STEP-1: The Trial That Set the Semaglutide Benchmark
Last verified May 2026 · Phase 3 · Finished; published February 2021 · NCT03548935 ↗
Before STEP-1, drugs for obesity delivered single-digit percentages and carried reputations that made prescribers cautious. This trial reported a mean 14.9% loss over 68 weeks and changed the conversation in a way the field is still absorbing. The design was plain: weekly semaglutide 2.4 mg against placebo, lifestyle counseling in both arms, in adults whose BMI cleared 30, or cleared 27 with a weight-related condition alongside it, and with type 2 diabetes ruled out. That exclusion matters when you compare this result against trials that enrolled people with diabetes, where weight loss is consistently smaller. What STEP-1 does not tell you is what happens when treatment stops; STEP-4 answered that separately, and the answer was not reassuring for anyone planning a finite course.
- Enrollment
- 1,961
- Duration
- 68 weeks on treatment, then a 7-week gap off the drug before a final week-75 check
- Drug
- Semaglutide 2.4 mg (Wegovy)
- Population
- Adults 18 and over with a BMI of 30 or more, or 27 or more alongside a weight-related condition — high blood pressure, abnormal cholesterol, sleep apnea or heart disease. Type 2 diabetes ruled you out, as did an HbA1c of 6.5% or higher at screening. ⚠ The group that enrolled was 74% women and 75% white, averaging 46 years old, 105.3 kg and a BMI of 37.9. Recent weight-loss drugs and recent bariatric surgery were also exclusions, so this is a drug-naive population.
Primary endpoint
How much body weight came off over 68 weeks
Treatment arm
−14.9%
Comparator
−2.4%
Treatment difference: Estimated treatment difference −12.4 percentage points (95% CI −13.4 to −11.5; P<0.001)
There was a second half to the primary endpoint that gets quoted less: losing at least 5% of body weight, which 86.4% of the drug group managed against 31.5% on placebo. ★ Note that nearly a third of placebo participants cleared 5% too — monthly counseling and a calorie deficit are doing real work in both arms.
Secondary endpoints
| Endpoint | Treatment | Comparator | Difference |
|---|---|---|---|
| Lost a tenth of their body weight or more Roughly seven in ten cleared 10%, against one in eight on placebo. | 69.1% (838/1,212) | 12.0% (69/577) | Odds ratio favoring semaglutide; P<0.001 |
| Lost at least 15% of their body weight ★ Half the treated group got here — the point where drug results start to overlap the lower end of what sleeve gastrectomy delivers at one year. | 50.5% (612/1,212) | 4.9% (28/577) | Odds ratio favoring semaglutide; P<0.001 |
| Lost a fifth of their body weight or more ⚠ About a third reached this, which is the other half of the story the 14.9% average hides: results scattered widely, and some people lost nothing at all. A mean is not a prediction for you. | 32.0% (388/1,212) | 1.7% (10/577) | Reported as supportive analysis in the publication |
| Weight lost in kilograms About 15 kg, or roughly 34 pounds, against under 6 pounds on placebo. | −15.3 kg | −2.6 kg | Estimated treatment difference −12.7 kg (95% CI −13.7 to −11.7) |
| Inches off the waist 13.5 cm is a little over 5 inches, and waist matters more for metabolic risk than total weight does. | −13.5 cm | −4.1 cm | Estimated treatment difference −9.4 cm (95% CI −10.3 to −8.5) |
| Top blood-pressure number A drop of about 5 points beyond placebo — modest individually, meaningful across a population, and the kind of change that can alter what else someone is prescribed. | −6.2 mmHg | −1.1 mmHg | Estimated treatment difference −5.1 mmHg (95% CI −6.3 to −3.9) |
| Three-month average blood sugar ⚠ Nobody here had diabetes, so this is movement within the normal-to-prediabetic band rather than treatment of anything. Do not read it as evidence about diabetes control. | −0.45% | −0.15% | Estimated treatment difference −0.30 percentage points (95% CI −0.34 to −0.26) |
