Once-Weekly Semaglutide in Adults with Overweight or Obesity

The STEP 1 trial was a randomized, double-blind, placebo-controlled study that included 1,961 adults with BMI >=30 (or >=27 with at least one weight-related comorbidity) without type 2 diabetes. Participants were randomized 2:1 to receive subcutaneous semaglutide 2.4 mg or placebo once weekly for 68 weeks, combined with lifestyle intervention (diet with a 500 kcal/day caloric deficit and at least 150 minutes of physical activity per week).

The results were notable: the semaglutide group achieved mean weight loss of 14.9% versus only 2.4% in the placebo group (estimated treatment difference: -12.4 percentage points; p<0.001). Categorical analyses reinforced the magnitude of the effect:

• 86.4% of semaglutide participants achieved >=5% loss
• 69.1% achieved >=10% loss
• 50.5% achieved >=15% loss
• 32.0% achieved >=20% loss

Beyond weight loss, semaglutide produced significant improvements in cardiometabolic risk factors, including waist circumference, blood pressure, C-reactive protein, lipids, and HbA1c. The most common adverse effects were gastrointestinal (nausea, diarrhea, vomiting), generally mild to moderate and transient.

This study was a landmark for demonstrating that a GLP-1 agonist could produce weight loss comparable to bariatric surgery in many patients, leading to the FDA approval of semaglutide 2.4 mg (Wegovy) for chronic obesity treatment and ushering in a new era in the pharmacological management of excess weight.