RapidMeta Cardiology | GLP-1 RA CVOT Ultra-Precision v12.0

Systematic Review Protocol

PROSPERO-style Registration — PRISMA 2020 & AMSTAR 2 Compliant

1. Registration & Administrative Information [PRISMA #24, AMSTAR #2]

Review Title	GLP-1 Receptor Agonists for Cardiovascular Outcomes: A Living Systematic Review and Meta-Analysis of Randomized Controlled Trials
Protocol Version	v1.0 (Living Protocol — auto-updating)
Date of First Registration	2026-03-03
Last Substantive Amendment	2026-03-03
Planned Update Frequency	Continuous (living review); formal snapshot at each new trial publication
Funding Source	No external funding (independent academic review)
Conflicts of Interest	None declared

2. Review Question — PICO Framework [PRISMA #3, AMSTAR #1]

Population
Intervention
Comparator
Primary Outcome
Secondary Outcomes	CV death; nonfatal MI; nonfatal stroke; all-cause mortality; HF hospitalization where reported
Subgroup Plan

3. Eligibility Criteria [PRISMA #5–6, AMSTAR #3]

Criterion	Inclusion	Exclusion
Study Design	Randomized controlled trials (RCTs), parallel or crossover	Non-randomized, observational, single-arm, case series
Phase	Phase III or IV	Phase I/II (including IIa/IIb), PK/PD, dose-finding, bioequivalence, first-in-human
Participants	Adults with T2D at CV risk	Healthy volunteers, paediatric, animal/in-vitro
Intervention	GLP-1 RA as primary experimental drug	GLP-1 RA as background only; open-label extensions without comparator
Comparator	Placebo, sham, or standard of care	Active comparator without placebo arm
Outcomes	≥1 cardiovascular clinical endpoint (MACE or component) with extractable 2×2 counts or published HR/RR with confidence interval	Biomarker-only, PK-only, no clinical event data
Publication	Published or registered post-2015; any language	Pre-2015; duplicate cohorts; editorials, letters, reviews
Follow-up	≥12 weeks (primary outcome assessment)	<12 weeks or acute/single-dose studies

4. Information Sources & Search Strategy [PRISMA #7–8, AMSTAR #4–5]

Database	Search String / API Query	Type
ClinicalTrials.gov	`https://clinicaltrials.gov/api/v2/studies?query.term=GLP-1%20receptor%20agonist%20cardiovascular&pageSize=100&filter.overallStatus=COMPLETED`	Registry (API v2)
PubMed (Europe PMC)	`(liraglutide OR semaglutide OR exenatide OR dulaglutide OR albiglutide OR lixisenatide OR efpeglenatide OR "GLP-1") AND (cardiovascular OR MACE OR "major adverse") AND (TITLE:randomized OR PUB_TYPE:"Randomized Controlled Trial") AND SRC:MED`	Bibliographic (REST)
OpenAlex	`search=GLP-1%20receptor%20agonist%20cardiovascular%20outcomes&per_page=50`	Bibliographic (REST)
Reference Check	Backward citation search: built-in landmark database cross-checked against API returns	Manual supplement

Deduplication [PRISMA #16a]

NCT-ID exact match → PubMed dbCrossReferenceList linkage → NCT pattern extraction from abstract → fuzzy title dedup (normalized alphanumeric). Enrichment: abstracts, authors, journal metadata merged from PubMed into registry stubs. All 3 fetches run in parallel via Promise.allSettled.

5. Study Selection Process [PRISMA #16, AMSTAR #5–7]

Stage 1: Auto-Screening	RCT relevance classifier (keyword + publication type scoring, 0–100). Auto-exclude <25. App location: Screening tab
Stage 2: Title/Abstract	Two-reviewer adjudication workflow with rationale note and second-review confirmation (I = propose include, E = propose exclude, C = second confirmation, N/P = navigate). App location: Screening tab
Stage 3: Full Text	Verify eligibility criteria against full manuscript; extract 2×2 table. App location: Extraction tab
Conflict Resolution	Re-review with exclusion reason recorded in audit log. PRISMA flow auto-generated.
PRISMA Flow Diagram	Auto-computed from search/screening counts. App location: Report tab → PRISMA section