| Blood sugar after an overnight fast A small drop, consistent with the HbA1c change and with the same caveat attached. | −8.4 mg/dL | −0.5 mg/dL | Estimated treatment difference −7.9 mg/dL (95% CI −9.3 to −6.5) |
| Inflammation in the blood, measured by hs-CRP Inflammation fell by about half, against 16% on placebo — the only inflammation marker the trial planned to measure, and the thread later picked up by the cardiovascular trials. | 0.45 (55% relative reduction) | 0.84 (16% relative reduction) | Estimated treatment ratio 0.53 (95% CI 0.49 to 0.58); the only prespecified inflammation biomarker |
| Self-reported physical functioning, general health questionnaire ⚠ Real but small: the gain over placebo was 1.9 points, and the usual bar for a difference a patient would notice is 3 points or more. | +2.3 points | +0.4 points | Estimated treatment difference 1.9 points; nominal P<0.001 vs placebo |
| Self-reported physical functioning, weight-specific questionnaire ★ The weight-specific instrument found what the general one did not — a 9-point advantage, clearing the responder threshold for many participants. Which questionnaire you ask changes the answer. | +15.0 points | +6.0 points | Estimated treatment difference 9.0 points; nominal P<0.001 vs placebo |
Adverse events
| Event | Treatment rate | Comparator rate |
|---|---|---|
| Nausea The most common complaint by far. Usually mild to moderate, worst during the 16 weeks of dose increases, then easing off. | 44.1% (576/1,306) | 17.4% (114/655) |
| Diarrhea Second most common, and usually passes. | 31.5% (411/1,306) | 15.9% (104/655) |
| Vomiting | 24.6% (321/1,306) | 6.6% (43/655) |
| Constipation | 23.4% (305/1,306) | 9.5% (62/655) |
| Headache | 15.2% (198/1,306) | 12.2% (80/655) |
| Dyspepsia | 10.3% (135/1,306) | 3.5% (23/655) |
| Abdominal pain (upper or general) | 9.7% (127/1,306) general; 9.6% (125/1,306) upper | 5.5% (36/655) general; 5.3% (35/655) upper |
| Belching ★ The biggest gap against placebo of anything in this table — 8.6% against 0.5%. Rarely serious, almost never mentioned in marketing. | 8.6% (112/1,306) | 0.5% (3/655) |
| Serious adverse events (any) | 9.8% (128/1,306) | 6.4% (42/655) |
| Quit the trial because of stomach and bowel problems Most of these happened while the dose was still being raised. Counting every reason for stopping, 7.0% left the drug group against 3.1% on placebo. | 4.5% (59/1,306) | 0.8% (5/655) |
Clinical significance
STEP-1 set the number that every later GLP-1 is measured against, and gave FDA the evidence for the Wegovy 2.4 mg dose. Read carefully, it also sets the limits. The 14.9% is a mean across a population selected for a BMI threshold and screened to exclude diabetes, supported by lifestyle counseling and the adherence a trial produces. Individual results in the trial spread widely — a third of participants lost more than 20%, and some lost nothing. ⛔ For anyone shopping, the most useful fact about STEP-1 is what it did NOT test: it studied the FDA-approved product from its manufacturer. Compounded semaglutide has never been through a trial of this kind, and this result does not transfer to it.
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.Wilding JPH, Batterham RL, Calanna S, et al.; STEP 1 Study Group. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021. PMID: 33567185.
- 2.U.S. National Library of Medicine. STEP 1: Research Study Investigating How Well Semaglutide Works in People Suffering From Overweight or Obesity — Study Results. ClinicalTrials.gov, NCT03548935. 2021. https://clinicaltrials.gov/study/NCT03548935
- 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.U.S. Food and Drug Administration. FDA Approves New Drug Treatment for Chronic Weight Management, First Since 2014 (Wegovy approval announcement). FDA News Release, June 4, 2021. 2021. https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treatment-chronic-weight-management-first-2014