There are an estimated 3 million men living with prostate cancer in the United States, with the majority (62%) of survivors over the age of 70 years.¹ Contemporary management has improved the 5-year and 10-year relative survival rate for all stages of prostate cancer combined to 99.7% and 98.8% respectively.¹ The focus has now shifted to treatment-related morbidity and noncancer-related mortality, of which ischemic heart disease is the most common.²

Androgen-deprivation therapy is a key reason for improvement in outcomes, and the benefits are well established in randomized clinical trials, with improvement in overall survival when used with radiation for intermediate- and high-risk localized disease in addition to locally advanced and positive nodes after prostatectomy.^3-6 There is also alleviation of bone pain and modest survival benefit when used for the palliation of metastatic disease.⁷ Recent estimates suggest that more than half a million men in the United States are receiving androgen-deprivation therapy.⁸

Treatment with gonadotropin-releasing hormone agonists (e.g., leuprolide, goserelin, and triptorelin) has become the most common form of androgen-deprivation therapy—largely replacing surgical bilateral orchiectomy—with the goal of suppressing serum testosterone level below 50 ng/dL and inducing a state of profound androgen deficiency. Antiandrogens (e.g., flutamide, bicalutamide, and enzalutamide) directly block the binding of androgen to its receptor without suppressing testosterone levels, but this treatment is usually combined with gonadotropin-releasing hormone agonists. Gonadotropin-releasing hormone agonists in particular are associated with several metabolic changes adversely affecting traditional cardiovascular (CV) risk factors (e.g., body composition, lipid profile, and insulin sensitivity) and potentially an increased risk of diabetes and CV events (Table 1). As a result, it is important to understand these metabolic changes to optimally manage risk and prevent future complications.

Table 1: Cardiometabolic Effects of Androgen-Deprivation Therapy

Target Effect	Observations	Comments
Body Composition:
Weight Increase	↑ in 12 months	~2% increase
Lean Mass	↓ in 3-12 months	Prospective exercise trials ongoing
Fat Mass	↑ in 3 months	Greater increase in subcutaneous fat compared with visceral fat
Lipids:
Total Cholesterol	↑ in 3-12 months
HDL	↑ in 3-6months	Distinct from metabolic syndrome
Low Density Lipoprotein	← → in 3-6 months
Triglycerides	↑ in 3-12 months
Insulin:
Insulin Sensitivity Insulin Levels	↓ in 3 months ↑ in 3 months	Serum glucose does not change significantly in first 3 months
Diabetes	↑	Usually with longer duration of treatment (>12 months)
CV Disease	↑ ← →	Observational studies with increased events within the first 6-12 months especially in those with prior heart disease or heart failure
		Analysis from RCTs suggests no increased CV mortality risk
		RCTs did not capture baseline CV disease risk factors or non-fatal events and often excluded older patients with multiple comorbidities

Androgens are important regulators of body composition, promoting lean body mass over fat mass; therefore, androgen-deprivation therapy appears to promote sarcopenic obesity and cause an increase in fat mass and reduction of muscle mass or strength.^9,10 Small prospective trials have shown that during the first year of androgen-deprivation therapy, there is an approximate 3-4% decrease in lean body mass, 10-11% increase in fat mass, and a weight increase of 2%.^9-13 These changes occur predominantly within the first 3 months of therapy; studies in which individuals have been on longer duration androgen-deprivation therapy had less incremental changes in their body composition.^11,14 The increase in percentage fat mass is largely driven by subcutaneous fat as opposed to intra-abdominal visceral fat.¹¹

Recent work suggests that skeletal muscle is a key regulator of adipose tissue and metabolism, with preclinical studies showing improvement of cardiometabolic outcomes with increase in skeletal-muscle mass and contractility.^15-17 Skeletal muscle is a key component of cardiorespiratory fitness, and exercise capacity is a strong predictor of CV mortality, which makes it a potentially clinically useful metric to capture in patients receiving androgen-deprivation therapy.¹⁸ A recent cross-sectional study at a single time point reported reduced cardiorespiratory capacity (maximum oxygen consumption) in patients with prostate cancer on androgen-deprivation therapy for more than 3 months compared with those on androgen-deprivation therapy for fewer than 3 months.¹⁹ Several studies (albeit with small sample sizes) have investigated the benefits of aerobic and resistance training in counteracting the adverse effects of androgen-deprivation therapy. A recent systematic review of randomized controlled trials (RCTs) evaluating the effects of exercise interventions for men receiving androgen-deprivation therapy for prostate cancer identified seven studies in which exercise significantly improved quality of life but had no significant effect on metabolic risk factors including weight, waist circumference, lean or fat mass, blood pressure, and lipid profile.²⁰ Larger RCTs are needed to evaluate the best exercise strategy for mitigating the metabolic effects of androgen-deprivation therapy, but it is still reasonable to encourage both aerobic and resistance exercise for patients while they are undergoing treatment.

