








































This is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited.  
© 2022 The Authors. Société Internationale d'Urologie Journal, published by the Société Internationale d'Urologie, Canada.

Key Words Competing Interests Article Information

Gonadotropin-releasing hormone, 
cardiovascular disease, myocardial infarction, 
androgen deprivation therapy, leuprolide, 
gonadotropin-releasing hormone agonist, 
androgen deprivation therapy antagonist

Laurence Klotz has no competing interests to 
declare.

Stephen Van Komen and Sanja Dragnic are 
employees of and own stock in AbbVie.

William B. White has received personal fees 
for cardiovascular drug safety consulting 
(including data safety monitoring boards, 
cardiovascular endpoint committees, and data 
analysis) to AbbVie, Alnylam, AstraZeneca, 
Bristol-Myers Squibb, Jazz, Marius, Mylan, 
Takeda-Millennium, and TerSera. He also 
receives royalties from Wolters Kluwer as  
an editor of UptoDate

Funding
AbbVie (North Chicago, IL)  sponsored the 
editorial assistance for this review and 
approved the final version. No honoraria and 
payments were made for authorship.

Received on April 6, 2022 
Accepted on May 2, 2022 
This article has been peer reviewed.

Soc Int Urol J. 2022;3(4):259–275

DOI: 10.48083/ VDNP9678

259SIUJ.ORG SIUJ  •  Volume 3, Number 4  •  July 2022

REVIEW

Impact of Androgen Deprivation Therapy on 
Cardiovascular Outcomes in Prostate Cancer

Laurence Klotz,1 Stephen Van Komen,2 Sanja Dragnic,3 William B. White4

1 Division of Urology, Sunnybrook Health Sciences Centre, Toronto, Canada, 2AbbVie, Mettawa, United States 3AbbVie, North Chicago, United States  
4Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington, United States

Abstract

Purpose Substantial evidence indicates that men with prostate cancer are at an increased risk for cardiovascular 
disease, and medical and surgical androgen deprivation therapy is associated with further increased cardiovascular 
risk. There are conflicting reports of differences in cardiovascular safety between gonadotropin-releasing hormone 
(GnRH) agonists and antagonists. The purpose of this narrative review is to compare data on the cardiovascular risks 
and safety outcomes associated with different hormonal treatment options in prostate cancer patients and to provide 
guidance on how to manage the increased risk associated with the condition.

Methods A PubMed search was conducted for papers published in the last 15 years using the following MeSH 
terms: “prostate neoplasms,” “gonadotropin-releasing hormone,” “androgen agonist,” “androgen antagonists,” 
“cardiovascular disease,” “epidemiology.”

Results Evidence regarding the risk of cardiovascular events during treatment with GnRH agonists and antagonists 
is conflicting. Some retrospective studies have shown that agonists are associated with a greater risk of cardiovascular 
disease and cardiovascular mortality and morbidity, and a similar risk with agonists and combined androgen 
blockade. Some studies have reported that antagonists are associated with a decreased risk of cardiovascular mortality 
and morbidity compared with agonists. With respect to coronary heart disease, ischemic heart disease, myocardial 
infarction, stroke, or sudden cardiac death, current evidence has failed to demonstrate a significant difference 
between antagonists and agonists. Cardiovascular risks in patients should be mitigated by regular monitoring of 
blood pressure, blood glucose, and lipids, as well as counseling patients to abstain from alcohol and improve their diet 
and exercise. Statins, metformin, and aspirin should also be considered.



Conclusions T he ev idence for t he i ncreased 
cardiovascular risk of GnRH agonists over antagonists 
for androgen deprivation therapy is unclear. Differences 
in methodology, population sizes, risk stratification, and 
outcomes between studies make direct comparisons 
problematic. The single prospective, randomized 
prostate cancer trial with a primary cardiovascular end 
point in men with pre-existing cardiovascular disease 
comparing GnRH agonist to antagonist was stopped 
early due to an interim futility analysis. The results are 
inconclusive.

Introduction

The burden of prostate cancer (PCa) is expected to 
increase owing to natural growth and aging of the 
global population[1]. Because of the high incidence-
to-mortality ratio of PCa, cardiovascular (CV) disease 
(CVD) is the leading cause of death in these men[2,3]. 
Aside from the high prevalence of slow-growing 
malignancy, there is substantial evidence that men 
with PCa are at an increased risk for CVD because 
of comorbid risk factors[4,5]. An analysis of the 
Surveillance, Epidemiology and End Results (SEER) 
program of the US National Cancer Institute, a network 
of population-based incident tumor registries, showed 
that men with PCa had a higher risk of CVD and CVD 
than the average US resident, after adjusting for age, 
race, and sex over the same period[4].

Van Hemelrijck et al. found that patients with PCa on 
surveillance (n = 19 526) had an elevated standardized 
incidence ratio (SIR) for all CVD subtypes (myocardial 
infarction [MI], arrhythmia, ischemic heart disease, 
heart failure, and stroke) compared with the general 
population[6]. The SIR was greater in patients with no 
circulatory disease detected at baseline (range 1.15 to 
1.49) for all subtypes except ischemic heart disease, 
which was more common in patients with circulatory 
disease at baseline.

PCa patients who have undergone surgical castra-
tion, or who are receiving medical androgen deprivation 

therapy (ADT), are at particularly high risk for CVD[6]. 
A cross-sectional analysis of the United States Veter-
ans Health Administration population examined the 
association between CV risk factors in men with PCa 
receiving ADT versus those not receiving ADT[7]. 
Among the two-thirds of men who received CV risk 
factor assessments (blood pressure measurements, 
serum cholesterol levels, blood glucose levels), about 
half had ≥ 1 uncontrolled CV risk factor, and 30% 
of those were not receiving treatment for it. Patients 
with PCa who had a history of atherosclerotic CVD, 
whether taking ADT or not, had about a 20% lower 
risk of having an untreated CV risk factor compared 
with those without a history of CVD or those who had 
no history of ADT. Patients on ADT with no history 
of CVD had a 5% lower risk for an untreated CV risk 
factor compared with patients with a CVD history 
who were ADT-naïve[7]. This ref lects the tendency 
for patients who have had a history of CVD to have 
more intensive management of their CV risk factors 
than those with no prior history. These data suggest 
that patients receiving ADT are at risk for the unrec-
ognized development of CVD or CV-related mortal-
ity. Whether the association between ADT and CVD 
is because of differential patient monitoring or because 
of adverse effects of ADT (or both) remains an unan-
swered question. CV risks in men with PCa are driven 
by a number of factors, including age (which might itself 
predict underlying health conditions), high-fat diet, 
visceral adiposity and low levels of high-density lipopro-
tein (HDL), pre-existing CV risk factors, and metabolic 
syndrome[2,8–10].

Recently, there have been studies reporting differ-
ences in CV safety between gonadotropin-releas-
ing hormone (GnRH) agonists and antagonists, with 
mixed results[11–14]. Some studies report differences in 
CV safety between GnRH agonists and antagonists in 
patients with pre-existing CVD, whereas others show no 
differences. Several mechanisms have been proposed to 
explain CV safety differences between GnRH agonists 
and antagonists, such as differences in follicle-stimu-
lating hormone levels, and the interaction between the 
agonists and GnRH receptors in endothelial plaque 
macrophages. These hypothesis-generating explanations 
remain speculative. The only randomized prospective 
study with CV event endpoints was closed early after 
an interim analysis because of a very low probability 
that a difference would be observed between agonists 
and antagonists (futility analysis)[12]. The purpose of 
this review is to elucidate the data on the CV risks and 
safety outcomes associated with different ADT options 
in patients with PCa and to consider strategies for miti-
gation of their CV risk.

Abbreviations 
ADT androgen deprivation therapy
CVD cardiovascular disease
GnRH gonadotropin-releasing hormone
MI myocardial infarction
PCa prostate cancer
SIR standardized incidence ratio

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Search Method
A search was conducted using PubMed, and articles 
published after 2006 were included in the initial search. 
This allowed for research published in the past 15 years 
to be eligible for inclusion in the literature review. The 
search method is shown in Figure 1. After selection, 71 
papers were included in this review.

