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Cited by 48Diabetes Treatment and ManagementDiabetes, Cardiovascular Risks, and LipoproteinsHeart Failure Treatment and Management

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

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Krüger, Nils, Schneeweiss, Sebastian, Desai, Rishi J., Sreedhara, Sushama Kattinakere, Kehoe, Anna R., Fuse, Kenshiro, Hahn, Georg, Schunkert, Heribert +1 more·2026·Nature Medicine
DOI 10.1038/s41591-025-04102-xPMC PMC12823426
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Abstract

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 .

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  • In SURPASS-CVOT, numerically higher proportions of participants taking tirzepatide 15 mg weekly reported nausea, vomiting, and diarrhea compared with those taking dulaglutide 1.5 mg weekly.

    “in a recent large cardiovascular outcomes trial (SURPASS-CVOT), numerically higher proportions of participants taking tirzepatide (15 mg weekly) reported nausea, vomiting, and diarrhea compared with those taking the selective GLP-1RA dulaglutide (1.5 mg weekly) (25).”

    From The science of safety: adverse effects of GLP-1 receptor agonists as glucose-lowering and obesity medications (2026) · cites this paper as [25]

    The Methods section ('Specification and emulation of the studies'; page unavailable) identifies SURPASS-CVOT as a once-weekly tirzepatide-versus-dulaglutide trial. Our copy does not give the stated doses or report trial participants’ proportions with nausea, vomiting, or diarrhea. Its Results section discusses gastrointestinal adverse events in the authors’ observational analysis, not those specific SURPASS-CVOT findings. (LLM, conf=0.82)

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Authors
Krüger, N., Schneeweiss, S., Desai, R. J., Sreedhara, S. K., Kehoe, A. R., Fuse, K., Hahn, G., Schunkert, H., & Wang, S. V.
Affiliations
  • Brigham and Women's Hospital (US)
  • German Centre for Cardiovascular Research (DE)
Corresponding author
Krüger, Nils
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2025-11-09
Volume
32
Issue
1
Pages
342-352
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/s41591-025-04102-x
PMC
PMC12823426
OpenAlex
W4416055414
Cited by
48
References
47
Citations by year
2026: 47 · 2025: 1
FWCI
32.74
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Medicine (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
Funders
  • Deutsche Herzstiftung (S/02/24, SRF-HF/24)
  • U.S. Department of Health & Human Services | National Institutes of Health (R01-HL141505, R01-AR080194)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
Keywords
semaglutide, tirzepatide, type 2 diabetes, cardiovascular outcomes, cardiovascular risk, obesity, GLP-1 receptor agonists, SUSTAIN 6, sitagliptin, dulaglutide, myocardial infarction, stroke, all-cause mortality, real-world evidence, head-to-head comparison, trial emulation
MeSH terms
Sitagliptin Phosphate, Tirzepatide, Aged, Cardiovascular Diseases, Diabetes Mellitus, Type 2, Glucagon-Like Peptides, Female, Humans, Hypoglycemic Agents, Immunoglobulin Fc Fragments, Male, Middle Aged, Recombinant Fusion Proteins, Treatment Outcome, Observational Studies as Topic

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