STEP UP: Higher Semaglutide Doses Yield Greater Weight Loss in Obesity

Use of semaglutide 7.2 mg (Wegovy) was associated with a mean reduction in body weight of 21% in people with obesity, according to results of the STEP UP trial.

Presented at the 85th Scientific Sessions of the American Diabetes Association (ADA 2025), results of the study demonstrate use of semaglutide 7.2 mg was associated with greater with loss than both placebo and semaglutide 2.4 mg, with more than 30% of semaglutide 7.2 mg users achieving weight loss of 25% or greater during the 72-week trial. Based on results of the trial, Novo Nordisk expects to file for a label update in the European Union in the second half of 2025, followed by regulatory submissions in other markets where semaglutide 2.4 mg is already approved.

“The STEP UP trial demonstrated that we can increase the dose of semaglutide and achieve greater weight loss than previously seen, and in line with semaglutide’s established safety profile. This may offer another option to people who do not attain their weight goals,” said lead investigator Sean Wharton, MD, medical director of the Wharton Medical Clinic in Canada. “We are already aware that semaglutide can have health benefits for people with heart disease, liver disease, knee osteoarthritis, type 2 diabetes and prediabetes. These findings help to give patients with obesity more options for improvements in their weight and overall health.”

In recent years, semaglutide has become synonymous with the fight to curb the type 2 diabetes and obesity epidemics, both among medical circles and the general public. Though it has been approved for more than a decade in the 2.0 mg formulation, the agent’s notoriety and potential applications soared as more and more data from the development of semaglutide 2.4 mg were released. This culminated in a historic approval in 2024 as the first drug treatment to receive FDA approval for chronic weight management since 2014. In 2024, the FDA expanded the labeling for the agent to include cardiovascular risk reduction.

Citing the continued unmet need and inability of some individuals to reach their weight management goals with semaglutide 2.4 mg, Novo Nordisk launched the STEP UP program in 2023 to assess the potential safety and efficacy of semaglutide 7.2 mg.

With this in mind, STEP UP was designed as a randomized, double-blinded, parallel-group, placebo-controlled, superiority trial comparing semaglutide 7.2 mg against semaglutide 2.4 mg and placebo as an adjunct to lifestyle intervention. The trial enrolled 1407 adult patients with a BMI of at least 30 kg/m2 without diabetes and randomized them in a 5:1:1 ratio to semaglutide 7.2 mg, semaglutide 2.4 mg, or placebo therapy.

The study cohort was 74% women, had a mean age of 47 years, a mean body weight of 113 kg, a mean BMI of 39.9 kg/m2, and a mean waist circumference of 119 cm. Overall, 1005 patients were randomized to semaglutide 7.2 mg, 201 were randomized to semaglutide 2.4 mg and 201 were randomized to placebo.

The primary endpoint of interest for the trial was the superiority of semaglutide 7.2 mg against placebo for body weight reduction at week 72. The trial also included multiple confirmatory outcomes, such the proportion of patients achieving 10%, 15%, 20% and 25% weight loss thresholds. In January 2025, Novo Nordisk announced topline results from the trial indicating it had achieved its primary endpoint. At ADA 2025, Wharton presented further data from the trial.

Results at ADA 2025 demonstrated most participants reached the full target dose, including 75.4% for semaglutide 7.2 mg, 89.3% for semaglutide 2.4 mg, and 96.5% for placebo. At week 72, the mean weight loss was 18.7% with semaglutide 7.2 mg, 15.6% with semaglutide 2.4 mg, and 3.9% with placebo (P <.001). Investigators pointed out trial product estimand results suggested 93.2% of the semaglutide 7.2 mg, 92.5% of the semaglutide 2.4 mg group, and 35.7% of the placebo group achieved weight loss of 5% or more at 72 weeks.

When assessing achievement of weight loss thresholds, investigators found more patients using semaglutide 7.2 mg achieved weight loss of 5%, 10%, 15%, 20%, and 25% than the semaglutide 2.4 mg group and the placebo group. Of note, the rate of achieving weight loss of 25% or greater occurred among 33.2% of the semaglutide 7.2 mg group, 16.7% of the semaglutide 2.4 mg group, and 0% among the placebo group, according to the trial product estimand.

“With these results, semaglutide reaffirms its significant weight loss for people with obesity. The STEP UP trial delivers a substantial weight loss of over 20%, in addition to health benefits previously demonstrated with semaglutide,” said Ludovic Helfgott, executive vice president of Product & Portfolio Strategy at Novo Nordisk.

References:

1. Wharton S, Freitas P, Hjelmsaeth J, et al. Efficacy and Safety of Semaglutide 7.2 mg in Obesity–STEP UP Trial. Presented at: 85th American Diabetes Association Scientific Sessions. June 20 – 23, 2025. Chicago, Illinois.

2. Novo Nordisk. Novo Nordisk: Higher dose of Wegovy® provided average weight loss of 21% in people with obesity – with a third achieving 25% or more – according to data presented at ADA. Novo Nordisk. Published June 20, 2025. Accessed June 21, 2025. https://www.novonordisk.com/content/nncorp/global/en/news-and-media/news-and-ir-materials/news-details.html?id=916352

3. FDA. FDA Approves First Treatment to Reduce Risk of Serious Heart Problems Specifically in Adults with Obesity or Overweight. FDA. Published March 8, 2024. Accessed June 21, 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-reduce-risk-serious-heart-problems-specifically-adults-obesity-or