STEP 4 — What Happens When You Stop Semaglutide (JAMA 2021)

STEP 4 (Rubino et al., JAMA 2021) was the pivotal weight-maintenance trial demonstrating that continued semaglutide is required to sustain weight loss. Stopping semaglutide leads to substantial weight regain — establishing obesity as a chronic condition requiring ongoing treatment. Trial design. A 68-week phase 3 RCT with a withdrawal design (NCT03548987). All participants received once-weekly subcutaneous semaglutide 2.4 mg + lifestyle intervention during a 20-week open-label run-in. At week 20, those who had reached the maintenance dose and tolerated it (803 of 902 enrolled) were re-randomized 2:1 to continue semaglutide 2.4 mg or switch to placebo for the remaining 48 weeks (week 20 to 68). Population. 803 adults (post-run-in cohort) with overweight or obesity (BMI ≥27 kg/m²) without type 2 diabetes. Mean baseline BMI ~38; mean age 46; 79% women. Primary endpoint. Percentage change in body weight from week 20 (re-randomization) to week 68. Key results. From week 20 to week 68: participants who continued semaglutide lost an additional 7.9% of body weight; those switched to placebo regained 6.9%. Cumulative weight change over the full 68 weeks: −17.4% on continued semaglutide vs −5.0% on those switched to placebo. The estimated treatment difference at week 68 was −14.8 percentage points. Cardiometabolic risk factors deteriorated in the placebo-switched group consistent with weight regain. Adverse events. Gastrointestinal events were the most common, similar to STEP 1 and STEP 2, mostly mild-to-moderate. Indian context. STEP 4 establishes obesity as a chronic disease requiring ongoing pharmacotherapy — analogous to hypertension or dyslipidemia. For Indian patients considering semaglutide, this means treatment is not short-course: discontinuing typically leads to weight regain. The decision to start semaglutide should account for long-term cost (₹220/shot to ₹4,500/month across DCGI-approved Indian generics) and adherence over years.