Systematic Review: GLP-1 and GIP/GLP-1 Agonists Preserve Cardiac Function in Doxorubicin Cardiotoxicity

Doxorubicin (DOX)-induced cardiotoxicity remains a severe, dose-limiting side effect of a widely used anticancer drug, often leading to irreversible heart failure. This cardiotoxicity is primarily driven by mitochondrial dysfunction and excessive reactive oxygen species (ROS) production. Current strategies to mitigate DOX cardiotoxicity are insufficient, leaving a critical gap in patient care. Incretin-based therapies, known for their cardiometabolic benefits, offer a promising avenue due to their pleiotropic cardiovascular effects beyond glucose regulation, warranting a systematic evaluation of their role in protecting against DOX-related cardiac injury.

Researchers conducted a PRISMA 2020-compliant systematic review to synthesize evidence on incretin-based therapies for DOX-induced cardiotoxicity. They searched PubMed/MEDLINE, Embase, Web of Science, and Scopus through October 2025. Eligible studies included in vivo rodent models of DOX cardiotoxicity and any clinical studies directly evaluating incretin-based therapy during DOX exposure. Excluded were in vitro studies, non-DOX models, combination treatments, and reviews. Risk of bias was assessed using the SYRCLE tool, and certainty of evidence with GRADE adapted for preclinical research. The review included 13 rodent studies, but no eligible human studies were found. Investigated agents included liraglutide (n=4), exenatide/exendin-4 (n=4), semaglutide (n=2), and tirzepatide (n=3).

Incretin-based therapies generally preserved left ventricular systolic function in chronic cumulative-dose DOX models. Improvements in left ventricular ejection fraction ranged from approximately 7-20 percentage points across studies, accompanied by significant reductions in cardiac injury biomarkers. These protective effects were consistently linked to the attenuation of oxidative stress, inflammation, apoptosis, and, in some instances, ferroptosis. The most reproducible protective signal was observed with co-treatment during DOX exposure. > Isolated pretreatment with liraglutide or tirzepatide, and post-treatment with exenatide, did not demonstrate a clear additional benefit, suggesting timing is crucial. Findings were notably less consistent in acute single-dose DOX models, highlighting the importance of the cardiotoxicity model type. The evidence suggests a robust protective role for these agents against chronic DOX-induced cardiac damage.