CV Risks Reported With ADT
A landmark population-based study by Keating et al. 
(n = 73 196) using retrospective data obtained from 
the SEER database demonstrated that GnRH agonists 
were associated with a significantly increased risk of 
coronary heart disease (CHD), MI, and sudden cardiac 
death compared with ADT-naïve adult men ≥ 66 years 
of age with local or regional PCa. CHD was defined as 
an inpatient admission with a primary or secondary 
diagnosis code of ischemic heart disease or MI. Sudden 
cardiac death was defined as a primary or secondary 
diagnosis code of sudden death or life-threatening 
ventricular arrhy thmia. Using Cox proportional 
hazard models and accounting for patient and tumor 

characteristics, the adjusted hazard ratios (aHRs) were 
1.16 (P < 0.001), 1.11 (P = 0.03), and 1.16 (P = 0.004) for 
CHD, MI, and sudden cardiac mortality, respectively, 
when using a GnRH agonist. Furthermore, patients 
given GnRH agonists showed a significantly increased 
risk of CHD after only 1 to 4 months of treatment (aHR, 
1.14; P = 0.007) compared with patients not receiving 
ADT. This risk stayed elevated as treatment duration 
continued for 5 to 12 months (aHR, 1.19; P < 0.001), 13 
to 14 months (aHR, 1.11; P = 0.04), and ≥ 25 months 
(aHR, 1.18; P = 0.001)[15]. These results led to a 2010 joint 
statement from the American Urological Association, 
the American Society for Radiation Oncology, and the 
American Heart Association alerting clinicians to a 
potential relationship between ADT and CVD risk[16]. 
The US labels for GnRH agonists were revised to add 
a safety statement stating that an increased risk of MI, 
sudden cardiac death, and stroke has been reported in 
association with use of GnRH analogs in men. The safety 
statements emphasize the importance of monitoring 
for the development of CVD and managing patients 
appropriately[17–20].

FIGURE 1.

Literature search

Records identied through PubMed 
database searching the following 
MeSH terms: prostate neoplasms, 
gonadotropin releasing hormone, 
androgen antagonists, androgen 
agonists, cardiovascular disease, 

epidemiology

Additional records identi�ed via
in-text citations 

(n=23)

Records screened
(n = 137)

Full-text articles assessed
for eligibility

(n=48)

Papers included in review
(n=71)

Records excluded (n=89)
Publication year earlier than 2006

(n=34)
No safety/CV data, abstract only,

no GnRH agonist/antagonist-speci�c data 
(n=55)

261SIUJ.ORG SIUJ  •  Volume 3, Number 4  •  July 2022

Impact of Androgen Deprivation Therapy on Cardiovascular Outcomes in Prostate Cancer



Quantifying the CV Risk of ADT and  
the Importance of Pre-Existing CVD
Several studies suggest that patients with pre-existing 
CVD are particularly at risk from the CV effects of 
ADT. Gandaglia et al. found a 5-year cumulative CV 
mortality estimate of 14.8% in patients with metastatic 
PCa receiving ADT (ie, GnRH agonist and/or bilateral 
orchiectomy) with underlying CV risk factors versus 
9.8% in those without baseline CV morbidities. Of 
the 9596 men on ADT, 31.8% had CV comorbidities 
(n = 3049) at baseline, and 1083 CV mortality events 
(11.3%) were recorded. Pre-existing CVD is the strongest 
predictor of CV mortality risk and warrants maximizing 
CV risk factor control before initiating ADT[21].

A similar observational study, also by Gandaglia et 
al.[22] assessed the 10-year cumulative incidence rates of 
CHD, MI, and CV mortality in patients with non-met-
astatic PCa. After propensity score matching and strat-
ifying patients according to treatment type, the study 
found that patients using GnRH agonists (n = 28 988) 
had significantly greater incidence (P < 0.001) of CHD, 
MI, and CV mortality events of 26.9%, 16.6%, and 17.7%, 
respectively, compared with 25.1%, 14.8%, and 14.2%, 
respectively, for those not on ADT (n = 29 984). A multi-
variable, competing-risks regression analysis of the 
score-matched GnRH agonist cohort identified a statis-
tically significant (P < 0.001) rate increase in CHD (aHR, 
1.11), MI (aHR, 1.09), and CV mortality (aHR, 1.18)[22]. 
These rates parallel those seen in Keating et al. (aHR, 
1.16, 1.11, and 1.16, respectively) and reinforce the signif-
icance of ADT-associated CV risks[15].

In contrast, a meta-analysis by Zhao et al. in 2014 
consisting of patients receiving ADT (GnRH agonist, 
antiandrogens, orchiectomy, or a combination of 
2 or more treatments) (n = 129 802) and non-ADT 
users (n = 165 605) failed to find a significant relation-
ship between ADT and CVD development (17.8% and 
16.0%, P = 0.06, respectively)[23]. They did, however, 
find a significant relationship between CVD and GnRH 
agonists taken alone (aHR, 1.19; P = 0.01) and GnRH 
agonists plus antiandrogens (aHR, 1.46; P = 0.04), 
but not with ADT using antiandrogens alone (aHR, 
0.95; P = 0.16). ADT use was significantly associ-
ated with a rise in CV mortality (aHR, 1.17; P = 0.01) 
compared with non-ADT use when the prevalence of 
CV mortality events was assessed (11.7% and 9.0%, 
respectively). GnRH agonists had a significantly higher 
risk of CV mortality compared with non-ADT (aHR, 
1.36; P = 0.004), although men on GnRH agonists plus 
antiandrogen or those who had undergone orchiectomy 
had an even higher risk (aHR, 1.44; P < 0.001 and aHR, 
1.69; P = 0.03, respectively). Although ADT did not have 
a significant association with MI incidence (P = 0.14), it 
did show a positive relationship with the GnRH agonist 

subgroup (aHR, 1.20; P = 0.008). Treatment with antian-
drogens alone reduced the MI aHR to 0.88 (P = 0.002)[23].

Nguyen et al. performed another meta-analysis 
(n = 2200) that compared patients with non-meta-
static PCa on GnRH agonists with those not on ADT 
(n = 1941)[24]. In this meta-analysis, GnRH agonist 
was not associated with a significant increase in risk for 
CV mortality (n = 255 events; relative risk [RR], 0.93; 
P = 0.41). Additional subgroup analyses of short- and 
long-term therapy, of supplemental therapy (ie, radi-
ation), and of older age cohorts also failed to find an 
association between GnRH agonist use and a significant 
increase in CV mortality.

The evidence regarding the CV risks of ADT is thus 
inconclusive (Table 1)[25,26]. Various confounding 
factors have been proposed to explain the variability in 
these studies. These include (1) that ADT is often used 
for patients who are not considered for curative treat-
ment. Men selected for ADT are typically older or in 
worse overall health and thereby may have an increased 
risk of CV mortality, although an important exception is 
the use of adjuvant ADT with radiation therapy; (2) the 
presence of unknown CVD risk factors in populations 
being studied is a potential confounder; and (3) patients 
with ADT in clinical trials are more likely to be closely 
monitored (so more likely that CV issues are detected) 
and treated than those in the general population[27].

The aim of ADT is to reduce serum testosterone levels 
to castrate levels (20 to 50 ng/dL); this promotes regres-
sion of the disease[28]. Patients with testosterone levels 
of >20 ng/dL (> 0.7 nmol/L) over the first year of ADT 
have a higher risk of dying, with an HR of 2.08 compared 
with those who have testosterone levels of < 20 ng/dL (< 
0.7 nmol/L). For those whose level was > 50 ng/dL (> 1.7 
nmol/L), the HR was higher still at 2.93[29].

CV Risk With Orchiectomy
Most studies of the effect of ADT on CV health have 
grouped all patients receiving ADT together, whether 
castration is surgical or medical. Since all of these 
techniques achieve castrate levels of testosterone in most 
patients, the metabolic syndrome associated with ADT 
occurs regardless of method. However, some pre-clinical 
and clinical data suggest that the cardiovascular effects 
of surgical castration are greater than with medical 
castration. In the hyperglycemic male ApoE -/-:Ins2 +/
Akita mouse model, orchiectomy induced greater weight 
gain, higher BMI, and necrotic plaque at the aortic root 
compared with LHRH agonist and antagonist[30]. The 
clinical data are more equivocal. Some studies that 
have addressed this question, but not all, have reported 
that men treated with surgical castration have a higher 
rate of CV disease than those treated with LHRH 
agonists[31–33].

