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Meta-Analysis
. 2024 Sep;9(3):530-539.
doi: 10.1177/23969873241234238. Epub 2024 Feb 23.

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

Maria-Ioanna Stefanou  1 , Aikaterini Theodorou  1 , Konark Malhotra  2 , Diana Aguiar de Sousa  3 , Mira Katan  4 , Lina Palaiodimou  1 , Aristeidis H Katsanos  5 , Ioanna Koutroulou  6 , Vaia Lambadiari  7 , Robin Lemmens  8 , Sotirios Giannopoulos  1 , Andrei V Alexandrov  9 , Gerasimos Siasos  10 , Georgios Tsivgoulis  1
Affiliations
Meta-Analysis

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

Maria-Ioanna Stefanou et al. Eur Stroke J. 2024 Sep.

Abstract

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; I2 = 37%), all-cause mortality (OR: 0.88; 95% CI: 0.82-0.96; p < 0.01; I2 = 21%) and cardiovascular-mortality (OR: 0.88; 95% CI: 0.80-0.96; p < 0.01; I2 = 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; I2 = 0%) and nonfatal stroke (OR: 0.85; 95% CI: 0.76-0.94; p < 0.01; I2 = 0%), whereas no association between fatal stroke and GLP-1RAs was uncovered (OR: 0.80; 95% CI: 0.61-1.05; p = 0.105; I2 = 0%). In secondary analyses, GLP-1 RAs prevented ischemic stroke (OR: 0.74; 95% CI: 0.61-0.91; p < 0.01; I2 = 0%) and MACE-recurrence, but not hemorrhagic stroke (OR: 0.92; 95% CI: 0.51-1.66; p = 0.792; I2 = 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.

Keywords: GIP/GLP-1 receptor agonist; GLP-1; MACE; stroke; tirzepatide.

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Conflict of interest statement

Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Graphical abstract
Graphical abstract
Figure 1.
Figure 1.
PRISMA flowchart diagram presenting the selection of eligible studies.
Figure 2.
Figure 2.
Forest plot comparing the risk of MACE in T2DM patients treated with GLP-1RAs or GIP/GLP-1 RAs versus placebo.
Figure 3.
Figure 3.
Forest plot comparing the risk of all-cause stroke in T2DM patients treated with GLP-1RAs versus placebo.
Figure 4.
Figure 4.
(a) Forest plot comparing the risk of nonfatal stroke in T2DM patients treated with GLP-1RAs versus placebo and (b) Forest plot comparing the risk of fatal stroke in T2DM patients treated with GLP-1RAs versus placebo.
Figure 5.
Figure 5.
Forest plot comparing the risk of ischemic stroke in treatment with GLP-1RAs versus placebo.
See this image and copyright information in PMC

References

    1. Khan MS, Fonarow GC, McGuire DK, et al.. Glucagon-like peptide 1 receptor agonists and heart failure: the need for further evidence generation and practice guidelines optimization. Circulation 2020; 142: 1205–1218. - PubMed
    1. Madsbad S. Review of head-to-head comparisons of glucagon-like peptide-1 receptor agonists. Diabetes Obes Metab 2016; 18: 317–332. - PMC - PubMed
    1. Kielgast U, Holst JJ, Madsbad S. Treatment of type 1 diabetic patients with glucagon-like peptide-1 (GLP-1) and GLP-1R agonists. Curr Diabetes Rev 2009; 5: 266–275. - PubMed
    1. Gupta V. Glucagon-like peptide-1 analogues: an overview. Indian J Endocrinol Metab 2013; 17: 413–421. - PMC - PubMed
    1. Marx N, Husain M, Lehrke M, et al.. GLP-1 receptor agonists for the reduction of atherosclerotic cardiovascular risk in patients with type 2 diabetes. Circulation 2022; 146: 1882–1894. - PubMed

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