6. Data Collection & Extraction [PRISMA #10, AMSTAR #6]

Data Item	Details	App Location
Study identifiers	NCT ID, PMID, DOI, first author, year	Extraction → Data Entry
Participants	N randomized per arm, age, sex distribution, indication, baseline eGFR	Extraction → Demographics
Intervention details	GLP-1 RA dose/regimen, trial phase, treatment duration	Extraction → Data Entry
Outcome events	2×2 table: Events(Tx), N(Tx), Events(Ctrl), N(Ctrl); or published HR/RR with confidence interval for recurrent/time-to-event estimands	Extraction → Data Entry
Risk of Bias	RoB 2 domains D1–D5, each rated Low/Some/High	Extraction → Risk of Bias
Source evidence	Verbatim extracts from published manuscripts with page/table references	Extraction → Evidence panels

7. Risk of Bias Assessment [PRISMA #11–12, AMSTAR #9]

Domain	Signalling Questions (RoB 2)	App Location
D1: Randomization	Sequence generation, allocation concealment	Extraction → RoB (click to cycle)
D2: Deviations	Blinding, ITT adherence, co-interventions	Extraction → RoB (click to cycle)
D3: Missing Data	Completeness, attrition handling, sensitivity for missing	Extraction → RoB (click to cycle)
D4: Measurement	Outcome assessment blinding, adjudication committees	Extraction → RoB (click to cycle)
D5: Selective Reporting	Pre-registered endpoints, protocol deviations	Extraction → RoB (click to cycle)
Presentation	Traffic-light summary table (per-study) + stacked horizontal bar chart (per-domain)	Analysis → Charts #16, Extraction → RoB

8. Synthesis & Statistical Methods [PRISMA #13, AMSTAR #11–12]

Method	Specification	App Location
Effect Measure	Odds Ratio (OR) computed on log scale; 0.5 continuity correction for zero cells	Analysis → Stats
Pooling Model	DerSimonian-Laird random-effects (inverse-variance weighting)	Analysis → Forest (#1)
CI Adjustment	Hartung-Knapp-Sidik-Jonkman (HKSJ); t-distribution with df = k−1	Analysis → Stats
Prediction Interval	t-distribution, df = k−2 (Higgins 2009)	Analysis → Stats
Heterogeneity	Cochran Q (p-value), I² (%), τ² (DL estimator)	Analysis → Stats
Subgroup Analysis	By drug class (short-acting vs long-acting GLP-1 RA); Q-between test for interaction	Analysis → Subgroup (#2)
Cumulative MA	Sequential addition by year; monitoring evidence accrual	Analysis → Cumulative (#3)
Leave-One-Out	Influence analysis: remove each study, re-pool	Analysis → LOO (#5)
Bayesian RE	Grid approximation (200 τ × 300 μ); half-normal prior on τ; posterior OR + CrI + P(OR<1)	Analysis → Posterior (#11)
Meta-Regression	WLS on log-OR; covariates: Year, Phase, Indication; Knapp-Hartung SE; permutation p (1000x)	Analysis → Meta-Reg (#12)
Fragility Index	Walsh method: sequential single-arm event modification until significance flips	Analysis → Stats
NNT / Clinical Utility	NNT = 1 / ARR; curve across baseline risk range	Analysis → NNT (#8)

9. Publication Bias Assessment [PRISMA #14–15, AMSTAR #15]

Method	Specification	App Location
Visual	Contour-enhanced funnel plot with significance regions (p < 0.01/0.05/0.10)	Analysis → Funnel (#9)
Statistical	Egger's weighted regression test: intercept ≠ 0 (k ≥ 3 required)	Analysis → Egger (#15)
Correction	Duval-Tweedie trim-and-fill (L0 estimator); imputed studies shown as open circles on funnel	Analysis → Stats chip
Sensitivity	Copas-style sensitivity (heuristic rank-reweighting, not Copas-Shi MLE): ρ sweep −0.99 to 0 (34 steps); classify Robust/Sensitive	Analysis → Copas (#13)
Power	RIS formula with D² diversity; conditional power curve (next-study N 100–2000)	Analysis → Power (#14)

