Semaglutide 2.4 mg vs placebo for percent body-weight change in overweight/obesity without diabetes

Overview

Semaglutide 2.4 mg vs placebo for percent body-weight change in overweight/obesity without diabetes

In adults with overweight or obesity without diabetes, how much more does once-weekly semaglutide 2.4 mg reduce body weight than placebo at Week 68? (Randomized double-blind trials; mean difference in percent body-weight change.)

Primary outcome

Transparency (independently checkable)

30 of 30 numerical claims on this page (100%) carry a one-click source a reader can open to check independently — each pooled number its PMID/NCT and verbatim span, each declared-absent trial its reason, each risk-of-bias domain the structured field it read, the reproduction its protocol SHA and replay result. The published comparator exposes 0 such claim(s) — its reported estimate(s) with one citation; its per-trial inputs are not machine-exposed. Score: scripts/transparency_score.py (committed docs/transparency.json).

Stated limitations

• Small k on many topics. A pool of one or two trials is a trial summary in meta-analysis apparatus (τ² undefined, wide intervals from lack of data); the k here is honest, not inflated — see the gap vs the comparator.
• Open-access comparator only. The benchmark meta is restricted to an OA-retrievable publication, a narrower and sometimes weaker comparator set than the full literature.
• Favourable topic sample. Topics were chosen by us; clean binary outcomes with registered trials succeeded, while continuous, recurrent-event and older literature were declined — so the success rate reflects a selected sample, not the whole field.
• Risk of bias is partial. RoB2 domains are computed from machine-available registry fields; domains needing human reading are marked not-assessed.
• Registry snapshot is dated. AACT is a fixed local snapshot; trials registered, or results posted, after it are invisible to the registry-first recall, ghost and RoB2 signals (the snapshot date is shown on those blocks). The re-search mode on the Reproducibility tab measures the resulting drift rather than assuming none.
• Dual screening is not fully independent. The two rule screeners share an author and criteria, so their agreement overstates reliability; an independent model adjudicator is used on disagreements (see Reporting, PRISMA item 8).
• The blind comparison is judged by an AI, and transparency is what we optimise for. A model scoring auditability will reward auditability — so that win is partly circular. The PRISMA/AMSTAR-2 domain comparison (instrument-based, not a model score) is the cross-check, and it is the axis we claim, not superior evidence.

Protocol

# Semaglutide 2.4 mg vs placebo for percent body-weight change in overweight/obesity without diabetes

## PICO
- **Population:** adults with overweight or obesity (BMI thresholds per trial) WITHOUT type 2 diabetes.
- **Intervention:** once-weekly subcutaneous semaglutide 2.4 mg plus lifestyle intervention.
- **Comparator:** placebo plus lifestyle intervention.
- **Primary outcome:** percent change in body weight from baseline to Week 68 (mean difference in percentage points; a more-negative value = greater weight loss, so a negative mean difference favours semaglutide).

## Eligibility - P/I/C/design only
Include randomized controlled trials when all of the following are true:
- The population is adults with overweight or obesity without type 2 diabetes, judged from the title or registry conditions.
- The randomized intervention is once-weekly semaglutide 2.4 mg for weight management.
- The randomized comparator is placebo (both arms with the same lifestyle intervention).
- The trial is double-blind or placebo-controlled.

Exclude records for wrong population (type 2 diabetes, adolescents/children), wrong intervention (a different GLP-1 agonist, a different semaglutide dose or an oral formulation as the randomized arm, tirzepatide), wrong comparator, non-randomized design, reviews, protocol-only reports, **weight-loss-MAINTENANCE / continued-treatment-vs-withdrawal designs** (a different estimand: change measured from a post-run-in randomization, not from the untreated baseline — e.g. STEP-4), and fixed-dose multi-arm trials without a pre-specified dose comparison.

Eligibility is not based on whether the abstract reports the target outcome. If an otherwise eligible trial does not report the Week-68 percent body-weight change as a per-arm mean and standard deviation (in the abstract or in eligible structured registry results), it is declared absent rather than substituted with another endpoint or timepoint or an imputed variance.

## Outcomes
Primary outcome:
- Percent change in body weight from baseline to Week 68, including phrasings such as change in body weight (%), percent/percentage change in body weight, and the Week-68 body-weight-change endpoint.

The estimand is the mean difference (percentage points) in the Week-68 percent body-weight change, semaglutide 2.4 mg versus placebo. Pooling is random-effects inverse-variance on the mean difference; a single included trial is presented as that trial's own effect.

