DPP-4 inhibitors vs placebo for 3-point MACE in type 2 diabetes

Overview

DPP-4 inhibitors vs placebo for 3-point MACE in type 2 diabetes

In adults with type 2 diabetes, do DPP-4 inhibitors change 3-point major adverse cardiovascular events versus placebo? (Double-blind placebo-controlled RCTs.)

Primary outcome

Transparency (independently checkable)

6 of 6 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

# Protocol - DPP-4 inhibitors for 3-point MACE in type 2 diabetes

**Registration.** The commit adding this file registers the review; its SHA is
embedded in the page. Committed before the synthesis runs. Eligibility is on
P/I/C/design only; outcome reporting affects extraction status, not screening.

## PICO
- **P** - adults with type 2 diabetes.
- **I** - DPP-4 inhibitors, including sitagliptin, saxagliptin, alogliptin, and
  linagliptin.
- **C** - placebo.
- **O (primary)** - 3-point major adverse cardiovascular events, using the
  trial-reported cardiovascular death, myocardial infarction, or stroke composite.

## Estimand / population / timepoint
- **Estimand** - hazard ratio (HR), DPP-4 inhibitor vs placebo, pooled on the log
  ratio scale.
- **Population** - intention-to-treat as randomised.
- **Timepoint** - trial end / longest trial-reported follow-up.

## Eligibility - P/I/C/DESIGN only
Include a record iff all hold:
- **I1** - randomised controlled trial;
- **I2** - population is adults with type 2 diabetes;
- **I3** - sitagliptin, saxagliptin, alogliptin, linagliptin, or a DPP-4 inhibitor
  as the randomised intervention;
- **I4** - placebo comparator;
- **design** - double-blind, placebo-controlled.

Exclude (reason must be true of the record):
- **X1** - not an RCT (review, guideline, observational, protocol-only, or
  meta-analysis);
- **X2** - wrong population, including type 1 diabetes;
- **X3** - wrong intervention/comparison, including active-comparator DPP-4 CVOTs
  such as CAROLINA;
- **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 an eligible trial reports 3-point
MACE, and whether it reports arm counts or only an effect plus confidence interval,
is recorded at extraction. A published effect plus 95% CI is a poolable input.

## Search
- PubMed: direct UID queries for SAVOR-TIMI 53, EXAMINE, TECOS, CARMELINA, and
  CAROLINA primary reports, plus a DPP-4 cardiovascular-outcome-trial
  meta-analysis comparator.
- ClinicalTrials.gov: condition "type 2 diabetes", intervention "DPP-4 inhibitor".

## Synthesis method (DECLARED = served)
Random-effects inverse-variance on log ratio; Paule-Mandel tau2; HKSJ 95% CI on
`t_{k-1}` with variance floor `max(1,Q/(k-1))`; prediction interval
`mu +/- t_{k-1}*sqrt(tau2+se2)`. DerSimonian-Laird forbidden. Published HR inputs
are pooled on the log ratio scale.

## Comparator (resolved; OA confirmed)
Patoulias et al., *World Journal of Cardiology* 2021, "Cardiovascular efficacy and
safety of dipeptidyl peptidase-4 inhibitors: A meta-analysis of cardiovascular
outcome trials" (PMID 34754403, PMC8554356, DOI 10.4330/wjc.v13.i10.585).

## Pivotal
- **TECOS** - NCT00790205; positive-control PMID 26052984.

## Controls
- **Positive** - the search must recover and include TECOS (PMID 26052984).
- **Negative** - DECLARE-TIMI 58 (dapagliflozin in type 2 diabetes, PMID 30415602)
  must be recovered and EXCLUDED as wrong intervention.

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_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

23992601[uid] OR 23992602[uid]

26052984[uid] OR 30418475[uid]

31536101[uid]

ClinicalTrials.gov

{"cond": "type 2 diabetes", "intr": "DPP-4 inhibitor"}

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 37 records: agreement 36/37, disagreement 2.7% (1 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.

37 records screened; 4 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 ['26052984'] that a comparator includes; none missed.
• Negative: Cross-topic trial(s) ['30415602'] recovered by the search and correctly EXCLUDED ['30415602'] by rule (same drug/design, wrong topic).

Results

3-point major adverse cardiovascular events (primary)

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

Harms

Comparator

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: 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 (23992601, 30418475) 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 type 2 diabetes, do DPP-4 inhibitors change 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 0fb7f9f4cd61); a registry-first search was screened by two independent rule screeners with adjudication (37 records assessed); every pooled number was extracted down a source ladder and verified against its committed source.

Results. Pooling 2 trials gave HR 1.01 (95% CI 0.57 to 1.78), random-effects (Paule-Mandel with a Hartung-Knapp interval). The 95% prediction interval was 0.57 to 1.78. 2 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 0fb7f9f4cd61) 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 HR 1.01 (95% CI 0.57 to 1.78), random-effects (Paule-Mandel with a Hartung-Knapp interval). The 95% prediction interval was 0.57 to 1.78.

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 0fb7f9f4cd61) and code regenerate this review byte-for-byte offline. Rebuild with a single command:

python scripts/build_topic.py dpp4-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