Androgen Deprivation Therapy and Cardiovascular Risk in Prostate Cancer

Abstract

Accumulating evidence suggests that androgen deprivation therapy (ADT) for prostate cancer (PCa) increases the risk of cardiovascular (CV) morbidity and mortality, though not all studies demonstrate an association. ADT may increase the risk of CV disease by causing detrimental changes in body composition, lipid profile, and insulin sensitivity. Specific populations of patients with PCa, including the elderly and patients with preexisting cardiac risk factors, appear to be the most vulnerable to CV risk secondary to ADT. Recent guidelines from the American College of Cardiology (ACC) and the American Heart Association (AHA) provide recommendations for CV risk assessment and management. In a shift from previous guidelines, the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults makes recommendations for statin therapy based on a 10-year calculated risk score, the Pooled Cohort Equation, that takes into account age, sex, race, systolic blood pressure, treatment for hypertension, history of diabetes mellitus, smoking status, and total cholesterol and high-density lipoprotein cholesterol levels rather than target lipid levels alone. The 2013 ACA/ AHA Guideline on Lifestyle Management offers specific recommendations to reduce CV risk, including avoidance of tobacco products, regular exercise, a heart-healthy diet, and maintenance of a healthy weight. While these guidelines are not specific to CV risk secondary to ADT, physicians who treat patients with PCa should be familiar with both the potential CV risks associated with ADT as well as the recommended approach to CV risk stratification, management, and prevention.

Chunkit Fung, MD, MS

Elizabeth A. Guancial, MD

Introduction

Complications from ischemic cardiovascular disease (CVD) are the leading cause of morbidity and mortality worldwide.¹ Due to significant advances in the understanding and treatment of advanced prostate cancer (PCa), patients are living longer with this disease. However, androgen deprivation therapy (ADT) carries with it an increased risk for metabolic changes that, while still regarded as controversial, may predispose to CVD and could compete with PCa to limit overall survival (OS). Therefore, screening for CVD and traditional risk factors that predispose to it, together with interventions to prevent and treat these conditions, are essential to ensuring that life expectancy is maximized for patients with PCa.

Does cardiovascular (CV) risk management require a unique approach when pharmacologic therapy predisposes to this complication? Importantly, it remains to be determined if screening and interventions for CVD and metabolic complications in patients with PCa treated with ADT should differ from the general population. Until data exist to support tailored therapy for patients with PCa and CVD, medical oncologists, radiation oncologists, and urologists who treat PCa with ADT should be cognizant of guidelines for CV risk assessment and treatment and address modifiable risk factors in a multidisciplinary approach together with primary care physicians, endocrinologists, and cardiologists.

Effects of ADT on CV Risk Factors

Prospective clinical trials have shown that ADT may increase the risks of cardiovascular disease by causing detrimental changes in body composition,^2-6 lipid profile,^5,7 and insulin sensitivity.^3,8,9 Recent retrospective studies demonstrate an additional association of ADT with acute kidney injury.^10,11 Rates of ADT-induced complications may be related to the mechanism by which androgen deprivation is achieved. Studies have demonstrated a lower risk of CV complications with orchiectomy versus endocrine therapy¹² and with luteinizing hormonereleasing hormone antagonists compared with agonists.^13,14 T cells express gonadotropin releasing hormone (GnRH) receptors and are present in atherosclerotic plaques. It is postulated that GnRH receptor activation by GnRH agonists could promote plaque destabilization and may contribute to the increased incidence of CV complications with this class of agents.¹³

Androgen plays a critical role in increasing and maintaining muscle mass while reducing fat mass.⁵ Among men treated with ADT for nonmetastatic PCa, two prospective studies^4,5 showed a decline in lean body mass by 2.7% to 3.8% and an increase in fat mass by 9.4% to 11.0% after 1 year of ADT. ADT increases subcutaneous rather than visceral abdominal fat,^4,15 and the change in body composition usually develops within the first few months of ADT.¹⁶

