Last updated: April 2026 · UK research-grade reference · For laboratory research use only — not for human consumption
Table of Contents
- 1. Overview — the STEP programme and what it measured
- 2. STEP-1 primary results — the 68-week headline
- 3. Week-by-week weight-loss trajectory
- 4. Response-rate distributions
- 5. STEP-5 — the 104-week long-term extension
- 6. STEP-4 — the withdrawal trial
- 7. STEP-2 — T2DM cohort (different dynamics)
- 8. STEP-3 — intensive behavioural therapy arm
- 9. STEP-6 — Asian cohort
- 10. STEP-8 — head-to-head vs liraglutide
- 11. Body composition — lean vs fat mass
- 12. Predictors of response
- 13. Weight regain after discontinuation
- 14. UK research protocol design implications
- FAQ
- References
1. Overview — the STEP programme and what it measured
The STEP programme (Semaglutide Treatment Effect in People with obesity) was Novo Nordisk’s Phase 3 clinical programme for semaglutide 2.4 mg weekly in obesity. It comprised eight pivotal trials running from 2018 through to 2023, with a total enrolled cohort of approximately 4,500 participants across diverse geographies and comorbidity subgroups. The primary reference trial is STEP-1 (NCT03548935), a 68-week global placebo-controlled obesity trial in adults without diabetes. The full STEP programme covers T2DM, paediatric adolescent obesity (STEP TEENS), Asian populations, and head-to-head comparison with liraglutide.
For UK laboratory research on semaglutide weight-loss dynamics, the combined STEP programme provides the most comprehensive time-course and dose-response dataset of any obesity pharmacotherapy.
2. STEP-1 primary results — the 68-week headline
STEP-1 (Wilding et al, N Engl J Med 2021) randomised 1,961 adults (BMI ≥30, or ≥27 with weight-related comorbidity, without diabetes) 2:1 to semaglutide 2.4 mg weekly or placebo for 68 weeks, with identical lifestyle intervention.
Primary endpoints:
- Mean body-weight change: semaglutide −14.9%, placebo −2.4% (p < 0.001)
- Mean absolute body-weight change: semaglutide −15.3 kg, placebo −2.6 kg
- ≥5% weight loss: semaglutide 86.4%, placebo 31.5%
- ≥10% weight loss: semaglutide 69.1%, placebo 12.0%
- ≥15% weight loss: semaglutide 50.5%, placebo 4.9%
- ≥20% weight loss: semaglutide 32.0%, placebo 1.7%
These are the reference numbers for all subsequent semaglutide obesity research and for cross-molecule comparisons (with liraglutide in STEP-8 and with tirzepatide in SURMOUNT-5).
3. Week-by-week weight-loss trajectory
The STEP-1 weight-loss curve follows a predictable shape: rapid early loss during the 16-week titration, continued loss through the maintenance phase, and approaching plateau around week 60-68. Approximate pooled time-course (semaglutide arm):
- Week 4: ~−2% (early titration, 0.25 mg weekly)
- Week 8: ~−3.5%
- Week 12: ~−6%
- Week 16: ~−7% (titration complete, now 2.4 mg maintenance)
- Week 20: ~−8.5%
- Week 24: ~−10%
- Week 28: ~−11%
- Week 36: ~−12%
- Week 44: ~−13%
- Week 52: ~−14%
- Week 60: ~−14.5%
- Week 68: −14.9% (primary endpoint)
The approximate plateau around week 60-68 reflects the new steady-state energy balance between reduced caloric intake (driven by sustained appetite suppression) and reduced basal metabolic rate (driven by both lean-mass loss and adaptive thermogenesis).
4. Response-rate distributions
Response distribution is more informative than the mean because semaglutide produces a broad response range. STEP-1 distribution at week 68:
- Weight loss >25%: 10.8%
- 20-25%: 21.2%
- 15-20%: 18.5%
- 10-15%: 18.6%
- 5-10%: 17.3%
- 0-5%: 7.7%
- No loss or weight gain: 5.9%
Roughly 10% of participants achieve very large weight loss (>25%) and ~6% have little or no response. The mean (−14.9%) therefore masks substantial individual variation.
5. STEP-5 — the 104-week long-term extension
STEP-5 (Garvey et al, Nat Med 2022) extended semaglutide 2.4 mg weekly in 304 participants to 104 weeks (approximately 2 years) to assess long-term effect:
104-week results:
- Mean body-weight change: semaglutide −15.2%, placebo −2.6%
- ≥10% weight loss: 77.1% vs 17.4%
- ≥15% weight loss: 61.8% vs 7.6%
- ≥20% weight loss: 39.2% vs 4.9%
Key findings: minimal additional weight loss between week 68 and week 104 (−14.9% → −15.2%), confirming the plateau pattern. Weight maintenance at 104 weeks suggests the new steady-state body weight is sustainable on continuous treatment — though without continuous treatment, weight regain is substantial (STEP-4).
6. STEP-4 — the withdrawal trial
STEP-4 (Rubino et al, JAMA 2021) was the critical withdrawal trial, designed to answer: “what happens if you stop semaglutide?”