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TABLE 1.

Summary of CV risk factors for patients receiving androgen deprivation therapy

CV Outcome ADT Effect GnRH Agonista
GnRH 

Antagonist
CABb References

CVD, MACE Inconclusive
• No difference between GnRH agonists and GnRH 

antagonists

Cardwell et al. (2020)[35]
Lopes et al. (2021)[12]
Wallach et al. (2021)[13]

CVD, CV mortality 
and morbidity

Mixed 

• Greatest risk with GnRH agonists among ADT types 
(versus non-ADT group)

• Unchanged to decrease in risk of CV mortality and 
morbidity (versus GnRH agonist group)

• Risk is similar between CAB and GnRH agonists

Keating et al. (2006)[15]  
D’Amico et al. (2008)[55]
Faris and Smith (2010)[56]
Nguyen et al. (2011)[24]  
O’Farrell et al. (2012)[57]
Zhao et al. (2014)[23]
Bosco et al. (2015)[58]
Lester and Mason (2015)[59]
Zareba et al. (2016)[10]
Lopes et al. (2021)[12]
Wallach et al. (2021)[13]

CVD, CV mortality 
and morbidity

Mixed 

• Greatest risk with GnRH agonists among ADT types 
(versus non-ADT group)

• Unchanged to decrease in risk of CV mortality and 
morbidity (versus GnRH agonist group)

• Risk is similar between CAB and GnRH agonists

Keating et al. (2006)[15]  
D’Amico et al. (2008)[55]
Faris and Smith (2010)[56]
Nguyen et al. (2011)[24]  
O’Farrell et al. (2012)[57]
Zhao et al. (2014)[23]
Bosco et al. (2015)[58]
Lester and Mason (2015)[59]
Zareba et al. (2016)[10]
Lopes et al. (2021)[12]
Wallach et al. (2021)[13]

CAD, IHD,  
and MI

Inconclusive

Increased risk  
(versus non-ADT 
and non-prostate 
cancer groups)

No significant
difference in risk  
(versus GnRH 
agonist group)

Greater risk with 
CAB compared 
with GnRH 
agonists

Faris and Smith (2010)[56]
Scailteux et al. (2017)[34]
Lopes et al. (2021)[12]
Wallach et al. (2021)[13]

Cerebrovascular 
accidents

Inconclusive

Increased risk  
(versus non-ADT 
and  
non-prostate 
cancer groups)

No significant
difference in risk  
(versus GnRH 
agonist group)

No significant 
difference in risk 
(versus GnRH 
agonist and non-
ADT groups)

Keating et al. (2006)[15]
Meng et al. (2016)[60]  
Scailteux et al. (2017)[34] 

Sudden cardiac
death

Inconclusive
Increased risk  
(versus non-ADT 
group)

No data 
available

No significant 
difference in risk 
(versus non-ADT 
group)

Keating et al. (2006)[15]
Faris and Smith (2010)[56] 

ADT: androgen deprivation therapy; CAB: combined androgen blockade; CV: cardiovascular; CVD: cardiovascular disease; GnRH: gonadotropin-releasing 
hormone; IHD: ischemic heart disease; MACE: major adverse cardiovascular event; MI: myocardial infarction.
a Some of the therapies evaluated in these studies were goserelin, histrelin, leuprorelin, and triptorelin. bCAB: (GnRH agonist + antiandrogen) and 
antiandrogen (flutamide, bicalutamide, nilutamide). Table adapted from Gupta et al. 2018[61].

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CV Risk With GnRH Antagonists and 
Agonists
In addition to the general lack of clarity about the CVD 
risks of ADT, there is an uncertainty as to whether the 
link between ADT and CV events is primarily a function 
of the reduction in testosterone, or whether it is a specific 
effect related to the type of ADT drug, specifically 
GnRH agonists versus antagonists[16,23]. The difference 
in CV risk associated with use of GnRH agonists and 
antagonists has been summarized in Table 2.

GnRH antagonists have been in clinical use since 
2008 and have had a lower rate of use than their agonist 
counterparts. Therefore, there are fewer data on their 
correlation with CVD. Scailteux et al. performed a 
retrospective analysis of 2010 to 2013 French Health 
Reimbursement Agency and French hospital discharge 
database data for adult men (≥ 18 years) with PCa who 

were newly prescribed ADT using a composite endpoint 
of “ischemic events” (MI or ischemic stroke, which-
ever came first after ADT initiation). Of the total stud-
ied population (n = 35 118), 71% of the patients received 
GnRH agonists versus 3.6% who received a GnRH 
antagonist. Relative to GnRH antagonists, agonist use 
did not have a significantly higher MI risk profile (aHR, 
1.17; 95% CI 0.48 to 2.86 antagonist versus agonist using 
Cox proportional hazard model), nor an increased risk 
for ischemic stroke (aHR, 1.28; 95% CI 0.60 to 2.72 
antagonist versus agonist). The overall mortality rate 
was the same for both agonists and antagonists (0.03 
per 100 person-years), and incidence of ischemic events 
was lower for agonists (0.74 per 100 person-years) than 
for antagonists (0.87 per 100 person-years)[34]. Albert-
sen et al.[14] measured CV mortality and CVD among 
patients using GnRH agonists (leuprolide or gosere-
lin n = 837) and the antagonist degarelix (n = 1491) by 

TABLE 2. 

Study compilation of CV risk assessment with GnRH agonists and antagonists in men with prostate cancer 

Study Design CV Results CV Conclusions
Summary of CVD Risk GnRH Agonist 

Versus GnRH Antagonist/Control 
Reference

Observational study
Patients (n = 73 196) ≥66 years old first diagnosed with locoregional 
PCa from 1992–1999 

GnRH agonist use was associated with increased risk of the following:
• CAD: aHR, 1.16; P < 0.001
• MI: aHR, 1.11; P = 0.03
• SCD: aHR, 1.16; P = 0.004

GnRH agonist use may be associated with an increased risk of CVD 
when compared to patients with untreated locoregional PCa 

GnRH agonist > control Keating et al. (2006)[15]

Retrospective study
Single institution, pooled data (n = 5077) from 1997 to 2006 of 
patients with PCa clinical stage T1 to T3 N0 M0

Agonist and antiandrogen use was not associated with an increased risk of 
CAD (aHR, 1.04; P = 0.82). For those with CAD-induced CHF or MI, use was 
associated with an increased risk of all-cause mortality (aHR, 1.96; P = 0.04)

No association with an increased risk of all-cause mortality in men 
with no comorbidity of CAD, but was increased in those with CAD 
morbidity

Inconclusive
GnRH agonist = control

Nanda et al. (2009)[62]

Prospective study
1-year RCT of leuprolide acetate versus degarelix (n = 504)

The incidence of the most common event (ischemic heart disease) was lower 
in the degarelix group with 18 patients (4%) versus leuprolide group with 21 
patients (10%)

No significant differences were found in either treatment group. 
Both have similar CV safety profiles

Inconclusive Smith et al. (2010)[63]

Meta-analysis of randomized trials
Pooled patient data (n =141) from RCTs from 1966 to 2011 of  
men with unfavorable-risk, non-metastatic PCa

CV mortality in patients receiving GnRH agonists versus control cohort (non-
ADT/delayed ADT) was not significantly different (11% versus 11.2%; 95% 
CI, 8.3%–15.0%, respectively; RR, 0.93, P = 0.41)

No association with GnRH agonist and increased risk of CVD
Inconclusive

GnRH agonist = control
Nguyen et al. (2011)[24]

Retrospective study
CaPSURE registry patients (n = 7248)

Agonist showed 2-fold greater likelihood of CV mortality (HR, 1.94);  
however, patients treated with WW/AS had >2-fold increased risk of  
CV mortality (HR, 2.46)

