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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    • "Guidelines include the use of lipid-lowering therapies, most commonly involving statins and antiplatelet therapy such as irreversible cyclooxygenase inhibitors (acetylsalicylic acid— aspirin) or adenosine diphosphate receptor inhibitors (e.g., clopidogrel). Several observational studies also report hypertension as a risk factor for CV events during GnRH agonist therapy [8,16,19]: blood pressure should therefore be monitored and hypertension treated appropriately in these patients. ADT is also associated with increases in blood glucose levels [13]. "
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    ABSTRACT: Androgen deprivation therapy (ADT) is frequently used for the treatment of advanced prostate cancer. ADT is associated with numerous side effects related to its mode of action, namely the suppression of testosterone to castrate levels. Recently, several large retrospective studies have also reported an increased risk of diabetes and cardiovascular disease in men receiving ADT, although these risks have not been confirmed by prospective randomized trials. We review the literature to consider the risk of cardiovascular disease with different forms of ADT and examine in detail potential mechanisms by which any such risk could be mediated. Mechanisms discussed include the metabolic syndrome resulting from low testosterone level and the potential roles of testosterone flare, gonadotropin-releasing hormone receptors outside the pituitary gland, and altered levels of follicle-stimulating hormone. Finally, the clinical implications for men prescribed ADT for the treatment of advanced prostate cancer are considered. Copyright © 2015 Elsevier Inc. All rights reserved.
    No preview · Article · Jun 2015 · Urologic Oncology
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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.
    Full-text · Article · Apr 2014 · Journal of Oncology
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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.
    Full-text · Article · Jan 2014 · Asian Journal of Andrology
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