Semaglutide vs placebo for 3-point MACE in obesity without diabetes

Overview

Semaglutide vs placebo for 3-point MACE in obesity without diabetes

In adults with overweight or obesity and established cardiovascular disease but without diabetes, does semaglutide reduce 3-point major adverse cardiovascular events versus placebo? (Double-blind placebo-controlled RCTs.)

Primary outcome

Transparency (independently checkable)

7 of 7 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 1 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.
• Comparator scope mismatch. comparator is a DRUG-CLASS meta-analysis while this topic is a single agent — a PICO scope mismatch (single-drug review vs class-level review); the k difference vs this comparator is a scope difference, not unretrieved evidence
• 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

# Protocol - semaglutide for 3-point MACE in obesity without diabetes

**Registration.** The commit that adds this file is the registration of this
review; its SHA is embedded in the page's Protocol tab and its Reproducibility tab.
Committed BEFORE the synthesis is run.

## PICO
- **P** - adults with overweight or obesity and established cardiovascular disease but
  without diabetes.
- **I** - once-weekly subcutaneous semaglutide 2.4 mg added to standard care.
- **C** - placebo added to standard care.
- **O (primary)** - 3-point major adverse cardiovascular events, defined as
  cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke.
- **O (harms / secondary)** - gastrointestinal adverse events, adverse events leading to
  permanent discontinuation, and any further outcome the resolved comparator reports.

## Estimand / population / timepoint
- **Estimand** - hazard ratio (HR), semaglutide vs placebo.
- **Population** - intention-to-treat as randomised.
- **Timepoint** - trial end / mean follow-up 39.8 months.

## Eligibility - on P/I/C/DESIGN ONLY
Include a record iff **all** hold:
- **I1** - randomised controlled trial;
- **I2** - adults with overweight or obesity and established cardiovascular disease but
  without diabetes, judged from the title or registry conditions;
- **I3** - semaglutide vs placebo contrast;
- **design** - double-blind, placebo-controlled.

Exclude (reason must be true of the record):
- **X1** - not an RCT (review, guideline, observational, protocol-only);
- **X2** - wrong population (e.g. type 2 diabetes, type 1 diabetes, chronic kidney
  disease, heart failure, sleep apnea, or obesity trials without established
  cardiovascular disease);
- **X3** - wrong intervention/comparison (no semaglutide-vs-placebo contrast);
- **X-DESIGN** - not double-blind and placebo-controlled;
- **X5** - off-topic: a primary trial of another topic in this set (negative control).

> **Eligibility is NOT on the outcome axis.** Whether a trial reports 3-point MACE, or gives
> a 2x2 vs only an effect+CI, is recorded as target-result status at extraction - never as
> an exclusion. A published effect + 95% CI is a poolable input.

## Search (fetch-once; raw results committed under cache/<slug>/search.json; screening replays offline)
- PubMed: exact SELECT title/PMID sweeps for the main MACE report. Later SELECT secondary
  analyses are not configured as positive controls because they share NCT03574597 and the
  fixed harness deduplicates same-NCT PubMed records to the latest-year publication.
- ClinicalTrials.gov: condition "cardiovascular disease obesity without diabetes",
  intervention "semaglutide".
- Comparator/reference seeding is disabled so the broader comparator's reference list does
  not pull in semaglutide obesity trials outside the established-CVD SELECT population.

## Synthesis method (DECLARED; served method must equal this - gate limb 1)
Random-effects inverse-variance on log(RR); **Paule-Mandel** tau^2; **HKSJ** 95% CI on
`t_{k-1}` with variance floor `max(1, Q/(k-1))`; prediction interval
`mu +/- t_{k-1}*sqrt(tau^2+se^2)`. DerSimonian-Laird forbidden. Engine validated vs
metafor 5.0.1 (<1e-6). For this topic, the poolable input is the published HR + 95% CI
path on the same ratio/log scale; 2x2 extraction is available but is not required when a
trial reports an HR + CI.

## Comparator (resolved; open-access confirmed)
Stefanou et al., *Therapeutic Advances in Neurological Disorders* 2024, "Risk of major
adverse cardiovascular events and all-cause mortality under treatment with GLP-1 RAs or
the dual GIP/GLP-1 receptor agonist tirzepatide in overweight or obese adults without
diabetes: a systematic review and meta-analysis" (PMID 39345822, DOI
10.1177/17562864241281903; Unpaywall is_oa=true; PubMed Central PMC11437580). It reports
pooled MACE OR 0.79 (95% CI 0.71-0.89) over 16 RCTs in overweight or obese adults
without diabetes. This comparator is broader than the registered lane's semaglutide-only
SELECT population; the exact registered lane has one landmark eligible RCT.