Patients matched on propensity to receive agonist did not show an 
association with CV mortality

Inconclusive
GnRH agonist < WW/AS

Punnen et al. (2011)[9]

Pooled data from prospective trials
Pooled analyses on CV incidence in patients (n = 1704) from  
9 degarelix clinical trials

CV events were 5.5 and 6.1 eventsa per 100 person-years, before and 
after degarelix treatment, respectively (HR, 1.10, P = 0.45). In men without 
established CVD, the event rate was numerically lower after the initiation of 
degarelix treatment (5.6 versus 4.3 per 100 person-years; HR, 0.77; P = 0.11)

CVD rates were similar before and after degarelix treatment
Inconclusive

GnRH antagonist = no GnRH antagonist 
treatment 

Smith et al. (2011)[64]

ADT: androgen deprivation therapy; aHR: adjusted hazard ratio; CAD: coronary artery disease; CV: cardiovascular; CVD: cardiovascular disease; GnRH: 
gonadotropin-releasing hormone; HF: heart failure; HR: hazard ratio; ICD-10: International Classification of Diseases, 10th edition; MACE: major 
adverse cardiovascular event; MedDRA: Medical Dictionary for Regulatory Activities; MI: myocardial infarction; PCa: prostate cancer; RCT: randomized 
controlled trial; SCD: sudden cardiac death; WW/AS: watchful waiting/active surveillance.

aCVD before and after degarelix initiation; bElevated risks of arrhythmia (adjusted HR, 1.44; 95% CI 1.02 to 2.01) were observed only among patients 
with pre-existing CVD; cIncludes GnRH agonists, GnRH antagonist (degarelix), oral antiandrogens, estrogens, and orchiectomy.

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TABLE 2. 

Study compilation of CV risk assessment with GnRH agonists and antagonists in men with prostate cancer 

Study Design CV Results CV Conclusions
Summary of CVD Risk GnRH Agonist 

Versus GnRH Antagonist/Control 
Reference

Observational study
Patients (n = 73 196) ≥66 years old first diagnosed with locoregional 
PCa from 1992–1999 

GnRH agonist use was associated with increased risk of the following:
• CAD: aHR, 1.16; P < 0.001
• MI: aHR, 1.11; P = 0.03
• SCD: aHR, 1.16; P = 0.004

GnRH agonist use may be associated with an increased risk of CVD 
when compared to patients with untreated locoregional PCa 

GnRH agonist > control Keating et al. (2006)[15]

Retrospective study
Single institution, pooled data (n = 5077) from 1997 to 2006 of 
patients with PCa clinical stage T1 to T3 N0 M0

Agonist and antiandrogen use was not associated with an increased risk of 
CAD (aHR, 1.04; P = 0.82). For those with CAD-induced CHF or MI, use was 
associated with an increased risk of all-cause mortality (aHR, 1.96; P = 0.04)

No association with an increased risk of all-cause mortality in men 
with no comorbidity of CAD, but was increased in those with CAD 
morbidity

Inconclusive
GnRH agonist = control

Nanda et al. (2009)[62]

Prospective study
1-year RCT of leuprolide acetate versus degarelix (n = 504)

The incidence of the most common event (ischemic heart disease) was lower 
in the degarelix group with 18 patients (4%) versus leuprolide group with 21 
patients (10%)

No significant differences were found in either treatment group. 
Both have similar CV safety profiles

Inconclusive Smith et al. (2010)[63]

Meta-analysis of randomized trials
Pooled patient data (n =141) from RCTs from 1966 to 2011 of  
men with unfavorable-risk, non-metastatic PCa

CV mortality in patients receiving GnRH agonists versus control cohort (non-
ADT/delayed ADT) was not significantly different (11% versus 11.2%; 95% 
CI, 8.3%–15.0%, respectively; RR, 0.93, P = 0.41)

No association with GnRH agonist and increased risk of CVD
Inconclusive

GnRH agonist = control
Nguyen et al. (2011)[24]

Retrospective study
CaPSURE registry patients (n = 7248)

Agonist showed 2-fold greater likelihood of CV mortality (HR, 1.94);  
however, patients treated with WW/AS had >2-fold increased risk of  
CV mortality (HR, 2.46)

Patients matched on propensity to receive agonist did not show an 
association with CV mortality

Inconclusive
GnRH agonist < WW/AS

Punnen et al. (2011)[9]

Pooled data from prospective trials
Pooled analyses on CV incidence in patients (n = 1704) from  
9 degarelix clinical trials

CV events were 5.5 and 6.1 eventsa per 100 person-years, before and 
after degarelix treatment, respectively (HR, 1.10, P = 0.45). In men without 
established CVD, the event rate was numerically lower after the initiation of 
degarelix treatment (5.6 versus 4.3 per 100 person-years; HR, 0.77; P = 0.11)

CVD rates were similar before and after degarelix treatment
Inconclusive

GnRH antagonist = no GnRH antagonist 
treatment 

Smith et al. (2011)[64]

ADT: androgen deprivation therapy; aHR: adjusted hazard ratio; CAD: coronary artery disease; CV: cardiovascular; CVD: cardiovascular disease; GnRH: 
gonadotropin-releasing hormone; HF: heart failure; HR: hazard ratio; ICD-10: International Classification of Diseases, 10th edition; MACE: major 
adverse cardiovascular event; MedDRA: Medical Dictionary for Regulatory Activities; MI: myocardial infarction; PCa: prostate cancer; RCT: randomized 
controlled trial; SCD: sudden cardiac death; WW/AS: watchful waiting/active surveillance.

aCVD before and after degarelix initiation; bElevated risks of arrhythmia (adjusted HR, 1.44; 95% CI 1.02 to 2.01) were observed only among patients 
with pre-existing CVD; cIncludes GnRH agonists, GnRH antagonist (degarelix), oral antiandrogens, estrogens, and orchiectomy.

continued on page 266

pooling data from 6 phase 3 prospective randomized 
trials (n = 2328). In men without pre-existing CVD, no 
differences in either the incidence of cardiac events or 
death form any cause was noted. In men with pre-ex-
isting CVD (n = 619), Cox regression modeling revealed 
an RR reduction of 56% of CV event or death with use of 
degarelix compared with GnRH agonists within 1 year 
of therapy initiation (aHR, 0.44; P = 0.002). In contrast, 
in this post hoc analysis, there were no significant differ-
ences in the incidence of a non-fatal cardiac event or 
death identified in patients without pre-existing CV 
morbidities. Follow-up was 1 year in 3 of the studies, and 
3 months in the other 3. All of the recorded CV events 
occurred in the 3 longer studies of 12 months’ duration. 
Importantly, these trials were not designed to evalu-
ate CV risk, nor were the events adjudicated by clinical 
CV event reviewers for their veracity. The authors also 
stated that the quality of the study data was “subject to 

bias” (according to The Cochrane Collaboration’s tool) 
because both patients and study personnel were not 
blinded regarding which form of ADT was adminis-
tered.

A retrospective database analysis by Cardwell et 
al. compared the CVD risk rate of degarelix (n = 387) 
and GnRH agonists (including goserelin, leuprolide, 
triptorelin, and histrelin) use in men (n = 10 480) with 
newly diagnosed PCa versus untreated patients receiving 
active surveillance or watchful waiting (n = 4903)[35]. 
Using Cox regression modeling, Cardwell et al. deter-
mined that degarelix use had a 50% increased risk of CV 
events (71 events; aHR, 1.5; 95% CI, 1.2–1.9) compared 
with a 30% increased risk for GnRH agonists (2075 
events; aHR, 1.3; 95% CI 1.2 to 1.4). GnRH agonists and 
degarelix continued to have an elevated CV event risk 
(20% to 50%) for both short-term (< 365 daily defined 

265SIUJ.ORG SIUJ  •  Volume 3, Number 4  •  July 2022

Impact of Androgen Deprivation Therapy on Cardiovascular Outcomes in Prostate Cancer



TABLE 2. 

