STEP-1 trial deep-dive: semaglutide 2.4 mg for obesity (Wilding 2021 NEJM)
Last verified 2026-05-27 · Phase 3 · Completed (results published Feb 2021) · NCT03548935 ↗
STEP-1 (NCT03548935) is the pivotal phase-3 trial that turned semaglutide into the first GLP-1 agonist FDA-approved for chronic weight management in people without diabetes. Novo Nordisk randomized 1,961 adults with BMI ≥30 (or ≥27 with a weight-related comorbidity) and no diabetes 2:1 to once-weekly subcutaneous semaglutide 2.4 mg or matching placebo, both layered on monthly lifestyle counseling, for 68 weeks. Results published by Wilding and colleagues in the New England Journal of Medicine on March 18, 2021 showed a mean weight reduction of 14.9% on semaglutide versus 2.4% on placebo, with more than half of treated participants losing at least 15% of baseline weight — magnitudes previously seen only after bariatric surgery.
- Enrollment
- 1,961
- Duration
- 68 weeks of treatment plus a 7-week off-drug extension (week 75 follow-up)
- Drug
- Semaglutide 2.4 mg (Wegovy)
- Population
- Adults aged ≥18 with BMI ≥30, or BMI ≥27 with at least one weight-related condition (hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease). Type 2 diabetes was excluded; HbA1c ≥6.5% at screening was an exclusion criterion. Mean baseline weight 105.3 kg, mean BMI 37.9 kg/m², 74% female, 75% white, mean age 46.
Primary endpoint
Percentage change in body weight from baseline to week 68 (coprimary, treatment-policy estimand)
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)
The coprimary endpoint also required a ≥5% weight reduction at week 68, which was met by 86.4% of semaglutide vs 31.5% of placebo participants (P<0.001).
Secondary endpoints
| Endpoint | Treatment | Comparator | Difference |
|---|---|---|---|
| Body-weight reduction ≥10% at week 68 | 69.1% (838/1,212) | 12.0% (69/577) | Odds ratio favoring semaglutide; P<0.001 |
| Body-weight reduction ≥15% at week 68 Threshold approaching the lower bound of weight loss reported with sleeve gastrectomy at one year. | 50.5% (612/1,212) | 4.9% (28/577) | Odds ratio favoring semaglutide; P<0.001 |
| Body-weight reduction ≥20% at week 68 | 32.0% (388/1,212) | 1.7% (10/577) | Reported as supportive analysis in the publication |
| Absolute body-weight change at week 68 (kg) | −15.3 kg | −2.6 kg | Estimated treatment difference −12.7 kg (95% CI −13.7 to −11.7) |
| Waist-circumference change at week 68 (cm) | −13.5 cm | −4.1 cm | Estimated treatment difference −9.4 cm (95% CI −10.3 to −8.5) |
| Systolic blood pressure change at week 68 (mmHg) | −6.2 mmHg | −1.1 mmHg | Estimated treatment difference −5.1 mmHg (95% CI −6.3 to −3.9) |
| HbA1c change at week 68 (%) Participants were non-diabetic at entry; the HbA1c drop reflects shifts within the normoglycemic / prediabetic range. | −0.45% | −0.15% | Estimated treatment difference −0.30 percentage points (95% CI −0.34 to −0.26) |
| Fasting plasma glucose change at week 68 (mg/dL) | −8.4 mg/dL | −0.5 mg/dL | Estimated treatment difference −7.9 mg/dL (95% CI −9.3 to −6.5) |
| High-sensitivity C-reactive protein (hs-CRP) at week 68 (ratio to baseline) | 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 |
| SF-36 physical-functioning score change at week 68 Patient-reported physical function on the validated SF-36v2; the clinically important difference is generally ≥3 points. | +2.3 points | +0.4 points | Estimated treatment difference 1.9 points; nominal P<0.001 vs placebo |
| IWQOL-Lite-CT physical-function domain score change at week 68 Weight-specific quality-of-life instrument; magnitude well above the 14.6-point responder threshold for many participants. | +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 Most common AE; typically mild-to-moderate, peaks during 16-week dose-escalation, then declines. | 44.1% (576/1,306) | 17.4% (114/655) |
| Diarrhea Second-most-common AE; usually transient. | 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 |
| Eructation (belching) Largest relative excess vs placebo of any AE. | 8.6% (112/1,306) | 0.5% (3/655) |
| Serious adverse events (any) | 9.8% (128/1,306) | 6.4% (42/655) |
| Discontinuation due to GI events Most discontinuations occurred during dose-escalation; overall study-drug discontinuation was 7.0% vs 3.1%. | 4.5% (59/1,306) | 0.8% (5/655) |
Clinical significance
STEP-1 established an entirely new ceiling for pharmacologic weight loss. Before semaglutide 2.4 mg, no anti-obesity medication had crossed the 10% mean-weight-loss line in a phase-3 trial in non-diabetic adults; STEP-1 cleared 14.9% and put more than half of treated participants past the 15% mark — a magnitude long associated only with bariatric surgery. The accompanying improvements in waist, blood pressure, hs-CRP, fasting glucose, and patient-reported physical function reframed obesity drugs as cardiometabolic agents, not cosmetic ones. STEP-1's results formed the regulatory basis for Wegovy's June 2021 FDA approval and seeded the design of every subsequent GLP-1 and dual-agonist obesity program, from SURMOUNT-1 to SELECT.