Design: 803 participants ran a 20-week open-label lead-in with semaglutide 2.4 mg weekly (all participants titrated to maintenance and began losing weight). At week 20, participants were randomised 2:1 to continue semaglutide or switch to placebo, for a further 48 weeks.
Results (week 20 to week 68):
- Continuing-semaglutide arm: additional −7.9% weight change (total from baseline: −17.4%)
- Switched-to-placebo arm: +6.9% weight regain (total from baseline: −5.0%)
- Difference at week 68 between arms: −14.8 percentage points
In plain terms: stopping semaglutide produces approximately 65-70% regain of the weight lost during the treatment phase, over the subsequent 48 weeks. Full baseline-weight return was not observed at 48 weeks post-withdrawal but was tracking upward at study end, suggesting continued regain with longer observation.
This is the empirical basis for the consensus view that GLP-1 receptor agonist obesity treatment is chronic disease management, not short-course intervention.
7. STEP-2 — T2DM cohort (different dynamics)
STEP-2 randomised 1,210 participants with T2DM (BMI ≥27) to semaglutide 2.4 mg weekly, semaglutide 1.0 mg weekly (the T2DM dose), or placebo for 68 weeks.
68-week results:
- Semaglutide 2.4 mg: −9.6% weight change
- Semaglutide 1.0 mg: −7.0%
- Placebo: −3.4%
The T2DM cohort consistently shows ~5 percentage points less weight loss than the non-diabetic STEP-1 cohort at the same 2.4 mg dose — a well-documented pattern across the GLP-1 class. Mechanism is incompletely understood but likely involves reduced caloric-deficit tolerance owing to glycaemic homeostasis, altered adipose insulin sensitivity, and participant-level factors (baseline HbA1c, diabetes duration).
8. STEP-3 — intensive behavioural therapy arm
STEP-3 randomised 611 adults to semaglutide 2.4 mg + intensive behavioural therapy or placebo + intensive behavioural therapy, for 68 weeks.
68-week results:
- Semaglutide + IBT: −16.0% weight change
- Placebo + IBT: −5.7%
IBT (a 30-session structured behavioural programme) added approximately 3 percentage points of loss in the placebo arm (−5.7% vs STEP-1’s −2.4%) and approximately 1 percentage point in the semaglutide arm (−16.0% vs STEP-1’s −14.9%). Semaglutide’s effect appears largely independent of the added behavioural intervention, with the behavioural intervention producing the most added benefit in non-pharmacologically-treated participants.
9. STEP-6 — Asian cohort
STEP-6 randomised 401 Asian adults (Japan and Korea, BMI ≥27 or ≥35 in Japan) to semaglutide 2.4 mg weekly, semaglutide 1.7 mg weekly, or placebo for 68 weeks.
68-week results:
- Semaglutide 2.4 mg: −13.2% weight change
- Semaglutide 1.7 mg: −9.6%
- Placebo: −2.1%
Effect magnitude in Asian cohort is approximately 1-2 percentage points less than the global STEP-1 cohort, consistent with pharmacogenomic and body-composition differences but broadly in the same range.
10. STEP-8 — head-to-head vs liraglutide
STEP-8 (Rubino et al, JAMA 2022) randomised 338 participants to semaglutide 2.4 mg weekly vs liraglutide 3.0 mg daily over 68 weeks.
68-week results:
- Semaglutide 2.4 mg: −15.8%
- Liraglutide 3.0 mg: −6.4%
Semaglutide produced approximately 2.5× the weight loss of liraglutide at maximum approved doses, with lower adverse-event discontinuation (13.5% vs 27.6%).
11. Body composition — lean vs fat mass
DEXA sub-studies of semaglutide trials show a consistent body-composition pattern:
- Total body weight loss at 68 weeks: ~−15 kg
- Fat mass loss: ~−12 kg (~80% of total loss)
- Lean body mass loss: ~−3 kg (~20% of total loss)
- Visceral adipose tissue (VAT) loss: disproportionately greater than subcutaneous
- Bone mineral density: modest decrease, typically within age-expected variability
The ~80% fat : 20% lean ratio is in the expected range for any sustained caloric-deficit weight loss. It is a common claim that GLP-1 agonists preferentially deplete lean mass; the evidence does not support this — the composition of GLP-1-driven weight loss is similar to diet-based weight loss. Lean-mass loss is proportional to magnitude of weight loss and is an active research area for adjunct therapy (bimagrumab, myostatin inhibitors).
12. Predictors of response
Post-hoc analyses of STEP data have identified modest predictors of weight-loss response:
- Baseline BMI: higher baseline BMI predicts greater absolute kg loss but slightly lower percentage loss
- Sex: women lose ~2 percentage points more than men on average
- T2DM status: T2DM cohorts lose ~5 percentage points less than non-diabetic cohorts
- Age: minor effect; middle-aged participants respond similarly to younger
- Early response: participants who lose >5% by week 20 have markedly higher probability of ≥15% loss by week 68 (positive predictive value ~75%)
- Ethnicity: small but measurable differences (see STEP-6)
Week-20 weight loss is the single most useful early predictor of eventual response, with research and clinical implications for “stopping rules” if individual response is inadequate.
