STEP-2 trial deep-dive: semaglutide 2.4 mg in obesity + type 2 diabetes (Davies 2021 Lancet)
Last verified 2026-05-28 · Phase 3 · Completed (results published March 2021) · NCT03552757 ↗
STEP-2 (NCT03552757) was the second of the four registrational STEP trials supporting FDA approval of semaglutide 2.4 mg (Wegovy) and the only one enrolled exclusively in adults with type 2 diabetes. Novo Nordisk randomized 1,210 adults aged 18 or older with BMI ≥27 kg/m², HbA1c 7-10%, and a T2D diagnosis at least 180 days before screening 1:1:1 to weekly subcutaneous semaglutide 2.4 mg, semaglutide 1.0 mg (the maintenance dose marketed as Ozempic), or matching placebo for 68 weeks of treatment with a 16-week dose-escalation phase, all layered on monthly individual lifestyle counseling. Results published by Davies and colleagues in The Lancet on March 13, 2021 showed mean body-weight reductions of −9.6% on semaglutide 2.4 mg, −7.0% on 1.0 mg, and −3.4% on placebo, with the 2.4 mg dose superior to both comparators on the coprimary endpoints. STEP-2 anchored Wegovy's labeling for use in adults with T2D pursuing weight loss in addition to glycemic control.
- Enrollment
- 1,210
- Duration
- 68 weeks of treatment (including a 16-week dose-escalation phase) plus a 7-week off-drug follow-up to week 75
- Drug
- Semaglutide 2.4 mg (Wegovy)
- Population
- Adults aged ≥18 with a BMI ≥27 kg/m², type 2 diabetes diagnosed at least 180 days before screening, HbA1c 7.0-10.0%, and treated with diet and exercise alone or with up to three stable oral antidiabetic drugs (metformin, sulfonylureas, SGLT2 inhibitors, or thiazolidinediones). Insulin use was an exclusion. Mean baseline body weight 99.8 kg, mean BMI 35.7 kg/m², mean HbA1c 8.1%, mean age 55 years, 50.9% female, 61.8% white, mean diabetes duration ~8 years. Enrolled at 149 sites across 12 countries from June 2018 through March 2020.
Primary endpoint
Percentage change in body weight from baseline to week 68, semaglutide 2.4 mg vs placebo (coprimary, treatment-policy estimand)
Treatment arm
−9.6%
Comparator
−3.4%
Treatment difference: Estimated treatment difference −6.2 percentage points (95% CI −7.3 to −5.2; P<0.0001)
The coprimary endpoint also required ≥5% weight loss at week 68, which was achieved by 68.8% of the semaglutide 2.4 mg group vs 28.5% of placebo (odds ratio 4.88, 95% CI 3.58 to 6.64; P<0.0001).
Secondary endpoints
| Endpoint | Treatment | Comparator | Difference |
|---|---|---|---|
| Percentage change in body weight at week 68, semaglutide 2.4 mg vs semaglutide 1.0 mg Direct head-to-head comparison of the obesity dose vs the Ozempic dose in T2D; the 2.4 mg arm produced an additional ~2.7 percentage points of weight loss over the 1.0 mg arm at the same 68-week endpoint. | −9.6% (2.4 mg) | −7.0% (1.0 mg) | Estimated treatment difference −2.7 percentage points (95% CI −3.7 to −1.6; P<0.0001) |
| Body-weight reduction ≥5% at week 68 | 68.8% (2.4 mg); 57.1% (1.0 mg) | 28.5% (placebo) | Odds ratio 4.88 (95% CI 3.58 to 6.64) for 2.4 mg vs placebo; P<0.0001 |
| Body-weight reduction ≥10% at week 68 More than five-fold higher absolute rate of clinically meaningful weight loss versus placebo in a population where most prior obesity drugs barely separated from placebo. | 45.6% (2.4 mg); 28.7% (1.0 mg) | 8.2% (placebo) | Odds ratio 7.41 (95% CI 4.95 to 11.08) for 2.4 mg vs placebo; P<0.0001 |
| Body-weight reduction ≥15% at week 68 | 25.8% (2.4 mg); 13.7% (1.0 mg) | 3.2% (placebo) | Odds ratio 7.65 (95% CI 4.44 to 13.20) for 2.4 mg vs placebo; P<0.0001 |
| Change in HbA1c at week 68 (percentage points) Glycemic effect of the two doses was essentially identical, suggesting the HbA1c benefit plateaus near the 1.0 mg dose while weight-loss benefit continues to scale. | −1.6 (2.4 mg); −1.5 (1.0 mg) | −0.4 (placebo) | Estimated treatment difference −1.2 percentage points (95% CI −1.4 to −1.1) for 2.4 mg vs placebo; P<0.0001 |
| Change in waist circumference at week 68 (cm) | −9.4 cm (2.4 mg) | −4.5 cm (placebo) | Estimated treatment difference −4.9 cm (95% CI −5.9 to −4.0); P<0.0001 |
| Change in systolic blood pressure at week 68 (mmHg) | −3.9 mmHg (2.4 mg) | −0.5 mmHg (placebo) | Estimated treatment difference −3.4 mmHg (95% CI −5.6 to −1.3); P=0.0016 |
