STEP 1 Trial — Semaglutide 2.4 mg Weight Loss: 68 Weeks (NEJM 2021)

STEP 1 (Semaglutide Treatment Effect in People with Obesity Trial 1) was the foundational randomized controlled trial establishing semaglutide 2.4 mg as an effective treatment for chronic weight management in adults without diabetes. Trial design. A 68-week, double-blind, placebo-controlled, phase 3 RCT (NCT03548935). Participants were randomized 2:1 to once-weekly subcutaneous semaglutide 2.4 mg or placebo, both with lifestyle intervention (reduced-calorie diet and increased physical activity). Conducted across approximately 16 countries. Population. 1,961 adults aged ≥18 with obesity (BMI ≥30 kg/m²) or overweight (BMI ≥27 kg/m²) with at least one weight-related comorbidity, but without type 2 diabetes. Mean baseline BMI was 37.9 kg/m²; mean age 46 years; 74% women. Primary endpoints. Percentage change in body weight from baseline at week 68, and the proportion achieving ≥5% weight loss. Key results. Mean body-weight loss was 15.3% on semaglutide versus 2.6% on placebo — an estimated treatment difference of approximately −12.7 percentage points. 86% of semaglutide recipients lost ≥5% of body weight (versus 32% on placebo); 69% lost ≥10%; 50% lost ≥15%; about 1 in 3 (32%) lost ≥20%. Improvements were also observed in cardiometabolic risk factors — waist circumference, systolic blood pressure, HbA1c, and lipid profile. Adverse events. Gastrointestinal events were the most common: nausea ~44%, diarrhea ~32%, vomiting ~24%, constipation ~24% on semaglutide. Most were mild-to-moderate and concentrated during dose escalation. 4.5% of semaglutide participants discontinued due to adverse events versus 0.8% on placebo. Indian context. South Asian subgroup data are limited in STEP 1. Indian regulators (CDSCO/ESI) recognise lower BMI thresholds for intervention — ≥27.5 kg/m², or ≥25 with comorbidity — reflecting higher visceral adiposity and metabolic risk at lower body weights. Clinical benefit in Indian patients is expected at body weights below the trial's average baseline.