PMID-33755728 — STEP 4: Continued Semaglutide vs Placebo on Weight-Loss Maintenance

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

Citation

Rubino D, Abrahamsson N, Davies M, Hesse D, Greenway FL, Jensen C, Lingvay I, Mosenzon O, Rosenstock J, Rubio MA, Rudofsky G, Tadayon S, Wadden TA, Dicker D; STEP 4 Investigators. Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity: The STEP 4 Randomized Clinical Trial. JAMA. 2021;325(14):1414-1425. doi: 10.1001/jama.2021.3224. PMID: 33755728.

External URL: PubMed

Study Design

Design: Randomized, double-blind, 68-week phase 3a withdrawal study
Setting: 73 sites in 10 countries, June 2018 – March 2020
Population: Adults with overweight or obesity (BMI ≥30 or ≥27 + comorbidity), without T2D
Pre-randomization: 20-week run-in with open-label once-weekly subcutaneous semaglutide titrated to 2.4 mg
Randomization at week 20: Continue semaglutide 2.4 mg vs switch to placebo for 48 weeks
N: 803 participants randomized after completing run-in
Primary outcome: Percent change in body weight from week 20 to week 68

Key Findings

Continue-semaglutide group: Mean body weight change from week 20 to week 68 = −7.9% (additional loss beyond the run-in weight reduction)
Switch-to-placebo group: Mean body weight change = +6.9% (weight regain)
Estimated treatment difference: −14.8 percentage points (95% CI −16.0 to −13.5, P<0.001)
Patients who switched to placebo regained approximately two-thirds of the weight lost during the 20-week run-in
Cardiometabolic risk factor improvements also reversed with placebo switch

Clinical Relevance

STEP 4 is the defining trial on weight-loss maintenance with semaglutide. It established three clinical realities:

Continued semaglutide therapy is required to sustain weight loss. Discontinuation produces substantial weight regain within 48 weeks.
Cardiometabolic improvements (blood pressure, lipids, glucose) reverse with withdrawal. The drug's benefits are on-treatment effects, not durable physiological resets.
Informed consent should anchor the "chronic-therapy" framing. Patients should be counseled that weight maintenance requires indefinite treatment under current evidence.

Linked Peptides

Semaglutide

Related Lessons

Lesson 5.2 — Semaglutide Deep Dive (STEP program; discontinuation discussion)
Lesson 5.4 — Discontinuation economics framing

PMID-33755728 – STEP 4 Rubino Weight Maintenance Withdrawal