Quick answer
Extended answer
What is the STEP programme?
Key facts
- Compound
- Semaglutide 2.4 mg SC weekly
- Design
- Randomised, double-blind, placebo- or active-controlled
- Population
- Adults with overweight or obesity
- Follow-up
- 68 weeks (STEP-1)
- Primary outcome (STEP-1)
- Percent change in body weight
- Lead publication (STEP-1)
- NEJM 2021
- DOI (STEP-1)
- 10.1056/NEJMoa2032183
Background
Earlier GLP-1 receptor agonist studies had reported modest weight change as a secondary outcome. The STEP programme was designed to evaluate once-weekly Semaglutide 2.4 mg at doses higher than those used in type 2 diabetes specifically for weight management.
Study design
Each STEP trial is randomised, double-blind and placebo-controlled (with active-comparator arms in some trials), typically over 68 weeks. All arms included lifestyle intervention (reduced-calorie diet and increased physical activity).
Population
- STEP-1: adults with overweight/obesity without diabetes.
- STEP-2: adults with overweight/obesity and type 2 diabetes.
- STEP-3: adults with overweight/obesity with intensive behavioural therapy.
- STEP-4: dose maintenance / withdrawal design.
- STEP-5: long-term (104 weeks).
- STEP-6 / 7 / 8: East Asian population, exercise-supported and comparator designs.
Primary outcomes
The primary endpoint across the programme is percent change in body weight from baseline. STEP-1 reported approximately −14.9% change from baseline with Semaglutide 2.4 mg vs −2.4% with placebo at 68 weeks.[2]STEP-2 reported ~ −9.6% with Semaglutide 2.4 mg vs ~ −3.4% with placebo in adults with type 2 diabetes.[3]
Scientific significance
- Established once-weekly Semaglutide 2.4 mg as a well-characterised weight-management intervention.
- Supported regulatory approvals for chronic weight management (as Wegovy).
- Framed subsequent large cardiovascular trials in obesity without diabetes (SELECT).
Limitations
Research limitations
- Weight regain has been documented after Semaglutide discontinuation in the STEP-4 maintenance/withdrawal design.
- Long-term data beyond 2 years remain limited relative to lifestyle-only comparators.
- Trial populations may not represent the full spectrum of adults with obesity in clinical practice.
- Weight change is a surrogate for downstream health outcomes evaluated separately in trials such as SELECT.
Research-use framing
Related reading: Semaglutide monograph, Semaglutide research applications, SUSTAIN-6 and SELECT trial.
References5
- 1.
Marso SP, Bain SC, Consoli A, et al.. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes (SUSTAIN-6).. New England Journal of Medicine. 2016;375(19):1834-1844.
- 2.
Wilding JPH, Batterham RL, Calanna S, et al.. Once-weekly semaglutide in adults with overweight or obesity (STEP 1).. New England Journal of Medicine. 2021;384(11):989-1002.
- 3.
Davies M, Færch L, Jeppesen OK, et al.. Semaglutide 2·4 mg once a week in adults with overweight or obesity and type 2 diabetes (STEP 2).. Lancet. 2021;397(10278):971-984.
- 4.
Lincoff AM, Brown-Frandsen K, Colhoun HM, et al.. Semaglutide and cardiovascular outcomes in obesity without diabetes (SELECT).. New England Journal of Medicine. 2023;389(24):2221-2232.
- 5.
Perkovic V, Tuttle KR, Rossing P, et al.. Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes (FLOW).. New England Journal of Medicine. 2024;391(2):109-121.
Evidence summary
- What is Semaglutide?
Beginner-friendly research-focused introduction to Semaglutide — a long-acting GLP-1 receptor agonist derived from native GLP-1(7-37).
- Semaglutide Mechanism of Action
Receptor-level explanation of Semaglutide's activity at GLP-1R — Gαs / cAMP / PKA / EPAC2 signalling, β-arrestin recruitment, insulinotropic and glucagonostatic effects, gastric emptying and central appetite modulation.
- Semaglutide FAQ
Comprehensive research-focused FAQ on Semaglutide — identity, receptor pharmacology, structural modifications, pharmacokinetics, laboratory handling, evidence base and regulatory status.
- Semaglutide Pharmacokinetics
Reported pharmacokinetics of Semaglutide — half-life, albumin binding, C18 di-acid acylation, absorption for subcutaneous vs oral formulations, distribution, steady state and research limitations.
- Semaglutide Research Applications
Overview of published Semaglutide research contexts — metabolic, cardiovascular, renal, neuroinflammation/CNS and NAFLD/MASH — with a clear preclinical vs human evidence split.
- Albumin Binding and Half-Life Extension
Reusable mechanism guide explaining how fatty-acid acylation supports reversible non-covalent binding to serum albumin, and how that extends the plasma half-life of GLP-1 peptides.
Research use only
Publication information
- Published
- 2026-10-15
- Updated
- 2026-10-15
- Reviewed
- 2026-10-15
- Version
- 1.0
Revision history
- v1.02026-10-15· Editorial Team
Authority Sprint 2D — initial publication of GLP-1 foundation study summaries.
Editorial standards
Content is reviewed against our editorial process for scientific accuracy, sourcing, and clarity. Read our editorial standards.
Conflict of interest
Next scheduled review: 2028-04-15. Our research methodology describes how the review is conducted.