The mechanisms for the increased cardiovascular disease (CVD) associated with androgen deprivation therapy (ADT) ADT are not completely elucidated. ADT has been shown to lead to the development of metabolic syndrome, a collection of risk factors for cardiovascular disease and type II diabetes mellitus. Characteristics include insulin resistance, glucose intolerance, hyperinsulinemia, increased very-low-density lipoprotein (VLDL), hypertriglyceridemia, decreased high-density lipoprotein (HDL), and hypertension. Diagnostic criteria for the syndrome include 3/5 of the following criteria: fasting plasma glucose level > 110 mg/dL, serum triglyceride level ≥ 150 mg/dL, serum HDL < 40 mg/dL, waist circumference > 102 cm, and blood pressure ≥ 130/85 mmHg ^[1][11]. A study of Asian men with prostate cancer who received ADT showed significant changes in metabolic parameters during the treatment course ^[2][12]. A 4.8% increase in fasting blood glucose and 2.7% increase in HbA1c were both noted at 6 months as well as increased triglycerides and mean body weight during follow-up. This study, among many others, has shown a clear association between ADT and metabolic changes that could potentially predispose patients to CVD (e.g., hyperlipidemia, elevated fasting blood glucose, hypertriglyceridemia, and increased weight) ^[3][4][13,14]. Other studies have shown that men treated with ADT develop increased fat mass located in subcutaneous tissue, decreased muscle strength, decreased sensitivity to insulin, and higher fasting insulin levels ^[5][10]. Other studies have suggested that changing hormone levels influence endothelial cell stability and activation, leading to conditions that favor formation and destabilization of atherosclerotic plaques ^[6][7][15,16]. Destabilization of plaques, visceral adiposity, insulin resistance, and endothelial dysfunction result in overall increased risk of MI, stroke and hypertension ^[8][6]. However, the exact mechanisms of ADT-induced CVD remain unclear and require more research.

While thwe researchers sstill have not found the reasons for why these metabolic changes exist, it is important to recognize them in the context of the prostate cancer (PCa)PCa patient population which frequently suffers from metabolic conditions prior to starting therapy. Many of these conditions have been found to bed directly associated with worse outcomes. Obesity, measured by body mass index (BMI) and waist circumference, has been found to be associated with higher mortality and higher-grade disease in PCa ^[9][10][17,18]. Data are lacking on whether weight loss could serve a preventative role in PCa patients, and more research into the mechanisms underlying these weight changes is needed to back clinical decision-making. Metabolic syndrome, discussed earlier in this resviearchw, has been found to be associated with a higher risk of fatal prostate cancer as well ^[11][19]. Hyperlipidemia is important to consider as cholesterol is a substrate for androgen synthesis. Studies have shown an association between triglycerides levels and recurrence rate of prostate cancer ^[12][20]. It is important for clinicians to consider the impact of these metabolic abnormalities on the course of their patients’ tumors and to incorporate the changes expected with hormonal therapies into proper monitoring.

Murine models have been used to investigate the association of ADT with cardiovascular events as well as the mechanisms underlying the observed increased risk. An investigation of GnRH agonist leuprolide in adult mice found that mice receiving leuprolide experienced significant increase in abdominal weight without a change in total body weight, increased cardiac troponins, but no echocardiographic findings of systolic or diastolic dysfunction ^[13][21]. Another study of ApoE^−/− mice with established atherosclerotic plaques compared those receiving leuprolide (GnRH agonist) vs. degarelix (GnRH antagonist) ^[14][22]. Mice receiving leuprolide were found to have more areas of necrosis and inflammation within plaques reflecting an increased risk of plaque rupture. Another study of ApoE^−/− mice found leuprolide again caused increased atherosclerosis in orchiectomized mice compared to similar mice receiving degarelix ^[15][23]. Interestingly, in the same study, there was no difference in atherosclerosis in mice who remained intact. These preclinical models support some of the proposed mechanisms of the increased CV risk of ADT like increased adiposity and increased atherosclerosis as well as raise interesting questions about the underlying mechanisms leading to the observed physiologic changes.

Whether or not ADT is the cause of the increased incidence of CVD is still a point of contention. Observational studies and random clinical trials have been conducted that found a significant positive association between ADT and certain CV events while others have found no significant association (see Appendix A). More recent research focuses on CVD outcomes of each class of ADT (i.e., GnRH agonists vs. antagonists vs. orchiectomy) and outcomes of patients with and without previous CVD (see Appendix A).

