GnRH Agonist Leuprolide Linked to Greater Coronary Plaque Growth Than Antagonist Relugolix

Men with prostate cancer who were treated with the gonadotropin-releasing hormone (GnRH) agonist leuprolide had significantly more coronary artery plaque progression than those receiving the GnRH antagonist relugolix in a randomized trial. Both total plaque volume and noncalcified plaque volume were significantly greater in leuprolide-treated men at 12 months.

The REVOLUTION trial enrolled 62 men with nonmetastatic prostate cancer scheduled for pelvic radiotherapy and a minimum of 6 months of androgen deprivation therapy (ADT). Patients were randomized to receive either relugolix or leuprolide. Coronary artery plaque volume was assessed by CT angiography at baseline and 12 months after starting ADT. The primary endpoint was change in total plaque volume, and the key secondary endpoint was change in coronary artery noncalcified plaque volume.

The primary analysis showed that total plaque volume increased in both groups but significantly more so in the leuprolide arm (adjusted mean difference +68.9 mm³, P=0.02). Median noncalcified plaque volume also increased significantly more in the leuprolide arm (adjusted mean difference +64.5 mm³, P=0.004). There was no significant difference in 12-month change in calcified plaque volume or low-attenuation plaque volume between patients treated with leuprolide versus relugolix.

The observed effect on total plaque volume suggests a potential mediating factor in ADT-associated cardiovascular risk. This effect appears unrelated to magnitude of testosterone suppression, as leuprolide and relugolix achieved similar levels of castration. The data demonstrate that the cardiovascular effect of ADT is detectable in the near term, at least partly mediated by coronary artery plaque progression, and is drug pathway-specific independent of testosterone suppression.

This is the first clinical trial to identify a biological basis for cardiovascular risk differences observed between ADT drug pathways in men with prostate cancer. The study adds to a large volume of evidence linking ADT to increased cardiovascular risk in men with prostate cancer. Cardiovascular disease has become a major cause of mortality in prostate cancer.

ADT targeting the GnRH pathway remains a cornerstone of treatment for prostate cancer, but drugs that have an agonistic effect on the pathway (such as leuprolide) are associated with significant cardiovascular morbidity. A mechanistic explanation for GnRH agonists' association with increased cardiovascular risk has remained unclear. Multiple studies have shown higher rates of cardiovascular morbidity in men treated with GnRH agonists compared with orchiectomy or antiandrogens, suggesting mechanistic differences in achieving testosterone suppression.

Studies involving preclinical models have suggested that GnRH activation promotes destabilization of existing vascular plaques, especially less stable plaques with thin, noncalcified caps. GnRH agonists may activate receptors expressed by T cells in atherosclerotic plaque, stimulating T-cell expansion into pro-inflammatory phenotypes implicated in plaque progression or rupture.

The randomized phase III HERO trial showed that relugolix led to greater testosterone suppression compared with leuprolide. Additionally, relugolix was associated with a 54% lower risk of major adverse cardiovascular events versus leuprolide.

Trial enrollment was completed between June 16, 2022, and March 6, 2024. Data analysis was completed between March 31, 2025, and June 23, 2025. The trial was conducted at 4 centers affiliated with a single academic institution in Atlanta, Georgia. Mean age was 68.5 years, and 35 of 62 participants (56%) were taking statins.