| Change in fasting plasma glucose at week 68 (mg/dL) | −43.8 mg/dL (2.4 mg) | −8.5 mg/dL (placebo) | Estimated treatment difference approximately −35 mg/dL (95% CI −41 to −29); P<0.0001 |
| Change in IWQOL-Lite-CT Physical Function score at week 68 Patient-reported physical function on the weight-specific IWQOL-Lite-CT instrument; the difference cleared the 14.6-point responder threshold for the 2.4 mg arm. | +14.1 points (2.4 mg) | +8.7 points (placebo) | Estimated treatment difference 5.3 points (95% CI 2.8 to 7.9); P<0.0001 |
| Triglycerides (ratio to baseline) at week 68 | 0.78 (2.4 mg; 22% relative reduction) | 0.93 (placebo; 7% relative reduction) | Estimated treatment ratio 0.84 (95% CI 0.79 to 0.89); P<0.0001 |
Adverse events
| Event | Treatment rate | Comparator rate |
|---|---|---|
| Nausea Most common AE; rates with the 1.0 mg dose were 25.6%. Typically mild-to-moderate and clustered during dose-escalation. | 33.7% (sema 2.4 mg) | 11.4% (placebo) |
| Diarrhea Rate with the 1.0 mg dose was 19.0%. | 21.5% (sema 2.4 mg) | 7.4% (placebo) |
| Vomiting Rate with the 1.0 mg dose was 12.4%. | 20.9% (sema 2.4 mg) | 5.4% (placebo) |
| Constipation | 17.8% (sema 2.4 mg) | 8.2% (placebo) |
| Dyspepsia | 8.7% (sema 2.4 mg) | 1.7% (placebo) |
| Documented symptomatic hypoglycemia (BG <56 mg/dL) Severe hypoglycemia was rare in all arms (0.7% on 2.4 mg vs 0.5% on placebo). The hypoglycemia signal was concentrated in participants on background sulfonylureas, consistent with the established risk of combining incretin therapy with insulin secretagogues. | 5.7% (sema 2.4 mg) | 3.0% (placebo) |
| Diabetic retinopathy (any event) Numerically higher than placebo but not significant; consistent with the early-treatment retinopathy signal seen in other semaglutide diabetes trials when glucose drops rapidly. | 3.2% (sema 2.4 mg) | 2.7% (placebo) |
| Cholelithiasis (gallstones) Known class effect of rapid weight loss. | 2.5% (sema 2.4 mg) | 0.5% (placebo) |
| Discontinuation due to adverse events Driven predominantly by gastrointestinal events during dose-escalation; rate with the 1.0 mg dose was 5.2%. | 6.7% (sema 2.4 mg) | 3.5% (placebo) |
| Serious adverse events (any) | 9.1% (sema 2.4 mg) | 7.9% (placebo) |
Clinical significance
STEP-2 is the trial that defined how semaglutide 2.4 mg behaves in adults who carry obesity and type 2 diabetes at the same time. Mean weight loss of 9.6% on the 2.4 mg dose was meaningfully smaller than the 14.9% seen in STEP-1 in non-diabetic participants, confirming the well-documented observation that T2D blunts pharmacologic weight loss by roughly a third to a half. Even so, the 2.4 mg dose was superior to the 1.0 mg dose (the maintenance dose marketed as Ozempic) for body weight, while both doses produced the same 1.5-1.6 percentage point drop in HbA1c. That dissociation reframed the choice: at the same molecule, the higher dose is preferred when weight is the primary target and the standard dose is adequate when the goal is glycemic control. The cardiometabolic profile (waist, systolic blood pressure, triglycerides, fasting glucose) all favored the 2.4 mg arm. Together with STEP-1, STEP-3, and STEP-4, the trial formed the regulatory basis for Wegovy's June 2021 FDA approval and, specifically, its labeling for use in adults with T2D.
Frequently asked questions
Why is weight loss with semaglutide 2.4 mg lower in people with type 2 diabetes?
Mean weight loss in STEP-2 was 9.6% on semaglutide 2.4 mg, compared with 14.9% on the same dose in STEP-1 in non-diabetic adults. The gap is consistent across the GLP-1 literature: people with T2D lose roughly a third to a half less weight on incretin therapy than people without diabetes, even at identical doses. Hypothesized mechanisms include differences in incretin-receptor signaling in long-standing hyperglycemia, the energy-conserving effect of improved glucose disposal, concomitant antihyperglycemic medications, and a smaller baseline gap between intake and expenditure in the diabetic population. The effect is not erased by higher doses, but it is partially offset; the 2.4 mg dose still produced 2.7 percentage points more weight loss than the 1.0 mg dose in the same trial.
