Use of semaglutide 7.2 mg vs 2.4 mg is associated with superior outcomes in reduction of body weight, waist circumference, and glycated hemoglobin (HbA1c) among individuals with obesity, including those with type 2 diabetes, according to study findings published in The Lancet Diabetes & Endocrinology.
Although semaglutide 2.4 mg is approved for weight management among adults with obesity and overweight, many individuals still do not reach their weight loss goals with this dose.
To assess the safety and efficacy of semaglutide 7.2 mg among patients with obesity and obesity plus type 2 diabetes, researchers conducted the randomized, double-blind, placebo-controlled STEP UP (ClinicalTrials.gov Identifier: NCT05646706)1 and STEP UP T2D (ClinicalTrials.gov Identifier: NCT05649137)2 trials, respectively. STEP UP comprised adults with a body mass index (BMI) of at least 30 kg/m2 without diabetes, whereas STEP UP T2D comprised adults with a BMI of at least 30 kg/m2 and an HbA1c between 7.0% and 10.0%.
The researchers randomly assigned participants to receive once-weekly subcutaneous semaglutide 7.2 mg or 2.4 mg or placebo in a 5:1:1 ratio in STEP UP and 3:1:1 ratio in STEP UP T2D for 72 weeks followed by 9 weeks of follow-up without treatment. Participants also received an adjunctive lifestyle intervention, which comprised counseling to increase physical activity and reduce caloric intake.
Results from the STEP UP trial therefore support a favourable benefit–risk profile of semaglutide 7.2 mg for weight management in people with obesity, and suggest that a higher dose of semaglutide up to 7.2 mg per week could be used to achieve greater clinical benefits in people not reaching therapeutic goals with once-weekly semaglutide 2.4 mg.
The primary endpoints were percentage change in body weight and the proportion of patients who achieved at least 5% body weight reduction on semaglutide 7.2 mg vs placebo. Secondary endpoints included change in body weight with semaglutide 7.2 mg vs 2.4 mg, change in waist circumference, and proportions of patients who achieved at least 10%, 15%, 20%, and 25% body weight reduction.
STEP UP included 1407 participants (mean age [SD], 47 [12] years; 73.7% women), whereas STEP UP T2D included 512 participants (mean age [SD], 56 [10] years; 51.8% women). Mean BMI was 39.9 kg/m2 and 38.6 kg/m2 in STEP UP and STEP UP T2D, respectively. Baseline characteristics were generally balanced across treatment groups.
In STEP UP, mean change in body weight from baseline to week 72 was significantly greater with semaglutide 7.2 mg (-18.7%) compared with semaglutide 2.4 mg (-15.6%; estimated treatment difference [ETD], -3.1%; P <.0001) and placebo (-3.9%; ETD, -14.8%; P <.0001). Achievement of at least 5% body weight reduction was significantly more likely with semaglutide 7.2 mg vs placebo (odds ratio [OR], 12.1; P <.0001) but not compared with semaglutide 2.4 mg. However, semaglutide 7.2 mg vs 2.4 mg was associated with greater likelihood for achieving body weight reduction of at least:
- 15% (OR, 1.6; 95% CI, 1.2-2.2; P =.002);
- 20% (OR, 1.8; 95% CI, 1.3-2.4; P =.0006); and,
- 25% (OR, 2.4; 95% CI, 1.6-3.5; P <.0001).
In STEP UP T2D, mean change in body weight from baseline to week 72 was also significantly greater with semaglutide 7.2 mg (-13.2%) compared with placebo (-3.9%; ETD, -9.3%; P <.0001) but not with semaglutide 2.4 mg (-2.8%). Achievement of at least 5% body weight reduction was significantly more likely with semaglutide 7.2 mg vs placebo (odds ratio [OR], 10.0; P <.0001) but not compared with semaglutide 2.4 mg. Semaglutide 7.2 mg was also superior to placebo in all other secondary endpoints.
Adverse events rates for patients receiving semaglutide 7.2 mg vs 2.4 mg vs placebo were 87.5%, 84.1%, and 77.6%, respectively, in STEP UP, and 80.1%, 74.8%, and 72.5%, respectively, in STEP UP T2D. Participants receiving semaglutide 7.2 mg vs 2.4 mg and placebo had higher rates of gastrointestinal events (70.8% vs 61.2% and 42.8%) and dysesthesia (22.9% vs 6.0% and 0.5%) in STEP UP and dysesthesia (18.9% vs 4.9% and 0%) in STEP UP T2D.
The researchers observed no increased risk for Level 2 to 3 hypoglycemia between semaglutide doses and placebo in either trial.
Study limitations include potential sex-specific biases due to a majority female population and underpowered exploratory post hoc comparisons in STEP UP, as well as underpowered comparisons of semaglutide 7.2 mg and 2.4 mg in STEP UP T2D.
The researchers concluded, “Results from the STEP UP trial therefore support a favourable benefit–risk profile of semaglutide 7.2 mg for weight management in people with obesity, and suggest that a higher dose of semaglutide up to 7.2 mg per week could be used to achieve greater clinical benefits in people not reaching therapeutic goals with once-weekly semaglutide 2.4 mg.”
1. Wharton S, Freitas P, Hjelmesæth J, et al; on behalf of the STEP UP trial group. Once-weekly semaglutide 7.2 mg in adults with obesity (STEP UP): a randomised, controlled, phase 3b trial. Lancet Diabetes Endocrinol. Published online September 14, 2025. doi: 10.1016/S2213-8587(25)00226-8 2. Lingvay I, Bergenheim S, Buse J, et al; on behalf of the STEP UP T2D trial group. Once-weekly semaglutide 7·2 mg in adults with obesity and type 2 diabetes (STEP UP T2D): a randomised, controlled, phase 3b trial. Lancet Diabetes Endocrinol. Published online September 14, 2025. doi: 10.1016/S2213-8587(25)00225-6