Study compilation of CV risk assessment with GnRH agonists and antagonists in men with prostate cancer 

Study Design CV Results CV Conclusions
Summary of CVD Risk GnRH Agonist 

Versus GnRH Antagonist/Control 
Reference

Pooled data from prospective randomized trials
Pooled patient data from 6 phase 3 prospective trials comparing 
GnRH agonists leuprolide or goserelin (n = 837) with antagonist 
degarelix (n = 1491)

Among patients with pre-existing CVD, the risk of CV events was 
significantly lower (56%) in the antagonist group versus the agonist  
group (HR, 0.44; P = 0.002). No difference in CV events for those without 
pre-existing CVD

These data suggest a greater risk of CV events for those using 
agonist with pre-existing CVD in patients with non-metastatic PCa

GnRH agonist > GnRH antagonist Albertsen et al. (2014)[14]

Pooled data from prospective randomized trials
Pooled patient data (n = 1925) from 5 trials in patients receiving 
degarelix and leuprolide or goserelin

Patients with underlying CVD at baseline (29.6%) showed a nonsignificant 
lower risk of death with degarelix versus GnRH agonist (HR, 0.40; P = 0.051)

Degarelix use may be associated with lower incidence of CVD in 
men with pre-existing CVD

GnRH agonist > GnRH antagonist Klotz et al. (2014)[65]

Meta-analysis of population-based observational studies
9 studies comparing GnRH agonists (n = 119 625) versus control 
(n = 150 975) in patients with locoregional and non-metastatic PCa 

GnRH agonists were associated with an increased risk of CVD (HR, 1.19; 
P = 0.01) compared with control cohort receiving non-ADT or WW/AS

ADT is associated with a 10% increased CV risk. Significantly 
increased risks of CV mortality were observed in GnRH cohorts

GnRH agonist > control Zhao et al. (2014)[23]

Prospective study
Large cohort (n = 7637) from healthcare records of patients who 
initially underwent active surveillance

GnRH agonist was associated with an increased risk of HF (aHR, 1.81) in men 
without pre-existing CVDb

GnRH agonist was associated with a greater risk of HF without  
any pre-existing CVD

GnRH agonist > control Haque et al. (2017)[66] 

Prospective study (HERO)
Randomized, open-label, phase 3 trial. Compared patients with 
advanced PCa (n = 930) who received relugolix (GnRH antagonist)  
or leuprolide (GnRH agonist) for 48 weeks

The incidence of MACE was 2.9% in the relugolix group and 6.2%  
in the leuprolide group (HR, 0.46)

MedDRA query showed a lower risk of MACE with relugolix over 
leuprolide. Any-grade MACE incidence was 2.9% for relugolix 
versus 6.2% for leuprolide. Incidence of grade 3 or 4 MACE was 
1.3% for both relugolix and leuprolide. Ischemic heart disease 
incidence was 4% for relugolix and 1.6% for leuprolide

GnRH agonist > GnRH antagonist Shore et al. (2020)[37]

Observational study
Utilized database to search ICD-10 codes of patients with newly 
diagnosed PCa with CV events (death or hospitalization due to CVD)  
(n = 20 216)

ADTc (includes GnRH agonists and antagonists) use had a 30% increase of 
CV events (aHR, 1.3; 95% CI 1.2–1.4). This reflected increases in CV events 
associated with GnRH agonists (aHR, 1.3) and degarelix (aHR, 1.5), but not 
bicalutamide monotherapy  
(aHR, 1.0)

Degarelix and GnRH agonists both increased risk of CV events Inconclusive Cardwell et al. (2020)[35]

Prospective study (PRONOUNCE)
Randomized, open-label, phase 3, assessor-blind, 12-month study 
in patients (n = 545) with advanced PCa and atherosclerotic CVD 
treated with ADT (degarelix or leuprolide) for 12 months. Primary 
endpoint was time to occurrence of MACE at 1 year

Primary endpoint: incidence of MACE was 15 (5.5%) for degarelix group 
versus 11 (4.1%) for leuprolide (HR, 1.28; P = 0.53). Composite endpoint of 
CV death, non-fatal MI, or non-fatal stroke occurred in 9 patients receiving 
degarelix and 7 receiving leuprolide (HR, 1.20; P = 0.71)

No significant differences were found in either treatment group. 
Both treatments have similar CV safety profiles

Inconclusive
Study terminated owing to futility

Lopes et al. (2021)[12]

Retrospective, propensity-matched cohort study designed to 
emulate the PRONOUNCE study. Adult men with PCa and CVD who 
initiated degarelix or leuprolide using deidentified administrative 
claims data. Primary endpoint was time to first occurrence of MACE

Primary efficacy outcome: incidence of MACE was 10.18 per 100 person-
years for degarelix group versus 8.6 per 100 person-years for leuprolide (HR, 
1.18; P = 0.30).
Secondary endpoints:
• Death: 7.43 (degarelix) versus 4.99/100 person/y (leuprolide) (HR 1.48, 

P = 0.046)
• MI: 2.18 per 100 person-years for degarelix versus 1.87 per 100 person-

years for leuprolide (HR, 1.16; P = 0.66)
• Stroke: 1.72 per 100 person-years for degarelix versus 1.87 per 100 

person-years for leuprolide (HR, 0.92; P = 0.81)
• Angina: < 11 events each for degarelix and leuprolide (HR, 1.36; P = 0.60) 

No significant differences were found in either treatment group No difference in MACE Wallach et al. (2021)[13]

ADT: androgen deprivation therapy; aHR: adjusted hazard ratio; CAD: coronary artery disease; CV: cardiovascular; CVD: cardiovascular disease; GnRH: 
gonadotropin-releasing hormone; HF: heart failure; HR: hazard ratio; ICD-10: International Classification of Diseases, 10th edition; MACE: major 
adverse cardiovascular event; MedDRA: Medical Dictionary for Regulatory Activities; MI: myocardial infarction; PCa: prostate cancer; RCT: randomized 
controlled trial; SCD: sudden cardiac death; WW/AS: watchful waiting/active surveillance.

aCVD before and after degarelix initiation; bElevated risks of arrhythmia (adjusted HR, 1.44; 95% CI 1.02 to 2.01) were observed only among patients 
with pre-existing CVD; cIncludes GnRH agonists, GnRH antagonist (degarelix), oral antiandrogens, estrogens, and orchiectomy.

, Cont’d

266 SIUJ  •  Volume 3, Number 4  •  July 2022 SIUJ.ORG

REVIEW



TABLE 2. 

Study compilation of CV risk assessment with GnRH agonists and antagonists in men with prostate cancer 

Study Design CV Results CV Conclusions
Summary of CVD Risk GnRH Agonist 

Versus GnRH Antagonist/Control 
Reference

Pooled data from prospective randomized trials
Pooled patient data from 6 phase 3 prospective trials comparing 
GnRH agonists leuprolide or goserelin (n = 837) with antagonist 
degarelix (n = 1491)

Among patients with pre-existing CVD, the risk of CV events was 
significantly lower (56%) in the antagonist group versus the agonist  
group (HR, 0.44; P = 0.002). No difference in CV events for those without 
pre-existing CVD

These data suggest a greater risk of CV events for those using 
agonist with pre-existing CVD in patients with non-metastatic PCa

GnRH agonist > GnRH antagonist Albertsen et al. (2014)[14]

Pooled data from prospective randomized trials
Pooled patient data (n = 1925) from 5 trials in patients receiving 
degarelix and leuprolide or goserelin

Patients with underlying CVD at baseline (29.6%) showed a nonsignificant 
lower risk of death with degarelix versus GnRH agonist (HR, 0.40; P = 0.051)

Degarelix use may be associated with lower incidence of CVD in 
men with pre-existing CVD

GnRH agonist > GnRH antagonist Klotz et al. (2014)[65]

Meta-analysis of population-based observational studies
9 studies comparing GnRH agonists (n = 119 625) versus control 
(n = 150 975) in patients with locoregional and non-metastatic PCa 

GnRH agonists were associated with an increased risk of CVD (HR, 1.19; 
P = 0.01) compared with control cohort receiving non-ADT or WW/AS

ADT is associated with a 10% increased CV risk. Significantly 
increased risks of CV mortality were observed in GnRH cohorts

