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Study · Observational study · 2026

5 results

Cardiovascular outcomes of semaglutide and tirzepatide for patients with type 2 diabetes in clinical practice.

Krüger N, Schneeweiss S, Desai RJ, Sreedhara SK, Kehoe AR, Fuse K, Hahn G, Schunkert H, Wang SV

Nature medicine9 Nov 2025Cited by 31 (Europe PMC)

PMID41207920 (opens in a new tab)PMCIDPMC12823426 (opens in a new tab)DOI10.1038/s41591-025-04102-x (opens in a new tab)PepBankPUB-41207920
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Summary

Cardiovascular outcome trials of the incretin-based medicines tirzepatide and semaglutide have shown benefits in populations with varying levels of cardiovascular risk. However, without direct head-to-head comparisons, treatment decisions rely on indirect evidence from heterogeneous trial populations, leaving optimal treatment choices uncertain. Here we conducted five cohort studies to assess the effectiveness of tirzepatide and semaglutide in patients with elevated cardiovascular risk, including obesity and type 2 diabetes, enrolled in insurance programs in the USA between 2018 and 2025. First, we emulated two cardiovascular outcome trials, SUSTAIN-6 (semaglutide versus sitagliptin as placebo proxy) and SURPASS-CVOT (tirzepatide versus dulaglutide), to benchmark and critically evaluate our design, data and analytic framework. Second, we assessed each drug in expanded populations reflective of patients routinely seen in clinical practice. Third, we directly compared tirzepatide versus semaglutide. Baseline confounders were balanced using propensity score matching. For the primary composite endpoint of myocardial infarction, stroke or all-cause mortality, benchmarking identified high agreement between the reference trials and their emulations for all individual endpoints except for all-cause mortality in SUSTAIN-6, informing subsequent analyses. In expanded populations, comparing semaglutide versus sitagliptin for the composite outcome of myocardial infarction or stroke yielded a hazard ratio of 0.82 (95% confidence interval (CI) 0.74 to 0.91), and comparing tirzepatide versus dulaglutide for the composite outcome including mortality yielded a hazard ratio of 0.87 (95% CI 0.75 to 1.01). In the head-to-head comparison of tirzepatide versus semaglutide, the hazard ratio was 1.06 (95% CI 0.95 to 1.18). These findings support a comparable cardiovascular benefit of tirzepatide and semaglutide in clinical practice and demonstrate how rigorously designed real-world evidence can complement randomized clinical trials. ClinicalTrials.gov registration: NCT06659744 , NCT07088718 , NCT07096063 .
CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study5

5 results from studies that gave the peptide. 5 results from people.

  1. 01HumanObservational studyEfficacy outcome

    In patients with elevated cardiovascular risk, semaglutide was linked to lower myocardial infarction or stroke risk than sitagliptin.

    In plain wordsIn patients with elevated cardiovascular risk, semaglutide was linked to fewer heart attacks or strokes than sitagliptin.

    Peptide
    Semaglutide
    Outcome
    DecreaseMyocardial infarction or stroke
    Study

    n: not reported in source

    Comparator
    Sitagliptin
    Outcome group
    Cardiovascular events · Cardiovascular
    Studied dose
    Dose not stated

    Measurements

    Hazard ratio
    0.82
    semaglutide versus sitagliptin
    95% CI lower
    0.74
    hazard ratio
    95% CI upper
    0.91
    hazard ratio

    Source sentences

    Summary
    In expanded populations, comparing semaglutide versus sitagliptin for the composite outcome of myocardial infarction or stroke yielded a hazard ratio of 0.82 (95% confidence interval (CI) 0.74 to 0.91)
    2 context sentences
    Summary · context
    Here we conducted five cohort studies to assess the effectiveness of tirzepatide and semaglutide in patients with elevated cardiovascular risk, including obesity and type 2 diabetes, enrolled in insurance programs in the USA between 2018 and 2025.
    Summary · context
    Baseline confounders were balanced using propensity score matching.
  2. 02HumanObservational studyEfficacy outcome

    In patients with elevated cardiovascular risk, the composite cardiovascular and mortality risk did not differ significantly between tirzepatide and dulaglutide.

    In plain wordsIn patients with elevated cardiovascular risk, tirzepatide and dulaglutide had no significant difference in combined cardiovascular and mortality risk.

    Peptide
    Tirzepatide
    Outcome
    No significant changeMyocardial infarction, stroke or mortality
    Study

    n: not reported in source

    Comparator
    Dulaglutide
    Outcome group
    Cardiovascular events · Cardiovascular
    Studied dose
    Dose not stated

    Measurements

    Hazard ratio
    0.87
    tirzepatide versus dulaglutide
    95% CI lower
    0.75
    hazard ratio
    95% CI upper
    1.01
    hazard ratio

    Source sentences

    Summary
    and comparing tirzepatide versus dulaglutide for the composite outcome including mortality yielded a hazard ratio of 0.87 (95% CI 0.75 to 1.01).
    2 context sentences
    Summary · context
    Here we conducted five cohort studies to assess the effectiveness of tirzepatide and semaglutide in patients with elevated cardiovascular risk, including obesity and type 2 diabetes, enrolled in insurance programs in the USA between 2018 and 2025.
    Summary · context
    Baseline confounders were balanced using propensity score matching.
  3. 03HumanObservational studyEfficacy outcome

    In expanded clinical-practice cohorts, the hazard ratio for myocardial infarction, stroke or all-cause mortality was 0.87 for tirzepatide versus dulaglutide.

