Impact of Androgen Deprivation Therapy on Cardiovascular Disease and Diabetes

Department of Surgery, University of Toronto, Toronto, Ontario, Canada
Journal of Clinical Oncology (Impact Factor: 18.43). 07/2009; 27(21):3452-8. DOI: 10.1200/JCO.2008.20.0923
Source: PubMed


PURPOSE Use of androgen deprivation therapy (ADT) may be associated with an increased risk of diabetes mellitus but the risk of both acute myocardial infarction (AMI) and cardiovascular mortality remain controversial because few outcomes and conflicting findings have been reported. We sought to clarify whether ADT is associated with these outcomes in a large, representative cohort. METHODS Using linked administrative databases in Ontario, Canada, men age 66 years or older with prostate cancer given continuous ADT for at least 6 months or who underwent bilateral orchiectomy (n = 19,079) were matched with men with prostate cancer who had never received ADT. Treated and untreated groups were matched 1:1 (ie, hard-matched) on age, prior cancer treatment, and year of diagnosis and propensity-matched on comorbidities, medications, cardiovascular risk factors, prior fractures, and socioeconomic variables. Primary outcomes were development of AMI, sudden cardiac death, and diabetes. Fragility fracture was also examined. Results The cohort was observed for a mean of 6.47 years. In time-to-event analyses, ADT use was associated with an increased risk of diabetes (hazard ratio [HR], 1.16; 95% CI, 1.11 to 1.21) and fragility fracture (HR, 1.65; 95% CI, 1.53 to 1.77) but not with AMI (HR, 0.91; 95% CI, 0.84 to 1.00) or sudden cardiac death (HR, 0.96; 95% CI, 0.83 to 1.10). Increasing duration of ADT was associated with an excess risk of fragility fractures and diabetes but not cardiac outcomes. CONCLUSION Continuous ADT use for at least 6 months in older men is associated with an increased risk of diabetes and fragility fracture but not AMI or sudden cardiac death.

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    • "However, clinical data concerning ADT-related adverse metabolic and cardiovascular effects remain conflicting [4]. There have been studies demonstrating that patients receiving ADT may have a higher incidence of diabetes mellitus [5] [6] [7], coronary artery disease [5] [6], stroke [6] [7], and/or even cardiovascular death [8] [9] [10], but other studies failed to show such associations [7] [11] [12]. This may be due to the fact that, in these studies, the presence of preexisting metabolic condition and other cardiovascular diseases had not been adequately characterized and/or controlled. "
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    ABSTRACT: Background. Androgen deprivation therapy (ADT) in nonmetastatic prostate cancer is unclear. Recent data suggests possible increase in the cardiovascular risks receiving ADT. The aim of the study was to investigate the cardiovascular outcomes in a cohort of Chinese nonmetastatic prostate cancer patients with no previously documented cardiovascular disease. Methods and Results. 745 patients with no previously documented cardiovascular disease and/or diabetes mellitus diagnosed to have nonmetastatic prostate cancer were recruited. Of these, 517 patients received ADT and the remaining 228 did not. After a mean follow-up of 5.3 years, 60 patients developed primary composite endpoint including (1) coronary artery disease, (2) congestive heart failure, and (3) ischemic stroke. Higher proportion of patients on ADT (51 patients, 9.9%) developed composite endpoint compared with those not on ADT (9 patients, 3.9%) with hazard ratio (HR) of 2.06 (95% confidence interval (CI): 1.03-3.24, P = 0.04). Furthermore, Cox regression analysis revealed that only the use of ADT (HR: 2.1, 95% CI: 1.03-4.25, P = 0.04) and hypertension (HR: 2.0, 95% CI: 1.21-3.33, P < 0.01) were independent predictors for primary composite endpoint. Conclusion. ADT in Chinese patients with nonmetastatic prostate cancer with no previously documented cardiovascular disease was associated with subsequent development of cardiovascular events.
    Journal of Oncology 04/2014; 2014:529468. DOI:10.1155/2014/529468
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    • "After an average of 45 months of therapy in 18 men, 44% satisfied the fasting glucose criterion for diabetes mellitus, compared with 11% of a noncancer control group (n = 18) and 12% of men with treated metastatic prostate cancer who did not have ADT (n = 17), although the numbers in this cross-sectional study were small.48 The risk of incident diabetes in large observational studies comparing men treated with ADT with those not receiving ADT have reported significantly elevated risks, with HR (adjusted for confounders) ranging from 1.16 to 1.44.525354 Two of these studies included only men 66 years or older5254 while the other included men of all ages with over 40% of the cohort younger than 66 years.53 "
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    ABSTRACT: Testosterone levels are lower in men with metabolic syndrome and type 2 diabetes mellitus (T2DM) and also predict the onset of these adverse metabolic states. Body composition (body mass index, waist circumference) is an important mediator of this relationship. Sex hormone binding globulin is also inversely associated with insulin resistance and T2DM but the data regarding estrogen are inconsistent. Clinical models of androgen deficiency including Klinefelter's syndrome and androgen deprivation therapy in the treatment of advanced prostate cancer confirm the association between androgens and glucose status. Experimental manipulation of the insulin/glucose milieu and suppression of endogenous testicular function suggests the relationship between androgens and insulin sensitivity is bidirectional. Androgen therapy in men without diabetes is not able to differentiate the effect on insulin resistance from that on fat mass, in particular visceral adiposity. Similarly, several small clinical studies have examined the efficacy of exogenous testosterone in men with T2DM, however, the role of androgens, independent of body composition, in modifying insulin resistance is uncertain.
    Asian Journal of Andrology 01/2014; 16(2). DOI:10.4103/1008-682X.122589 · 2.60 Impact Factor
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    • "In contrast, the US FDA has highlighted an increased risk of diabetes, heart attack, stroke and sudden death with GnRH agonists, with the consequent requirement to add warnings of such risks to GnRH agonist labels [US Food and Drug Administration, 2010]. Interestingly, most but not all studies show no association of orchiectomy with an increased risk of CV events [Levine et al. 2010; Keating et al. 2006, 2010; Alibhai et al. 2009], raising the possibility that CV risk may vary for different forms of ADT [Smith et al. 2011]. "
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    ABSTRACT: Degarelix is a gonadotrophin-releasing hormone (GnRH) antagonist for the first-line treatment of androgen-dependent advanced prostate cancer. It has a direct mechanism of action that blocks the action of GnRH on the pituitary with no initial surge in gonadotrophin or testosterone levels. Degarelix is the most extensively studied and widely available GnRH antagonist worldwide. Clinical studies have demonstrated similar efficacy to the GnRH agonist leuprolide in achieving testosterone suppression in patients with prostate cancer. However, degarelix produces a faster suppression of testosterone and prostate-specific antigen (PSA), with no testosterone surge or microsurges, thus preventing the risk of clinical flare in advanced disease. Clinical trials have demonstrated that degarelix can offer improved disease control when compared with a GnRH agonist in terms of superior PSA progression-free survival (suggesting that degarelix likely delays progression to castration-resistant disease), and a more significant impact on bone serum alkaline phosphatase and follicle-stimulating hormone. Degarelix is generally well tolerated, with no reports of systemic allergic reactions in any clinical studies. In conclusion, degarelix offers clinicians a rational first-line hormonal monotherapy option for the management of advanced prostate cancer.
    Therapeutic Advances in Urology 02/2013; 5(1):11-24. DOI:10.1177/1756287212461048
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