GnRH agonist > control Zhao et al. (2014)[23]

Prospective study
Large cohort (n = 7637) from healthcare records of patients who 
initially underwent active surveillance

GnRH agonist was associated with an increased risk of HF (aHR, 1.81) in men 
without pre-existing CVDb

GnRH agonist was associated with a greater risk of HF without  
any pre-existing CVD

GnRH agonist > control Haque et al. (2017)[66] 

Prospective study (HERO)
Randomized, open-label, phase 3 trial. Compared patients with 
advanced PCa (n = 930) who received relugolix (GnRH antagonist)  
or leuprolide (GnRH agonist) for 48 weeks

The incidence of MACE was 2.9% in the relugolix group and 6.2%  
in the leuprolide group (HR, 0.46)

MedDRA query showed a lower risk of MACE with relugolix over 
leuprolide. Any-grade MACE incidence was 2.9% for relugolix 
versus 6.2% for leuprolide. Incidence of grade 3 or 4 MACE was 
1.3% for both relugolix and leuprolide. Ischemic heart disease 
incidence was 4% for relugolix and 1.6% for leuprolide

GnRH agonist > GnRH antagonist Shore et al. (2020)[37]

Observational study
Utilized database to search ICD-10 codes of patients with newly 
diagnosed PCa with CV events (death or hospitalization due to CVD)  
(n = 20 216)

ADTc (includes GnRH agonists and antagonists) use had a 30% increase of 
CV events (aHR, 1.3; 95% CI 1.2–1.4). This reflected increases in CV events 
associated with GnRH agonists (aHR, 1.3) and degarelix (aHR, 1.5), but not 
bicalutamide monotherapy  
(aHR, 1.0)

Degarelix and GnRH agonists both increased risk of CV events Inconclusive Cardwell et al. (2020)[35]

Prospective study (PRONOUNCE)
Randomized, open-label, phase 3, assessor-blind, 12-month study 
in patients (n = 545) with advanced PCa and atherosclerotic CVD 
treated with ADT (degarelix or leuprolide) for 12 months. Primary 
endpoint was time to occurrence of MACE at 1 year

Primary endpoint: incidence of MACE was 15 (5.5%) for degarelix group 
versus 11 (4.1%) for leuprolide (HR, 1.28; P = 0.53). Composite endpoint of 
CV death, non-fatal MI, or non-fatal stroke occurred in 9 patients receiving 
degarelix and 7 receiving leuprolide (HR, 1.20; P = 0.71)

No significant differences were found in either treatment group. 
Both treatments have similar CV safety profiles

Inconclusive
Study terminated owing to futility

Lopes et al. (2021)[12]

Retrospective, propensity-matched cohort study designed to 
emulate the PRONOUNCE study. Adult men with PCa and CVD who 
initiated degarelix or leuprolide using deidentified administrative 
claims data. Primary endpoint was time to first occurrence of MACE

Primary efficacy outcome: incidence of MACE was 10.18 per 100 person-
years for degarelix group versus 8.6 per 100 person-years for leuprolide (HR, 
1.18; P = 0.30).
Secondary endpoints:
• Death: 7.43 (degarelix) versus 4.99/100 person/y (leuprolide) (HR 1.48, 

P = 0.046)
• MI: 2.18 per 100 person-years for degarelix versus 1.87 per 100 person-

years for leuprolide (HR, 1.16; P = 0.66)
• Stroke: 1.72 per 100 person-years for degarelix versus 1.87 per 100 

person-years for leuprolide (HR, 0.92; P = 0.81)
• Angina: < 11 events each for degarelix and leuprolide (HR, 1.36; P = 0.60) 

No significant differences were found in either treatment group No difference in MACE Wallach et al. (2021)[13]

ADT: androgen deprivation therapy; aHR: adjusted hazard ratio; CAD: coronary artery disease; CV: cardiovascular; CVD: cardiovascular disease; GnRH: 
gonadotropin-releasing hormone; HF: heart failure; HR: hazard ratio; ICD-10: International Classification of Diseases, 10th edition; MACE: major 
adverse cardiovascular event; MedDRA: Medical Dictionary for Regulatory Activities; MI: myocardial infarction; PCa: prostate cancer; RCT: randomized 
controlled trial; SCD: sudden cardiac death; WW/AS: watchful waiting/active surveillance.

aCVD before and after degarelix initiation; bElevated risks of arrhythmia (adjusted HR, 1.44; 95% CI 1.02 to 2.01) were observed only among patients 
with pre-existing CVD; cIncludes GnRH agonists, GnRH antagonist (degarelix), oral antiandrogens, estrogens, and orchiectomy.

267SIUJ.ORG SIUJ  •  Volume 3, Number 4  •  July 2022

Impact of Androgen Deprivation Therapy on Cardiovascular Outcomes in Prostate Cancer



doses) and long-term use (≥ 365 daily defined doses). 
Further analysis revealed that GnRH agonist only use 
had a statistically significant risk increase of 20% for 
developing an MI (aHR, 1.2; 95% CI 1.0 to 1.5) relative to 
untreated patients. They also found that GnRH agonist 
use in patients with baseline CV morbidities had a 20% 
increased risk for a CV event (aHR, 1.2; 95% CI 1.0 to 
1.3). Both GnRH agonists (aHR, 1.3; 95% CI 1.2 to 1.5) 
and degarelix (aHR, 1.8; 95% CI 1.3 to 2.6), however, 
had an elevated risk for CV events in patients without 
baseline CV morbidities relative to untreated patients. A 
recent meta-analysis by Ma et al. of 6 controlled studies 
(4 RCTs and 2 controlled clinical trials) concluded that 
the risk of CVD was the same for GnRH agonists as for 
GnRH antagonists for patients with PCa[36].

The prospective phase 3 HERO trial (n = 930) by 
Shore et al. compared the GnRH antagonist relugo-
lix with the GnRH agonist leuprolide and identified a 
lower incidence of major adverse CV events (MACE) 
in the relugolix cohort[37]. However, the study was not 
powered to make distinctions in CV events. The report-
ing of CV events was based on a descriptive analysis of 
the non-adjudicated adverse events. The incidence of 
ischemic heart disease was reported as 2.4% for relu-
golix compared with 1.6% for leuprolide. The reported 
any-grade MACE incidence was 2.9% for relugolix 
versus 6.2% for leuprolide. Importantly, the incidences 
of grade 3 or 4 MACEs were identical (1.3%)[37]. Because 
the incidence of MACE grades 3 and 4 were identical 
between the 2 treatments and there was no adjudication 
by blinded clinical event reviewers, the clinical relevance 
of the difference in the incidence of all MACE events 
with relugolix compared with leuprolide should be 
treated with caution. The reported difference in MACE 
did not lead to a difference in castration resistance-free 
survival in the subgroup of men with metastatic disease 
treated with relugolix versus those treated with leupro-
lide (74% versus 75% of men, respectively; HR, 1.03, 
P = 0.84). MACEs were defined as non-fatal MI, non-fa-
tal stroke, and all-cause mortality[37]. The US Food and 
Drug Administration have historically defined MACEs 
differently, as non-fatal MI, non-fatal stroke, and 
mortality due to CV causes when labeling traditional 
ADT drugs and testosterone replacement therapies[38]. 
The HERO study[37], however, defined MACEs differ-
ently from the Keating et al.[15] study and other phase 3 
hormonal drug trials, making direct comparisons chal-
lenging[39,40].

A limitation of most ADT studies is that they were 
not designed, or statistically powered, to evaluate cardiac 
events. Rather they were reported as adverse events and 
may not have been comprehensive[14]. Directly compar-
ing studies is also hindered by differences in methodol-
ogy, risk stratification, and assessed outcomes.

The Cardwell et al. analysis comparing 6 stud-
ies acknowledged incomplete patient data sets (stage, 
Gleason score, lifestyle) that may have confounded 
the results. Medication adherence was determined 
via dispensing record, so actual adherence cannot be 
confirmed. Additionally, patients receiving ADT would 
have had increased monitoring and therefore there 
would have been an increased likelihood of CVD being 
identified[35]. In Scailteux et al., the composite outcome 
of “ischemic events” (MI or ischemic stroke, which-
ever came first) does not account for clinical differ-
ences among subgroup analyses (eg, MI and stroke are 
considered equal), and no significant heterogeneity was 
observed across these subgroups[34] This approach may 
have its limitations because a direct study comparison 
cannot be performed[36].

