Incretin-Based Therapies in Doxorubicin-Induced Cardiotoxicity: A Systematic Review of GLP-1 and Dual GIP/GLP-1 Agonists

This systematic review synthesised 13 rodent studies and found that GLP-1 and dual GIP/GLP-1 receptor agonists generally preserved left ventricular systolic function and reduced cardiac injury markers in doxorubicin-induced cardiotoxicity, particularly in chronic cumulative-dose models. It identified no eligible human studies, and because the evidence was judged low-to-very-low certainty, the authors regard the findings as hypothesis-generating.

Systematic review — PRISMA 2020-compliant systematic review. Population: In vivo rodent models of doxorubicin-induced cardiotoxicity; no eligible human studies. Sample size: 13 rodent studies. Interventions: liraglutide; exenatide/exendin-4; semaglutide; tirzepatide.

Thirteen rodent studies were included, and no eligible human study was identified. In chronic cumulative-dose doxorubicin models, incretin-based therapies were generally associated with preservation of left ventricular systolic function, with between-study improvements of approximately 7-20 percentage points in left ventricular ejection fraction, and with reductions in injury biomarkers. These effects were accompanied by attenuation of oxidative stress, inflammation, apoptosis, and, in some studies, ferroptosis. Findings were less consistent in acute single-dose models. Co-treatment during doxorubicin exposure showed the most reproducible protective signal, whereas isolated pretreatment with liraglutide or tirzepatide and post-treatment with exenatide did not show a clear additional benefit.

For researchers studying tirzepatide, this systematic review places tirzepatide among incretin-based therapies with biologically plausible cardioprotective effects in doxorubicin cardiotoxicity, and it included three rodent studies of tirzepatide. It does not establish clinical benefit, dosing, or timing for tirzepatide in humans, because no eligible human study was found and the evidence was judged low-to-very-low certainty.

Key findings

Thirteen rodent studies were included, and no eligible human study was identified.
Investigated agents included liraglutide (n = 4), exenatide/exendin-4 (n = 4), semaglutide (n = 2), and tirzepatide (n = 3).
In chronic cumulative-dose doxorubicin models, incretin-based therapies were associated with preservation of left ventricular systolic function, with between-study improvements of approximately 7-20 percentage points in left ventricular ejection fraction.
Incretin-based therapies were associated with reductions in injury biomarkers and attenuation of oxidative stress, inflammation, apoptosis, and, in some studies, ferroptosis.
Findings were less consistent in acute single-dose models.
Co-treatment during doxorubicin exposure showed the most reproducible protective signal, whereas isolated pretreatment with liraglutide or tirzepatide and post-treatment with exenatide did not show a clear additional benefit.

Limitations

Exclusive reliance on small, heterogeneous animal studies.
Predominantly male models.
Variable dosing and timing protocols.
Low-to-very-low certainty of evidence and no eligible human study, so clinical translation is uncertain.

The record

Journal: Cardiovascular toxicology 26(7): 81
Published: 2026-07-15
PMID: 42455418 — DOI: 10.1007/s12012-026-10119-6
MeSH terms: Myocytes, Cardiac, Animals, Humans, Heart Diseases, Doxorubicin, Gastric Inhibitory Polypeptide, Antibiotics, Antineoplastic, Signal Transduction, Glucagon-Like Peptide 1, Incretins, Cardiotoxicity, Glucagon-Like Peptide-1 Receptor, Exenatide, Glucagon-Like Peptide-1 Receptor Agonists, Tirzepatide, Semaglutide
Author countries: Iran, Poland

Peptide profiles: Tirzepatide.

All indexed evidence: Tirzepatide trials & papers.