Another early development with androgen-deprivation therapy even in the setting of euglycemia is impaired insulin sensitivity in addition to increased fasting insulin levels.^11,13,21 Long-term androgen-deprivation therapy (>12 months) in small prospective studies has also shown significantly higher fasting glucose in nearly half the participants in the diabetic range.²² Increased fat mass and insulin resistance are associated with type 2 diabetes. Given that these changes occur with androgen-deprivation therapy as well, a link between androgen-deprivation therapy and diabetes from these observations has been confirmed by several large population-based studies, including the US-based SEER-Medicare Database of men >65 years of age and a US-based study of veterans with prostate cancer yielding a 44% and 28% increased risk respectively of incident diabetes among men with prostate cancer being treated with gonadotropin-releasing hormone agonists.^23,24 It is therefore reasonable to manage patients on androgen-deprivation therapy as high risk for diabetes (screening fasting glucose and hemoglobin A1c) and, in those with diabetes, monitor fasting glucose at regular intervals per the American Diabetes Association guidelines.²⁵

During the first 3 months of gonadotropin-releasing hormone agonist therapy, there are also several characteristic changes in serum lipids, including elevation of triglycerides, total cholesterol, and high-density lipoprotein (HDL). Before initiating androgen-deprivation therapy, it is important to obtain a baseline fasting lipid panel and adhere to the new American Heart Association and American College of Cardiology lipid guidelines and risk calculator to facilitate initiating statin therapy.²⁶ Interestingly, in addition to known CV benefit with statin therapy, a recent retrospective study noted statin use at the time of androgen-deprivation therapy initiation was associated with a longer time to progression in patients with prostate cancer with and without metastases.²⁷

Recent observational data suggest that there may be an association between androgen-deprivation therapy and increased incidence of CV disease and mortality, especially in those with prior history of heart attack or heart failure. Those data have led the US Food and Drug Administration to issue a safety warning in 2010 that requires "increased risk of diabetes and certain CV disease (heart attack, sudden cardiac death, and stroke)" labeling on androgen-deprivation therapy.²⁸ Unlike population studies, post-randomization analyses from clinical trials, including a recent meta-analysis, have yielded conflicting data suggesting no increased risk of CV mortality in men undergoing androgen-deprivation therapy.²⁹ Clinical trials, however, did not capture nonfatal CV events and often excluded individuals with multiple comorbidities and older patients. Long-term follow-up (median 16.62 years) has recently been reported on the only randomized prostate cancer trial that has included CV history (indirectly via a comorbidity score using the Adult Comorbidity Evaluation), which evaluated 206 men (49 with moderate or severe comorbidity) with unfavorable-risk prostate cancer randomized to receive radiation therapy alone or radiation therapy and 6 months of androgen-deprivation therapy.³⁰ In this post-randomization hypothesis-generating analysis, men with moderate or severe comorbidity had significantly decreased overall (hazard ratio [HR] 0.36; 95% confidence interval [CI], 0.19-0.67; p = 0.001) and cardiac mortality (HR 0.17; 95% CI, 0.06-0.46) with radiation therapy alone versus radiation therapy and androgen-deprivation therapy.³⁰ On the observational side, a unique study linked to the Swedish national health care registries on filled drug prescriptions allowed distinction of androgen-deprivation therapy and duration in addition to patients' history of CV disease, which revealed among 26,959 patients on gonadotropin-releasing hormone agonists an increased CV disease risk, highest during the first 6 months of therapy (HR 1.91; 95% CI, 1.66-2.20) in men who experienced 2 or more CV events before therapy.³¹ A recent systematic review also confirmed the lack of published data from clinical trials describing the effects of androgen-deprivation therapy on known baseline CV disease risk factors because they have not been routinely reported in prostate cancer trials.³²

In summary, evidence from observational studies and uncontrolled trials suggest that androgen-deprivation therapy decreases insulin sensitivity and lean body mass and increases HDL and total cholesterol, triglycerides, and subcutaneous fat, underscoring the important role of androgens as regulators of muscle mass and metabolism. The effects of androgen-deprivation therapy are distinct from metabolic syndrome; key differences include increase in subcutaneous fat over visceral fat and increase in HDL cholesterol, suggesting a different mechanism beyond insulin resistance. Current data support monitoring closely for diabetes and CV disease, although it is still unclear if the increased CV events are related to uncontrolled baseline CV risk factors or a direct effect of gonadotropin-releasing hormone agonist therapy. More importantly, key cardiometabolic changes occur within the first few months of androgen-deprivation therapy initiation, underscoring a vulnerable time period at which establishment of baseline cardiac risk factors and subsequent changes is vital.

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Keywords: Androgen Antagonists, Androgens, Blood Pressure, Body Composition, Cholesterol, HDL, Comorbidity, Confidence Intervals, Cross-Sectional Studies, Death, Sudden, Cardiac, Diabetes Mellitus, Type 2, Flutamide, Glucose, Gonadotropin-Releasing Hormone, Goserelin, Heart Diseases, Heart Failure, Hemoglobins, Insulin, Insulin Resistance, Intra-Abdominal Fat, Leuprolide, Lipids, Lipoproteins, HDL, Lipoproteins, LDL, Metabolic Syndrome, Muscle, Skeletal, Myocardial Infarction, Myocardial Ischemia, Obesity, Orchiectomy, Oxygen Consumption, Phenylthiohydantoin, Prospective Studies, Prostatectomy, Prostatic Neoplasms, Random Allocation, Randomized Controlled Trials as Topic, Resistance Training, Retrospective Studies, Risk Factors, Stroke, Subcutaneous Fat, Survival Rate, Testosterone, Triglycerides, Triptorelin Pamoate, Waist Circumference, Cardiotoxicity

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