ADT also increases serum cholesterol and triglyceride levels, ^5,7 with changes in serum lipids usually occurring within the first 3 months of treatment.⁹ After 48 weeks of treatment with ADT among 40 men with locally advanced, node-positive or biochemically recurrent PCa without radiographic evidence of metastases, serum total cholesterol, HDL cholesterol, and LDL cholesterol increased by 9.0% (P <.001), 11.3% (P <.001), and 7.3% (P = .05), respectively.⁵

There is a positive correlation between the increase in fat mass during ADT and insulin levels,^9,17 which is a marker of insulin resistance in men with PCa.^3,8 In particular, two studies^18,19 reported hyperinsulinemia to be an independent risk factor for cardiovascular disease. A prospective study that assessed the effects of short-term ADT (12 weeks) on insulin sensitivity among patients with PCa reported a decrease of insulin sensitivity index of 12.9% (P = .02) and a rise in fasting plasma insulin levels of 25.9% (P = .04).⁹ To examine the long-term effects of ADT on fasting glucose and insulin resistance, a cross-sectional study was performed among 18 men with PCa who received ADT for ≥12 months, 17 age-matched men with nonmetastatic PCa who did not receive ADT, and 18 age-matched controls.²⁰ Glucose levels were 131.0 mg/dL in the ADT group compared with 103.0 mg/dL in the non- ADT group (P = .01) and 99.0 mg/dL in the control group (P <.01). Insulin level was highest in the ADT group, 45.0 uU/ mL compared with 24.0 uU/mL in the non-ADT (P = .05), and 19.0 uU/mL in the control group (P = .02). Based on the homeostatic model assessment for insulin resistance (HOMAIR), patients in the ADT group had the highest risk of insulin resistance with HOMAIR of 17.0 compared with HOMAIR of 6.0 in the non-ADT (P <.01) and HOMAIR of 5.0 in the control group (P = .01). Furthermore, a population-based study of 73,196 Medicare enrollees aged ≥66 years with localized PCa reported an association of ADT with increased risks of incident diabetes (adjusted hazard ratio = 1.44; P <.001).²¹

Metabolic syndrome is defined by a constellation of CVD risk factors, including low HDL, increased waist circumference, increased triglycerides, hypertension, and increased fasting glucose.²² A cross-sectional study that examined patients with PCa undergoing ADT for ≥12 months showed a significantly higher prevalence of metabolic syndrome in the ADT group (55%) than the non-ADT (22%) and control groups (20%) (P = .03).²³ In contrast to the classical features of metabolic syndrome, ADT increases HDL cholesterol,⁵ increases subcutaneous rather than visceral fat,^4,15 and increases level of adiponectin without alteration in the C-reactive protein level.^15,17

Summary of Major Studies of ADT Use and CV Morbidity and Mortality

Several large population-based studies^21,24-28 and post randomization analysis of existing clinical trials²⁹ suggested that ADT may increase incident CVD and mortality, characterized by coronary artery disease, myocardial infarction, or sudden cardiac death. Despite these data, the relationship between ADT and cardiovascular events remains controversial, as some studies^21,24-29 showed a statistically significant association, whereas others^30-36 have not. The Table summarizes the major studies that examined this question. Based on the existing evidence from these studies, the US Food and Drug Administration issued a safety warning in 2010 regarding the potential increased risk of diabetes and CVD in men receiving ADT for prostate cancer treatment.³⁷ Similarly, a science advisory from the American Heart Association (AHA), American Cancer Society (ACS), and American Urological Association (AUA) put forth a summary statement detailing the potential risks of CVD related to ADT.³⁸

Heterogeneity in study populations and designs, potential selection bias in men who received ADT (eg, less cardiovascular risk factors among men who received ADT than those who did not), and the limited number of cardiovascular events reported in some studies may explain the discordant results regarding the association of ADT with cardiovascular mortality. In studies that did not identify a relationship between ADT and cardiovascular mortality, the competing risk of prostate cancer—specific mortality may have decreased their ability to accurately measure the elevated risk of cardiovascular mortality related to ADT.^32,33,35,36