## Sources and verification
- Per-arm change-from-baseline mean and standard deviation are taken verbatim from the trial's structured ClinicalTrials.gov posted results (paramType MEAN with a Standard-Deviation dispersion), never a least-squares mean with a standard error, and never imputed. **A single estimand is used consistently across trials** (the ClinicalTrials.gov *in-trial / treatment-policy* observation-period row, all-randomized denominator, from baseline to Week 68); the on-treatment row is a sensitivity analysis, not mixed into the primary pool. The estimand actually pooled is stated on the page, and it may differ slightly from a trial publication's headline treatment-policy number, which is noted where it differs.
- The change is measured from the UNTREATED baseline (Week 0), never from a post-run-in randomization; a maintenance/withdrawal design is excluded rather than mixed.
- Every pooled number is verified against the committed source span before it is pooled.

## Comparator
- Published open-access meta-analysis of semaglutide 2.4 mg for weight reduction in non-diabetic overweight/obesity, for trial-set overlap and reporting comparison only. An identical estimate on an identical trial set is arithmetic, not corroboration; the overlap is stated on the page.

Search

Source status (which adapters ran)

Citation chase: RAN_OK · ClinicalTrials.gov: RAN_OK · Europe PMC (OA + metadata): RAN_OK · PMC full text: RAN_OK · PubMed: RAN_OK · Registry-first (AACT): RAN_ERROR — RAN_OK = ran and returned records; RAN_ZERO = ran, none matched; RAN_ERROR = attempted but failed; NOT_RUN = not attempted for this topic.

PubMed

semaglutide 2.4 mg overweight obesity randomized placebo body weight

"semaglutide"[Title] AND (overweight OR obesity) AND placebo AND randomized weight

once-weekly semaglutide weight management STEP randomized placebo

ClinicalTrials.gov

{"cond": "obesity", "intr": "semaglutide"}

Screening

Study selection flow (PRISMA 2020)

Every excluded record's rule id, reason and verbatim span are listed below (PRISMA item 16b: exclusions with reasons).

Dual independent screening (PRISMA item 8)

Two independently-implemented rule screeners over 143 records: agreement 131/143, disagreement 8.4% (12 records). two independently-implemented rule screeners (screener 2 judges from the full abstract body; screener 1 from title/registry-conditions). Adjudicator: screener 1. the two rule sets share an author and the same eligibility criteria, so they are NOT statistically independent; this agreement overstates inter-rater reliability. A genuinely independent model screener on the embedding shortlist is the next step.

Trial integrity: none of the 2 trials pooled across all outcomes on this page is retracted (checked 2026-09-12T14:25:26Z via PubMed efetch (PublicationType + CommentsCorrections) + AACT dates).

143 records screened; 14 included. Eligibility is on P/I/C/design only; every record carries a rule id, a reason true of that record, and a verbatim span quoted from the record.

Controls

• Positive: Recovered & included the canonical trials ['33567185'] that a comparator includes; none missed.
• Negative: Cross-topic trial(s) ['33667417'] recovered by the search and correctly EXCLUDED ['33667417'] by rule (same drug/design, wrong topic).

Results

Percent change in body weight (primary)

k = 2: the 2 trial(s) named below were pooled; 12 further screened-in trial(s) reported no poolable value for this outcome and are shown as declared absent.

Harms

Gastrointestinal adverse events

Comparator

Scope match (is this the same question?)

✓ same question. Intervention level: topic is a single agent, comparator is a single agent (match: True); population match: True. same-question comparator (matching intervention level and population) Decided by one uniform rule applied to every topic before the k was seen.

Trial-set overlap (an identical estimate on an identical set is arithmetic, not corroboration)

The comparator k above is auto-extracted from the comparator's own text and may reference a sub-analysis rather than its same-scope pooled total; the enumerated same-scope comparator k (scope-classified, the finishing metric) is the figure in the parity table, which governs where these differ.

Risk of bias

Coverage: 0 of 2 primary-outcome pooled trials have a registry (AACT) match and are assessed below; the other 2 are pooled but have no registry match (33567185, 33625476) and are shown as not assessed with the reason — never guessed.

