Effects of subcutaneous or oral semaglutide on cardiovascular outcomes in patients with type 2 diabetes mellitus: a meta-analysis of randomized controlled trials.

Tan S, Yin Y, Lu J

Frontiers in cardiovascular medicine15 Dec 2025Cited by 1 (Europe PMC)

PMID41472878PMCIDPMC12745249DOI10.3389/fcvm.2025.1731127PepBankPUB-41472878

Summary

BackgroundGlucagon-like peptide-1 receptor agonists (GLP-1 RAs), such as semaglutide, reduce cardiovascular risk in type 2 diabetes mellitus (T2DM), but the consistency between oral and subcutaneous formulations remains unclear.MethodsThis meta-analysis was registered prospectively in PROSPERO (CRD 420251147337). A systematic search of PubMed, Embase, Cochrane Library, and Web of Science identified randomized controlled trials (RCTs) on semaglutide and cardiovascular outcomes. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using fixed-/random-effects models, with sensitivity, subgroup, and GRADE assessments.ResultsFour RCTs (n = 19,663) showed semaglutide significantly reduced primary outcome risk (HR 0.83; 95% CI 0.76-0.91), nonfatal myocardial infarction (HR 0.79; 0.67-0.92), and revascularization (HR 0.71; 0.61-0.83), with a modest decrease in heart failure hospitalization (HR 0.85; 0.72-1.00). No significant effects were seen for cardiovascular death, all-cause death, nonfatal stroke, or unstable angina hospitalization. Subgroup analyses confirmed no efficacy differences between formulations. Evidence quality was "moderate" for cardiovascular death, all-cause death, nonfatal stroke, unstable angina hospitalization, and "high" for the remainder.ConclusionsSemaglutide lowers cardiovascular risk in T2DM, primarily improving major adverse cardiovascular events, nonfatal myocardial infarction, and revascularization, with oral and subcutaneous forms demonstrating consistent efficacy.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/view/CRD420251147337, PROSPERO CRD420251147337.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study9

9 results from studies that gave the peptide. 9 results from people.

