Cardiovascular Morbidity Associated with Gonadotropin Releasing Hormone Agonists and an Antagonist

Albertsen, Peter C.; Klotz, Laurence; Tombal, Bertrand; Grady, James J.; Olesen, Tine Kold; Nilsson, Jan

doi:10.1016/j.eururo.2013.10.032

Cited by 306 publications

(283 citation statements)

References 29 publications

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“…However, even though LDL particles fuel the atherosclerotic disease process and it is well known that changes in LDL levels upon statin treatment can exert relatively rapid effects on CVD end points,27 the ADT‐associated LDL increase is modest (<10%),3 and it is doubtful whether the combined metabolic changes associated with testosterone deficiency can provide a comprehensive explanation for the acutely increased CVD risk associated with ADT initiation. Interestingly, recent observational studies and a meta‐analysis of randomized controlled trials suggested that non–testosterone‐mediated effects of GnRH agonists may be important for the increased risk of atherosclerotic CVD 4, 5. Bosco et al, using registry data, found that GnRH agonist‐based ADT was associated with a higher risk of CVD than surgical orchiectomy 5.…”

Section: Discussionmentioning

confidence: 99%

“…Observational studies are limited by selection bias because the choice of treatment is not random, and some of the characteristics of PCa patients used to guide those decisions (eg, comorbidity, age, etc) could well influence the rate of CVD events. Furthermore, being a post‐hoc and subgroup analysis based on pooled data, the finding by Albertsen et al4 needs confirmation in randomized trials with prespecified CVD end points.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies, however, have suggested that the number of CVD events in PCa patients differs between different types of ADT, indicating that other mechanisms than the mere lack of testosterone is involved. In observational studies and a post hoc analysis of randomized controlled trials, a higher rate of CVD events was found in patients treated with GnRH receptor agonists compared with bilateral orchiectomy or GnRH antagonists 4, 5, 9. These studies are hypothesis‐generating and the findings await confirmation in randomized trials with CVD as a prespecified end point, but the idea of a divergent effect of orchiectomy, GnRH agonists and antagonists on atherosclerosis‐related disease is supported by experimental studies.…”

Section: Introductionmentioning

confidence: 99%

“…ADT is the first‐line treatment for metastatic PCa and an adjuvant therapy to radiotherapy for locally advanced PCa. Unfortunately, apart from improving survival and quality of life, ADT treatment has been associated with an excess risk of cardiovascular disease (CVD), including myocardial infarction 2, 3, 4, 5, 6, 7…”

Section: Introductionmentioning

confidence: 99%

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Differences in Hypercholesterolemia and Atherogenesis Induced by Common Androgen Deprivation Therapies in Male Mice

Poulsen

Mortensen

Koechling

et al. 2016

JAHA

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BackgroundTreatment of prostate cancer often involves androgen deprivation therapy (ADT) by gonadotropin‐releasing hormone (GnRH) receptor agonists, GnRH receptor antagonists, or orchiectomy. ADT may increase the rate of cardiovascular disease events, but recent clinical studies suggested that not all means of ADT carry the same risk, raising the possibility of non–testosterone‐mediated effects of different forms of ADT on atherosclerosis. Here we compared effects of ADT on atherosclerosis in intact and orchiectomized Apoe‐deficient mice.Methods and ResultsChow‐fed Apoe‐deficient mice were allocated to orchiectomy and/or monthly injections with the GnRH receptor agonist leuprolide or the GnRH receptor antagonist degarelix. Atherosclerosis was quantified at 26 weeks of age in the aortic arch by en face examination and in the aortic root by histology. In intact Apoe‐deficient mice, all types of ADT reduced testosterone production to castration levels. Although hypercholesterolemia was accentuated in leuprolide‐treated mice, the amount and composition of atherosclerosis was not different between the different types of ADT. In orchiectomized Apoe‐deficient mice, leuprolide, but not degarelix, augmented hypercholesterolemia, changed body, thymus, and spleen weights, and increased atherosclerosis in the aortic root. No direct effects of the drugs were detectable on cytokine secretion from murine bone marrow–derived macrophages or on splenocyte proliferation.ConclusionsNo differences in the development of atherosclerosis were detected among groups of intact Apoe‐deficient mice treated with different types of ADT. A pro‐atherogenic, possibly cholesterol‐mediated, effect of leuprolide was seen in orchiectomized mice that might be relevant for understanding the potential cardiovascular risk associated with GnRH agonist‐based ADT.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Differences in Hypercholesterolemia and Atherogenesis Induced by Common Androgen Deprivation Therapies in Male Mice