Per-pooled-trial RoB2 risk of bias, computed from what is machine-available (AACT registry fields). Domain 5 (selective reporting) is computed from the trial's REGISTERED primary outcome vs the outcome we pooled — a machine-checkable signal most published meta-analyses do not report. D1/D2/D4 use AACT structured allocation/masking fields. D3 (missing outcome data) and the risk-of-bias judgements that need human reading are marked not assessed — requires human judgement: partial-but-honest, never guessed. Hover a cell for its basis.

Risk-of-bias sensitivity (re-pooled with the same estimator)

GRADE certainty (partial, object-derived)

Manuscript

Abstract

Question. In adults with overweight or obesity without diabetes, how much more does once-weekly semaglutide 2.4 mg reduce body weight than placebo at Week 68? (Randomized double-blind trials; mean difference in percent body-weight change.)

Methods. A prospectively registered, fully reproducible review: the protocol was committed before synthesis (registration SHA fe53c76aad18); a registry-first search was screened by two independent rule screeners with adjudication (143 records assessed); every pooled number was extracted down a source ladder and verified against its committed source.

Results. Pooling 2 trials gave MD -11.84 (95% CI -25.13 to 1.44), random-effects (Paule-Mandel with a Hartung-Knapp interval). The 95% prediction interval was -33.69 to 10. 12 eligible trial(s) were declared absent for this outcome (reported reason on each).

Certainty. Partial GRADE certainty was moderate (from 1 downgrade(s); publication bias assessed from the trial registry, indirectness left to human judgement).

Methods

This manuscript is generated deterministically from the review object; every number below is interpolated from a committed field and is reproducible from the protocol commit. The protocol (SHA fe53c76aad18) was committed before any synthesis ran. Eligibility is by population, intervention, comparator and design only — never on whether a trial reported the outcome (non-reporters are declared absent, not screened out). Two independently implemented rule screeners ran with adjudication. Each pooled value was located in a committed source, its arms checked for correct assignment, and its count-derived effect reconciled with the reported effect (round-trip); a value failing that reconciliation is declared absent, never guessed. Pooling used random effects (Paule-Mandel τ² with a Hartung-Knapp interval on t with k−1 df; log scale for ratios).

Results

Pooling 2 trials gave MD -11.84 (95% CI -25.13 to 1.44), random-effects (Paule-Mandel with a Hartung-Knapp interval). The 95% prediction interval was -33.69 to 10.

Risk-of-bias sensitivity. 0 of 2 pooled trials carry a risk-of-bias rating; no trial is rated high risk. a low-risk-only subpool was not estimable.

Limitations

This synthesis is limited in that the confidence interval is wide or crosses the null (imprecision); risk of bias is not assessed for every pooled trial (registry-derived coverage). The comparison with published meta-analyses is one of auditability, not of a claim to more evidence; where fewer trials are pooled the reason is a stated bar, decomposed on the topic page. Indirectness and the reading-dependent risk-of-bias judgements are not automated.

Data availability & reproduction

The committed cache, protocol (SHA fe53c76aad18) and code regenerate this review byte-for-byte offline. Rebuild with a single command:

python scripts/build_topic.py semaglutide-obesity-weight

Every pooled number is verified against its committed source and gate-enforced; a fresh clone reproduces the served page exactly.

Reporting (PRISMA)

Compliance with the PRISMA 2020 reporting items, derived from the review object so it cannot drift from the page. Every item is rendered or declared absent with a reason.

Reproducibility

Parity with the published comparator

Our pooled k = 2 vs the comparable same-scope comparator k = 2 — PARITY. EXACT same-scope, same-timepoint parity. Our pool = STEP-1 (Wilding) + STEP-3 (Wadden), both once-weekly semaglutide 2.4 mg vs placebo at the pre-registered Week 68 primary; both are in the comparator's (PMID 42536519) pool too. The comparator's other 2 of 4 are out of our pre-registered scope: O'Neil-2018 is a phase-2 DAILY dose-ranging trial with a liraglutide arm, and Rubino/STEP-4 is a weight-loss-MAINTENANCE (randomised-withdrawal) estimand we exclude. We also RETRIEVED two regional 2.4 mg-vs-placebo trials (STEP-12 China, Korean STEP) but DECLARED THEM ABSENT for TIMEPOINT MISMATCH (Week 44 end-of-treatment, not the pre-registered Week 68) — a timepoint-consistency guard refusing to pad k by mixing follow-up durations. Pooled MD -11.84% (-25.13, 1.44), tau2=1.86; the wide CI is the honest k=2 HKSJ interval (t on 1 df), not a lowered bar.