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02-11-2021 | Semaglutide | At a glance | Article

Updated November 2022

A quick guide to the STEP trials

Author: Eleanor McDermid

Semaglutide is a weekly injectable glucagon-like peptide (GLP)-1 receptor agonist currently approved for the treatment of people with type 2 diabetes at weekly doses of up to 1.0 mg.

Here we round up the STEP trials, which are testing semaglutide at the higher dose of 2.4 mg/week, specifically for promoting weight loss, regardless of the presence of type 2 diabetes. We will update the page as new results become available.

See also:

STEP 1: Published

Trial population: Obese or overweight people with related comorbidities, but not diabetes

Comparator treatment: Placebo

NCT03548935

The STEP 1 trial involved 1961 participants and was published in The New England Journal of Medicine in early 2021.

The findings revealed an average 14.9% reduction in bodyweight from baseline during 68 weeks of treatment with semaglutide 2.4 mg plus a lifestyle intervention, compared with just a 2.4% reduction in the placebo plus lifestyle intervention group.

In total, 86.4% of the semaglutide group lost at least 5% of their bodyweight, and adverse effects were in line with those expected for the medication class.

Related news stories: 

STEP 2: Published

Trial population: Overweight or obese people with type 2 diabetes

Comparator treatments: semaglutide 1.0 mg and placebo

NCT03552757

This trial, published in The Lancet, recruited 1210 participants with type 2 diabetes and overweight or obesity and tested the standard approved 1.0 mg dose versus the higher 2.4 mg dose and matched placebos over 68 weeks.

Average bodyweight reductions were 9.64%, 6.99%, and 3.42% with semaglutide 2.4 mg, 1.0 mg, and placebo, respectively. The higher dose also achieved slightly better glycemic control, reductions in cardiometabolic risk, and improved physical function relative to the standard dose.

Related news story: STEP 2 shows benefits of higher semaglutide dose in type 2 diabetes

STEP 3: Published

Trial population: Overweight or obese people with related comorbidities, but not diabetes

Comparator treatment: Placebo

NCT03611582

The 611 participants of STEP 3 were randomly assigned to receive semaglutide 2.4 mg or placebo in addition to intensive behavioral therapy to support them to adopt a healthier lifestyle.

As reported in JAMA, the average weight reduction after 68 weeks of treatment was 16.0% with semaglutide versus 5.7% with placebo. The co-primary endpoint of at least a 5% reduction in bodyweight was met by 86.6% versus 47.6%.

Related news story: STEP 3: Semaglutide boosts weight loss in intensive behavioral therapy setting

STEP 4: Published

Trial population: Overweight or obese people with related comorbidities, but not diabetes

Comparator treatment: Placebo

NCT03548987

In this trial, the 902 participants all received semaglutide 2.4 mg for the first 20 weeks, after which they were randomly assigned to receive either semaglutide or placebo for the remaining 48 weeks.

The investigators reported in JAMA that participants who continued to take semaglutide after randomization lost an additional 7.9% of their bodyweight, on average, to give a total 17.4% weight loss over the whole trial, whereas those who switched to placebo regained an average 6.9%, giving a total weight loss of 5.0%.

Related news story: STEP 4: Long-term treatment needed for full semaglutide benefit

STEP 5: Published

Trial population: Obese or overweight people with related comorbidities, but not diabetes

Comparator treatment: Placebo

NCT03693430

This trial, published in Nature Medicine, tested the durability of weight loss with semaglutide 2.4 mg versus placebo across a full 2 years of treatment in 304 participants.

Semaglutide resulted in decreasing weight until about week 60, and the weight loss was maintained through week 104, at which point there was an average placebo-corrected weight loss of 12.6 percentage points.

Related news story: STEP 5: Sustained semaglutide treatment maintains weight loss

STEP 6: Published

Trial population: Obese or overweight East Asian people with related comorbidities.

Comparator treatment: Placebo

NCT03811574

This trial, reported in The Lancet Diabetes & Endocrinology, focused on Asian people (n=401), specifically those from Japan and South Korea.

The researchers found significantly greater bodyweight reductions in people given semaglutide 2.4 or 1.7 mg/week versus placebo, at 13.2%, 9.6%, and 2.1%, respectively.

Semaglutide treatment also produced a significant reduction in abdominal visceral fat in a subset of people who underwent computed tomography and a significant reduction in glycated hemoglobin in people (~25%) with type 2 diabetes.

Related news story: STEP 6: Semaglutide addresses ‘pathophysiology of metabolic syndrome’ in Asians

STEP 7: Completed, not yet published

Trial population: Overweight or obese people with or without type 2 diabetes

Comparator treatment: Placebo

NCT04251156

This trial aims to recruit 375 people – with or without type 2 diabetes – largely across China, but also Hong Kong, the Republic of Korea and Brazil. The participants will receive semaglutide 2.4 mg or placebo for 44 weeks.

STEP 8: Published

Trial population: Overweight or obese people with type 2 diabetes

Comparator treatment: Liraglutide, placebo

NCT04074161

STEP 8 compared the weight loss efficacy of semaglutide 2.4 mg against the daily injectable GLP-1 receptor agonist liraglutide at its approved dose for obesity, of 3.0 mg. 

The results, published in JAMA, showed a significantly greater average bodyweight reduction of 15.8% with semaglutide, compared with 6.4% with liraglutide. This equated to average 15.3 and 6.8 kg decreases.

Related news story: STEP 8: Semaglutide better than liraglutide at weight-management doses

STEP TEENS: Published

Trial population: Adolescents with obesity, or overweight plus related comorbidities

Comparator treatment: Placebo

NCT04102189

As the name suggests, the STEP TEENS trial tested the weight-loss efficacy of semaglutide 2.4 mg in adolescents aged 12–17 years.

Active treatment was associated with a substantial and significant 16.1% reduction in baseline BMI, whereas placebo was associated with a 0.6% increase. Adolescents taking semaglutide also had marked improvements in their lipid profiles, particularly triglycerides.

The findings are published in The New England Journal of Medicine.

Related news story: STEP TEENS: High-dose semaglutide weight loss benefits shown in adolescents

The SELECT trial: Active, not recruiting

Trial population: Overweight or obese people without diabetes but with established cardiovascular disease

Comparator treatment: Placebo

NCT03574597 

SELECT is the companion cardiovascular outcomes trial for semaglutide 2.4 mg in people with obesity. This event-driven trial aims to enroll 17,500 participants and follow them up for an estimated 31 to 59 months.

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