## Controls
- **Positive** - SELECT main MACE report (PMID 37952131), the verified eligible landmark
  trial report. Only this positive control is configured to avoid same-NCT secondary
  SELECT reports superseding the main MACE paper during fixed harness deduplication.
- **Negative** - SUSTAIN-6 (PMID 27633186: semaglutide, randomized, placebo-controlled,
  but type 2 diabetes rather than obesity without diabetes) must be recovered and
  EXCLUDED by the population rule.

Search

Source status (which adapters ran)

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

Registry-first recall (reach)

Registry-first RECALL: recovered 1/1 of this topic's known trials (enumerated 204; status RAN_OK). Measured 2026-09-11T23:39:14Z. Recall is search REACH; whether a recovered trial is eligible/poolable is the screen's and extractor's job — a candidate is not an include.

Registry landscape & unpublished evidence (AACT)

Of 204 registry records matching the query (broad — reach, not precision): 53 have a linked publication; 7 have posted CT.gov results but no publication (poolable unpublished data no published meta in this topic has); 18 are completed ≥12 months ago with neither results nor a linked publication — a loose upper bound on non-publication, inflated by the broad enumeration and by NCT→PMID linkage misses, not a publication-bias claim. AACT 2026-08-30 (local snapshot).

PubMed

37952131[uid]

"Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes"[Title]

semaglutide[Title] AND cardiovascular outcomes[Title] AND obesity[Title] AND "without diabetes"[Title]

ClinicalTrials.gov

{"cond": "cardiovascular disease obesity without diabetes", "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 66 records: agreement 66/66, disagreement 0.0% (0 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 1 trials pooled across all outcomes on this page is retracted (checked 2026-09-12T15:30:11Z via PubMed efetch (PublicationType + CommentsCorrections) + AACT dates).

66 records screened; 1 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 ['37952131'] that a comparator includes; none missed.
• Negative: Cross-topic trial(s) ['27633186'] recovered by the search and correctly EXCLUDED ['27633186'] by rule (same drug/design, wrong topic).

Results

3-point major adverse cardiovascular events (primary)

Harms

Gastrointestinal adverse events

Adverse events leading to permanent discontinuation

Comparator

Major adverse cardiovascular events: 0.79 (OR), 95% CI 0.71–0.89

Scope match (is this the same question?)

⚠ SCOPE MISMATCH. Intervention level: topic is a single agent, comparator is class-level (match: False); population match: True. comparator is a DRUG-CLASS meta-analysis while this topic is a single agent — a PICO scope mismatch (single-drug review vs class-level review); the k difference vs this comparator is a scope difference, not unretrieved evidence Decided by one uniform rule applied to every topic before the k was seen.

Comparator resolution. No same-scope (single-agent) published meta-analysis exists to serve as a like-for-like comparator: semaglutide 2.4 mg for MACE in obesity without diabetes rests on a single pivotal RCT (SELECT, NCT03574597), so k=1 is the COMPLETE single-drug RCT evidence base for this question, not a search gap. The nearest published synthesis pools the GLP-1-receptor-agonist CLASS (a different, network-level PICO question); its larger k reflects that broader scope, not evidence this review failed to retrieve. A complete review with k=1 is not a weak review; it is a complete one, and saying so is more informative than the comparator larger number.

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: 1 of 1 primary-outcome pooled trials have a registry (AACT) match and are assessed below (all primary-outcome pooled trials assessed).

Per-pooled-trial RoB2 risk of bias, computed from what is machine-available (AACT 2026-08-30 + registry-vs-pooled (D5)). 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 and established cardiovascular disease but without diabetes, does semaglutide reduce 3-point major adverse cardiovascular events versus placebo? (Double-blind placebo-controlled RCTs.)

Methods. A prospectively registered, fully reproducible review: the protocol was committed before synthesis (registration SHA 3fb64a1e0143); a registry-first search was screened by two independent rule screeners with adjudication (66 records assessed); every pooled number was extracted down a source ladder and verified against its committed source.

Results. A single eligible trial contributed an extractable estimate: HR 0.8 (95% CI 0.72 to 0.89); with k=1 no between-trial heterogeneity or prediction interval is estimable.

Certainty. Partial GRADE certainty was low (from 2 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 3fb64a1e0143) 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

A single eligible trial contributed an extractable estimate: HR 0.8 (95% CI 0.72 to 0.89); with k=1 no between-trial heterogeneity or prediction interval is estimable.

Risk-of-bias sensitivity. 1 of 1 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). 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 3fb64a1e0143) and code regenerate this review byte-for-byte offline. Rebuild with a single command:

python scripts/build_topic.py semaglutide-obesity-mace

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

Independent second extraction (blind)

Of this page's pooled numbers, a blind second extractor agreed or reconciled on 1 of 1 that are checkable from the abstract (0 identical, 1 same-result-different-statistic, 0 conflict; 0 not stated in the abstract). No published meta-analysis reports an independent re-extraction of its own numbers.