Risk of major adverse cardiovascular events and stroke associated with treatment with GLP-1 or the dual GIP/GLP-1 receptor agonist tirzepatide for type 2 diabetes: A systematic review and meta-analysis
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Introduction: Mounting evidence suggests that glucagon-like-peptide-1 receptor-agonists (GLP-1 RAs) attenuate cardiovascular-risk in type-2 diabetes (T2DM). Tirzepatide is the first-in-class, dual glucose-dependent-insulinotropic-polypeptide GIP/GLP-1 RA approved for T2DM. Patients and methods: A systematic review and meta-analysis of randomized-controlled clinical trials (RCTs) was performed to estimate: (i) the incidence of major adverse cardiovascular events (MACE); and (ii) incidence of stroke, fatal, and nonfatal stroke in T2DM-patients treated with GLP-1 or GIP/GLP-1 RAs (vs placebo). Results: Thirteen RCTs (9 and 4 on GLP-1 RAs and tirzepatide, respectively) comprising 65,878 T2DM patients were included. Compared to placebo, GLP-1RAs or GIP/GLP-1 RAs reduced MACE (OR: 0.87; 95% CI: 0.81–0.94; p < 0.01; I 2 = 37%), all-cause mortality (OR: 0.88; 95% CI: 0.82–0.96; p < 0.01; I 2 = 21%) and cardiovascular-mortality (OR: 0.88; 95% CI: 0.80–0.96; p < 0.01; I 2 = 14%), without differences between GLP-1 versus GIP/GLP-1 RAs. Additionally, GLP-1 RAs reduced the odds of stroke (OR: 0.84; 95% CI: 0.76–0.93; p < 0.01; I 2 = 0%) and nonfatal stroke (OR: 0.85; 95% CI: 0.76–0.94; p < 0.01; I 2 = 0%), whereas no association between fatal stroke and GLP-1RAs was uncovered (OR: 0.80; 95% CI: 0.61–1.05; p = 0.105; I 2 = 0%). In secondary analyses, GLP-1 RAs prevented ischemic stroke (OR: 0.74; 95% CI: 0.61–0.91; p < 0.01; I 2 = 0%) and MACE-recurrence, but not hemorrhagic stroke (OR: 0.92; 95% CI: 0.51–1.66; p = 0.792; I 2 = 0%). There was no association between GLP-1RAs or GIP/GLP-1 RAs and fatal or nonfatal myocardial infarction. Discussion and conclusion: GLP-1 and GIP/GLP-1 RAs reduce cardiovascular-risk and mortality in T2DM. While there is solid evidence that GLP-1 RAs significantly attenuate the risk of ischemic stroke in T2DM, dedicated RCTs are needed to evaluate the efficacy of novel GIP/GLP-1 RAs for primary and secondary stroke prevention.
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Meta-analyses confirm GLP-1 and dual GIP/GLP-1 receptor agonists significantly lower major adverse cardiovascular events (MACE) and mortality during active therapy.
“Meta-analyses confirm that GLP-1 and dual GIP/GLP-1 receptor agonists significantly lower major adverse cardiovascular events (MACE) and mortality during active therapy.16,44,45”
From Metabolic rebound after GLP-1 receptor agonist discontinuation: a systematic review and meta-analysis (2025) · cites this paper as [45]
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“16,44,45 However, the consequences of treatment withdrawal remain largely uncharacterized, underscoring the need for longitudinal studies on potential rebound risks.”
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- Authors
- Stefanou, M.-I., Theodorou, A., Malhotra, K., Aguiar de Sousa, D., Katan, M., Palaiodimou, L., Katsanos, A. H., Koutroulou, I., Lambadiari, V., Lemmens, R., Giannopoulos, S., Alexandrov, A. V., Siasos, G., & Tsivgoulis, G.
- Affiliations
- National and Kapodistrian University of Athens (GR)
- Allegheny Health Network (US)
- Stroke Center, Centro Hospitalar Universitário Lisboa Central and Institute of Anatomy, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal 3
- Department of Neurology, University Hospital Basel and University of Basel, Basel, Switzerland 4
- Population Health Research Institute (CA)
- Aristotle University of Thessaloniki (GR)
- KU Leuven (BE)
- University of Tennessee Health Science Center (US)
- Corresponding author
- Tsivgoulis, Georgios
- ORCID
- Venue
- European Stroke Journal
- Publisher
- Oxford University Press (OUP)
- Published
- 2024-09-01
- Volume
- 9
- Issue
- 3
- Pages
- 530-539
- ISSN
- 2396-9873 (ISSN-L)
- 2396-9881
- PMC
- PMC11418422
- OpenAlex
- W4392137095
- Cited by
- 60
- References
- 19
- Citations by year
- 2026: 23 · 2025: 26 · 2024: 11
- FWCI
- 3.51
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- European Stroke Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Lirias (KU Leuven) (submittedVersion)
- 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 › Pharmacology › Pharmacology and Obesity Treatment
- Keywords
- GLP-1 receptor agonists, tirzepatide, GIP/GLP-1 receptor agonist, type 2 diabetes, major adverse cardiovascular events, stroke, cardiovascular safety, all-cause mortality, cardiovascular mortality, cardiovascular risk reduction, GLP-1 receptor antagonists
- MeSH terms
- Glucagon-Like Peptide-2 Receptor, Glucagon-Like Peptide-1 Receptor Agonists, Tirzepatide, Cardiovascular Diseases, Diabetes Mellitus, Type 2, Gastric Inhibitory Polypeptide, Humans, Hypoglycemic Agents, Receptors, Gastrointestinal Hormone, Randomized Controlled Trials as Topic, Stroke, Glucagon-Like Peptide 1
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