Should a patient with type 2 diabetes use Wegovy (2.4 mg) or Ozempic (1.0 mg)?
STEP-2 is the closest the literature gets to a head-to-head answer. Both doses produced essentially identical HbA1c reductions of about 1.5-1.6 percentage points, so for glycemic control alone the 1.0 mg dose is sufficient. The 2.4 mg dose produced about 2.7 percentage points more weight loss and meaningfully higher rates of ≥10% and ≥15% weight reduction, at the cost of somewhat higher gastrointestinal AE rates and a higher discontinuation rate (6.7% vs 5.2%). The clinical decision usually turns on the patient's primary goal and insurance coverage: Ozempic is FDA-approved for diabetes and typically covered by commercial plans; Wegovy is FDA-approved for chronic weight management and historically faces more restrictive coverage even in patients with T2D.
How does STEP-2 compare with SURMOUNT-2 (tirzepatide in T2D)?
SURMOUNT-2 (Garvey 2023, Lancet) was the analogous registrational trial for tirzepatide in adults with T2D and obesity, with a 72-week treatment period and 10 mg and 15 mg doses. Mean weight loss in SURMOUNT-2 was −13.4% on tirzepatide 10 mg and −15.7% on 15 mg, versus −3.3% on placebo. Direct cross-trial comparison should be made cautiously because protocols, populations, and durations differed, but the placebo-subtracted weight loss in the T2D population was roughly 6-10 percentage points larger for tirzepatide than for semaglutide 2.4 mg in STEP-2. HbA1c reductions were also larger with tirzepatide (about −2.0 percentage points on 15 mg vs −1.6 with sema 2.4 mg). SURMOUNT-2 supported the November 2024 FDA approval of Zepbound for T2D-associated weight management.
Was hypoglycemia a problem in STEP-2?
Documented symptomatic hypoglycemia (blood glucose under 56 mg/dL) occurred in 5.7% of the semaglutide 2.4 mg arm versus 3.0% on placebo. Severe hypoglycemia was rare (0.7% on 2.4 mg vs 0.5% on placebo). The bulk of the excess was concentrated in participants taking background sulfonylureas, a known interaction; semaglutide itself is not insulinotropic in the absence of elevated glucose, so the hypoglycemia signal in the trial reflects sulfonylurea-driven insulin release in patients whose glucose was falling because of the GLP-1 effect. Practical implication is the same as for any GLP-1 in T2D: down-titrate or stop the sulfonylurea (and reduce insulin if present) when semaglutide is started.
Did the HbA1c improvement persist through week 68?
Yes. HbA1c trajectories in the published figures show both active arms reaching nadir around weeks 20-28 and remaining at that nadir through week 68, with the 2.4 mg arm landing at −1.6 percentage points and the 1.0 mg arm at −1.5. By week 68, 67.5% of the 2.4 mg arm and 64.0% of the 1.0 mg arm reached HbA1c <7% (the ADA glycemic target), compared with 15.6% on placebo. The composite endpoint of ≥10% weight loss plus HbA1c <7% was achieved by 30.9% of the 2.4 mg arm vs 4.2% of placebo — the metabolic remission target that conventional T2D pharmacotherapy reaches in only a minority of patients.
Did STEP-2 result in a specific FDA label change?
STEP-2 was one of the four pivotal trials in Novo Nordisk's June 2021 Biologics License Application for Wegovy, alongside STEP-1, STEP-3, and STEP-4. The FDA's initial Wegovy approval (June 4, 2021) covered chronic weight management in adults with BMI ≥30 or ≥27 with a weight-related comorbidity, with type 2 diabetes explicitly listed as one of the qualifying comorbidities. STEP-2 supplied the dedicated efficacy and safety dataset for the T2D-with-obesity subpopulation that allowed the label to extend uniformly into diabetic patients without a separate restriction. The trial did not change which dose is marketed for diabetes versus obesity; Ozempic (semaglutide 0.5-2.0 mg) remains the diabetes-labeled formulation and Wegovy (semaglutide 2.4 mg) the obesity-labeled one.
References
- 1.Davies M, Færch L, Jeppesen OK, Pakseresht A, Pedersen SD, Perreault L, Rosenstock J, Shimomura I, Viljoen A, Wadden TA, Lingvay I; STEP 2 Study Group. Semaglutide 2·4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial. Lancet. 2021. PMID: 33667417.
- 2.U.S. National Library of Medicine. Research Study Investigating How Well Semaglutide Works in People With Type 2 Diabetes Suffering From Overweight or Obesity (STEP 2). ClinicalTrials.gov, NCT03552757. 2021. https://clinicaltrials.gov/study/NCT03552757
- 3.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.
- 4.Garvey WT, Frias JP, Jastreboff AM, et al.; SURMOUNT-2 investigators. Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2023. PMID: 37315391.
- 5.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