GLP-1 Receptor Agonists and Cardiovascular Events During Androgen Receptor Pathway Inhibitor Therapy
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Background
Androgen receptor pathway inhibitors (ARPIs) have transformed the treatment of high risk and metastatic prostate cancer, though are associated with increased cardiovascular risk. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been shown to reduce cardiovascular events in non-cancer populations, but their role in patients receiving ARPIs is unclear.
Methods
Retrospective analysis of 120 men with PC treated with ARPIs between 2015-2025 with any GLP-1 RA exposure. The time of GLP-1 RA use was categorized relative to ARPI initiation (pre- vs post-ARPI). Cumulative incidences for major adverse cardiac events (MACE) any grade 2 or greater cardiac common terminology criteria for adverse events (CTCAE) were estimated. Fine-Gray regressions were performed (non-cardiac death as a competing risk).
Results
The median follow-up was 2.3 years (interquartile range [IQR] 1.3-3.7). The median age was 72 years (IQR 66-78). Atherosclerotic cardiovascular disease (ASCVD) was present in 45.0% (n=54). Overall, 55.0% (n=66) initiated GLP-1 RA therapy prior to ARPI and 45.0% (n=54) after ARPI initiation, with a median duration of GLP-1 RA use of 4.0 years (IQR, 2.3-7.0) and 1.3 years (IQR, 0.6-2.1), respectively. Four patients experienced MACE, including three coronary revascularizations and one ischemic stroke. 25 patients experienced at least one grade 2 or greater cardiac event, most commonly arrhythmia (n=20) and thromboembolic disease (n=11). The 2-year cumulative incidence of MACE and grade ≥2 cardiac events was 1.7% and 16.1%, respectively. Adjusting for pre-existing cardiovascular risk, GLP-1 RA duration, and pre- ARPI androgen deprivation therapy use, GLP-1RA use prior to ARPI initiation (vs. after ARPI start) was associated with reduced risk of grade ≥2 cardiac events (subdistribution hazard ratio 0.26, 95% CI 0.08-0.91; p=0.036).
Conclusion
GLP-1 RA use prior to ARPI initiation was associated with reduced risk of cardiac events, suggesting that earlier metabolic optimization may influence cardiovascular outcomes. These hypothesis-generating findings support investigation of early GLP-1 RA initiation as a potential cardiovascular risk mitigation strategy during ARPI therapy.
