Comparative Cardiovascular Safety Profile of Semaglutide, Liraglutide, and Tirzepatide: A Pharmacovigilance Analysis Based on The FDA Adverse Event Reporting System Reports

INTRODUCTION: Glucagon-like peptide-1 receptor (GLP-1) agonists and the dual glucose-dependent insulinotropic polypeptide/GLP-1 agonist tirzepatide are increasingly prescribed for type 2 diabetes and obesity, with clinical trials suggesting favorable cardiovascular (CV) profiles. However, post-marketing comparative data on CV adverse events (CVAEs) across these agents remain limited.
METHODS: We extracted FDA adverse event reporting system (FAERS) reports between 2020 and 2025 where semaglutide, liraglutide, or tirzepatide appeared as the sole suspect drug. Reports with at least one CVAE – defined across four domains (arrhythmia, ischemic, hemodynamic, thromboembolic) were identified. We calculated CVAE proportions, summarized CVAE spectra, and compared serious outcomes (hospitalization, life-threatening events, death) between agents using χ2 tests and risk ratios.
RESULTS: Among 26,930 monotherapy reports, 1,765 (6.6%) included ≥1 CVAE. CVAE proportions were highest for liraglutide (12.8%), followed by semaglutide (9.5%) and tirzepatide (5.3%) (p<0.0001). Common CVAEs included palpitations, heart rate increases, blood pressure fluctuations, and syncope. Major ischemic or thrombotic events were rare across all drugs. Serious outcomes occurred in 36.0% of CVAE reports for liraglutide, 29.7% for semaglutide, and 31.3% for tirzepatide (p=0.38). Tirzepatide reports had a higher proportion of life-threatening events (9.0%) than liraglutide (4.8%) or semaglutide (4.4%) (p=0.0013).
DISCUSSION AND CONCLUSION: Semaglutide, liraglutide, and tirzepatide show comparable CV safety profiles in FAERS data, with most CVAEs reflecting known pharmacologic effects rather than severe toxicity. To our knowledge, this is the first FAERS-based study to directly compare these agents’ CVAE patterns, offering complementary insight to existing clinical trial evidence.

Keywords: FDA adverse event reporting system, glucagon-like peptide-1 receptor agonists, liraglutide, pharmacovigilance, semaglutide, tirzepatide.