STEP 1 study - semaglutide in people with obesity

Last edited 03/2023 and last reviewed 10/2023

Obesity is a global health challenge with few pharmacologic options. The STEP 1 study investigated whether adults with obesity can achieve weight loss with once-weekly semaglutide at a dose of 2.4 mg as an adjunct to lifestyle intervention has not been confirmed.

• double-blind trial
  • enrolled 1961 adults with a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or greater (>=27 in persons with >=1 weight-related coexisting condition), who did not have diabetes, and randomly assigned them, in a 2:1 ratio, to 68 weeks of treatment with once-weekly subcutaneous semaglutide (at a dose of 2.4 mg) or placebo, plus lifestyle intervention
  • coprimary end points were the percentage change in body weight and weight reduction of at least 5%
  • primary estimand (a precise description of the treatment effect reflecting the objective of the clinical trial) assessed effects regardless of treatment discontinuation or rescue interventions.

• mean change in body weight from baseline to week 68 was -14.9% in the semaglutide group as compared with -2.4% with placebo, for an estimated treatment difference of -12.4 percentage points (95% confidence interval [CI], -13.4 to -11.5; P<0.001)
• more participants in the semaglutide group than in the placebo group achieved weight reductions of 5% or more (1047 participants [86.4%] vs. 182 [31.5%]), 10% or more (838 [69.1%] vs. 69 [12.0%]), and 15% or more (612 [50.5%] vs. 28 [4.9%]) at week 68 (P<0.001 for all three comparisons of odds)
• change in body weight from baseline to week 68 was -15.3 kg in the semaglutide group as compared with -2.6 kg in the placebo group (estimated treatment difference, -12.7 kg; 95% CI, -13.7 to -11.7)
• participants who received semaglutide had a greater improvement with respect to cardiometabolic risk factors and a greater increase in participant-reported physical functioning from baseline than those who received placebo
• nausea and diarrhea were the most common adverse events with semaglutide; they were typically transient and mild-to-moderate in severity and subsided with time
  • more participants in the semaglutide group than in the placebo group discontinued treatment owing to gastrointestinal events (59 [4.5%] vs. 5 [0.8%])

Comments Relating to Trial Design:

• 44% of the participants had prediabetes (45.4% in the semaglutide group and 40.2% in the placebo group)
  • raises questions regarding the efficacy of semaglutide for weight loss specifically in those with normal glucose tolerance
• trial population over-represented the female sex (73.1%) and white race (74.5%) compared to the US and global populations
• given the relatively short duration of the trial (68 weeks), the results may not generalize to long-term effects.

• in participants with overweight or obesity, 2.4 mg of semaglutide once weekly plus lifestyle intervention was associated with sustained, clinically relevant reduction in body weight
• semaglutide was associated with a significantly greater proportion of participants achieving weight loss of >= 5% compared with placebo. Semaglutide was well-tolerated with similar frequency of adverse events and serious adverse events between treatment arms. More participants in the semaglutide group had to discontinue study drug due to gastrointestinal events
• once-weekly dosing of semaglutide may improve medication adherence

Prediabetes in the Step 1 trial cohort:

• analysis of patients with prediabetes in STEP 1, 3 and 4 trials (n=1,536) found semaglutide arms had more patients with normoglycaemia than placebo at week 68 (84.1% vs 47.8%, 89.5% vs 55.0% and 89.8% vs 70.4% for STEP trials 1, 3, 4 respectively, p<0.0001 for all)

Reference:

• Wilding JP et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity.N Engl J Med 2021; 384:989-1002
• Perreault, L et al. Changes in Glucose Metabolism and Glycemic Status With Once-Weekly Subcutaneous Semaglutide 2.4 mg Among Participants With Prediabetes in the STEP Program. Diabetes Care 2022; dc211785. https://doi.org/10.2337/dc21-1785