High-dose semaglutide drives greater weight loss. Safety remains favorable but needs further study.
A weekly semaglutide dose of 7.2 mg has been shown to markedly enhance weight loss and improve health outcomes for adults with obesity, including those who also have type 2 diabetes (T2D).
Evidence from two large, international phase 3 clinical trials, published in The Lancet Diabetes & Endocrinology, indicates that this higher dose may provide an important treatment alternative for people who have not achieved sufficient results with current therapies.
STEP UP clinical trials design
The STEP UP and STEP UP T2D trials represent the first investigations into whether raising the semaglutide dose from the standard 2.4 mg to 7.2 mg is both safe and more effective for weight reduction. Participants were randomly assigned to receive either the higher 7.2 mg dose, the approved 2.4 mg dose, or a placebo for 72 weeks. Regardless of group assignment, all participants also received lifestyle guidance, including dietary support and physical activity recommendations.
In participants without diabetes, treatment with the 7.2 mg dose resulted in an average weight loss of nearly 19%, outperforming the 16% reduction seen with 2.4 mg and the 4% seen with placebo. Almost half of those taking the higher dose lost at least 20% of their body weight, and roughly one-third achieved a reduction of 25% or more.
These individuals also recorded improvements in waist size, blood pressure, blood sugar, and cholesterol—factors closely tied to obesity-related risks. For participants with obesity and T2D, the higher dose produced an average weight loss of 13%, compared with 10% on 2.4 mg and 3.9% on placebo, alongside meaningful reductions in blood sugar levels and waist circumference.
Both trials reported that the higher dose of semaglutide was safe and generally well tolerated. Gastrointestinal side effects like nausea and diarrhea, and some sensory symptoms like tingling, were the most common. However, most side effects were manageable, resolved over time, and did not lead to participants dropping out of the trial. No increase in serious adverse events or severe hypoglycaemia was observed with the higher dose.
Potential impact and next steps
By delivering greater weight reduction and metabolic benefits while maintaining a favorable safety profile, the authors say this higher dose could help more people reach their health goals and reduce the burden of obesity-related complications worldwide. However, they highlight that further research is needed to fully understand the long-term benefits and risks.
Reference: “Once-weekly semaglutide 7·2 mg in adults with obesity (STEP UP): a randomised, controlled, phase 3b trial” by Sean Wharton, Paula Freitas, Jøran Hjelmesæth, Maria Kabisch, Kristian Kandler, Ildiko Lingvay, Maria Quiroga, Julio Rosenstock and W Timothy Garvey, 14 September 2025, The Lancet Diabetes & Endocrinology.
DOI: 10.1016/S2213-8587(25)00226-8
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