Description

Evidence from STEP‑1, STEP‑4, and SURMOUNT‑4 shows that stopping GLP‑1 or multiagonist therapy commonly causes substantial weight regain and reversal of cardiometabolic gains. In STEP‑1’s extension, semaglutide participants lost −17.3% at week 68 but lost only −5.6% at week 120 after discontinuation, recouping roughly two‑thirds of lost weight within a year. STEP‑4 and SURMOUNT‑4 provide controlled confirmation: continued therapy produced further loss while placebo‑switch arms rapidly regained weight (between‑arm differences ~14.8 percentage points and 19.5 percentage points, respectively). Metabolic markers—waist circumference, blood pressure, HbA1c, lipids—reverted alongside weight. Mechanistically, appetite returns within weeks, and adaptive thermogenesis plus hormonal shifts (↑ghrelin, ↓leptin/PYY) defend a higher set point, making relapse biological rather than behavioural. These findings support framing obesity pharmacotherapy as a long‑term, disease‑modifying treatment that requires planning for sustained use, monitoring for safety, and realistic patient counselling—especially where cost and access constrain continuous therapy.