Poulsen

Mortensen

Koechling

et al. 2016

JAHA

View full text Add to dashboard Cite

show abstract

“…GnRH agonist-based ADT is associated with an increased risk of CV events, including arterial embolic or thrombotic events, haemorrhagic or ischaemic cerebrovascular conditions, myocardial infarction (MI), heart failure and other ischaemic heart disease. 3,7,10 ADT may increase aortic stiffness, 11 and arterial wall thickening and endothelial dysfunction, thereby promoting formation of atherosclerotic plaques. 12 Testosterone removal is not the only mechanism by which GnRH agonists elevate CV risk.…”

Section: Testosterone Depletion and CV Riskmentioning

confidence: 99%

Managing cardiovascular risk in high‐risk prostate cancer

Plummer¹,

Collins²,

Rosario³

et al. 2017

Trends Urol & Men's Health

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Men living with prostate cancer have a high rate of cardiovascular events, and many of them have risk factors that would be an indication for primary prevention under current guidance. These risks may be increased by certain androgen deprivation therapies. This article reports the outcome of a consensus meeting at which the authors discussed these issues. They suggest a simple assessment tool for use with prostate cancer patients to rapidly assess cardiovascular risk and allow appropriate risk‐management strategies to be implemented.

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Real-world Cardiovascular Outcomes Associated With Degarelix vs Leuprolide for Prostate Cancer Treatment

Wallach¹,

Deng

McCoy

et al. 2021

JAMA Netw Open

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IMPORTANCE With a growing interest in the use of real-world evidence for regulatory decisionmaking, it is important to understand whether real-world data can be used to emulate the results of randomized clinical trials. OBJECTIVETo use electronic health record and administrative claims data to emulate the ongoing PRONOUNCE trial (A Trial Comparing Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Advanced Prostate Cancer and Cardiovascular Disease). DESIGN, SETTING, AND PARTICIPANTS This retrospective, propensity-matched cohort study included adult men with a diagnosis of prostate cancer and cardiovascular disease who initiated either degarelix or leuprolide between December 24, 2008, and June 30, 2019. Participants were commercially insured individuals and Medicare Advantage beneficiaries included in a large US administrative claims database. EXPOSURES Degarelix or leuprolide. MAIN OUTCOMES AND MEASURESThe primary end point was time to first occurrence of a major adverse cardiovascular event (MACE), defined as death due to any cause, myocardial infarction, or stroke, analogous to the PRONOUNCE trial. Secondary end points were time to death due to any cause, myocardial infarction, stroke, and angina. Cox proportional hazards regression was used to evaluate primary and secondary end points. RESULTSA total of 32 172 men initiated degarelix or leuprolide for prostate cancer; of them, 9490 (29.5%) had cardiovascular disease, and 7800 (24.2%) met the PRONOUNCE trial eligibility criteria and were included in this study. Overall, 165 participants (2.1%) were Asian, 1390 (17.8%) were Black, 663 (8.5%) were Hispanic, and 5258 (67.4%) were White. The mean (SD) age was 74.4 (7.4) years.Among 2226 propensity score-matched patients, no significant difference was observed in the risk of MACE for patients taking degarelix vs those taking leuprolide (10.18 vs 8.60 events per 100 person-years; hazard ratio [

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Cardiovascular Morbidity Associated with Gonadotropin Releasing Hormone Agonists and an Antagonist

Cited by 306 publications

References 29 publications

Differences in Hypercholesterolemia and Atherogenesis Induced by Common Androgen Deprivation Therapies in Male Mice

Differences in Hypercholesterolemia and Atherogenesis Induced by Common Androgen Deprivation Therapies in Male Mice

Managing cardiovascular risk in high‐risk prostate cancer

Real-world Cardiovascular Outcomes Associated With Degarelix vs Leuprolide for Prostate Cancer Treatment

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