10. Certainty of Evidence [PRISMA #22, AMSTAR #14]

GRADE Domain	Criteria for Downgrading	App Location
Risk of Bias	≥50% studies rated Some Concerns or High on any domain	Report → GRADE
Inconsistency	I² ≥ 50% or prediction interval crosses null	Report → GRADE
Indirectness	Population, intervention, or outcome mismatch with review question	Report → GRADE
Imprecision	CI crosses MID (OR = 0.80 or 1.25) or optimal information size not met	Report → GRADE
Publication Bias	Egger p < 0.10, asymmetric funnel, Copas sensitivity, trim-fill k0 > 0	Report → GRADE
Supplementary	Bayesian P(OR < 1), Information Fraction (RIS), Summary of Findings table	Report → SoF table

11. AMSTAR 2 Critical Domains Compliance

#	AMSTAR 2 Item	Critical?	How Addressed
1	PICO components for research question	No	Section 2 above
2	Protocol registered before commencement	Yes	This protocol tab (living protocol)
4	Comprehensive literature search strategy	Yes	Section 4: 3 databases + reference check; search strings visible
7	List of excluded studies with justifications	Yes	Screening tab: excluded with auto/manual reason
9	Satisfactory RoB assessment technique	Yes	Section 7: Cochrane RoB 2, 5 domains
11	Appropriate meta-analytical methods	Yes	Section 8: DL RE + HKSJ, R/Python cross-validated
13	RoB impact on results considered	Yes	GRADE domain 1, Extraction → RoB tab
15	Publication bias assessment	Yes	Section 9: Funnel + Egger + Trim-Fill + Copas

12. Reporting & Dissemination [PRISMA #23–27, AMSTAR #16]

Reporting Guideline	PRISMA 2020 (27-item checklist auto-generated as CSV)
Export Formats	CSV (study data), JSON (full state), R validation script, Python validation script, PRISMA checklist CSV, HTML standalone report
Data Integrity	SHA-256 data seal (cryptographic fingerprint) on every report; version timeline with delta alerts
Cross-Validation	R (`metafor`) and Python (`scipy`) scripts included for independent replication of pooled OR, CI, τ²
Patient Mode	Plain-language summary with traffic-light visual; hides technical statistics for lay audiences

Search History Log [PRISMA #8]

No searches recorded yet. Run an acquisition from the Search tab to log results here.

Evidence Acquisition

Multi-Source: ClinicalTrials.gov + PubMed + OpenAlex

Saved Search Log

No searches recorded yet.

Pooled Odds Ratio (REML)

Precision (95% CI)

Heterogeneity (I²)

HKSJ-Adjusted CI

Prediction Interval

Q-test (Cochran)

τ² (95% CI)

DL Estimate (sensitivity)

DL τ²

MH Estimate

Bayesian CrI

P(OR < 1)

Information Fraction

Bayesian Prior:

Meta-Regression:

Subgroup By:

Egger's: --

ROB-ME: --

Fragility: --

Trim-Fill: --

Copas: --

RIS: --

HR Sensitivity: --

Sensitivity:

RoB Sensitivity: --

Method Sensitivity: --

Study Characteristics

Trial	Year	Phase	Indication	N (Tx)	N (Ctrl)	ER Tx%	ER Ctrl%	RoB

ER = Event Rate. Values extracted from registry records — verify against published manuscripts before finalizing.

