Gonadotropin-releasing hormone antagonist associated with lower cardiovascular risk compared with gonadotropin-releasing hormone agonist in prostate cancer: A nationwide cohort and in vitro study

  • Prostate. 2021 Sep;81(12):902-912. doi: 10.1002/pros.24187.
Dong-Yi Chen  1 ,  Po-Jung Su  2 ,  Lai-Chu See  3  4  5 ,  Jia-Rou Liu  3 ,  Cheng-Keng Chuang  6 ,  See-Tong Pang  6 ,  Chi-Nan Tseng  7 ,  Shao-Wei Chen  7 ,  I-Chang Hsieh  1 ,  Pao-Hsien Chu  1 ,  Yung-Chang Lin  2 ,  Cheng-Lung Hsu  2 ,  John Wen-Cheng Chang  2 ,  Miao-Sui Lin  1 ,  Jong-Hwei S Pang  8  9 ,  Ming-Jer Hsieh  1 ,  Wen-Kuan Huang  2
Affiliations
  • 1. Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan.
  • 2. Division of Hematology/Oncology, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan.
  • 3. Department of Public Health, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
  • 4. Biostatistics Core Laboratory, Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan.
  • 5. Division of Rheumatology, Allergy and Immunology, Department of Internal Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
  • 6. Division of Urology, Department of Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan.
  • 7. Department of Thoracic and Cardiovascular Surgery, Chang Gung Memorial Hospital Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan.
  • 8. Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
  • 9. Department of Physical Medicine and Rehabilitation, Chang Gung Memorial Hospital Linkou, Taiwan.
PMID: 34196430 DOI: 10.1002/pros.24187
Abstract

Background: We aimed to determine whether cardiovascular (CV) risk in patients with prostate Cancer (PCa) differs between those who receive gonadotropin-releasing hormone (GnRH) agonist (GnRHa) therapy and those who receive GnRH antagonist therapy.

Methods: Using the Taiwan National Health Insurance Research Database, we analyzed data by comparing 666 participants receiving GnRH antagonists and 1332 propensity score-matched participants treated with GnRHa in a 1:2 fashion during the period from May 1, 2015, to September 30, 2018. COX proportional-hazards models were used to estimate the treatment effect on CV outcomes. Furthermore, we conducted an in vitro study to investigate the effect of a GnRHa (leuprolide) or a GnRH antagonist (degarelix) on matrix metalloproteinase-9 (MMP-9) expression and invasion ability in THP-1 differentiated macrophages.

Results: GnRH antagonist therapy was associated with a lower risk of composite CV events of myocardial infarction, ischemic stroke, or CV death (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.25-0.90) than GnRHa therapy, with a mean follow-up period of 1.21 years. Significantly lower risks of CV death (HR, 0.21; 95% CI, 0.06-0.70) and all-cause mortality (HR, 0.77; 95% CI, 0.61-0.97) were observed in the GnRH antagonist group. In the in vitro study, leuprolide, but not degarelix, significantly increased the expression of MMP-9 activity and the invasive ability of THP-1 differentiated macrophages through gelatin zymography and the matrix invasion assay, respectively.

Conclusion: GnRH antagonists were associated with reduced risk CV events compared with the GnRHa among patients with PCa, which may be through effects on macrophages.

Keywords
GnRH antagonist; GnRHa; androgen deprivation therapy; degarelix; leuprolide; prostate cancer.
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