ORLANDO — With increasing use of androgen deprivation hormone therapy for men with prostate cancer come growing concerns about an increased risk of diabetes, cardiovascular morbidity, and other adverse treatment effects.
Consider these risks when prescribing gonadotropin-releasing hormone agonist therapy for men with prostate cancer, and screen for comorbidities, Dr. Matthew Smith advised. Educate patients about adverse treatment effects and counsel them on lifestyle modifications that could ultimately decrease these risks, he added.
A gradual improvement in prostate cancer-specific mortality since the early 1990s has been accompanied by the rising use of GnRH agonists in the United States, so physicians might start seeing more patients with adverse effects from these agents. About 3% of the entire male Medicare population and one-third of approximately 2 million prostate cancer survivors now take GnRH agonists, Dr. Smith said at the annual meeting of the American Urological Association.
Loss of libido, vasomotor flushing, fatigue, anemia, and increased risk of osteoporosis are among the adverse events associated with androgen deprivation, said Dr. Smith, director of genitourinary medical oncology at Massachusetts General Hospital in Boston.
“GnRH agonists also make a common problem—obesity—worse,” Dr. Smith said. These agents decrease muscle mass and increase fat mass, according to a previous study by Dr. Smith and his associates (J. Clin. Endocrinol. Metab. 2002;87:599-603).
Changes can become apparent as soon as 12 weeks after initiating therapy, Dr. Smith said. Also, 2- to 3-kg muscle loss and 3-kg fat accumulation can occur in 1 year, he and his associates reported (Cancer 2008;112:2188-94). These agents selectively increase subcutaneous fat mass, with approximately 94% of the fat accumulation occurring in the abdomen. Because accumulation of abdominal fat is often associated with adverse health outcomes, “it's not just a cosmetic issue.”
Lipid changes are more prevalent among men treated with GnRH agonists, compared with those not treated with these agents, according to a cross-sectional study by other researchers (Int. J. Impot. Res. 2006;18:494-8).
Dr. Smith said lipid changes can occur rapidly, in as little as 3 months after initiation of GnRH agonist therapy. However, overall cardiovascular risk is less clear because patients can experience increases in total cholesterol, LDL cholesterol, and triglyceride levels as well as increases in HDL cholesterol. “Overall cardiovascular risk effect warrants further study.”
Also consider monitoring patients for changes in insulin sensitivity during GnRH agonist therapy, Dr. Smith said. In one study, there was a “fairly dramatic rise in compensatory insulin levels in nondiabetic men—changes consistent with nondiabetic insulin resistance” (J. Clin. Endocrinol. Metab. 2006;91:1305-8).
A 44% excess risk for diabetes and 16% excess risk for coronary heart disease were among the findings of another study by Dr. Smith and colleagues (J. Clin. Oncol. 2006;24:4448-56). More than one-third of 73,196 Medicare enrollees aged 66 years and older received androgen deprivation therapy in this Surveillance Epidemiology and End Results (SEER) database study. After controlling for baseline covariates, GnRH agonist exposure was associated with a greater risk for diagnosis of incident diabetes (hazard ratio, 1.44), coronary heart disease (HR, 1.16), myocardial infarction (HR, 1.11), and sudden death (HR, 1.16), Dr. Smith said.
Even slightly elevated risks associated with GnRH agonist treatment are clinically relevant given the increased risks already associated with advanced age in the prostate cancer population, Dr. Smith said.
What is less clear is whether GnRH agonists alter cardiovascular mortality. Dr. Smith said, “It's premature to conclude that GnRH agonists increase cardiovascular disease mortality. More studies are needed.”