Precision Analytics Suite

1. Forest Plot (Fixed/Random Effects)

2. Subgroup Synthesis (Short-acting vs Long-acting GLP-1 RA)

3. Cumulative Meta-Analysis

4. Cumulative Z-Curve Analysis

5. Leave-One-Out Sensitivity

6. L'Abbe Plot (Event Incidence)

7. Galbraith Plot (Heterogeneity Check)

8. Clinical Utility (NNT Curve)

9. Funnel Plot (Publication Bias)

10. Baujat Plot (Influence x Heterogeneity)

11. Bayesian Posterior Density

12. Meta-Regression

13. Copas Sensitivity Curve

14. Conditional Power Curve

15. Egger's Regression Plot

16. Risk of Bias Summary

17. Method Sensitivity

18. Network Meta-Analysis (League Table)

19. Safety Profile (Published Adverse Events)

20. Fragility Index

21. Trial Sequential Analysis

22. NMA League Table

23. NMA Ranking Dashboard

24. Dose-Response Analysis

25. Safety Forest Plots (Per-AE Meta-Analysis)

26. Time-to-Benefit Analysis

27. TruthCert Evidence Verdict

37. Cook's Distance & DFBETAS

38. Baujat Plot

39. GOSH Plot

40. Forward Search

41. Credibility Ceiling

30. Mathur-VanderWeele Worst-Case

31. PET-PEESE Regression

32. Z-Curve

33. Vevea-Hedges Weight Function

34. WAAP-WLS

35. Sunset Funnel Plot

36. E-Values

28. Component NMA

29. Riley Multivariate MA

44. Multiverse Specification Curve

45. Threshold Analysis

46. Conformal Prediction Intervals

47. Credibility Ceiling (Robustness)

42. CT.gov Evidence Delta

43. Evidence Gap Matrix

48. Galaxy Plot

49. Kilim Plot

50. Radial SUCRA

51. E-Value Profile

52. Fragility Quotient Dashboard

What does this mean for you?

This is a summary for general understanding. Always discuss with your healthcare provider.

9. Quality Appraisal (RoB 2.0)

WebR: Validate with R in Your Browser

Not loaded

Runs metafor::rma() directly in your browser via WebAssembly. No server needed. First load installs R + metafor (~20-40s).

10. Evidence Summary (GRADE)

TruthCert R-Metafor Script (DL Model)

R Cross-Validation (metafor v4.8)

Click "Validate" after running the analysis to compare JS engine output against R (metafor).

Auto-Generated Manuscript Text

Click "Generate Output" to create manuscript text.

Scientific Synthesis

Generating Visual Abstract & PRISMA Diagram...

PRISMA 2020 Flow Diagram (SVG)

GLP-1 Receptor Agonists & Cardiovascular Outcomes

Multi-source meta-analysis of landmark RCTs

Patient Population

N = -- Patients

Acquisition Era

Post-2015 Enrollment

Primary MACE Composite Result

Odds Ratio [95% CI]

Consistency (I²)

Scientific Verdict

Waiting Room Summary

--/100

NNT Pictogram

--%

Risk Change

Odds Ratio

For general understanding only. Discuss treatment decisions with your healthcare provider.

PRISMA 2020 Flow Diagram

Databases & Registers

Records from ClinicalTrials.gov
(n = --)

Records removed before screening
Duplicates / Ineligible
(n = --)

Records screened
(n = --)

Records excluded
(n = --)

Other Sources

Records from PubMed
(n = --)

Records from OpenAlex
(n = --)

Reference-checked trials
(n = --)

Reports assessed for eligibility
(n = --)

Reports excluded
(n = --)

Included in synthesis
(n = --)

The GLP-1 RA CVOT Evidence

A quantitative synthesis of landmark randomized trials.

Pooled OR

NNT

I² Heterogeneity

Trials Included

Confidence Interval Comparison

Visual comparison of estimation methods on the odds ratio scale. The pooled point estimate is identical; interval widths differ by method.

Fig. — DerSimonian-Laird (standard), Hartung-Knapp-Sidik-Jonkman (adjusted), and Prediction Interval estimates

Publication-Quality Forest Plot

Annotated forest plot with trial-level statistics and weight contributions. Suitable for manuscript figures.

Fig. — Forest plot of GLP-1 receptor agonist vs placebo for 3-point MACE (random-effects, DL estimator)

Summary of Findings

Outcome	No. Trials	Total N	Effect (OR)	95% CI	I²	GRADE

SoF table follows GRADE Working Group recommendations. Verify values against R validation script output.

GRADE Evidence Profile (Summary of Findings)

Cumulative Meta-Analysis

Click "Run Cumulative" to generate a cumulative meta-analysis ordered by publication year.

Quality Assurance (18 Checks)

Click "Run QA" to execute 18 automated quality checks on the current analysis.

Version Timeline

Generate a report to create the first snapshot.

Data Seal: -- · --