The STEP Program: Semaglutide 2.4 mg for Chronic Weight Management

What the STEP program set out to answer

Semaglutide had already been approved for type 2 diabetes at 0.5 and 1.0 mg weekly doses (Ozempic) when Novo Nordisk asked whether nearly doubling the dose to 2.4 mg and targeting obesity as the primary indication could generate a weight-loss profile competitive with the best available surgical or intensive behavioral options. The STEP program (Semaglutide Treatment Effect in People with obesity) was the vehicle for that question.

The program enrolled adults with overweight (BMI at least 27) or obesity (BMI at least 30) across multiple designs: placebo-controlled with lifestyle counseling, an arm specifically for those with T2DM, a trial that layered semaglutide on top of intensive behavioral therapy, a withdrawal study to test treatment dependence, a two-year extension, two trials in non-Western populations (East Asian, Chinese), and a head-to-head against liraglutide 3.0 mg.

Constituent trials

Results are approximate from primary publications. STEP-7 data are published in Chinese-language registries and local journals; the approximate result listed reflects available translated reporting.

STEP 1: The foundational trial

STEP 1 (NCT03548935) enrolled 1,961 adults without type 2 diabetes who had a BMI of 30 or greater, or 27 or greater with one comorbidity. All participants received lifestyle counseling, and were randomized to semaglutide 2.4 mg or placebo for 68 weeks.^[1]

The mean body-weight reduction was 14.9% with semaglutide versus 2.4% with placebo. About 86% of semaglutide participants lost at least 5% of body weight; 69% lost at least 10%, and 51% lost at least 15%. These proportions were roughly four to eight times higher than those observed in the placebo group. Systolic blood pressure, waist circumference, lipids, and HbA1c all improved to a greater degree in the semaglutide arm.

Gastrointestinal adverse events were the most common reason for discontinuation. Nausea was reported in about 44% of the semaglutide group versus 16% with placebo, though most events were mild to moderate and occurred during the dose-escalation period. The discontinuation rate due to adverse events was approximately 7% with semaglutide versus 3% with placebo.

STEP 2 and STEP 3: Broadening the evidence

STEP 2 (NCT03552757) enrolled adults with T2DM and obesity or overweight, adding a 1.0 mg semaglutide arm to allow within-program dose comparison. The 2.4 mg dose achieved approximately 9.6% weight reduction versus 7.0% for the 1.0 mg dose and 3.4% for placebo, confirming that the higher dose provides meaningful additional benefit even in a metabolically challenged population where weight loss is generally attenuated.^[2]

STEP 3 (NCT03611582) asked whether adding intensive behavioral therapy on top of semaglutide 2.4 mg could achieve results closer to those seen in bariatric surgery. With 30 in-person counseling visits over 68 weeks, the trial achieved approximately 16.0% weight reduction with semaglutide plus intensive behavioral support versus 5.7% with placebo plus the same counseling schedule.^[3]The incremental weight loss beyond STEP 1 was modest, suggesting that semaglutide 2.4 mg already captures much of the benefit achievable from lifestyle modification at this dose level.

STEP 4 and STEP 5: Durability and long-term treatment

STEP 4 (NCT03548961) established the pattern seen across all GLP-1-class anti-obesity agents: weight regain follows treatment withdrawal. After a 20-week open-label run-in in which all participants received semaglutide 2.4 mg and lost approximately 10.6% of body weight, randomization to continue or switch to placebo revealed that continuation added a further 7.9% reduction while withdrawal resulted in approximately 6.9% regain over 48 weeks.^[4]

STEP 5 (NCT03693430) was a two-year trial designed to characterize the longer plateau of semaglutide's effect. At 104 weeks, participants who continued active treatment had lost approximately 15.2% of body weight versus 2.6% for placebo. The curve appeared to approach plateau by week 60 to 68, with modest additional loss from week 68 to 104, indicating that most weight reduction from this dose is achieved within the first year and a half.^[5]

STEP 6, STEP 7, and STEP 8: Populations and comparators

STEP 6 (NCT03811574) enrolled participants from Japan and South Korea, where approved BMI thresholds for weight management treatment are lower than in Western guidelines. The trial included 1.7 mg and 2.4 mg doses and showed significant weight reduction in East Asian participants, with acceptable safety, supporting regulatory filings in Japan and Korea.^[6]

STEP 8 (NCT04074161) provided the most clinically actionable head-to-head comparison: semaglutide 2.4 mg versus liraglutide 3.0 mg (Saxenda), the then FDA-approved injectable anti-obesity agent. Semaglutide achieved approximately 15.8% weight reduction at 68 weeks versus 6.4% with liraglutide, a difference of about 9.4 percentage points.^[7] The superior efficacy of once-weekly semaglutide over once-daily liraglutide accelerated the latter's commercial decline in markets where both were available.

Regulatory outcome and access challenges

The FDA approved Wegovy (semaglutide 2.4 mg injection) for chronic weight management in June 2021, the second GLP-1 receptor agonist approved for obesity in the United States after liraglutide 3.0 mg (Saxenda, 2014). The EMA followed with approval in 2022, and the MHRA approved in the UK in 2023.

Access has been dramatically uneven across markets. In the United States, widespread off-label demand for Ozempic (1 mg semaglutide) for weight management created supply shortages affecting both diabetes and obesity prescribing for several years. Wegovy was placed on the FDA drug shortage list in 2022-2023. In the UK, NHS rollout began through specialist weight management services, limited by manufacturing capacity and commissioning constraints.

The SELECT trial subsequently established a cardiovascular benefit for semaglutide 2.4 mg in adults with established CVD and overweight/obesity without diabetes, and that data supported an FDA label update in 2024. That cardiovascular indication has opened additional coverage pathways in some payer systems because it reframes the drug as a treatment for cardiovascular risk rather than solely for obesity.