GLP-1 receptor agonists vs placebo for 3-point MACE in type 2 diabetes

Overview

GLP-1 receptor agonists vs placebo for 3-point MACE in type 2 diabetes

In adults with type 2 diabetes, do GLP-1 receptor agonists reduce 3-point major adverse cardiovascular events versus placebo? (Double-blind placebo-controlled RCTs.)

Primary outcome

Transparency (independently checkable)

33 of 33 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.
• 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 - GLP-1 receptor agonists for 3-point MACE in type 2 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 type 2 diabetes.
- **I** - GLP-1 receptor agonist therapy (liraglutide, semaglutide, dulaglutide,
  albiglutide, efpeglenatide, exenatide, or lixisenatide) added to usual care.
- **C** - placebo added to usual 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, discontinuation for adverse
  events, and any further harm outcome the resolved comparator reports.

## Estimand / population / timepoint
- **Estimand** - hazard ratio (HR), GLP-1 receptor agonist vs placebo.
- **Population** - intention-to-treat as randomised.
- **Timepoint** - trial end / longest primary cardiovascular outcome follow-up.

## Eligibility - on P/I/C/DESIGN ONLY
Include a record iff **all** hold:
- **I1** - randomised controlled trial;
- **I2** - population is adults with type 2 diabetes, judged from the title or registry
  conditions;
- **I3** - a GLP-1 receptor agonist 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. obesity without diabetes, type 1 diabetes, or gestational
  diabetes);
- **X3** - wrong intervention/comparison (no GLP-1 receptor agonist-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-title sweeps for the large GLP-1 receptor agonist cardiovascular outcome
  trials in type 2 diabetes (LEADER, SUSTAIN-6, REWIND, HARMONY Outcomes, AMPLITUDE-O,
  PIONEER-6, EXSCEL, and ELIXA).
- ClinicalTrials.gov: condition "type 2 diabetes cardiovascular", intervention
  "efpeglenatide".
- Fixed-screen note: several PubMed abstracts for verified double-blind CVOTs do not use
  the literal phrase "double-blind"; the config therefore does not require that literal
  abstract/title string, while the protocol eligibility criterion remains double-blind
  placebo-controlled design.

## 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)
Giugliano et al., *Cardiovascular Diabetology* 2021, "GLP-1 receptor agonists and
cardiorenal outcomes in type 2 diabetes: an updated meta-analysis of eight CVOTs" (PMID
34526024, DOI 10.1186/s12933-021-01366-8; Unpaywall is_oa=true; PubMed Central
PMC8442438). It reports pooled MACE HR 0.86 (95% CI 0.79-0.94) over 8 cardiovascular
outcome trials.

## Controls
- **Positive** - the search must recover and include LEADER, SUSTAIN-6, and REWIND.
- **Negative** - SELECT (semaglutide, double-blind, placebo-controlled, but obesity without
  diabetes - another disease population) 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 6/7 of this topic's known trials (enumerated 708; status RAN_OK). Reachable ceiling 7/7: 1 trial(s) are registered but not enumerated by the committed query (registry vocabulary limit — improvable). Missed: 30291013. 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 708 registry records matching the query (broad — reach, not precision): 397 have a linked publication; 62 have posted CT.gov results but no publication (poolable unpublished data no published meta in this topic has); 118 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

27295427[uid] OR 27633186[uid] OR 31185157[uid]

31189511[uid] OR 30291013[uid] OR 34215025[uid]

28910237[uid] OR 26630143[uid]

ClinicalTrials.gov

{"cond": "type 2 diabetes cardiovascular", "intr": "efpeglenatide"}

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 10 records: agreement 10/10, 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 7 trials pooled across all outcomes on this page is retracted (checked 2026-09-11T23:50:08Z via PubMed efetch (PublicationType + CommentsCorrections) + AACT dates).

10 records screened; 8 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 ['27295427', '27633186', '31189511'] that a comparator includes; none missed.
• Negative: Cross-topic trial(s) ['37952131'] recovered by the search and correctly EXCLUDED ['37952131'] by rule (same drug/design, wrong topic).

Results

3-point major adverse cardiovascular events (primary)

k = 7: the 7 trial(s) named below were pooled; 1 further screened-in trial(s) reported no poolable value for this outcome and are shown as declared absent.

Harms

Gastrointestinal adverse events

Adverse events leading to discontinuation

Comparator

Major adverse cardiovascular events: 0.86 (HR), 95% CI 0.79–0.94

Scope match (is this the same question?)

✓ same question. Intervention level: topic is class-level, comparator is class-level (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: 7 of 7 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 type 2 diabetes, do GLP-1 receptor agonists 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 4091958ce4af); a registry-first search was screened by two independent rule screeners with adjudication (10 records assessed); every pooled number was extracted down a source ladder and verified against its committed source.

Results. Pooling 7 trials gave HR 0.85 (95% CI 0.79 to 0.91), random-effects (Paule-Mandel with a Hartung-Knapp interval). The 95% prediction interval was 0.77 to 0.94. 1 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 4091958ce4af) 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 7 trials gave HR 0.85 (95% CI 0.79 to 0.91), random-effects (Paule-Mandel with a Hartung-Knapp interval). The 95% prediction interval was 0.77 to 0.94.

Risk-of-bias sensitivity. 7 of 7 pooled trials carry a risk-of-bias rating; no trial is rated high risk. Restricted to low-risk trials the estimate was HR 0.78 (95% CI 0.68 to 0.9, k=1); read the widened interval with the coverage caveat.

Limitations

No GRADE domain was downgraded from the machine-computable signals. 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 4091958ce4af) and code regenerate this review byte-for-byte offline. Rebuild with a single command:

python scripts/build_topic.py glp1-ra-mace-t2d

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 = 7 vs the comparable same-scope comparator k = 7 — PARITY. 7/8; the 1 gap ELIXA is a 4-point MACE (estimand) correctly declared-absent

Independent second extraction (blind)

Of this page's pooled numbers, a blind second extractor agreed or reconciled on 5 of 5 that are checkable from the abstract (0 identical, 5 same-result-different-statistic, 0 conflict; 2 not stated in the abstract). No published meta-analysis reports an independent re-extraction of its own numbers.