HarmfulDecrease
Cardiovascular death
Liraglutide → Cardiovascular death
Liraglutide → Cardiovascular death
Evidence profile
HarmfulDecreaseClinical Outcomes
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Research Summary
Analyzed using Evidence Intelligence™
HbA1c mediates cardiovascular benefits of GLP-1 receptor agonists
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.
Evidence strength
Moderate confidence
Study type
RCTs
Follow-up
Extended (5–20+ y)
High bias
Last updated July 8, 2026Quick read
Study at a glance
The essential study design details in one scan.
Population
Young Adult (19–39), Middle Aged (40-64), Male, Female, Asia-Pacific (APAC), with T2 Diabetes
Intervention
Liraglutide, Semaglutide
Study type
RCTs
Follow-up
Extended (5–20+ y)
Primary outcome
Incidence of nonfatal stroke
Comparator
Placebo, Placebo
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
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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
Primary intervention
Liraglutide
Primary outcomes
- Cardiovascular death
- Composite cardiovascular events (CV death, MI, stroke, HF hospitalization)
- Incidence of myocardial infarction
Evidence topics
Primary intervention
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
85
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
Core evidence
Study findings
The primary outcomes reported in this study.
StrongIncrease
Composite cardiovascular events (CV death, MI, stroke, HF hospitalization)
Liraglutide → Composite cardiovascular events (CV death, MI, stroke, HF hospitalization)
Liraglutide → Composite cardiovascular events (CV death, MI, stroke, HF hospitalization)
Evidence profile
StrongIncreaseClinical Outcomes
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StrongDecrease
Incidence of myocardial infarction
Liraglutide → Incidence of myocardial infarction
Liraglutide → Incidence of myocardial infarction
Evidence profile
StrongDecreaseClinical Outcomes
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HarmfulDecrease
Nonfatal stroke
Liraglutide → Nonfatal stroke
Liraglutide → Nonfatal stroke
Evidence profile
HarmfulDecreaseClinical Outcomes
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HarmfulDecrease
Cardiovascular death
Semaglutide → Cardiovascular death
Semaglutide → Cardiovascular death
Evidence profile
HarmfulDecreaseClinical Outcomes
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StrongIncrease
Composite cardiovascular events (CV death, MI, stroke, HF hospitalization)
Semaglutide → Composite cardiovascular events (CV death, MI, stroke, HF hospitalization)
Semaglutide → Composite cardiovascular events (CV death, MI, stroke, HF hospitalization)
Evidence profile
StrongIncreaseClinical Outcomes
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StrongDecrease
Incidence of myocardial infarction
Semaglutide → Incidence of myocardial infarction
Semaglutide → Incidence of myocardial infarction
Evidence profile
StrongDecreaseClinical Outcomes
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HarmfulDecrease
Nonfatal stroke
Semaglutide → Nonfatal stroke
Semaglutide → Nonfatal stroke
Evidence profile
HarmfulDecreaseClinical Outcomes
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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 to
- Adults with type 2 diabetes.
- Patients at risk for cardiovascular events.
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
- 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.
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Connected Evidence
Explore related studies, evidence collections, and research questions.
Relationships organized using the Dediabetes Evidence Intelligence™ framework.
This study contributes to evidence on GLP-1 Receptor Agonists and Cardiovascular Outcomes, GLP-1 Receptor Agonists and Nonfatal stroke.
Related evidence relationships
Explore in Evidence ArchiveThis study contributes to the evidence on the following intervention-outcome relationships.
Included in these evidence collections
Curated evidence collections and hubs this study is part of.
Cardiovascular Outcomes Evidence Hub
All studies measuring Cardiovascular Outcomes
5 studies
outcome_hubMeasures Cardiovascular Outcomes as a key outcome.
GLP-1 Receptor Agonists Evidence Hub
All studies on GLP-1 Receptor Agonists
5 studies
intervention_hubContributes to GLP-1 Receptor Agonists evidence base.
Nonfatal stroke Evidence Hub
All studies measuring Nonfatal stroke
3 studies
outcome_hubMeasures Nonfatal stroke as a key outcome.
Recent Diabetes Research
Latest published studies
recency_collection
Published within the last 2 years.
Explore more in the evidence archive
Jump to pre-filtered views in the evidence archive.
All studies on Semaglutide and Composite cardiovascular events (CV death, MI, stroke, HF hospitalization)
Intervention: SemaglutideOutcome: Composite cardiovascular events (CV death, MI, stroke, HF hospitalization)
5 results
All studies on Semaglutide and Nonfatal stroke
Intervention: SemaglutideOutcome: Nonfatal stroke
3 results
All studies on Semaglutide
Intervention: Semaglutide
5 results
All studies measuring Composite cardiovascular events (CV death, MI, stroke, HF hospitalization)
Outcome: Composite cardiovascular events (CV death, MI, stroke, HF hospitalization)
5 results
All studies measuring Nonfatal stroke
Outcome: Nonfatal stroke
3 results
Questions answered by this study
Generated from the study's connected evidence using Evidence Intelligence™.
Does GLP-1 Receptor Agonists improve cardiovascular outcomes?
Emerging Evidence
GLP-1 Receptor Agonists may improve Cardiovascular Outcomes.
ConsensusScore™: Results are generally consistent across studies.
Ranked evidence signals
- 1
Composite cardiovascular events (CV death, MI, stroke, HF hospitalization)
EvidenceScore™ Emerging | EvidenceScore™ 57.7 | moderate positive | ConsensusScore™ Generally Consistent | 1 study
Why this answer: This answer is based on 9 supporting studies with generally consistent results and a positive effect signal.
Limitations
- Population details are unavailable.
Does Liraglutide improve incidence of myocardial infarction?
Emerging Evidence
Liraglutide appears to improve Incidence of myocardial infarction.
ConsensusScore™: Consistency cannot yet be determined from the available evidence.
Ranked evidence signals
- 1
Incidence of myocardial infarction
EvidenceScore™ Emerging | EvidenceScore™ 49.1 | strong positive | ConsensusScore™ Unclear | 1 study
Why this answer: This answer is based on a single supporting study.
Limitations
- Only one supporting study is available.
- Consistency cannot yet be determined.
- Population details are unavailable.
Does Semaglutide improve incidence of myocardial infarction?
Emerging Evidence
Semaglutide appears to improve Incidence of myocardial infarction.
ConsensusScore™: Consistency cannot yet be determined from the available evidence.
Ranked evidence signals
- 1
Incidence of myocardial infarction
EvidenceScore™ Emerging | EvidenceScore™ 49.1 | strong positive | ConsensusScore™ Unclear | 1 study
Why this answer: This answer is based on a single supporting study.
Limitations
- Only one supporting study is available.
- Consistency cannot yet be determined.
- Population details are unavailable.
Does Semaglutide improve nonfatal stroke?
Limited Evidence
Semaglutide may worsen Nonfatal stroke or be associated with harm.
ConsensusScore™: Results are generally consistent across studies.
Ranked evidence signals
- 1
Nonfatal stroke
EvidenceScore™ Limited | EvidenceScore™ 39.2 | weak negative | ConsensusScore™ Generally Consistent | 1 study
Why this answer: This answer is based on a single supporting study.
Limitations
- Only one supporting study is available.
- Population details are unavailable.
Next steps
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Evidence topics
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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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