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Research Summary
Analyzed using Evidence Intelligence™

HbA1c mediates cardiovascular benefits of GLP-1 receptor agonists

Powered by the Dediabetes Evidence Intelligence™ framework

Last updated July 8, 2026

Key finding

Total effect of liraglutide on 3P-MACE was -0.0177.

This study investigated the effects of GLP-1 receptor agonists, liraglutide and semaglutide, on cardiovascular outcomes in diabetes, finding significant reductions in major adverse cardiovascular events.

Quick read

Study at a glance

The essential study design details in one scan.

EvidenceScore™

Moderate

Study type

RCTs

Follow-up

Extended (5–20+ y)

Risk of bias

High Risk

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Plain-language summary

What this paper says

A plain-language read of the study’s main message and where it applies.

Study focus

This study investigated the effects of GLP-1 receptor agonists, liraglutide and semaglutide, on cardiovascular outcomes in diabetes, finding significant reductions in major adverse cardiovascular events.

Clinical relevance

These findings are crucial as they highlight the cardiovascular benefits of GLP-1 receptor agonists for diabetes patients, which can inform treatment decisions and improve patient outcomes. Reducing major cardiovascular events can lead to better overall health and longevity for individuals living with diabetes.

Keep in mind

The effectiveness of the interventions remains unclear due to unspecified p-values. Potential limitations in generalizability due to the specific population studied. Lack of detailed information on long-term outcomes beyond the study duration.

Published in

Journal Reference

Publication details and source links for this paper.

Zi-Yang P, Yu-Hsuan L, Huang-Tz O, Shihchen K. Causal mediation analysis of GLP-1 receptor agonists on cardiovascular outcomes in diabetes. Cardiovascular Diabetology. 2025;24:465. doi:10.1186/s12933-025-03007-w

View DOIView on PubMedView on PMC

Main Effects

Liraglutide significantly reduced the incidence of nonfatal stroke and myocardial infarction, as well as cardiovascular death compared to placebo.

HbA1c contributed 38.2% to liraglutide's effect on 3P-MACE.

Semaglutide significantly reduced the incidence of nonfatal stroke and myocardial infarction, as well as cardiovascular death compared to placebo.

HbA1c contributed 51.8% to semaglutide's effect on 3P-MACE.

Evidence network

How this study fits

Understand where this research contributes within the broader evidence network.

Evidence Context

This study contributes evidence to Liraglutide, Semaglutide and Cardiovascular death, Composite cardiovascular events (CV death, MI, stroke, HF hospitalization), Incidence of myocardial infarction, and 1 more.

This study contributes evidence to

Intervention

Liraglutide

Outcome

Cardiovascular death

Evidence topic

Cardiovascular Risk

Primary intervention

Liraglutide

Primary outcomes

  • Cardiovascular death
  • Composite cardiovascular events (CV death, MI, stroke, HF hospitalization)
  • Incidence of myocardial infarction

Evidence topics

Cardiovascular RiskGLP-1 Receptor AgonistsLiraglutide

Primary intervention

Liraglutide

Primary outcomes

Cardiovascular deathComposite cardiovascular events (CV death, MI, stroke, HF hospitalization)Incidence of myocardial infarction

Evidence relationships

Intervention and outcome relationships this study adds to the evidence network.

8
Evidence pairs
8
Relationships
3
Evidence topics
contributes_evidence

Editorial context

Why this study matters

See why this paper is useful beyond its individual results.

Evidence network role

This section describes how the study fits into the current evidence network. It does not determine whether an intervention works on its own.

Moderate contributionModerate confidenceNetwork score: 72

3

Related topics

8

Evidence pairs

125

Related studies

High relevance in at least one topic

Why it is useful

  • Contributes to 8 evidence relationships
  • Includes primary outcome data
  • Linked to 3 direct semantic evidence topics

Topic contributions

Evidence topic

Contributes evidence

Evidence topic

Contributes evidence

Evidence topic

Contributes evidence

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Primary evidence

Evidence relationship

GLP-1 Receptor Agonists and Cardiovascular Outcomes

Related evidence

Evidence topic

Cardiovascular Risk

Save evidence

Evidence topic

GLP-1 Receptor Agonists

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Core evidence

Study findings

The primary outcomes reported in this study.