Interestingly, several studies suggested that ADT increased the risks of cardiovascular mortality the most in patients who were elderly (eg, ≥65 years old)²⁹ and/or had preexisting cardiac risk factors.²⁵ Recently, Morgan et al reported that prolonged ADT (≥2 years) and increasing age are associated with elevated risks of CVD.³⁹ Regardless of duration of ADT exposure, no significantly increased risk of CVD was reported in men <70 years at prostate cancer diagnosis. However, the risks for CVD with prolonged ADT became statistically significant for patients aged 74 years (odds ratio [OR] = 1.89; 95% confidence interval [CI] 1.02-3.49) and 80 years (OR = 3.19; 95% CI 1.25-8.17) of age at prostate cancer diagnosis. Furthermore, compared with those without any medical comorbidities, those with ≥3 medical comorbidities had an 8.1-fold increased odds for cardiovascular disease (P <.001). Therefore, ADT may potentiate preexisting cardiac risk factors, and this hypothesis may explain its adverse impact among those who are at the highest risk of developing CVD even before initiation of ADT for PCa treatment.

Assessment of CV Risk and Risk Reduction

Assessment of CV Risk and Risk Reduction In November 2013, the American College of Cardiology (ACC) and the AHA released guidelines that address the assessment of CV risk,⁴⁰ lifestyle modifications to reduce CV risk,⁴¹ and management of elevated blood cholesterol⁴² and body weight in adults.⁴³ A guideline on hypertension will be forthcoming. The 2013 Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults is a radical departure from previous guidelines for the treatment of elevated cholesterol, which specified target lowdensity- lipoprotein cholesterol (LDL-C) or non—high density lipoprotein-cholesterol (non-HDL-C) thresholds that warranted initiation of medication or “lower is better” treatment target goals.⁴² Instead, the authors recommend the use of statins for primary and secondary prevention of fatal and non-fatal atherosclerotic cardiovascular disease (ASCVD) in patients with an increased 10-year calculated risk score who are anticipated to derive a net benefit from pharmacologic therapy based on higher-quality evidence derived from randomized controlled trials. The guideline identifies four “statin benefit groups,” which include those with known clinical ASCVD, primary hyperlipidemia, or diabetes, as well as a category for patients between the ages of 40 and 75 years without these identified diseases but with an estimated 10-year risk of an ASCVD event (nonfatal myocardial infarction, fatal cardiovascular heart disease, or nonfatal or fatal stroke in people free of ASCVD at the beginning of the time period) of 7.5% or greater as calculated by the Pooled Cohort Equations for ASCVD risk prediction (http://my.americanheart.org/professional/StatementsGuidelines/ Prevention-Guidelines_UCM_457698_ SubHomePage.jsp) described in the 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk.⁴⁰ The Pooled Cohort Equations are applicable for black and non-Hispanic white men and women. For other ethnic groups, the non- Hispanic white formula should be used; however, risk may be overestimated for some populations (East Asian Americans and Mexican Americans) and underestimated for others (American Indians and Americans of South Asian or Puerto Rican ancestry).

The new Pooled Cohort Equations risk score is derived from sex- and race-specific models that include the following covariates: patient age, total cholesterol, high-density lipoprotein cholesterol, systolic blood pressure, treatment for high blood pressure, history of diabetes mellitus, and smoking status.⁴⁰ Although some applaud the decision by the ACC/AHA guideline members to focus on global CV risk assessment rather than specific cholesterol levels,^44,45 others criticize the Pooled Cohort Equation as being too cumbersome for clinical use, perceived conflict of interest among guideline writers, and potential overestimation of CV risk.⁴⁶ By some calculations, nearly 1 billion people worldwide would be determined to have risk scores of ≥7.5%, warranting statin therapy.⁴⁷

Thus, the true impact of these recommendations on clinical practice remains to be determined.

The ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults emphasizes shared decision making between physicians and patients, informed by the global ASCVD risk score and net risk/benefit treatment ratio and incorporation of patient preferences, rather than an automatic recommendation for or against statin therapy in any individual based on quantitative parameters.⁴² The guidelines recommend incorporation of nonquantitative factors such as family history to inform treatment decision making if a decision is uncertain after review of the quantitative risk score. Therefore, while not included in the Pooled Cohort Equation, the use of ADT and related factors such as anticipated length of therapy should be a part of this discussion for patients with PCa. For patients without ASCVD, the ACC/AHA guidelines recommend that risk be reassessed every 4 to 6 years. However, given that metabolic changes can occur within 3 months of initiation of ADT, the science advisory from the AHA, ACS, and AUA suggested that an early follow-up of 3 to 6 months after initiation of treatment was reasonable to assess blood pressure, lipid profile, and glucose level.³⁸ This seems especially prudent since we do not yet know if baseline risk prior to ADT initiation necessarily reflects future risk of ADT. Furthermore, patients should receive ongoing counseling on potential adverse effects of ADT on CV heath and encouragement to address modifiable CV risk factors, as outlined in the 2013 AHA/ACC Guideline on Lifestyle Management to Reduce Cardiovascular Risk⁴¹ and the 2013 ACC/AHA/TOS (The Obesity Society) Guideline for the Management of Overweight and Obesity in Adults.⁴³

The Guideline on Lifestyle Management offers specific recommendations to reduce CV risk, including avoidance of tobacco products, regular exercise, a heart-healthy diet, and maintenance of a healthy weight.⁴¹ Moderate to vigorous physical activity, 3 to 4 times per week, lasting an average of 40 minutes, is recommended to improve both lipid profiles and blood pressure. Characteristics of a healthy diet include a high consumption of whole grains, fruits, and vegetables; low-fat dairy, fish, poultry, and legumes as primary protein sources; limited use of sugar-sweetened beverages and red meat; and an upper limit of 2400 mg of sodium per day while acknowledging that further reduction in sodium to 1500 mg per day is associated with greater reductions in hypertension. In addition to supporting these exercise and diet recommendations, the guideline reaffirms the appropriateness of current definitions of overweight (body mass index [BMI] >25.0-29.9 kg/m²) and obesity (BMI ≥30 kg/m²).⁴³ BMI should be calculated at least annually for patients to guide physician-led counseling and weight loss recommendations, since overweight and obesity predispose to CVD, diabetes, and all-cause mortality, and modest reductions in weight of 3% to 5% can result in clinically meaningful improvements in blood pressure, triglycerides, and glycemic control. Given that ADT is associated with metabolic changes that predispose to weight gain through multiple mechanisms, patients with PCa should be counseled on preventive weight management strategies through diet and exercise prior to initiation of ADT and throughout the course of therapy, especially patients for whom long-term ADT is advised.

Conclusion

It is imperative that physicians who prescribe ADT understand the potential adverse metabolic side effects of this treatment so they can better inform patients with PCa of the possible CV risk with ADT. Furthermore, physicians should initiate or refer for screening and interventions for the prevention or treatment of CVD based on expert guidelines. The recent 2013 ACC/AHA guidelines address cardiovascular risk assessment, lifestyle modifications to reduce cardiovascular risk, and management of elevated blood cholesterol and body weight in adults. While not specific to patients with PCa, these guidelines serve as a starting point as we await studies to determine if CV risk assessment and intervention should be tailored to the setting of ADT.

Acknowledgments: The authors thank Joshua Vega, MD, for his contributions to this manuscript.

ABOUT THE AUTHORS

Affiliations: Chunkit Fung, MD, MS, is assistant professor, and Elizabeth A. Guancial, MD, is assistant professor at the James P. Wilmot Cancer Center, University of Rochester, Rochester, NY.

Disclosures: Drs. Fung and Guancial report no conflicts of interest to disclose.

Address correspondence to: Elizabeth Guancial, MD, Division of Medical Oncology, University of Rochester Medical Center, James P. Wilmot Cancer Center, 601 Elmwood Avenue, Box 704, Rochester, NY 14642; phone: (585)273-5573; fax: (585)276-0350; e-mail: elizabeth_ guancial@urmc.rochester.edu.

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