Published in Nature Medicine on October 10, 2022, this phase 3, double-blind, randomized, placebo-controlled trial (STEP 5) evaluates the long-term efficacy and safety of once-weekly subcutaneous semaglutide (2.4 mg) in adults with overweight or obesity but without diabetes. The study enrolled 304 participants with a body mass index (BMI) of ≥30 kg/m² or ≥27 kg/m² with at least one weight-related comorbidity. Participants were randomized 1:1 to receive semaglutide or placebo, alongside lifestyle interventions, for 104 weeks (2 years) across 37 sites in five countries.
Key Findings:
- Weight Loss: Semaglutide led to a mean body weight reduction of 15.2% from baseline compared to 2.6% with placebo (estimated treatment difference, -12.6%; 95% CI, -15.3 to -9.8; P<0.0001). Weight loss was sustained over the 2-year period.
- Weight Reduction Goals: A significantly higher proportion of semaglutide-treated participants achieved ≥5%, ≥10%, ≥15%, and ≥20% weight loss (77.1% vs. 34.4% for ≥5%; P<0.0001), with 36.1% achieving ≥20% loss compared to 2.0% in the placebo group.
- Cardiometabolic Benefits: Semaglutide improved waist circumference, systolic blood pressure, lipid profiles, and HbA1c levels, reducing the risk of developing type 2 diabetes.
- Safety Profile: Adverse events were consistent with GLP-1 receptor agonists, with gastrointestinal issues (e.g., nausea, diarrhea) being most common, mostly mild to moderate and transient. Serious adverse events occurred in 17.1% of the semaglutide group versus 15.8% in the placebo group, with no new safety signals.
- Clinical Implications: The sustained weight loss and cardiometabolic improvements over 2 years highlight semaglutide’s potential as a long-term treatment for obesity, addressing a critical need for effective, durable therapies.
This study, part of the STEP program, reinforces semaglutide’s role as a transformative option for obesity management, offering significant and sustained weight loss when combined with lifestyle changes.
Links to Related Studies for Further Reading
For readers interested in exploring more research on semaglutide and obesity management, here are additional studies:
- Once-Weekly Semaglutide in Adults with Overweight or Obesity
New England Journal of Medicine (February 10, 2021)
This phase 3 trial (STEP 1) reports semaglutide (2.4 mg weekly) achieving a 14.9% mean weight reduction in nondiabetic adults with obesity, compared to 2.4% with placebo, providing foundational evidence for its efficacy.
Read More - Tirzepatide as Compared with Semaglutide for the Treatment of Obesity
New England Journal of Medicine (May 11, 2025)
This phase 3b trial compares tirzepatide (10 or 15 mg weekly) with semaglutide (1.7 or 2.4 mg weekly) in adults with obesity, finding superior weight loss with tirzepatide (-20.2% vs. -13.7%).
Read More - Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes
New England Journal of Medicine (June 13, 2019)
This trial evaluates oral semaglutide’s cardiovascular safety in type 2 diabetes, showing noninferiority to placebo for major adverse cardiovascular events, with benefits in glycemic control and weight loss.
Read More - Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes
New England Journal of Medicine (July 8, 2021)
This trial demonstrates semaglutide (1.0 mg weekly) reducing the risk of kidney failure and cardiovascular events by 24% in patients with type 2 diabetes and chronic kidney disease.
Read More
These studies provide a comprehensive view of semaglutide’s applications across obesity.
Note: Always consult healthcare professionals before considering treatments discussed in these studies. For the full text of the STEP 5 trial, visit Nature Medicine.
