A 65-year-old man presented with locally advanced, high-risk prostate cancer. His medical history was remarkable for type 2 diabetes mellitus (T2DM) treated with metformin, 500 mg BID. He was also overweight and had dyslipidemia and hypertension, although he was not receiving medical therapy for any of these problems. He was an active smoker with a 27 pack-year history.
His prostate-specific antigen (PSA) level was 32 ng/mL; no other recent PSA measurements were available. Digital rectal examination revealed a fixed prostate (cT4) not amenable to surgical resection; his prostate biopsy showed an acinar adenocarcinoma in 8 of 12 cores, with a Gleason score of 4+4=8. He underwent a bone scan and CT scanning of the chest, abdomen, and pelvis, which showed no evidence of metastatic disease. He was offered treatment with external beam radiation therapy (EBRT) and androgen deprivation therapy (ADT) with degarelix.
Upon ADT initiation, his blood pressure (BP) was 140/90 mm Hg and his body mass index (BMI) was 27.2 kg/m2. Laboratory workup revealed a fasting glucose level of 123 mg/dL and a glycosylated hemoglobin (HbA1c) of 7.1%. His lipid profile showed: triglycerides, 180 mg/dL; total cholesterol, 170 mg/dL; high-density lipoprotein cholesterol (HDL-C), 30 mg/dL; and low-density lipoprotein cholesterol (LDL-C), 140 mg/dL. His serum creatinine level was 0.7 mg/dL and his calculated creatinine clearance, adjusted for overweight, was 103 mL/min. An electrocardiogram was normal.
According to the American College of Cardiology (ACC)/American Heart Association (AHA) Cardiovascular (CV) Risk Calculator, the patient’s 10-year risk for atherosclerotic cardiovascular disease (CVD)—defined as coronary death, nonfatal myocardial infarction, or fatal or nonfatal stroke—was 49.6%. This CV risk calculation mandated strict metabolic control for the management of his CV risk factors.
Which of the following is the best way to manage cardiovascular comorbidities in this patient?
A. Lifestyle interventions only
B. Lifestyle interventions + moderate- intensity statin + BP target < 140/90 mm Hg
C. Lifestyle interventions + highintensity statin + BP target < 140/90 mm Hg
D. Lifestyle interventions + high-intensity statin + BP target < 130/80 mm Hg
E. Lifestyle interventions + highintensity statin + BP target < 130/80 mm Hg + aspirin
Correct Answer: E
Prostate cancer is an exquisitely hormone-sensitive malignancy, and ADT is the mainstay of treatment in locally advanced and metastatic disease.[2,3] The therapeutic benefits of ADT are offset by a plethora of side effects, among which CVD is of greatest concern. The association between ADT and fatal and nonfatal CVD is attested to by large retrospective and observational studies.[5,6] These data led to a joint statement issued by the AHA, the American Cancer Society, the American Urological Association, and the American Society for Radiation Oncology to raise awareness about CV consequences of ADT. The aforementioned findings were not confirmed in a recent meta-analysis of randomized trials. Potential reasons for this discrepancy may be the selection of a healthier population in clinical trials, underpowered post-hoc analysis, and short follow-up.
The mechanism of action of the type of hormonal therapy prescribed may impact CVD risk. Hormonal treatment can be accomplished by reducing testosterone production (surgical orchiectomy or medical castration) or by blocking the interaction of androgen receptors with testosterone. The Swedish National Data Service reported an increased risk of incident CVD with gonadotropin-releasing hormone (GnRH) agonists and orchiectomy, and a decreased risk with anti-androgens. In the meta-analysis by Zhao et al, GnRH agonists, and GnRH agonists plus anti-androgens, were associated with CVD, but not anti-androgens alone or orchiectomy. A meta-analysis by Bosco et al showed an increased risk of nonfatal CVD with GnRH agonists, anti-androgens, and orchiectomy. Recently, orchiectomy was reported to be associated with higher rates of CV events in older patients and those with a history of CV comorbidities within 1.5 years of initiating ADT. With regard to GnRH antagonists vs agonists, reports are divergent. A nationwide French database reported no difference in CVD risk between GnRH agonists and antagonists. However, post-hoc pooled data from six randomized trials showed that GnRH antagonists were associated with a significantly lower risk of cardiac events, compared with GnRH agonists. These same data led clinicians to the conclusion that it may be safer to prescribe antagonists in men at high risk for CVD. These data supported our decision to start hormonal therapy with degarelix, a GnRH antagonist, in this case.
Several potential pathophysiologic mechanisms link ADT with CVD. Pro-atherogenic metabolic changes, similar to those of metabolic syndrome, have been described in patients receiving ADT. These include sarcopenic obesity (decrease in lean body mass and subcutaneous fat increase), dyslipidemia (increase in triglycerides, total cholesterol, LDL-C, and HDL-C), insulin resistance, and increased fasting plasma glucose levels.[14,15] However, in some respects, the metabolic changes seen with ADT are different from metabolic syndrome: an increase in subcutaneous rather than visceral fat, and an increase in HDL-C levels instead of the decrease typically seen in metabolic syndrome.
The greatest risk of a first CV event after the initiation of ADT is within the first year of treatment. These early events may not be due solely to accelerated atherosclerosis, since this develops more chronically than acutely. Testosterone at physiologic levels has many antithrombotic effects, including stimulation of nitric oxide production, reduction of thromboxane A2 release from platelets, and increased expression of tissue plasminogen activator.[16-18] Testosterone has also been noted to have a potential antiarrhythmic effect—shortening the QT interval. Therefore, testosterone depletion may impact a man’s health through multiple physiologic channels. In addition, ADT has been associated with cytokine derangements in the tumor microenviroment, resulting in increased IFN-γ production by T lymphocytes (activated by stimulation of GnRH receptors in these cells), with subsequent plaque instability and rupture.
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