PMID-35441470 — STEP 1 Extension: Weight Regain After Semaglutide Withdrawal

[DRAFT — authored 2026-04-19. Citation verified against PubMed/Wiley 2026-04-19.]

Citation

Wilding JPH, Batterham RL, Davies M, Van Gaal LF, Kandler K, Konakli K, Lingvay I, McGowan BM, Oral TK, Rosenstock J, Wadden TA, Wharton S, Yokote K, Kushner RF; STEP 1 Study Group. Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension. Diabetes Obes Metab. 2022;24(8):1553-1564. doi: 10.1111/dom.14725. PMID: 35441470.

External URL: PubMed

Study Design

Design: 1-year off-treatment extension of STEP 1 (parent trial: PMID: 33567185)
Parent trial: 68-week RCT of semaglutide 2.4 mg weekly vs placebo + lifestyle intervention in adults with BMI ≥30 (or ≥27 + comorbidity) without T2D (n=1,961)
Extension design: Representative subset who completed 68 weeks of treatment followed for an additional year off treatment (no semaglutide, no lifestyle intervention)
Primary endpoint: Change in body weight from trial end (wk 68) to wk 120 (52 weeks off treatment)

Key Findings

Participants who had received semaglutide 2.4 mg regained approximately two-thirds of the weight they had lost during the 68-week on-treatment period, by the end of the 52-week off-treatment extension.
Cardiometabolic variables (waist circumference, systolic blood pressure, HbA1c, lipid profile, CRP) showed parallel reversal — the benefits observed during treatment partially reversed during the off-treatment year.
Placebo-group participants showed minimal additional change during the extension (no further weight change).

Clinical Relevance

STEP 1 extension confirms and extends the STEP 4 finding: the effects of semaglutide on weight and cardiometabolic parameters are largely on-treatment effects. The evidence supports:

Chronicity framing — Obesity is a chronic relapsing disease; weight-management therapy should be viewed as indefinite treatment, not a time-limited course.
Shared decision-making at initiation — Patients should be counseled upfront that 12+ month persistence is required to sustain benefit, and that regain is expected on cessation.
Paired with SELECT 4-year data (PMID-38740993 – SELECT 4-Year Long-term Weight Loss Ryan), the counter-finding is that WITH continued therapy, weight loss is sustained over at least 4 years.

Linked Peptides

Semaglutide

Related Lessons

Lesson 5.2 — Semaglutide Deep Dive (STEP 1 + extension)
Lesson 5.4 — Discontinuation economics; durability framework

PMID-35441470 – STEP 1 Extension Wilding Weight Regain After Withdrawal