The Lopes et al. PRONOUNCE study was designed 
to determine whether there was a significant difference 
favoring GnRH antagonists versus agonists in patients 
with pre-existing CVD, as hypothesized from the retro-
spective Albertsen et al. meta-analysis described previ-
ously[12]. It was the first prospective, randomized CV 
outcomes study of men with advanced PCa receiving 
ADT. Unlike most other trials to date, including the 
HERO trial, there was a clinical event classification 
committee, composed of a cardiologist, a neurologist, 
and an oncologist, whose purpose was to provide inde-
pendent, blinded adjudication of MACEs throughout 
the trial, as is the common standard for CV outcomes 
trials. In addition, the investigators were required to 
ensure that a cardiologist was treating the enrolled 
participant so that their CVD treatment was optimized. 
The primary outcome was the time from randomization 
to first occurrence of centrally adjudicated MACE. Key 
secondary outcomes were the time to first occurrence of 
CV-related death, non-fatal MI, or non-fatal stroke; time 
to first occurrence of CV-related death; and time to first 
occurrence of MI. The study had markedly fewer than 
expected MACE events. Sixty-six MACE events were 
required to reject the null hypothesis of equal hazard for 
degarelix and leuprolide. Hence, the study was termi-
nated early after the enrollment of 545 participants (61% 
of the planned 900) owing to futility. The total number of 
MACE events recorded over 12 months was 26: 15 (5.5%) 
for degarelix, and 11 (4.1%) for leuprolide (P = 0.53). 
Thus, even if completed with full accrual, the study likely 
would have had insufficient statistical power to compare 
the relative CV safety of the 2 treatments with precision. 
The number of events for the secondary outcomes was 
also very low, and there were no significant differences 
between treatments for any of these outcomes.

A similar study by Wallach et al. was designed to 
replicate the PRONOUNCE trial, but using retrospec-
tive data from health care insurance claims[13]. This 
study could not replicate many features of the original 
prospective trial, including the assurance of having 

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REVIEW



cardiologist involvement and adjudicated events, but 
used proxy selection criteria and outcomes to try to repli-
cate it as closely as possible. The results from this real-
world study are supportive of those in PRONOUNCE. 
Among propensity-matched patients (n = 2226), no 
significant difference was observed in the risk of MACEs 
(defined as a composite endpoint of death from any 
cause, MI, or stroke) between degarelix and leuprolide 
(10.18 versus 8.60 events per 100 person-years; HR, 1.18; 
P = 0.30). Degarelix was associated with a higher risk of 
death from any cause (HR, 1.48; P = 0.046) but not of 
MI (HR, 1.16; P = 0.66), stroke (HR, 0.92.; P = 0.81), or 
angina (HR, 1.36; P = 0.60).

In summary, the sole randomized, prospective CV 
outcome study did not demonstrate a difference in CV 
risk between GnRH agonists and antagonists. The event 
rate in this study was too low to provide sufficient power 
to identify a difference, and the evidence remains incon-
clusive. It is possible that the low event rate reflected the 
optimization of CV care provided to the patients in the 
trial.

Management of CV Risks in Men With PCa 
Who Are Receiving ADT
Patients with PCa who have undergone surgical 
castration, or are receiving medical ADT, are at 
particularly high risk for CVD[6]. Because of comorbid 
risk factors, men with PCa have a higher risk of CVD 
even if they are not receiving ADT[5,7], and those 
who have undergone surgical or medical castration 
with ADT are at an even higher risk for CVD and CV 
mortality[6]. Although many of the CV risks in men 
with PCa can be mitigated by controlling the underlying 
comorbid risk factors, recent data indicate that many are 
not being controlled[7]. In the recent Veterans Health 
Administration study, about half the population of men 
with PCa who were receiving ADT and who had been 
assessed had ≥ 1 uncontrolled CV risk factor, and almost 
one-third of those with important CV risk factors 
were not receiving treatment to control their CV risk 
factors, suggesting that PCa patients receiving ADT are 
not being adequately assessed or their underlying risk 
factors treated for CVD in accordance with the various 
consensus recommendations[7].

In addition to potentially undesirable side effects, 
such as decreased libido, impotence, decreased muscle 
mass, increased fat mass, anemia, fatigue, and osteopo-
rosis, changes in patient body composition as a result 
of medical castration create the potential for more 
severe metabolic complications and CV morbidities. 
For instance, the increase of adipose tissue and body 
weight in patients receiving ADT could be associated 
with rising insulin levels; insulin resistance; and an 
elevation in HDL, low-density lipoprotein (LDL), and 

triglycerides. These conditions predispose individuals to 
diabetes and CV events (Figure 2)[41]. ADT, by reducing 
androgen levels, is thought to reduce the androgen-me-
diated inhibition of stem cell differentiation into adipo-
cytes, thereby increasing visceral and subcutaneous fat 
and decreasing lean body mass[42]. This is a factor that 
may increase obesity and fat mass, which also contrib-
ute to insulin resistance and metabolic syndrome[10]. 
ADT may be associated with an increase in arterial wall 
thickness and endothelial dysfunction as a result of low 
testosterone levels; this change in vascular structure 
could promote atherosclerosis and could, eventually, 
lead to plaque rupture (Figure 3)[41].

Many associations have developed recommendations 
regarding assessment of baseline CVD in men initiating 
ADT[43–47]. Most guidelines offer generic advice. Men 
with CV comorbidities are encouraged to discuss treat-
ment options with their care providers[41]. Risk miti-
gation strategies include an assessment of the patient’s 
CV health before the initiation of ADT and during 
treatment; frequent monitoring of blood pressure, blood 
glucose levels, and lipid profile; diet and regular exer-
cise; cessation of smoking; and reduction in alcohol 
consumption (Figure 4). The American Heart Associ-
ation (AHA) recommends that ADT users be treated 
with antihypertensive therapy to lower blood pressure 
to < 130/80 mmHg, as dictated by specific comorbidi-
ties, and with glucose-lowering therapies in prediabetic 
and diabetic individuals. The AHA also recommends 
low-dose aspirin therapy and statin therapy to reduce 
serum LDL levels to < 100 mg/dL[16]. The National 
Comprehensive Cancer Network also recommends that 
patients receiving ADT should be treated with statins 
and undergo frequent screening and monitoring for 
metabolic and CV disorders[48]. In a large observational 
study (n = 87 346) of men with advanced PCa being 
treated with ADT, Anderson-Carter et al. showed that 
those taking statins had longer overall survival (median, 
6.5 years versus 4.0 years; P < 0.001) and decreased 
death from cancer (5-year Pca-specific survival [94.0% 
versus 87.3%; P < 0.001]) than those who were not statin 
users[49]. Another study of patients starting ADT 
showed that statin use was associated with reduced HRs 
for overall mortality and Pca-specific mortality[50]. 
Statins may exert their effect by competitively binding 
to the organic anionic transporter SLCO2B1, which 
decreases the level of dehydroepiandrosterone sulfate 
(a precursor of androgens such as dihydrotestosterone), 
thereby depriving the tumor of endogenous andro-
gens[51]. Interventional studies have also found potential 
benefits in the use of metformin combined with lifestyle 
changes in men receiving ADT. The rationale for its use 
is based on its ability to reduce hyperinsulinemia and 
improve metabolic syndrome. A systematic review and 
meta-analysis of 30 cohort studies in patients with PCa 

269SIUJ.ORG SIUJ  •  Volume 3, Number 4  •  July 2022

Impact of Androgen Deprivation Therapy on Cardiovascular Outcomes in Prostate Cancer



(n = 1 660 795) concluded that metformin treatment 
improves overall survival (HR, 0.72; P = 0.001), Pca-spe-
cific survival (HR, 0.78; P = 0.001), and recurrence-free 
survival (HR, 0.60; P = 0.001) compared with non-met-
formin treatment[52]. The risk reduction was also seen 
in those patients receiving ADT who had an overall 
survival HR of 0.77 and a Pca-specific survival of 0.72 (P 
< 0.00001 for both)[52,53]. Metformin use has also led to 
improvements in abdominal girth in men with PCa after 
6 months of ADT treatment compared with the control 
population (mean 0.58% reduction for metformin 
group versus 2.15% increase for the control), as well as 
in weight (3.19% decrease versus 2.18% increase), body 
mass index (3.15% decrease versus 2.10% increase), and 

systolic blood pressure (5.96% decrease versus 1.77% 
increase)[54].