01HumanSystematic reviewEfficacy outcome
In a meta-analysis of four randomised trials in type 2 diabetes, semaglutide reduced the risk of the primary cardiovascular outcome (hazard ratio 0.83).
In plain wordsAcross four trials in type 2 diabetes, semaglutide lowered the risk of major heart and blood vessel events.
Peptide
Semaglutide
Outcome
DecreasePrimary cardiovascular outcome risk
Study
n = 19,663
Comparator
Control
Outcome group
Cardiovascular events · Cardiovascular
Studied dose
Dose not stated
Measurements
Hazard ratio
0.83 ratio
primary outcome
Source sentences
Summary
Four RCTs (n = 19,663) showed semaglutide significantly reduced primary outcome risk (HR 0.83; 95% CI 0.76-0.91)
1 context sentence(design, population, supporting numbers)
Summary · context
A systematic search of PubMed, Embase, Cochrane Library, and Web of Science identified randomized controlled trials (RCTs) on semaglutide and cardiovascular outcomes.
Show in the study text Report a problemFND-4147287801
02HumanSystematic reviewEfficacy outcome
In a meta-analysis of four randomised trials in type 2 diabetes, semaglutide reduced nonfatal myocardial infarction (hazard ratio 0.79).
In plain wordsAcross four trials in type 2 diabetes, semaglutide lowered the risk of non-fatal heart attack.
Peptide
Semaglutide
Outcome
DecreaseNonfatal myocardial infarction
Study
n = 19,663
Comparator
Control
Outcome group
Cardiovascular events · Cardiovascular
Studied dose
Dose not stated
Measurements
Hazard ratio
0.79 ratio
nonfatal myocardial infarction
Source sentences
Summary
nonfatal myocardial infarction (HR 0.79; 0.67-0.92)
1 context sentence(design, population, supporting numbers)
Summary · context
A systematic search of PubMed, Embase, Cochrane Library, and Web of Science identified randomized controlled trials (RCTs) on semaglutide and cardiovascular outcomes.
Show in the study text Report a problemFND-4147287802
03HumanSystematic reviewEfficacy outcome
In a meta-analysis of four randomised trials in type 2 diabetes, semaglutide reduced revascularization (hazard ratio 0.71).
In plain wordsAcross four trials in type 2 diabetes, semaglutide lowered the risk of procedures to restore blood flow to the heart.
Peptide
Semaglutide
Outcome
DecreaseRevascularization
Study
n = 19,663
Comparator
Control
Outcome group
Cardiovascular events · Cardiovascular
Studied dose
Dose not stated
Measurements
Hazard ratio
0.71 ratio
revascularization
Source sentences
Summary
revascularization (HR 0.71; 0.61-0.83)
1 context sentence(design, population, supporting numbers)
Summary · context
A systematic search of PubMed, Embase, Cochrane Library, and Web of Science identified randomized controlled trials (RCTs) on semaglutide and cardiovascular outcomes.
Show in the study text Report a problemFND-4147287803
04HumanSystematic reviewEfficacy outcome
In a meta-analysis of four randomised trials in type 2 diabetes, semaglutide gave a modest decrease in heart failure hospitalization (hazard ratio 0.85; 0.72-1.00).
In plain wordsAcross four trials in type 2 diabetes, semaglutide modestly lowered the risk of hospital stays for heart failure.
Peptide
Semaglutide
Outcome
DecreaseHeart failure hospitalization
Study
n = 19,663
Comparator
Control
Outcome group
Cardiovascular events · Cardiovascular
Studied dose
Dose not stated
Measurements
Hazard ratio
0.85 ratio
heart failure hospitalization
Source sentences
Summary
with a modest decrease in heart failure hospitalization (HR 0.85; 0.72-1.00).
1 context sentence(design, population, supporting numbers)
Summary · context
A systematic search of PubMed, Embase, Cochrane Library, and Web of Science identified randomized controlled trials (RCTs) on semaglutide and cardiovascular outcomes.
Show in the study text Report a problemFND-4147287804
05HumanSystematic reviewEfficacy outcome
In the meta-analysis, semaglutide had no significant effect on cardiovascular death.
In plain wordsAcross the trials, semaglutide did not clearly change the risk of cardiovascular death.
Peptide
Semaglutide
Outcome
No significant changeCardiovascular death
Study
n = 19,663
Comparator
Control
Outcome group
Mortality · Cardiovascular
Studied dose
Dose not stated
Source sentences
Summary
No significant effects were seen for cardiovascular death, all-cause death, nonfatal stroke, or unstable angina hospitalization.
1 context sentence(design, population, supporting numbers)
Summary · context
A systematic search of PubMed, Embase, Cochrane Library, and Web of Science identified randomized controlled trials (RCTs) on semaglutide and cardiovascular outcomes.
Show in the study text Report a problemFND-4147287805
06HumanSystematic reviewEfficacy outcome
In the meta-analysis, semaglutide had no significant effect on all-cause death.
In plain wordsAcross the trials, semaglutide did not clearly change the risk of death from any cause.
Peptide
Semaglutide
Outcome
No significant changeAll-cause death
Study
n = 19,663
Comparator
Control
Outcome group
Mortality · Whole body
Studied dose
Dose not stated
Source sentences
Summary
No significant effects were seen for cardiovascular death, all-cause death, nonfatal stroke, or unstable angina hospitalization.
1 context sentence(design, population, supporting numbers)
Summary · context
A systematic search of PubMed, Embase, Cochrane Library, and Web of Science identified randomized controlled trials (RCTs) on semaglutide and cardiovascular outcomes.
Show in the study text Report a problemFND-4147287806
07HumanSystematic reviewEfficacy outcome
In the meta-analysis, semaglutide had no significant effect on nonfatal stroke.
In plain wordsAcross the trials, semaglutide did not clearly change the risk of non-fatal stroke.
Peptide
Semaglutide
Outcome
No significant changeNonfatal stroke
Study
n = 19,663
Comparator
Control
Outcome group
Cardiovascular events · Cardiovascular
Studied dose
Dose not stated
Source sentences
Summary
No significant effects were seen for cardiovascular death, all-cause death, nonfatal stroke, or unstable angina hospitalization.
1 context sentence(design, population, supporting numbers)
Summary · context
A systematic search of PubMed, Embase, Cochrane Library, and Web of Science identified randomized controlled trials (RCTs) on semaglutide and cardiovascular outcomes.
Show in the study text Report a problemFND-4147287807
08HumanSystematic reviewEfficacy outcome
In the meta-analysis, semaglutide had no significant effect on unstable angina hospitalization.
In plain wordsAcross the trials, semaglutide did not clearly change the risk of hospital stays for unstable angina.
Peptide
Semaglutide
Outcome
No significant changeUnstable angina hospitalization
Study
n = 19,663
Comparator
Control
Outcome group
Cardiovascular events · Cardiovascular
Studied dose
Dose not stated
Source sentences
Summary
No significant effects were seen for cardiovascular death, all-cause death, nonfatal stroke, or unstable angina hospitalization.
1 context sentence(design, population, supporting numbers)
Summary · context
A systematic search of PubMed, Embase, Cochrane Library, and Web of Science identified randomized controlled trials (RCTs) on semaglutide and cardiovascular outcomes.
Show in the study text Report a problemFND-4147287808
09HumanSystematic reviewEfficacy outcome
In the subgroup analyses of the meta-analysis, cardiovascular efficacy did not differ between oral and subcutaneous semaglutide.
In plain wordsIn the trials combined, oral and injected semaglutide showed no difference in heart protection.
Peptide
Semaglutide
Outcome
No significant changeEfficacy difference between oral and subcutaneous semaglutide
Study
n = 19,663
Comparator
Oral versus subcutaneous semaglutide
Outcome group
Cardiovascular events · Cardiovascular
Studied dose
Dose not stated
Source sentences
Summary
Subgroup analyses confirmed no efficacy differences between formulations.
1 context sentence(design, population, supporting numbers)
Summary · context
A systematic search of PubMed, Embase, Cochrane Library, and Web of Science identified randomized controlled trials (RCTs) on semaglutide and cardiovascular outcomes.
Show in the study text Report a problemFND-4147287809

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Version history

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Version 2Current
11 Oct 2026, 00:04 UTC
Study results updated
Version 1
9 Oct 2026, 03:06 UTC
First added · source update from Europe PMC

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