STEP-1 Trial: Semaglutide 2.4 mg for Obesity

Trial design

STEP-1 (NCT03548935) was a 68-week, randomized, double-blind, placebo-controlled, multicenter Phase 3 trial conducted at 129 sites across 16 countries¹. Investigators enrolled 1,961 adults with a body mass index of 30 kg/m² or greater, or 27 kg/m² or greater with at least one weight-related comorbidity (excluding diabetes). Participants were randomized 2:1 to semaglutide 2.4 mg subcutaneous once weekly or matching placebo, both combined with a lifestyle intervention consisting of a 500 kcal/day energy deficit and at least 150 minutes per week of physical activity.

The semaglutide dose was titrated over 16 weeks from 0.25 mg to 2.4 mg per week and maintained at 2.4 mg for the remainder of the trial. The primary endpoints were percentage change in body weight from baseline to week 68 and the proportion of participants achieving at least 5% weight loss. Pre-specified secondary endpoints included weight loss thresholds of 10%, 15%, and 20%, as well as changes in waist circumference, systolic blood pressure, glycated hemoglobin, lipid panel, and quality-of-life scores.

Primary outcomes

At week 68, mean change in body weight was −14.9% in the semaglutide group versus −2.4% in the placebo group (estimated treatment difference −12.4 percentage points; 95% CI −13.4 to −11.5; P<0.001)¹. The proportion of participants achieving at least 5% weight loss was 86.4% in the semaglutide group versus 31.5% in the placebo group. Higher weight-loss thresholds showed the same pattern: 69.1% versus 12.0% achieved at least 10% loss, 50.5% versus 4.9% achieved at least 15% loss, and 32.0% versus 1.7% achieved at least 20% loss.

Mean absolute weight loss in the semaglutide group was approximately 15.3 kg (33.7 lb) versus 2.6 kg (5.7 lb) in placebo. The weight-loss curve continued to descend through approximately week 60 before plateauing, suggesting that the trial duration captured most but not all of the maximum effect achievable with the regimen.

Secondary outcomes

Cardiometabolic secondary endpoints favored semaglutide across the board. Mean waist circumference decreased by 13.5 cm versus 4.1 cm with placebo. Systolic blood pressure decreased by 6.2 mm Hg versus 1.1 mm Hg. Glycated hemoglobin (HbA1c) decreased by 0.45 percentage points in semaglutide-treated participants versus 0.15 percentage points with placebo (the trial excluded participants with type 2 diabetes, so most participants had HbA1c in the normal or pre-diabetic range at baseline)¹.

Lipid changes included reductions in total cholesterol (−3.4% vs −0.7%), LDL cholesterol (−3.0% vs −1.2%), and triglycerides (−22.4% vs −7.4%). HDL cholesterol increased modestly (+5.0% vs +2.4%). Health-related quality of life, measured by the IWQOL-Lite-CT and SF-36 instruments, improved significantly in the semaglutide group versus placebo.

Adverse events and tolerability

Gastrointestinal adverse events were the most common reason for treatment discontinuation. Nausea (44.2% vs 17.4% placebo), diarrhea (31.5% vs 15.9%), vomiting (24.8% vs 6.6%), and constipation (23.4% vs 9.5%) were significantly more common in the semaglutide group¹. Most GI events were mild to moderate and occurred during dose titration. Discontinuation due to adverse events occurred in 7.0% of semaglutide-treated participants versus 3.1% of placebo.

Serious adverse events were similar between groups (9.8% vs 6.4%). Hypoglycemic events were rare. Five cases of acute pancreatitis occurred in the semaglutide group (0.4%) versus one in placebo (0.1%); independent adjudication concluded that the rate of pancreatitis was not significantly elevated. Gallbladder-related disorders were more common with semaglutide (2.6% vs 1.2%), consistent with rapid weight loss as a known risk factor for cholelithiasis.

Clinical context within the STEP program

STEP-1 was the first of a series of STEP (Semaglutide Treatment Effect in People with obesity) trials. STEP-2 evaluated semaglutide 2.4 mg in adults with type 2 diabetes (mean weight loss 9.6% versus 3.4% placebo at 68 weeks)². STEP-3 added intensive behavioral therapy and showed similar weight loss to STEP-1. STEP-4 examined weight-loss maintenance after 20 weeks of run-in: participants who continued semaglutide lost an additional 7.9%, while those switched to placebo regained 6.9%³.

STEP-5 extended treatment to 104 weeks and showed sustained weight loss of 15.2% versus 2.6% placebo, with the weight-loss plateau maintained through year two. STEP-8 directly compared semaglutide 2.4 mg with liraglutide 3.0 mg over 68 weeks: semaglutide produced 15.8% mean weight loss versus 6.4% with liraglutide⁴.

Generalizability and limitations

STEP-1 excluded participants with type 2 diabetes, prior bariatric surgery, weight changes greater than 5 kg in the 90 days before screening, and several other conditions; results may not generalize to those populations. The trial population was 74.1% female, 75.1% White, with mean age 46 years and mean baseline BMI 37.9 kg/m². Performance in older adults, men, and racially diverse populations was supported by subgroup analyses but with reduced precision.

The 68-week duration captures most but not all of the time-to-plateau. Long-term outcomes (cardiovascular events, durability beyond 2 years, off-treatment trajectory) were not assessed in STEP-1; subsequent trials including SELECT addressed cardiovascular outcomes specifically.

Related editorial coverage

• Semaglutide profile: mechanism, dosing, and FDA status
• SELECT trial: semaglutide cardiovascular outcomes
• STEP program overview (STEP-1 through STEP-8)
• Weight-loss therapeutics category

Frequently asked questions

How much weight did participants lose in the STEP-1 trial?

At week 68, semaglutide-treated participants lost a mean 14.9% of body weight versus 2.4% in the placebo group. Approximately 50% of semaglutide-treated participants achieved at least 15% body weight loss, and 32% achieved at least 20%¹.

Is the STEP-1 dose of semaglutide the same as Wegovy?

Yes. Wegovy is FDA-approved at the 2.4 mg/week dose evaluated in STEP-1. Ozempic is the same molecule at a maximum dose of 2.0 mg/week, approved for type 2 diabetes. Compounded semaglutide formulations may use the same 2.4 mg/week titration schedule under physician supervision.

What were the most common side effects in STEP-1?

Gastrointestinal: nausea (44.2%), diarrhea (31.5%), vomiting (24.8%), and constipation (23.4%). Most were mild to moderate and concentrated during dose titration. Severe GI events were uncommon¹.

Did STEP-1 evaluate cardiovascular outcomes?

No. STEP-1 was a weight-loss trial that excluded participants with diabetes and was not powered to evaluate hard cardiovascular endpoints. The SELECT trial subsequently demonstrated a 20% reduction in major adverse cardiovascular events with semaglutide in adults with obesity and established cardiovascular disease but without diabetes⁵.