or 27 or higher in people with at least one weight-related coexisting condition such as hypertension or dyslipidemia. Crucially, the trial excluded people with diabetes — a deliberate design choice, because weight loss is typically harder to achieve when diabetes is present, and Novo Nordisk wanted a clean read on the weight effect in an overweight-or-obese population without that complication. Semaglutide in people who also have type 2 diabetes was tested separately in STEP 2.
Because both groups also followed a reduced-calorie diet and increased physical activity, STEP 1 measured what semaglutide added on top of lifestyle change rather than the drug in isolation — the same framing used across the modern weight-loss peptide trials.
What did participants receive?
Participants in the active arm received semaglutide 2.4 mg once weekly by subcutaneous injection. The dose was not started at 2.4 mg; it was reached through a gradual escalation schedule over the opening weeks, a standard approach for this drug class intended to reduce the gastrointestinal side effects that are worst during titration. The comparator arm received a matching placebo injection on the same schedule, and every participant received structured lifestyle counseling.
Stating what the trial administered is simply reporting the study. It is not a recommendation, a protocol, or dosing guidance for any reader — how and whether semaglutide is used is a clinical decision. The active ingredient here is the same one later marketed for weight management as Wegovy; the mechanism is covered in our semaglutide research summary.
Primary results
The headline result is the one every newer obesity drug is now measured against. At week 68, the semaglutide group had lost a mean 14.9% of body weight, compared with 2.4% on placebo — a treatment difference of 12.4 percentage points. In absolute terms that was roughly 15.3 kg versus 2.6 kg, a difference of about 12.7 kg (PMID 33567185).
The responder analysis tells the same story from a different angle. The share of participants reaching each weight-loss threshold was far higher on semaglutide than on placebo:
| Outcome at week 68 | Semaglutide 2.4 mg | Placebo |
|---|---|---|
| Mean change in body weight | −14.9% | −2.4% |
| Mean absolute change | −15.3 kg | −2.6 kg |
| Reached ≥ 5% weight loss | 86.4% | 31.5% |
| Reached ≥ 10% weight loss | 69.1% | 12.0% |
| Reached ≥ 15% weight loss | 50.5% | 4.9% |
Put plainly, about half of the semaglutide group lost at least 15% of their body weight, and roughly a third reached at least 20% — magnitudes that had not been seen with a non-surgical treatment before this trial.
Secondary results
Beyond the scale, STEP 1 tracked a set of cardiometabolic and patient-reported secondary endpoints, and these moved in the same favorable direction as weight. Compared with placebo, the semaglutide group showed greater improvements in waist circumference, systolic blood pressure, glycated hemoglobin (HbA1c) and C-reactive protein, a marker of inflammation, along with a greater improvement in self-reported physical functioning (PMID 33567185).
These are reported here qualitatively and by direction of effect. The trial's own analysis is the authoritative source for the exact secondary-endpoint figures, and this summary does not assign numbers to them beyond what the primary weight results state above.
Safety and side effects reported
The safety picture in STEP 1 matches what has since become familiar for this drug class. The most common adverse events were gastrointestinal — chiefly nausea and diarrhea — and they were typically transient and mild to moderate in severity, most intense while the dose was being escalated. Gastrointestinal events led about 4.5% of the semaglutide group to discontinue treatment, versus 0.8% on placebo (PMID 33567185).
This is a summary of adverse events reported in a controlled trial, not a safety assessment for any individual and not a complete list of the drug's warnings. The full label carries additional cautions and contraindications that a prescriber weighs before treatment.
Limitations and what it does not prove
STEP 1 is a strong trial, but reading it well means noting what it did and did not establish.
- Duration. The core trial ran 68 weeks. It does not, on its own, describe outcomes over many years of continuous use.
- Weight, not events. The primary endpoint was weight change, not hard clinical outcomes such as heart attack or stroke. That cardiovascular question was answered by a different trial, SELECT, not by STEP 1.
- Population. Participants had overweight or obesity and no diabetes, so the results do not transfer directly to people with type 2 diabetes, who were studied in STEP 2 and generally show smaller mean loss.
- Durability. The main paper reports weight change on treatment. A separate STEP 1 extension found that most of the lost weight returned within a year of stopping — evidence that the effect depends on continued use.
- Averages hide spread. Every figure here is a mean; individual responses in the trial ranged widely, and a trial average is not a personal forecast.
Why the STEP 1 trial matters
STEP 1 reset expectations for what a medication could do for body weight. Before it, drug-based weight loss was generally measured in single-digit percentages; STEP 1 put a mean of about 15% on the table in a rigorous phase 3 design, with roughly half of participants losing 15% or more. It was the evidentiary backbone of semaglutide's approval as Wegovy for weight management, and it became the benchmark that later molecules are compared against — including tirzepatide, which was tested head-to-head with semaglutide in SURMOUNT-5 (see our tirzepatide vs semaglutide comparison).
It also framed how the whole class is now understood: highly effective while taken, paired with gastrointestinal side effects during dose escalation, and dependent on continued use to hold the result. For anyone following the research, STEP 1 is the trial the rest of the field is written in reference to. Explore more landmark studies in the PepMate research library.
Frequently asked questions
What was the STEP 1 trial?
STEP 1 was a randomized, double-blind, placebo-controlled phase 3 trial sponsored by Novo Nordisk that tested once-weekly semaglutide 2.4 mg against placebo, both alongside lifestyle intervention, over 68 weeks. It enrolled 1,961 adults with overweight or obesity who did not have diabetes, and its primary results were published in the New England Journal of Medicine in 2021.
How much weight did people lose in STEP 1?
At week 68 the semaglutide group had lost a mean 14.9% of body weight versus 2.4% on placebo, a treatment difference of 12.4 percentage points, which corresponds to about 15.3 kg versus 2.6 kg. These are mean changes from the trial, not a result any individual should expect.
What dose of semaglutide was used in STEP 1?
Participants in the active arm received semaglutide 2.4 mg once weekly by subcutaneous injection, reached through a gradual dose-escalation schedule intended to limit gastrointestinal side effects. Reporting the dose the trial administered is not dosing guidance; PepMate does not prescribe or recommend any regimen.
Who was eligible for the STEP 1 trial?
STEP 1 enrolled adults with a body-mass index of 30 or higher, or 27 or higher with at least one weight-related coexisting condition, who did not have diabetes. Both groups also received a reduced-calorie diet and increased physical activity, so the trial measured the drug effect on top of lifestyle change.
What were the main side effects in STEP 1?
Gastrointestinal effects were the most common, chiefly nausea and diarrhea, and were typically transient and mild to moderate. Gastrointestinal events led about 4.5% of the semaglutide group to discontinue treatment versus 0.8% on placebo. This summarizes reported trial data and is not a safety assessment for any individual.
Did STEP 1 include people with diabetes?
No. STEP 1 deliberately excluded people with diabetes to measure semaglutide's effect on body weight in adults with overweight or obesity alone. Semaglutide in people who also have type 2 diabetes was studied separately in STEP 2, which generally reports smaller mean weight loss than STEP 1.
Does STEP 1 show what happens after stopping semaglutide?
The main 68-week STEP 1 paper reports weight change while participants stayed on treatment. A separate STEP 1 extension analysis followed people after they stopped and found most of the lost weight was regained within a year, which is why clinicians frame these drugs as long-term therapy rather than a fixed course.
Sources
This summary traces to the trial's peer-reviewed publication and its registration:
- Wilding JPH, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021 — PubMed 33567185
- STEP 1 trial registration — ClinicalTrials.gov NCT03548935
- Drug reference record: semaglutide.