Conclusions
Men with PCa have a higher risk for CVD than those 
without PCa, and there is substantial evidence that 
ADT increases this risk, although the evidence is not 
conclusive. In these men, CV history and the CV risk 
factors that may trigger a MACE should be evaluated 
and steps taken to mitigate them. The published CV risk 
data for GnRH agonists and antagonists are inconsistent 
and ref lect different populations, sizes, and study 
designs. The only rigorous, prospective, randomized 

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REVIEW

FIGURE 2.

Interconnections between hypogonadism and cardiovascular risk factors on atherosclerosis development 

Hypogonadism is associated with several risk factors of atherosclerosis (obesity, type 2 DM, dyslipidemia, and hypertension). IMT is a known 
marker of early atherosclerosis. Hypogonadism increases inflammation and affects endothelial function through other mechanisms of pathogenesis.  
Low testosterone increases the risk of myocardial ischemia. Erectile dysfunction is a symptom of hypogonadism, but also an end result of atherosclerosis 
and a predictor of coronary artery disease.
Red boxes = atherosclerotic risk factors; dark green boxes = potential side effects of either hypogonadism or atherosclerosis.
CAD: coronary artery disease; CRP: C-reactive protein; DM: diabetes mellitus; EPC: endothelial progenitor cell; IMT: intima-media thickness; VCAM: vascular 
cell adhesion molecule.
Reproduced with permission from Fahed AC, Gholmieh JM, Azar ST. Int J Endocrinol.2012;2012:793953)[67]

IMT

Hypogonadism

Hypertension

Dyslipidemia

Type II DM

Obesity

Erectile dysfunction

Atherosclerosis

CAD

Myocardial
ischemia

Inflammatory cytokines, CRP, vascular
endothelial factors, VCAM, EPCs



trial comparing CV events for men with pre-existing 
CVD receiving a GnRH agonist or antagonist was 
inconclusive over the time period studied, and the study 
was discontinued owing to there being insufficient 
events to achieve adequate power. There is currently no 
prospective study that will resolve this issue. Although 
the data are conf licting, both GnRH agonists and 
antagonists are associated with increased CVD and CV 
mortality, but no randomized controlled trial (versus 
pooled approaches) supports the hypothesis of a CV risk 
difference between GnRH agonists and antagonists. An 
important factor to mitigate potential adverse events 
associated with receiving ADT is to promote patient 
awareness of the increased risk of CVD and to provide 
education on how to improve CV health. This includes 
careful monitoring and lowering of blood pressure, 

glucose levels, and total and LDL cholesterol levels 
by making appropriate lifestyle changes and by using 
statins for hyperlipidemia. However, the focus of CV 
risk in people with PCa should be mitigation strategies 
with individualized treatment options addressed by 
experienced cardiologists or cardio-oncologists working 
with urologists and oncologists.

Acknowledgments
Editorial support was provided by Connor Hunter, 
PharmD, and Robin Smith, PhD, of The Curr y 
Rockefeller Group, LLC (Tarrytown, NY), and was 
funded by AbbVie (North Chicago, IL). Additional 
thanks go to Gabriel Krigsfeld, PhD, of AbbVie 
(Mettawa, IL), for providing support in the writing of 
the paper.

271SIUJ.ORG SIUJ  •  Volume 3, Number 4  •  July 2022

Impact of Androgen Deprivation Therapy on Cardiovascular Outcomes in Prostate Cancer

FIGURE 3.

Clinical measurements and resultant mechanistic processes in the relation between hypogonadism and 
specific stages of atherosclerosis

=increase; =decrease.
BP: blood pressure; CRP: C-reactive protein; CVD: cardiovascular disease; DM II: type 2 diabetes mellitus; ED: erectile dysfunction; EPC: endothelial 
progenitor cell; FMD: flow-mediated dilation; HDL: high-density lipoprotein; IMT: intima-media thickness; LDL: low-density lipoprotein; MetS: metabolic 
syndrome; TG: triglyceride; VCAM: vascular cell adhesion molecule. Reproduced with permission from Fahed AC, Gholmieh JM, Azar ST. Int J Endocrinol. 
2012;2012:793953).[67]

Ruptured plaque

Mature plaque

Clinical measurements

Dyslipidemia

Obesity

MetS

DM II

Hypertension

Plaques on carotid duplex scan

Hypogonadism and atherosclerosis

�FMD

�CRP

�IMT

�ST depression

�Exercise tolerance

�CVD

�ED

�Mortality

�Anginal episodes

Mechanisms

Lipid deposition

Endothelial dysfunction

Myocardial susceptibility to
ischemia

�LDL

�TG

�HDL

�Lipoprotien a

�BP

�EPCs

�VCAM

�Vascular tone

�Anti-inflammatory cytokines

Insulin resistance

�Pro-inflammatory cytokines

Normal artery

Early plaque



272 SIUJ  •  Volume 3, Number 4  •  July 2022 SIUJ.ORG

REVIEW

FIGURE 4.

CVD risk mitigation and recommended management for men receiving ADT

ADT: androgen deprivation therapy; BP: blood pressure; CSS: cancer-specific survival; CVD: cardiovascular disease; HbA1c: hemoglobin A1C;  
HDL: high-density lipoprotein; LDL: low-density lipoprotein; OS: overall survival; PSA: prostate-specific antigen; TG: triglyceride; TTP: time to 
progression. 1. Rhee et al. 2015[27]  2. Bhatia et al. 2016[8] 3. Schmitz et al. 2010[68] 4. Galvão et al. 2016[69] 4. Anderson-Carter et al. 2019[49]  
5. Hamilton et al. 2021[50] 6. Saraei et al. 2019[70] 7. Alghandour et al. 2020[71] 8. He et al. 2019[52] 9. Harshman et al. 2015[51]

Measure Regular Blood Pressure, Weight, Fasting Glucose, 
and ipid Profile Levels at Baseline1,2

Lifestyle and Dietary Modifications1-3

Treatment Management

• Hypertension
• Chronic obstructive airway disease
• Renal impairment

Maintain Optimal Blood Glucose Level
•    Aim for HbA1c 7%

Smoking Cessation Minimize or Avoid Alcohol

Maintain Lipid ProfileMaintain Optimal Blood Pressure
•    BP <130/80 mm Hg • LDL <100 mg/dL

• HDL = 40 mg/dL or higher
• TG <150 mg/dL
• Non-HDL cholesterol <130 mg/dL

Diet and Exercise
• Refer to dietitian, exercise
 physiologist, or weight loss expert
• 150 minutes/week moderate intensity, 
 75 min/week of vigorous exercise, 
 resistance training

Frequent Monitoring of Blood Pressure, Blood Glucose, Lipid Profile

• History of myocardial infarction
• History of cerebrovascular events
• Congestive heart failure
• Peripheral arterial disease

Assess Patient Awareness of Signs and Symptoms of CVD

Addition of Statins May be Beneficial4,5
• Use of statin at the time of ADT initiation
 signi cantly prolongs TTP
• Statin users had longer OS, CSS and  
 skeletal related events controlling for 
 age, race, Charlson comorbidity index, 
 PSA, and Gleason score

Addition of Metformin Should be Considered1–3,6–9

• Reduces the damaging effects of ADT
 physiologist, or weight loss expert
• Potentially lengthens time to progression 
 when combined with ADT
• Reduced weight gain, waist circumference,
 glucose, insulin levels

Consider 81 mg acetylsalicylic 
acid daily1,2



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