The document discusses the metabolic effects of androgen deprivation therapy (ADT) for prostate cancer and their potential link to cardiovascular risks. It reports that ADT decreases muscle mass and increases fat mass, body weight, and abdominal obesity in men. This leads to insulin resistance, increased serum lipids, and changes in other metabolic markers related to cardiovascular disease risk. Several large population studies are reviewed that show inconsistent or unclear associations between ADT and increased risks of diabetes, myocardial infarction, and cardiovascular mortality. The conclusions state that the relationship between ADT and cardiovascular disease is uncertain and not consistently observed across all studies.

1. Predicting Toxicity after Androgen Deprivation: Cardiovascular Events Matthew R. Smith, M.D., Ph.D. Professor of Medicine Harvard Medical School Director, Genitourinary Oncology Program Massachusetts General Hospital

2. May 3, 2010 US Food and Drug Administration announces investigation into link between androgen deprivation therapy for and risk for diabetes and heart disease in men with prostate cancer

3. GnRH Agonists Decrease Muscle Mass and Increase Fat Mass Weight Muscle Mass Fat Mass Smith MR et al (2002) J Clin Endocrinol Metab 87:599-603 12-month changes P<0.001 for each comparison

4. Abdominal Obesity and Sarcopenia during ADT Eugonadal young man Older man on ADT Smith MR et al (2002) J Clin Endocrinol Metab 87:599-603 Saylor PJ and Smith MR et al (2009) J Urol Figure 2: GnRH agonist-associated sarcopenic obesity. GnRH agonists increase abdominal cross sectional area primarily through the accumulation of subcutaneous fat. Cross sectional images of a young healthy man (A) and of an obese man receiving long term GnRH agonist therapy (B). Note the relative paucity of abdominal and paraspinal musculature and the accumulation of subcutaneous fat. (A) (B)

5. Smith MR et al (2006) J Clin Endocrinol Metab 91:1305-8 Shift in insulin response c/w insulin resistance Insulin Sensitivity During GnRH Agonist Therapy

6. GnRH Agonists Increase Serum Lipids Smith et al (2002) J Clin Endocrinol Metab 87(2): 599-603

7. Metabolic Effects of ADT and Predicted CVD Risk Decreased Risk No effect Increased Risk ↑ HDL cholesterol -> Blood pressure ↑ LDL cholesterol -> CRP ↓ Insulin sensitivity

8. Strength and Consistency of Association SEER-Medicare Analyses 0.5 1.0 2.0 0.5 1.0 2.0 Diabetes Adjusted HR, 95% CI GnRH agonist Orchiectomy ADT Better ADT Worse ADT Better ADT Worse MI Adjusted HR, 95% CI Keating, O’Malley, and Smith (2006) J Clin Oncol 24(27): 4448-56 P=0.03 P=0.44 P<0.001 P=0.005

9. References: Keating et al (2006) JCO; Alibhai et al (2009) JCO; Keating et al (2010) JNCI Consistency of Association Comparison of Large Population-Based Studies 0.5 1.0 2.0 0.5 1.0 2.0 Diabetes Adjusted HR, 95% CI SEER-Medicare (n= 73,196) Ontario registry (n= 39,418) Veterans Administration (n= 37,433) ADT Better ADT Worse ADT Better ADT Worse MI Adjusted HR, 95% CI 3917 events 4967 events 2573 events 7055 events 2034 events 847 events

10. RTOG 85-31 Cardiovascular Mortality Efstathiou et al J Clin Oncol 2009