13. Weight regain after discontinuation
STEP-4 data on regain after discontinuation:
- Week 0 (baseline): starting weight
- Week 20 (post-titration, pre-randomisation): −10.6% (shared across both arms)
- Week 32 (12 weeks post-switch): placebo arm regained ~2%
- Week 44 (24 weeks post-switch): placebo arm regained ~4%
- Week 56 (36 weeks post-switch): placebo arm regained ~5.5%
- Week 68 (48 weeks post-switch): placebo arm regained ~6.9% (cumulative from week 20)
Regain trajectory is approximately linear through 48 weeks post-withdrawal with no sign of stabilisation, suggesting continued regain would occur with longer observation.
14. UK research protocol design implications
Protocol-design implications of the STEP data:
- Primary endpoint: 68-72 weeks is the standard duration for obesity endpoints; nadir weight is reached in this window
- Shorter studies: 24 weeks captures ~70% of eventual loss; 36-40 weeks captures ~85%; 52 weeks captures ~95%
- Dose selection: 2.4 mg weekly is the maintenance dose in non-diabetic cohorts; 1.0 mg is the maximum approved T2DM maintenance dose; 1.7 mg is an intermediate sometimes used in Asian cohorts
- Titration period: 16 weeks from 0.25 mg to 2.4 mg with 4-week steps
- Measurement cadence: weight weekly for first 12 weeks, then every 4 weeks to endpoint
- Body composition: DEXA at baseline, week 36, week 68
- Withdrawal design: include if long-term maintenance is a research question (STEP-4 model)
- Population selection: non-diabetic cohort gives cleaner weight-loss signal; T2DM cohort adds ~5 percentage point response attenuation
FAQ
How fast does semaglutide weight loss start?
Measurable loss begins in week 1-2. Initial loss at the 0.25 mg starting dose is modest (~0.5-1% per 4 weeks). The rate accelerates during titration, reaching roughly 1% per week at maintenance dose in the early maintenance phase.
What is the maximum semaglutide weight loss I should plan for in a research protocol?
Mean −15% at 68 weeks; ~10% of participants lose >25%. Very rare responses >30% occur but are outside the expected range.
Does the weight loss keep going indefinitely?
No. Plateau approaches around week 60-68. STEP-5 showed only modest additional loss (−14.9% → −15.2%) between week 68 and week 104.
Does stopping semaglutide reverse the weight loss?
Yes, largely. STEP-4 showed ~65-70% regain of lost weight over 48 weeks after withdrawal. This is the core argument for chronic treatment.
Is semaglutide weight loss mostly water, fat, or muscle?
Predominantly fat (~80%), with lean mass accounting for ~20%. Water loss is a minor and transient component of the earliest weeks.
How does semaglutide compare to tirzepatide?
Tirzepatide at 15 mg weekly produces ~20% weight loss at 72 weeks (SURMOUNT-1) — approximately 5 percentage points more than semaglutide 2.4 mg at 68 weeks. SURMOUNT-5 head-to-head confirmed tirzepatide superiority (−20.2% vs −13.7%).
What is the week-16 titration weight loss target?
Typical week-16 loss is ~7-8%, but this varies widely with individual response. Week-20 >5% is the most useful “early responder” marker for predicting week-68 outcome.
References
- Wilding JPH et al. Once-weekly semaglutide in adults with overweight or obesity (STEP 1). N Engl J Med 2021;384:989–1002.
- Davies M et al. Semaglutide 2.4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2). Lancet 2021;397:971–984.
- Wadden TA et al. Effect of subcutaneous semaglutide vs placebo as an adjunct to intensive behavioral therapy (STEP 3). JAMA 2021;325:1403–1413.
- Rubino D et al. Effect of continued weekly subcutaneous semaglutide vs placebo on weight loss maintenance (STEP 4). JAMA 2021;325:1414–1425.
- Garvey WT et al. Two-year effects of semaglutide in adults with overweight or obesity (STEP 5). Nat Med 2022;28:2083–2091.
- Kadowaki T et al. Semaglutide once a week in adults with overweight or obesity, with or without type 2 diabetes, in an East Asian population (STEP 6). Lancet Diabetes Endocrinol 2022;10:193–206.
- Rubino DM et al. Effect of weekly subcutaneous semaglutide vs daily liraglutide on body weight (STEP 8). JAMA 2022;327:138–150.
- Weghuber D et al. Once-weekly semaglutide in adolescents with obesity (STEP TEENS). N Engl J Med 2022;387:2245–2257.
- Lincoff AM et al. Semaglutide and cardiovascular outcomes in obesity without diabetes (SELECT). N Engl J Med 2023;389:2221–2232.
- Aronne LJ et al. Tirzepatide vs semaglutide in adults with obesity (SURMOUNT-5). N Engl J Med 2025 (pre-publication; topline announced 2024).
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