A weekly dose of semaglutide at three times the currently approved level was associated with significant weight loss compared to both the currently approved dose and placebo, according to the results of a pair of large, international studies involving adults with obesity, with and without diabetes.

“Many patients [with obesity] have done well on semaglutide at 2.4-mg doses, yet some do not reach their goals of health or weight change,” Sean Wharton, MD, an obesity specialist and assistant professor at the University of Toronto, Toronto, Ontario, Canada, said in an interview. More intensive treatment may be beneficial to achieve these goals, he said.

The studies were designed to test the safety and effectiveness of a 7.2-mg weekly dose of semaglutide for weight management in individuals who have not achieved desired weight loss on other therapies. The results of both studies, known as STEP UP and STEP UP T2D, were presented at the European Association for the Study of Diabetes (EASD) 2025 Annual Meeting and recently published in The Lancet Diabetes & Endocrinology.

The phase 3b, randomized, placebo-controlled STEP UP study was conducted across 95 hospitals in 11 countries by Wharton and an international team of researchers. A total of 1407 adults with obesity were randomly assigned to a weekly injection of 7.2 mg semaglutide (1005 participants), 2.4 mg semaglutide (201 participants), or a placebo (201 participants) for 72 weeks. The mean age of the participants was 47 years; 73.7% were women, and the mean BMI at baseline was 39.9. All participants also received lifestyle intervention guidance on diet and physical activity.

Overall, participants in the 7.2 mg semaglutide group averaged a significantly greater change in body weight than either the 2.4 mg group (-18.7% vs -15.6%) or the placebo group (-18.7% vs -3.9%; P < .001 for both). In addition, those in the 7.2 mg group were significantly more likely than those in the 2.4 mg group to achieve reductions in body weight of at least 20% or 25%, with odds ratios of 1.8 and 2.4, respectively. Individuals in the 7.2 mg group were significantly more likely than those in the placebo group to achieve body weight reductions of at least 5%, 10%, 15%, 20%, or 25%, with odds ratios of 12.1, 14.5, 20.3, 27.3, and 127.4, respectively.

Individuals in the 7.2 mg group also showed significantly greater reductions in waist circumference after 72 weeks than those in the placebo group, with an estimated treatment difference of -11.7 cm.

Safety Signals Consistent

Reports of serious adverse events were relatively low and similar across the 7.2 mg semaglutide, 2.4 mg semaglutide, and placebo groups (6.8%, 10.9%, and 5.5%, respectively). Gastrointestinal (GI) adverse events were more frequent in the 7.2 mg group than in the 2.4 mg and placebo groups (70.8%, 61.2%, and 42.8%, respectively), but these were mainly mild to moderate.

Reports of dysesthesia events such as sensations of tingling, numbness, and burning were more frequent in the 7.2 mg group than in the other groups, and this side effect merits additional investigation, the researchers wrote. Most events were mild and resolved by the end of the study period.

The findings were limited by several factors including the potential for sex-specific bias given the mainly female population, and the relatively short follow-up period for assessing resolution of adverse events, the researchers noted.

Overall, the results suggest a favorable risk-benefit profile and support a 7.2-mg dose of semaglutide for clinical benefits in individuals who could not achieve their therapeutic goals with a 2.4-mg dose, they said.

Benefits Beyond Weight Loss

Wharton was pleased by the additional weight loss with the higher dose; however, he was even more pleased with the minimal side effects that dissipated over time. The majority of GI side effects occur during dose escalation and then improve, and that was the case in this study, he said.

In addition, individuals in the 7.2 mg group experienced greater improvements in blood pressure, blood sugar, and cholesterol levels than those in the 2.4 mg and placebo groups.

Looking ahead to clinical practice, the results suggest that patients who would like to benefit from the many improvements in complications of obesity, such as coronary artery disease and metabolic dysfunction-associated steatohepatitis, can take semaglutide and have the option to increase in dose to get greater effect, Wharton told Medscape Medical News. But more research is needed to understand the mechanism of dysesthesia to prevent it, he noted.

Another research question is whether patients can maintain weight at a lower dose of semaglutide once weight is lost at the higher doses, he added.

