STEP 1

Population

• 1961 adults with BMI of 30 or greater, or 27 or greater with at least one weight-related coexisting condition, who did not have diabetes.

Intervention

Once-weekly subcutaneous semaglutide 2.4 mg plus lifestyle intervention for 68 weeks (2:1 randomization).

Comparator

Placebo plus lifestyle intervention.

Key results

• Coprimary percentage change: mean body-weight change from baseline to week 68 was -14.9% with semaglutide versus -2.4% with placebo; estimated treatment difference -12.4 percentage points (95% CI -13.4 to -11.5; P<0.001).
• Coprimary 5% responder: 1047 participants (86.4%) with semaglutide versus 182 (31.5%) with placebo achieved weight reduction of 5% or more at week 68 (P<0.001 for the comparison of odds).
• Additional thresholds at week 68, not coprimary: 10% or more weight loss in 838 (69.1%) versus 69 (12.0%), and 15% or more in 612 (50.5%) versus 28 (4.9%); P<0.001 for both comparisons of odds. Absolute weight change was -15.3 kg versus -2.6 kg (estimated treatment difference -12.7 kg; 95% CI -13.7 to -11.7).
• Participants who received semaglutide had a greater improvement in cardiometabolic risk factors and in participant-reported physical functioning than those who received placebo; the abstract does not give numeric effect sizes for those outcomes.

Harms

• Nausea and diarrhea were the most common adverse events with semaglutide; they were typically transient and mild-to-moderate 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%]).

Practice impact

• Offer once-weekly semaglutide 2.4 mg with lifestyle intervention when the goal is substantial weight loss in adults without diabetes who meet the BMI criteria used here.

Applicability

• Adults with BMI of 30 or higher, or 27 or higher plus at least one weight-related coexisting condition, without diabetes.
• Both groups received lifestyle intervention; the comparison is drug plus lifestyle versus lifestyle plus placebo.

Limitations

• This is a weight-loss trial, not a cardiovascular-outcomes trial.
• The 10% and 15% responder rates are additional results, not coprimary end points.
• Cardiometabolic and physical-functioning improvements are described without numeric estimates.

Common misinterpretations

• Do not quote only the 5% responder rate or only the mean percent change; both were coprimary.
• These participants did not have diabetes; do not treat this as a glycemic-control trial.