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GLP-1 Receptor Agonists and Cardiovascular Events During Androgen Receptor Pathway Inhibitor Therapy
Katelyn M Atkins1,2, Nikhil Chakravarty1, Maria Oorloff1
1Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
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.
Insights
Early use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) before androgen receptor pathway inhibitors (ARPIs) may reduce cardiac events in prostate cancer patients. This suggests GLP-1 RAs could mitigate cardiovascular risk during ARPI therapy.
Area of Science:
- Cardiology
- Oncology
- Pharmacology
Background:
- Androgen receptor pathway inhibitors (ARPIs) are crucial for high-risk and metastatic prostate cancer but increase cardiovascular risk.
- Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are known to reduce cardiovascular events in general populations.
- The cardiovascular impact of GLP-1 RAs in patients undergoing ARPI therapy remains unclear.
Purpose of the Study:
- To investigate the association between GLP-1 RA use and cardiovascular events in men receiving ARPIs for prostate cancer.
- To determine if the timing of GLP-1 RA initiation (before or after ARPIs) influences cardiac event risk.
Main Methods:
- Retrospective analysis of 120 men with prostate cancer treated with ARPIs (2015-2025).
- Categorized GLP-1 RA use as pre- or post-ARPI initiation.
- Estimated cumulative incidences of major adverse cardiac events (MACE) and grade ≥2 cardiac events using Fine-Gray regression, accounting for non-cardiac death.
Main Results:
- Median follow-up was 2.3 years; 45% had pre-existing atherosclerotic cardiovascular disease.
- GLP-1 RA use prior to ARPI initiation (55% of patients) was associated with a reduced risk of grade ≥2 cardiac events (SHR 0.26, p=0.036) after adjustment.
- The 2-year cumulative incidence of MACE was 1.7%, and grade ≥2 cardiac events was 16.1%.
Conclusions:
- Initiating GLP-1 RAs before ARPI therapy may lower the risk of cardiac events in prostate cancer patients.
- Early metabolic optimization with GLP-1 RAs could be a strategy to mitigate cardiovascular risk during ARPI treatment.
- Further investigation is warranted to confirm these hypothesis-generating findings.
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