Improved Outcomes Extend to Individuals With Diabetes

The goal of the STEP UP T2D trial was to explore the safety and efficacy of a 7.2-mg weekly dose of semaglutide for weight loss in individuals with both obesity and type 2 diabetes. The mean age of study participants was 56 years; 51.8% were women, and mean BMI was 38.6.

Following the same design as the STEP UP study, 512 patients were randomly assigned to 7.2 mg semaglutide (307 participants), 2.4 mg semaglutide (103 participants), or placebo (102 participants). Similar to the STEP UP study, the 7.2 mg group averaged a higher body weight loss after 72 weeks than the other treatment group and the placebo group, with mean changes of -13.2%, -10.4%, and -3.9%, respectively.

In addition, significantly more participants in the 7.2 mg group than in the 2.4 mg and placebo groups achieved the secondary endpoints of body weight reductions from baseline of more than 10%, 15%, or 20%. Safety and side effect profiles were similar to those seen in the STEP UP study.

“As expected, more people achieved treatment goals with the higher dose of semaglutide,” said study investigator Ildiko Lingvay, MD, an endocrinologist and professor of internal medicine at the University of Texas Southwestern Medical Center, Dallas.

“What we were pleasantly surprised by was that the frequency of side effects was not proportionally higher, and this much higher dose of semaglutide was well tolerated overall,” she told Medscape Medical News.

Based on the new data, the clinical implications of the STEP UP studies are that those who need more effective treatment may have a safe and effective option of increasing the semaglutide dose to achieve their treatment goals, Lingvay said.

More Research Needed to Confirm Safety

The higher dose of semaglutide was associated with more side effects, particularly GI effects, than placebo, said Lora Heisler, PhD, of the University of Aberdeen, Aberdeen, Scotland, who was not involved in the study, in an online comment through the Science Media Centre.

The 7.2-mg dose of semaglutide used in the STEP UP studies was notably higher than the current dose that has undergone rigorous safety testing, she said. This dose is still under investigation, and its benefit needs to be considered alongside safety by regulatory bodies, she added.

Most of the weight loss with semaglutide was body fat, noted Heisler, but “something to follow up in future is whether some muscle is also lost with this higher degree of weight loss produced by semaglutide.”

“Every person is different and what is right for one person may not be right for another, and it is important for patients to discuss treatment with their healthcare provider to find out what is best for them, if this higher dose of semaglutide does get approved for widespread use in future,” Heisler said.

The STEP UP and STEP UP T2D studies were funded by Novo Nordisk.

Wharton disclosed receiving payment or honoraria from AstraZeneca, Bausch Health Canada, Boehringer Ingelheim, Eli Lilly, Metsera, Neurogastrx, Novo Nordisk, and Regeneron for academic talks to colleagues; receiving medical writing support from AstraZeneca, Boehringer Ingelheim, Bausch Health Canada, Eli Lilly, and Novo Nordisk; and having unpaid leadership roles in The Obesity Society and Obesity Canada.

Lingvay disclosed receiving grants from Boehringer Ingelheim, Dexcom, Eli Lilly, Novo Nordisk, Roche, and Pfizer, with all payments made to her institution, as well as receiving payment or honoraria from AbbVie, Altimmune, Alveus Therapeutics, Amgen, Antag Therapeutics, AstraZeneca, Bayer, Betagenon, Bioio, Biomea, Boehringer Ingelheim, Carmot, Cytoki Pharma, Eli Lilly, Intercept, Janssen/J&J, Juvena, Keros Therapeutics, Mediflix, Merck, Metsera, Neurocrine, Novo Nordisk, PharmaVentures, Pfizer, Regeneron, Roche, Sanofi, Shionogi, Source Bio, Structure Therapeutics, Target RWE, Terns Pharma, The Comm Group, Verdiva Bio, WebMD, and Zealand Pharma. Lingvay also disclosed receiving support to attend meetings from AstraZeneca, Boehringer Ingelheim, Novo Nordisk, and Eli Lilly.

Heisler disclosed serving as a consultant, serving on a scientific advisory board, and receiving research funding from multiple pharmaceutical companies but reported having no relationship with study sponsor Novo Nordisk.