Cardiovascular risk profiles of GnRH agonists and antagonists: real-world analysis from UK general practice

Prostate cancer accounts for ~ 20% of new cancer diagnoses in the USA and the EU, and is now the most commonly diagnosed cancer in England [1‐3]. In the UK, there were around 47,700 new annual cases of prostate cancer from 2014 to 2016, 49,029 new annual cases in 2018, and incidence rates are estimated to rise by 12% between 2014 and 2035, to 233 cases per 100,000 men by 2035 [3]. In 2017, prostate cancer accounted for 14% of all cancer deaths in men in the UK [4]. Data released by Public Health England in 2018 indicate that prostate cancer is now the most diagnosed cancer in England, with almost 8000 more diagnoses of prostate cancer in 2018 than the previous year [5].

Androgen deprivation therapy (ADT) is the mainstay for the management of metastatic prostate cancer, and surgical castration has been superseded by non-surgical therapies, which are now the standard of care [5‐7]. Available pharmaceutical ADTs include gonadotropin-releasing hormone (GnRH) agonists, such as leuprolide, goserelin, triptorelin and buserelin acetate, and more recently, GnRH antagonists, such as degarelix and abarelix (approved in Germany and The Netherlands) [5, 8].

The incidence of cardiovascular disease (CVD) and prostate cancer increases with age, and CVD incidence and mortality are high in men with prostate cancer [9‐11]. ADTs, and specifically GnRH agonists, have been associated with increased cardiovascular (CV) morbidity and mortality in observational studies, and men with pre-existing CVD are most at risk [12‐17]. Data suggest that the risk for cardiac events might be lower with the GnRH antagonist degarelix, compared with GnRH agonists, particularly in patients with pre-existing CVD [18‐21].

A recent analysis of real-world data from a UK general practitioner database comparing CV outcomes in patients treated with degarelix vs GnRH agonists is presented and discussed in this context.

ADT lowers testosterone levels, which prevents androgen receptor signalling; however, GnRH agonists and antagonists suppress testosterone levels through different mechanisms, which may confer different CV risk as measured by event rates for patients with prostate cancer who receive ADT. GnRH agonists stimulate luteinizing hormone (LH) and follicle-stimulating hormone (FSH) release; this leads to reduced LH and FSH levels by receptor desensitization, resulting in suppressed testosterone secretion from the testicles [27‐29]. In contrast, GnRH antagonists such as degarelix bind directly to GnRH receptors, leading to rapid suppression of LH and FSH and immediate decrease in testosterone secretion from the testicles, without an initial testosterone surge [30‐32]. GnRH antagonists suppress FSH levels to a greater extent than GnRH agonists [33] and their differential effects on FSH levels might explain the differences in CV risk, development of atherosclerotic plaque formation, metabolic syndrome, and insulin resistance [34].

Treatment with GnRH agonists has been associated with increased CV morbidity and mortality [12, 13, 17, 35, 36]. The explanation of the differential CV risk between GnRH antagonists and agonists centres on T lymphocyte activation and destabilization of atherosclerotic plaques [37]. The GnRH receptor is expressed on pro-inflammatory T lymphocytes [38, 39] and upon activation an inflammatory cascade stimulates T cell proliferation, cytokine production, and macrophage activity leading to increased risk of atherosclerotic plaque rupture [20, 37], disruption of atheromatous plaques, and fatal coronary thrombi [40]. Unlike GnRH agonists, GnRH antagonists lack the ability to activate T lymphocytes, thus maintaining plaque stability [37].

Preclinical studies showed that treatment with leuprolide, but not with degarelix, induced atherosclerotic plaque instability and that degarelix was associated with reduced atherosclerosis, decreased adiposity, and reduced characteristics of metabolic syndrome, compared with leuprolide [41].

In the current study, real-world data from UK primary care settings was used to investigate whether the risk of cardiac events may be lower in patients receiving degarelix compared with GnRH agonists. The study found that the relative risk of experiencing any cardiac event was lower with degarelix than all GnRH agonists (p = 0.01). Differences in the RR were statistically significant for degarelix compared with leuprorelin and goserelin (both p = 0.01), but not for triptorelin (p > 0.05). The effect of degarelix on cardiac events appeared to be largely driven by reductions in heart failure and arrythmia. It should be noted that the number of patients taking degarelix in the UK is low, with clinicians currently using GnRH agonists as first-line treatments. However, the preliminary results of this study support findings from several other studies that suggest GnRH antagonists are associated with a lower cardiac risk than agonists.

Most but not all real-world observational data suggest that treatment with GnRH antagonists is associated with fewer cardiovascular event rates than treatment with GnRH agonists [35]. Real-world observational data from 2382 patients with advanced prostate cancer from a German claims database showed no significant differences in the incidence of CVD or diabetes between GnRH agonists or antagonists overall, although there was a significant increase in hypertension in patients receiving a GnRH agonist (16.4%) compared with those receiving a GnRH antagonist (6.9%, p = 0.022) [42]. Similarly, data from 35,118 ADT users identified from a French population-based claims reimbursement database demonstrated no significant association between GnRH antagonists and CV risk [43]. Finally, a retrospective analysis from the Scottish Cancer Registry reported a 30% and 50% increase in CVD risk with GnRH agonists and degarelix, respectively, compared with untreated patients. However, the authors state the association of higher CV risk with ADT compared with untreated patients was largely driven by CV events in GnRH agonist-treated patients [44].

