Higher-Dose Semaglutide Achieves Historic 21% Weight Loss in Landmark STEP UP Trial

The landmark STEP UP trial has established a new milestone in obesity management, with semaglutide 7.2 mg delivering a first-time 21% average weight loss over 72 weeks, significantly outperforming the currently approved 2.4 mg dose and setting a new standard for pharmaceutical weight management interventions.

Once-weekly semaglutide 7.2 mg has been demonstrated to significantly enhance weight loss efficacy compared to the currently approved 2.4 mg dose in adults living with obesity, as published recently in The Lancet Diabetes & Endocrinology journal. This milestone finding was established through the rigorous phase 3b STEP UP trial, which assessed the safety and effectiveness of this higher dose over a 72-week period. This represents a clinically important advance for obesity treatment, where higher dose options are needed to manage the global obesity epidemic. Obesity continues to contribute to catastrophic comorbidities such as cardiovascular disease, type 2 diabetes, and metabolic syndrome, highlighting the public health importance of such advances in pharmacotherapy.

Semaglutide Mechanism and Current Approvals

Semaglutide is a glucagon-like peptide-1 receptor agonist (GLP-1 RA) that mimics the hormone glucagon-like peptide-1, which regulates insulin secretion and appetite control. The drug has established a strong therapeutic foundation with semaglutide 2.4 mg approved for chronic weight management in adults with obesity or overweight, with a label expansion in March 2024 adding cardiovascular risk reduction indications.

Clinical Trial Design and Comprehensive Results

Study Design and Methodology

STEP UP trial (NCT05646706) was designed as a phase 3b, randomized, double-blinded, parallel-group, placebo-controlled trial conducted across 95 hospitals, specialist clinics, and medical centers in 11 countries. The 72-week treatment duration with a 9-week off-treatment follow-up period provided robust long-term efficacy and safety data. Between January 1, 2023, and November 26, 2024, researchers enrolled 1,407 adults with obesity (BMI ≥30 kg/m²) without diabetes, randomly assigning participants to receive semaglutide 7.2 mg (n=1,005), semaglutide 2.4 mg (n=201), or placebo (n=201).​

The study population was predominantly female with a mean age of 47 years, mean body weight of 113 kg, and BMI of approximately 40 kg/m². All participants received comprehensive lifestyle interventions including dietary counseling and increased physical activity recommendations every four weeks throughout the study period, ensuring optimal treatment conditions.

The trial achieved its primary endpoint by demonstrating statistically significant and superior weight loss at week 72 with semaglutide 7.2 mg versus placebo. Key secondary endpoints included the proportion of participants achieving weight loss thresholds of 5%, 10%, 15%, 20%, and 25%, with the 7.2 mg dose meeting all secondary endpoints. Additional metabolic benefits included improvements in waist circumference, blood pressure, blood sugar levels, and cholesterol profiles, all critical factors in reducing obesity-related health risks.​

Results

Semaglutide 7.2 mg achieved a mean weight reduction of 20.7% when evaluating treatment adherence effects, compared to 17.5% with semaglutide 2.4 mg and only 2.4% with placebo. In intention-to-treat analyses, semaglutide 7.2 mg still delivered impressive results with 18.7% average weight loss versus 15.6% for the 2.4 mg dose and 3.9% for placebo.

Over 93% of participants on semaglutide 7.2 mg achieved at least 5% weight loss compared to 92.5% on the 2.4 mg dose and only 35.7% on placebo. More remarkably, 33.2% of participants on the 7.2 mg dose achieved 25% or more weight loss, compared to 16.7% on the 2.4 mg dose and 0% on placebo. Nearly half of participants on the higher dose lost 20% or more of their body weight, representing outcomes that approach bariatric surgery-level effectiveness.

Metabolic Health Improvements

Beyond weight loss, participants on semaglutide 7.2 mg experienced comprehensive metabolic improvements including significant reductions in waist circumference, improvements in blood pressure control, enhanced glycemic parameters, and favorable cholesterol profile changes. These multifaceted benefits suggest that the higher dose could provide enhanced protection against obesity-related comorbidities.