STEP-3 Trial Summary: Semaglutide with Intensive Behavioral Therapy

Design

Randomized, double-blind, placebo-controlled phase 3 trial enrolling 611 adults with BMI of 30 or greater (or 27 or greater with at least one weight-related comorbidity) without diabetes. Participants were randomized 2:1 to once-weekly subcutaneous semaglutide 2.4 mg or placebo, both combined with intensive behavioral therapy (IBT). The IBT program consisted of 30 counseling sessions over 68 weeks, including dietary guidance, physical activity recommendations, and behavioral strategies. All participants also underwent an initial 8-week low-calorie diet (1,000-1,200 kcal/day using meal replacements) before randomization, followed by a transition to a conventional reduced-calorie diet for the remainder of the trial. The treatment period was 68 weeks.

Primary result

Mean body weight change from randomization to week 68 was -16.0% with semaglutide versus -5.7% with placebo, a treatment difference of -10.3 percentage points. Among semaglutide-treated participants, 86.6% achieved at least 5% weight loss, 75.3% achieved at least 10% weight loss, and 55.8% achieved at least 15% weight loss, compared with 47.6%, 27.0%, and 13.2% with placebo, respectively.

Secondary outcomes

Semaglutide produced greater improvements in waist circumference, systolic and diastolic blood pressure, C-reactive protein, and lipid parameters compared with placebo. Physical functioning as measured by the SF-36 physical component score improved more with semaglutide. Glycemic parameters including fasting glucose and HbA1c also improved, consistent with enhanced insulin sensitivity from weight loss. The combination of semaglutide with IBT and an initial low-calorie diet produced numerically greater weight loss than semaglutide with standard lifestyle counseling in the STEP-1 trial, though cross-trial comparisons have inherent limitations.

Adverse events

Gastrointestinal events were the most common adverse effects with semaglutide: nausea (53.0%), diarrhea (35.7%), constipation (26.1%), and vomiting (31.8%). GI event rates were higher than in STEP-1, which may reflect the initial low-calorie diet period or the higher intensity of dietary intervention. Discontinuation of treatment due to adverse events was 5.9% with semaglutide versus 2.9% with placebo. Serious adverse events occurred in 9.1% of semaglutide-treated participants versus 2.9% of placebo-treated participants. Cholelithiasis occurred more frequently with semaglutide, consistent with rapid weight loss.

Interpretation

STEP-3 demonstrated that combining semaglutide 2.4 mg with intensive behavioral therapy and an initial low-calorie diet produces substantial weight reduction approaching 16%, exceeding the results achieved by either pharmacotherapy with standard counseling or intensive behavioral therapy alone. The trial addressed the clinically relevant question of whether maximizing both pharmacologic and behavioral components would yield additive benefit. The result was affirmative. The higher GI adverse event rate relative to STEP-1 is notable and may require clinical attention during the low-calorie diet phase. STEP-3 contributed to the evidence base supporting FDA approval of semaglutide 2.4 mg (Wegovy) for chronic weight management.