    In plain wordsIn clinical-practice cohorts, the combined outcome hazard ratio was 0.87 for tirzepatide versus dulaglutide.

    Peptide
    Dulaglutide (Trulicity)
    Outcome
    Direction not reportedMyocardial infarction, stroke or mortality
    Study

    n: not reported in source

    Comparator
    Tirzepatide
    Outcome group
    Cardiovascular events · Cardiovascular
    Studied dose
    Dose not stated

    Measurements

    Hazard ratio
    0.87
    tirzepatide versus dulaglutide
    95% CI lower
    0.75
    hazard ratio
    95% CI upper
    1.01
    hazard ratio

    Source sentences

    Summary
    and comparing tirzepatide versus dulaglutide for the composite outcome including mortality yielded a hazard ratio of 0.87 (95% CI 0.75 to 1.01).
    2 context sentences
    Summary · context
    Here we conducted five cohort studies to assess the effectiveness of tirzepatide and semaglutide in patients with elevated cardiovascular risk, including obesity and type 2 diabetes, enrolled in insurance programs in the USA between 2018 and 2025.
    Summary · context
    Baseline confounders were balanced using propensity score matching.
  4. 04HumanObservational studyEfficacy outcome

    In patients with elevated cardiovascular risk, the head-to-head composite outcome did not differ significantly between tirzepatide and semaglutide.

    In plain wordsIn patients with elevated cardiovascular risk, the combined outcome did not differ significantly between tirzepatide and semaglutide.

    Peptide
    Tirzepatide
    Outcome
    No significant changeHead-to-head cardiovascular composite
    Study

    n: not reported in source

    Comparator
    Semaglutide
    Outcome group
    Cardiovascular events · Cardiovascular
    Studied dose
    Dose not stated

    Measurements

    Hazard ratio
    1.06
    tirzepatide versus semaglutide
    95% CI lower
    0.95
    hazard ratio
    95% CI upper
    1.18
    hazard ratio

    Source sentences

    Summary
    In the head-to-head comparison of tirzepatide versus semaglutide, the hazard ratio was 1.06 (95% CI 0.95 to 1.18).
    2 context sentences
    Summary · context
    Here we conducted five cohort studies to assess the effectiveness of tirzepatide and semaglutide in patients with elevated cardiovascular risk, including obesity and type 2 diabetes, enrolled in insurance programs in the USA between 2018 and 2025.
    Summary · context
    Baseline confounders were balanced using propensity score matching.
  5. 05HumanObservational studyEfficacy outcome

    In patients with elevated cardiovascular risk, the head-to-head composite outcome did not differ significantly between semaglutide and tirzepatide.

    In plain wordsIn patients with elevated cardiovascular risk, the combined outcome did not differ significantly between semaglutide and tirzepatide.

    Peptide
    Semaglutide
    Outcome
    No significant changeHead-to-head cardiovascular composite
    Study

    n: not reported in source

    Comparator
    Tirzepatide
    Outcome group
    Cardiovascular events · Cardiovascular
    Studied dose
    Dose not stated

    Measurements

    Hazard ratio
    1.06
    tirzepatide versus semaglutide
    95% CI lower
    0.95
    hazard ratio
    95% CI upper
    1.18
    hazard ratio

    Source sentences

    Summary
    In the head-to-head comparison of tirzepatide versus semaglutide, the hazard ratio was 1.06 (95% CI 0.95 to 1.18).
    2 context sentences
    Summary · context
    Here we conducted five cohort studies to assess the effectiveness of tirzepatide and semaglutide in patients with elevated cardiovascular risk, including obesity and type 2 diabetes, enrolled in insurance programs in the USA between 2018 and 2025.
    Summary · context
    Baseline confounders were balanced using propensity score matching.

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Registered trials3

Trials this study reports on, or that list this study as a reference. Registry data from ClinicalTrials.gov.

3 trials · 3 completed · source ClinicalTrials.gov (opens in a new tab)

CompletedPhase not statedNCT06659744

Emulation of the SUSTAIN6 Diabetes Trial Using Healthcare Claims

Brigham and Women's Hospitaln = 158,31024 Oct 2024 to 6 Mar 2025

Diabetes Mellitus, Type 2

Trial pageClinicalTrials.govUpdated 15 Oct 2025
CompletedPhase not statedNCT07088718

Prediction of the SURPASS-CVOT Cardiovascular Outcome Trial in Healthcare Claims Data

Brigham and Women's Hospitaln = 44,6711 Oct 2024 to 30 Jul 2025

Type 2 Diabetes · Major Adverse Cardiac Events · Cardiovascular (CV) Risk

Trial pageClinicalTrials.govUpdated 15 Oct 2025
CompletedPhase not statedNCT07096063

Comparative Effectiveness of Tirzepatide and Semaglutide in Individuals at Cardiovascular Risk

Brigham and Women's Hospitaln = 887,1321 Oct 2024 to 15 Jul 2025

Type 2 Diabetes · Overweight · Cardiovascular (CV) Risk

Trial pageClinicalTrials.govUpdated 15 Oct 2025

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

  1. Version 4Current

    22 Oct 2026, 02:25 UTC

    Study results updated

  2. Versions 2 to 3

    21 Oct 2026, 18:59 UTC

    The same notice was added 2 times, first on 9 Oct 2026, 03:07 UTC. The status did not change between them.

    Study data updated · source update from Europe PMC

  3. Version 1

    9 Oct 2026, 03:06 UTC

    First added · source update from Europe PMC

Subjects

Terms as the source lists them.

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