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Review
. 2024 Sep 25:17:17562864241281903.
doi: 10.1177/17562864241281903. eCollection 2024.

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

Maria-Ioanna Stefanou  1 , Lina Palaiodimou  1 , Aikaterini Theodorou  1 , Apostolos Safouris  1   2 , Urs Fischer  3 , Peter J Kelly  4 , Jesse Dawson  5 , Mira Katan  3 , Aristeidis H Katsanos  6 , Vaia Lambadiari  7 , Sotirios Giannopoulos  1 , Andrei V Alexandrov  8 , Gerasimos Siasos  9 , Georgios Tsivgoulis  10
Affiliations
Review

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

Maria-Ioanna Stefanou et al. Ther Adv Neurol Disord. .

Abstract

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.

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

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Figures

Figure 1.
Figure 1.
PRISMA flowchart diagram presenting the selection of eligible studies. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.
Figure 2.
Figure 2.
Forest plot comparing the risk of MACE in overweight or obese adults without diabetes treated with GLP-1 or GIP/GLP-1 RAs versus placebo. GIP, glucose-dependent insulinotropic polypeptide; GLP-1 RA, glucagon-like peptide-1 receptor agonists; MACE, major adverse cardiovascular event.
Figure 3.
Figure 3.
Forest plot comparing the risk of all-cause mortality (a) and cardiovascular mortality (b) in overweight or obese adults without diabetes treated with GLP-1 or GIP/GLP-1 RAs versus placebo. GIP, glucose-dependent insulinotropic polypeptide; GLP-1 RA, glucagon-like peptide-1 receptor agonists.
Figure 4.
Figure 4.
Forest plot comparing the risk of stroke in overweight or obese adults without diabetes treated with GLP-1 or GIP/GLP-1 RAs versus placebo. GIP, glucose-dependent insulinotropic polypeptide; GLP-1 RAs, glucagon-like peptide-1 receptor agonists.
See this image and copyright information in PMC

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