In contrast and in line with the results from this study, an Italian real-world analysis showed the incidence of CV events was significantly higher in patients treated with GnRH agonists compared with antagonists (6.2 vs 8.8 per 100 person-year, p = 0.002) [45]. Further, disproportionality analysis from the pharmacovigilance database, Vigibase, found that of 10,504 and 1606 adverse drug reactions reported for GnRH agonists and antagonists, respectively, the respective numbers of cardiac-related events were 805 (7.7%) and 102 (6.4%). The time from initiation of therapy to onset of adverse event was over 1 year (mean 541.9 days, SD 909.6) [36].

There is conflicting data from randomized trials concerning cardiovascular event rates in GnRH agonist vs antagonist therapy. However, most of these trials were not set up to determine cardiovascular outcomes. One trial that was specifically set up to look at cardiovascular outcomes in (n = 80) those with pre-existing cardiovascular disease, showed GnRH antagonist treatment was associated with fewer major CV and cerebrovascular events than treatment with GnRH agonists. The absolute risk reduction for a major CV event (defined as either death, MI, cerebrovascular event, or percutaneous-angioplasty with coronary stent insertion) at 12 months using a GnRH antagonist was 18.1% (95% CI 4.6–31.2, p = 0.032) [19]. Further, a post hoc analysis of six Phase 3 trials (n = 2328) reported a significantly lower 1-year risk of cardiac events (arterial embolic and thrombotic events, haemorrhagic or ischaemic cerebrovascular conditions, MI, or other IHD) among men with pre-existing CVD initiating degarelix compared with GnRH agonist therapy. The absolute risk reduction during the first year was 8.2% and the number of patients needed to be treated to avoid one CV event or death was 12 [18].

The findings of the current study are also in line with a recent Phase 3 trial which investigated CV risk as a pre-specified safety analysis in 622 patients with advanced prostate cancer who received a GnRH antagonist (relugolix) compared with 308 patients who received a GnRH agonist (leuprolide), and suggested reduced CV risks with GnRH antagonists compared with agonists [46]. Among all patients, the incidence of major adverse CV events (defined as non-fatal MI, non-fatal stroke, and death from any cause) was 2.9% (exact 95% CI 1.7–4.5) in the relugolix group and 6.2% (exact 95% CI 3.8–9.5) in the leuprolide group (hazard ratio 0.46; 95% CI 0.24–0.88). Kaplan–Meier estimates of the major CV event incidence rate were consistent with a 54% lower risk in patients who received relugolix vs leuprolide (hazard ratio 0.46; 95% CI 0.24–0.88). In a subgroup of patients with a reported medical history of CV events, the incidence of major adverse CV events was 3.6% in the relugolix group vs 17.8% in the leuprolide group.

In the current study, more patients who were treated with degarelix as first-line treatment switched treatment than those who received first-line treatment with a GnRH agonist. Most patients switched either within the first 3 months of first-line treatment or after 12 months, and most switched to leuprorelin or triptorelin. Therapeutic drug switching does occur and may be done for convenience, to reduce cost or to reduce side effects [47]. However, while there is some evidence of clinical benefit in switching a patient from a GnRH agonist to an antagonist [48] there is limited evidence for the opposite approach with no established protocols for switching between these different classes of drug [47]. Further, with real-world evidence studies showing mean time to CV event beyond 1-year [36], long-term treatment on an antagonist may be required to reduce CV risk.

In summary, the available data suggests that GnRH agonists increase CV events, and this effect appears to be greatest in patients with pre-existing CVD, and GnRH antagonists may be associated with lower rates of certain CV events vs GnRH agonists, particularly in patients with pre-existing CVD. The results in the present study support the hypothesis that the risk of cardiac events may be lower in patients receiving a GnRH antagonist such as degarelix, compared with GnRH agonists. However, there are several important limitations to consider.

Although the recent UK real-word study had several important limitations, the data showed that the relative risk of cardiac events was significantly lower with degarelix as first-line ADT (specifically heart failure and arrythmia) compared with GnRH agonists. While not definitive, the literature has previously shown that GnRH agonist treatment increases CVD and diabetes risk and that negative effects may be greatest in patients with pre-existing CVD. In contrast, it appears that GnRH antagonist therapy in this study and others is associated with lower rates of CVD than in those treated with GnRH agonists.

Given these findings, screening for known and undiagnosed metabolic and CV risk factors may be the key to risk mitigation in patients with prostate cancer receiving ADT. Appropriate therapy for prostate cancer, lifestyle, and other pharmacological interventions should be recommended, and CV risk factors should be monitored regularly.