Highlight
- Once-weekly semaglutide 7.2 mg achieved superior weight reduction over the approved 2.4 mg dose and placebo in adults with obesity without diabetes.
- Participants receiving the higher dose experienced mean bodyweight reductions of 18.7% at 72 weeks versus 15.6% with 2.4 mg and 3.9% with placebo.
- The 7.2 mg dose was associated with significantly higher proportions of participants attaining clinically meaningful weight loss thresholds (up to ≥25%).
- The safety profile of semaglutide 7.2 mg retained overall tolerability, with gastrointestinal events being the most common adverse effects.
Background and Clinical Context
Obesity remains a critical public health challenge worldwide, contributing substantially to morbidity, mortality, and healthcare costs through its association with metabolic, cardiovascular, and musculoskeletal complications. Pharmacologic interventions are vital adjuncts to lifestyle changes for achieving and sustaining meaningful weight loss in individuals with obesity. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), such as semaglutide, have revolutionized obesity management due to their efficacy in appetite suppression and weight reduction. Currently, once-weekly subcutaneous semaglutide at 2.4 mg is approved for weight management in individuals with obesity or overweight with related comorbidities. However, a subset of patients does not achieve optimal weight loss with this dosing regimen, motivating the exploration of higher dosing strategies to augment therapeutic effectiveness while maintaining safety.
Study Design and Methods
The STEP UP trial was a randomized, double-blind, placebo-controlled, phase 3b study conducted at 95 sites across 11 countries, enrolling adults (aged ≥18 years) with a body mass index (BMI) ≥30 kg/m2 but without diabetes, thus focusing on the population with obesity alone. Participants were randomized in a 5:1:1 ratio to receive once-weekly subcutaneous semaglutide at 7.2 mg, 2.4 mg, or placebo, respectively, alongside a standardized lifestyle intervention comprising diet and physical activity recommendations. The treatment duration was 72 weeks.
The coprimary efficacy endpoints assessed were the percent change in bodyweight from baseline to week 72 and the proportion of participants achieving ≥5% weight loss compared to placebo. Confirmatory secondary endpoints included comparisons of weight change between 7.2 mg and 2.4 mg semaglutide groups, changes in waist circumference, and proportions of participants reaching incremental weight loss benchmarks (≥10%, ≥15%, ≥20%, and ≥25%) compared to placebo and between active doses.
Safety evaluations included adverse event monitoring, with gastrointestinal symptoms and serious adverse events being closely scrutinized. The trial was registered with ClinicalTrials.gov (NCT05646706).
Key Findings
Between January 2023 and November 2024, 1407 participants were randomized: 1005 received semaglutide 7.2 mg, 201 received 2.4 mg, and 201 received placebo. Baseline demographics were balanced across groups with a mean age of 47 years, predominance of female participants (73.7%), mean bodyweight of approximately 113 kg, and mean BMI near 40 kg/m2.
The semaglutide 7.2 mg group achieved a mean weight reduction of 18.7% (SE 0.4) at 72 weeks versus 15.6% (SE 0.7) with 2.4 mg, yielding a statistically significant estimated treatment difference (ETD) of -3.1% (95% CI, -4.7 to -1.6, p<0.0001). Compared with placebo, the 7.2 mg dose resulted in a -14.8% ETD (-16.2 to -13.4; p<0.0001).
The proportion of participants achieving ≥5% weight loss with semaglutide 7.2 mg was 12.1 times higher than placebo (95% CI, 8.3–17.6; p<0.0001). Notably, this group also demonstrated superior odds of reaching thresholds up to and including ≥25% weight reduction, with an odds ratio of 127.4 (95% CI, 36.8–441.4; p<0.0001) compared to placebo and significantly better outcomes than the 2.4 mg cohort for ≥20% and ≥25% weight loss.
Waist circumference, a surrogate marker for visceral adiposity, showed an average reduction of 11.7 cm (95% CI, -13.0 to -10.4; p<0.0001) with the 7.2 mg dose versus placebo, indicating substantial central fat loss.
In terms of safety, gastrointestinal adverse events were the most commonly reported, affecting 70.8% of participants treated with 7.2 mg semaglutide, compared to 61.2% with 2.4 mg and 42.8% with placebo. Dysaesthesia incidents were more frequent in the high-dose group (22.9%) relative to lower dose (6.0%) and placebo (0.5%). Serious adverse events occurred in 6.8% of participants on 7.2 mg, 10.9% on 2.4 mg, and 5.5% on placebo, with no unexpected safety signals emerging.
Expert Commentary
These results provide compelling evidence for the enhanced efficacy of semaglutide at the 7.2 mg dose in adults with obesity who may not have achieved sufficient weight loss on the 2.4 mg regimen. The additional 3.1% mean bodyweight reduction is clinically meaningful, potentially translating into improved metabolic and cardiovascular outcomes. The progressive increase in the proportion of patients reaching higher weight loss categories substantiates the dose-dependent response of semaglutide’s GLP-1 receptor agonism on appetite regulation and energy homeostasis.
While the increased incidence of gastrointestinal adverse events requires careful patient counseling and monitoring, the overall safety profile remains consistent with the pharmacologic class and earlier studies, supporting the favorable risk-benefit balance. It is noteworthy that serious adverse events did not increase proportionally with the higher dose, alleviating concerns about dose-related toxicity.
The study excludes individuals with diabetes, limiting direct extrapolation to that population; however, given semaglutide’s efficacy among patients with type 2 diabetes at lower doses, similar benefits may be anticipated. Furthermore, the trial’s robust design, large sample size, and international multicenter setting enhance the generalizability of findings across diverse populations.
Conclusion
The STEP UP phase 3b trial robustly demonstrates that once-weekly semaglutide at 7.2 mg provides superior weight loss efficacy compared to the approved 2.4 mg dose and placebo in adults with obesity without diabetes. Importantly, this therapeutic option retains an acceptable safety and tolerability profile consistent with GLP-1 receptor agonists. These results support consideration of semaglutide 7.2 mg as a next-step dose for patients inadequately responding to current standard therapy, potentially improving treatment outcomes in obesity management.
Future research should focus on long-term outcomes, cardiovascular risk reduction, and quality-of-life measures, as well as investigations in populations with diverse metabolic profiles. Personalized approaches to dosing and careful assessment of tolerability will be essential in clinical practice.
Funding and Trial Registration
This study was funded by Novo Nordisk. The trial is registered on ClinicalTrials.gov under the identifier NCT05646706.
References
Wharton S, Freitas P, Hjelmesæth J, Kabisch M, Kandler K, Lingvay I, Quiroga M, Rosenstock J, Garvey WT; 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. 2025 Nov;13(11):949-963. doi: 10.1016/S2213-8587(25)00226-8. Epub 2025 Sep 14. PMID: 40961952.