In 2006, Keating et al. were the first to publish data regarding an increased incidence of CVD and diabetes in men receiving ADT ^[16][24]. They conducted an observational study of 73,196 Medicare enrollees, aged 66 years or older, diagnosed with prostate cancer between 1992 and 1999. The study found GnRH agonists to be associated with an increased incidence of diabetes (HR, 1.44; p < 0.001), coronary heart disease (HR, 1.16; p < 0.001), myocardial infarction (HR, 1.11; p = 0.03), and sudden cardiac death (HR, 1.16; p = 0.004). These results demonstrated a need to further characterize the nature of the relationship between ADT and CVD as well as identify patients at high risk for these adverse events and develop strategies of prevention. Since 2006, many other studies have supported these initial findings. A 2015 study revealed a similarly increased risk of CVD in men receiving a GnRH agonist for treatment of prostate cancer (HR, 1.21; 95% CI, 1.18 to 1.25) ^[17][25]. Jespersen et al. conducted a national cohort study using the Danish Cancer Registry investigating the incidence of MI and stroke in men receiving ADT. The study found a significantly increased risk of MI (HR, 1.31; 95% CI, 1.16–1.49) and stroke (HR, 1.19; 95% CI, 1.06–1.35) in men receiving ADT ^[18][26]. Furthermore, men with no preexisting MI or stroke had a significant increase in risk of MI or stroke on ADT, while men with one or more prior MI or stroke showed no significant increase in risk of additional CV events. A 2013 observational study of 185,106 US men with prostate cancer receiving ADT revealed an increased risk of MI (HR, 1.09; 95% CI, 1.02–1.16) and diabetes (HR, 1.33; 95% CI, 1.27–1.39) in patients with no comorbidities ^[19][27]. The study also revealed that men with significant comorbidities including prior MI, stroke, hypertension, and COPD had an increased but non-significant increase in MI and stroke while receiving ADT. Not all studies agree on the increased risk of cardiovascular events in men receiving ADT. Efstathiou et al. conducted a large phase III randomized trial of 945 men treated with or without goserelin (GnRH agonist) after radiation therapy for locally advanced prostate cancer ^[20][28]. They found that the treatment arm had no significant change in cardiovascular mortality as compared to the control group receiving just radiation therapy (HR, 0.73; 95% CI, 0.47–1.15; p = 0.16). Of note, this was one of the few trials that compared the treatment group receiving ADT to a control group receiving radiation as opposed to a different ADT drug.

Studies have also focused on the risk of cardiac events in men with preexisting CVD as well as outcomes in those treated with GnRH antagonists as compared to GnRH agonists. One study pooled data from three prospective randomized trials and found that men with preexisting CVD had significantly decreased risk of cardiac events within 1 year of beginning treatment when on a GnRH antagonist as compared to a GnRH agonist (HR, 0.44; 95% CI, 0.26–0.74; p = 0.002) ^[21][29]. Another study comparing GnRH agonists and antagonists in men with prior CVD found a decrease in risk of heart failure (HR, 0.46; 95% CI, 0.26–0.79) and ischemic heart disease (HR, 0.26; 95% CI, 0.11–0.65) ^[22][30]. A 2019 phase II randomized trial compared the cardiovascular risk of GnRH agonists and antagonists ^[23][31]. This study corroborated previous research, finding a significant reduction in major cardiovascular and cerebrovascular events after one month of ADT using GnRH antagonists as compared to agonists (ARR, 18.1%; 95% CI 4.6–31.2, p = 0.032). Another systematic review compared available data on CV risk between GnRH agonists and degarelix. This study found degarelix to be protective for CV risk, to reduce new CV events, and to reduce CV interventions ^[24][32]. Relugolix, another new GnRH antagonist, was found by a recent phase III trial to have improved testosterone suppression as compared to degarelix along with a 54% reduction in major adverse cardiovascular events ^[25][33].

Other studies focused on the CV risk with androgen receptor inhibitors and androgen synthesis inhibitors. Recent meta-analyses of the use of abiraterone and enzalutamide in men with PCa revealed significant increases in adverse cardiac events and HTN ^[26][27][34,35]. A 2020 study revealed that men with a preexisting history of three or more CVDs who were taking abiraterone or enzalutamide experienced a significant increase in 6-month mortality as compared to men with no prior CVD (RR, 1.56; 95% CI, 1.29–1.88) ^[28][36]. Another meta-analysis revealed an increased risk of CV adverse events (RR, 1.41; 95% CI, 1.21–1.64) and HTN (RR, 1.79; 95% CI, 1.45–2.21) in men receiving abiraterone for prostate cancer treatment ^[29][37].

An important point to note is that men with clinically apparent CVD represent a significant population to monitor for complications while receiving ADT, but men with sub-clinical CVD must be considered as well. These patients could be at increased risk for complications while on hormonal therapy due to lack of regular monitoring for conditions like hypertension, diabetes, and coronary artery disease, among others. Additionally, patients with uncontrolled hypertension or significant preexisting CVDs are often excluded from clinical trials; therefore, the findings from the clinical trials might not be applicable to patients with significant preexisting CVD. Additionally, many trials have limited follow-up and sub-optimal data on participants’ previous CVD and risk factors. Larger-scale trials and longer follow-up with more in-depth patient demographics and risk factors will be needed to fully understand the present risk of ADT ^[24][32]. As of now, official guidelines have only come from the FDA, who in October 2010, determined that the available evidence showed a small but significant increase in risk of CV events and mandated labels on GnRH agonists to show safety information regarding its CV risks ^[30][38].