Cardiovascular death

Liraglutide → Cardiovascular death

Liraglutide → Cardiovascular death

Evidence Intelligence™
EvidenceScore™
Emerging
Score 59 · Based on 1 study
ImpactScore™
25
Negative
ConsistencyScore™
unclear
Not enough independent studies
Supporting studies: Based on 1 study
Add to Evidence Tracker

Incidence of myocardial infarction

Liraglutide → Incidence of myocardial infarction

Liraglutide → Incidence of myocardial infarction

Evidence Intelligence™
EvidenceScore™
Emerging
Score 59 · Based on 1 study
ImpactScore™
100
Very Positive
ConsistencyScore™
unclear
Not enough independent studies
Supporting studies: Based on 1 study
Add to Evidence Tracker

Nonfatal stroke

Liraglutide → Nonfatal stroke

Liraglutide → Nonfatal stroke

Evidence Intelligence™
EvidenceScore™
Emerging
Score 59 · Based on 1 study
ImpactScore™
25
Negative
ConsistencyScore™
unclear
Not enough independent studies
Supporting studies: Based on 1 study
Add to Evidence Tracker

Cardiovascular death

Semaglutide → Cardiovascular death

Semaglutide → Cardiovascular death

Evidence Intelligence™
EvidenceScore™
77
Strong
ImpactScore™
33
Slightly Negative
ConsistencyScore™
67
generally_consistent
Supporting studies: Based on 3 studies
Add to Evidence Tracker

Incidence of myocardial infarction

Semaglutide → Incidence of myocardial infarction

Semaglutide → Incidence of myocardial infarction

Evidence Intelligence™
EvidenceScore™
Moderate
Score 69 · Based on 2 studies
ImpactScore™
100
Very Positive
ConsistencyScore™
100
consistent
Supporting studies: Based on 2 studies
Add to Evidence Tracker

Nonfatal stroke

Semaglutide → Nonfatal stroke

Semaglutide → Nonfatal stroke

Evidence Intelligence™
EvidenceScore™
Strong
Score 79 · Based on 4 studies
ImpactScore™
38
Slightly Negative
ConsistencyScore™
35
mixed
Supporting studies: Based on 4 studies
Add to Evidence Tracker

Evidence Library

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evidence suggest

Evidence Suggest

  • Liraglutide reduced the risk of nonfatal stroke and myocardial infarction, with a cumulative hazard decrease of -0.0177.
  • Semaglutide also significantly reduced the risk of nonfatal stroke and myocardial infarction, with a cumulative hazard decrease of -0.1035.
  • HbA1c levels mediated a significant portion of the cardiovascular benefits for both medications.
who this applies

Who this applies to

  • Adults with type 2 diabetes.
  • Patients at risk for cardiovascular events.
keep in mind

Keep in Mind

  • The study's findings may not be applicable to all diabetes populations.
  • Further research is needed to confirm long-term benefits and safety.
  • The specific mechanisms by which HbA1c mediates these effects require further exploration.
between the lines

Between the Lines

  • The effectiveness of the interventions remains unclear due to unspecified p-values.
  • Potential limitations in generalizability due to the specific population studied.
  • Lack of detailed information on long-term outcomes beyond the study duration.

Evidence Library

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Connected Evidence

Explore related studies, evidence collections, and research questions.

Relationships organized using the Dediabetes Evidence Intelligence™ framework.

Powered by the Dediabetes Evidence Intelligence™ framework

This study contributes to evidence on GLP-1 Receptor Agonists and Cardiovascular Outcomes, GLP-1 Receptor Agonists and Cardiovascular Outcomes.

Related evidence relationships

Explore in Evidence Explorer

This study contributes to the evidence on the following intervention-outcome relationships.

Questions answered by this study

Generated from the study's connected evidence using Evidence Intelligence™.

Does GLP-1 Receptor Agonists improve cardiovascular outcomes?

Strong Evidence

GLP-1 Receptor Agonists may improve Cardiovascular Outcomes.

ConsistencyScore™: Results are mixed and should be interpreted cautiously.

Evidence caveat: The available evidence reports mixed findings.

Ranked evidence signals

  1. 1

    Composite cardiovascular events (CV death, MI, stroke, HF hospitalization)

    EvidenceScore™ Strong | EvidenceScore™ 83.2 | strong positive | ConsistencyScore™ Generally Consistent | 1 study

  2. 2

    Nonfatal stroke

    EvidenceScore™ Strong | EvidenceScore™ 79.0 | weak negative | ConsistencyScore™ Mixed | 1 study

  3. 3

    Cardiovascular death

    EvidenceScore™ Strong | EvidenceScore™ 77.1 | weak negative | ConsistencyScore™ Generally Consistent | 1 study

Why this answer: This answer is cautious because the available studies report mixed findings.

Limitations

  • Population details are unavailable.
12 supporting studiesUpdated: Aug 2026
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Next steps

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Evidence topics

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Cardiovascular Risk Evidence HubGLP-1 Receptor Agonists Evidence HubLiraglutide Evidence Hub

Explore in Evidence Explorer

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All studies on Semaglutide and Nonfatal strokeAll studies on Semaglutide and Cardiovascular deathAll studies on Semaglutide and Incidence of myocardial infarctionAll studies on Liraglutide and Cardiovascular death

Related research

Read related research summaries.

Liraglutide is well tolerated in diabetes patients undergoing hemodialysis.Liraglutide may reduce stroke recurrence in type 2 diabetes patientsSemaglutide may reduce cardiovascular events in non-diabetic patients.Oral semaglutide reduces cardiovascular events in type 2 diabetesHigher semaglutide doses improve glucose control in type 2 diabetes

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