Frequently asked questions
Who qualified for STEP-1?
Adults aged 18 or older with a body-mass index of at least 30 kg/m², or at least 27 kg/m² with a weight-related coexisting condition such as hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease. Anyone with type 2 diabetes was excluded; HbA1c at or above 6.5% at screening was an exclusion criterion. The enrolled population skewed female (74%) and white (75%), with a mean age of 46 years, mean baseline weight of 105.3 kg, and mean BMI of 37.9 kg/m². Prior anti-obesity medications and bariatric surgery within recent windows were also exclusions.
Was there a placebo run-in period before randomization?
No. STEP-1 used a standard screening period and went directly to randomization once eligibility was confirmed; there was no lead-in lifestyle phase used to weed out non-responders or non-adherent participants before the drug started. Both arms received the same monthly individual counseling sessions on a 500-kcal/day deficit diet and 150 minutes/week of physical activity throughout the 68-week treatment period. The 16-week dose-escalation phase that titrated semaglutide from 0.25 mg up to 2.4 mg happened after randomization, inside the trial proper, which is why the gastrointestinal-event curve peaks early.
Did everyone tolerate the full 2.4 mg dose?
Most participants reached and maintained 2.4 mg, but not all. Per the published manuscript and the ClinicalTrials.gov results posting, 7.0% of the semaglutide group discontinued the study drug for any reason compared with 3.1% on placebo, and 4.5% discontinued specifically because of gastrointestinal adverse events versus 0.8% on placebo. Dose-reduction or temporary holds were allowed in the protocol when participants could not tolerate the next escalation step. The trial's treatment-policy primary estimand included these participants in the analysis whether or not they stayed on assigned therapy.
How does STEP-1 compare with SURMOUNT-1?
STEP-1 and SURMOUNT-1 are the pivotal weight-loss trials for semaglutide 2.4 mg and tirzepatide, respectively. Both enrolled non-diabetic adults with obesity and ran for roughly the same duration (68 vs 72 weeks). Mean placebo-subtracted weight loss in STEP-1 was 12.4 percentage points on semaglutide; SURMOUNT-1 reported 17.8 percentage points on tirzepatide 15 mg. Direct comparisons across separately conducted trials should be made cautiously, since populations and lifestyle-intervention intensity differed. The head-to-head SURMOUNT-5 trial (Aronne 2025) later directly compared the two drugs in a randomized design.
Are STEP-1 results durable after the trial ends?
The STEP-1 extension data published by Wilding and colleagues in Diabetes, Obesity and Metabolism (2022) followed participants for one year after treatment stopped at week 68. Within a year off drug, the semaglutide group regained roughly two-thirds of the weight they had lost, while the placebo group similarly regained much of their smaller loss; the between-group difference narrowed substantially. Cardiometabolic improvements followed the same trajectory, supporting the framing of semaglutide 2.4 mg as chronic therapy for a chronic disease rather than a finite course.
How did STEP-1 affect FDA approval and downstream trials?
The FDA approved semaglutide 2.4 mg as Wegovy on June 4, 2021 for chronic weight management in adults with BMI ≥30 or ≥27 with a weight-related comorbidity, with STEP-1 serving as the principal pivotal trial alongside STEP-2, STEP-3, and STEP-4. Approval was later extended to adolescents aged 12 and older based on STEP-TEENS, and to cardiovascular risk reduction in adults with established cardiovascular disease and overweight or obesity based on the SELECT trial. STEP-1's effect-size benchmark also informed the statistical-power assumptions of subsequent obesity trials including SURMOUNT-1.
Sources
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