Risk of major adverse cardiovascular events and all-cause mortality under treatment with GLP-1 RAs or the dual GIP/GLP-1 receptor agonist tirzepatide in overweight or obese adults without diabetes: a systematic review and meta-analysis
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Background: Among the currently approved antiobesity medications, the glucagon-like-peptide-1 receptor-agonists (GLP-1 RAs) liraglutide and semaglutide, and the dual glucose-dependent-insulinotropic-polypeptide (GIP)/GLP-1 RA tirzepatide have been suggested to reduce cardiovascular-risk in overweight or obesity without diabetes. Objectives: The objective of this study was to evaluate the cardio- and neuroprotective potential of these novel agents in the nondiabetic overweight/obese adult population. Data sources and methods: A systematic review and meta-analysis of randomized-controlled clinical trials (RCTs) was performed to estimate the risk of major adverse cardiovascular events (MACE), all-cause and cardiovascular mortality in overweight or obese adults without diabetes treated with GLP-1 or GIP/GLP-1 RAs (vs placebo). Secondary outcomes included the risk of myocardial infarction (MI) and stroke. Results: Sixteen RCTs (13 and 3 on GLP-1 RAs and tirzepatide, respectively) comprising 28,168 participants were included. GLP-1 or GIP/GLP-1 RAs reduced MACE (odds ratio (OR): 0.79; 95% confidence interval (CI): 0.71–0.89; p < 0.01; I 2 = 0) and all-cause mortality (OR: 0.80; 95% CI: 0.70–0.92; p < 0.01; I 2 = 0), while there was a trend toward lower cardiovascular-mortality (OR: 0.84; 95% CI: 0.71–1.01; p = 0.06; I 2 = 0%) compared to placebo. Additionally, GLP-1 or GIP/GLP-1 RAs reduced the odds of MI (OR: 0.72; 95% CI: 0.61–0.86; p < 0.01; I 2 = 0%) and nonfatal-MI (OR: 0.72; 95% CI: 0.61–0.85; p < 0.01; I 2 = 0%); while no associations between antiobesity treatment and fatal-MI, stroke, nonfatal, or fatal stroke were uncovered. Conclusion: GLP-1 and GIP/GLP-1 RAs reduce cardiovascular-risk and all-cause mortality in overweight or obese adults without diabetes. Additionally, GLP-1 RAs and GIP/GLP-1 RAs attenuate the risk of MI. Since data on stroke are still limited, future RCTs are warranted to evaluate the neuroprotective potential of these novel antiobesity agents. Trial registration: PROSPERO CRD42024515966.
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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 [44]
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- Authors
- Stefanou, M.-I., Palaiodimou, L., Theodorou, A., Safouris, A., Fischer, U., Kelly, P. J., Dawson, J., Katan, M., Katsanos, A. H., Lambadiari, V., Giannopoulos, S., Alexandrov, A. V., Siasos, G., & Tsivgoulis, G.
- Affiliations
- National and Kapodistrian University of Athens (GR)
- Second Department of Neurology, “Attikon” University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
- University of Basel (CH)
- University College Dublin (IE)
- Queen Elizabeth University Hospital (GB)
- Department of Neurology, University Hospital Basel, University of Basel, Basel, Switzerland
- Population Health Research Institute (CA)
- University of Tennessee Health Science Center (US)
- Corresponding author
- Tsivgoulis, Georgios
- ORCID
- Venue
- Therapeutic Advances in Neurological Disorders
- Publisher
- SAGE Publications
- Published
- 2024-01
- Volume
- 17
- Pages
- 17562864241281903-17562864241281903
- ISSN
- 1756-2856 (ISSN-L)
- 1756-2864
- PMC
- PMC11437580
- OpenAlex
- W4402890485
- Cited by
- 36
- References
- 49
- Citations by year
- 2026: 14 · 2025: 21 · 2024: 1
- FWCI
- 2.25
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Therapeutic Advances in Neurological Disorders (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Topics
- Health Sciences › Medicine › Pharmacology › Pharmacology and Obesity Treatment
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- GLP-1 receptor agonists, tirzepatide, GIP/GLP-1 receptor agonist, major adverse cardiovascular events, cardiovascular mortality, all-cause mortality, myocardial infarction, stroke, anti-obesity drugs, obesity, overweight, non-diabetic adults, liraglutide, semaglutide, cardiovascular safety, neuroprotection
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