Cardiovascular risk during androgen deprivation therapy for prostate cancerBMJ 2011; 342 doi: http://dx.doi.org/10.1136/bmj.d3105 (Published 24 May 2011) Cite this as: BMJ 2011;342:d3105
- Thomas Hugh Jones, consultant physician and endocrinologist
Accumulating evidence suggests that androgen deprivation therapy for prostate cancer is associated with adverse effects on cardiovascular risk factors such as diabetes, the incidence of cardiovascular events, and, in some studies, death from cardiovascular disease.1 2 3 4 5 6 Although not all studies concur, a science advisory statement from the American Heart Association, American Cancer Society, and the American Urological Association has recommended that all patients receiving such treatment should have periodic follow-ups for assessment of cardiovascular risk factors and those with coexisting cardiovascular disease should have their treatment for secondary prevention optimised.1
A large follow-up study of 73 196 men (>65 years) with locoregional prostate cancer in which about a third were given androgen deprivation therapy reported a higher incidence of cardiovascular disease, diabetes, myocardial infarction, and sudden death from cardiac disease or life threatening ventricular arrhythmia.2 Observational studies of men over 65 given androgen deprivation therapy have found a greater risk of fatal myocardial infarction in the first six months and death from cardiovascular disease during a mean follow-up of 3.8 years.3 4 A study (n=22 816) reported a 20% higher risk of morbidity from cardiovascular disease within the first year of treatment.5 Another study (n=30 642) also found that the treatment increased the relative risk of non-fatal and fatal cardiovascular disease—risk was greater in men without cardiovascular disease than in those with known disease, presumably because these men were already receiving secondary prevention measures.6 However, not all studies—including the recently reported EORTC 22863 trial—have found an increased risk of morbidity and mortality from cardiovascular disease.1 7 Because of the confounding evidence from studies with different designs and subject selection, and especially because the data are mainly retrospective, the findings are not conclusive.
Testosterone deficiency is associated with adverse cardiovascular risk parameters including central obesity, insulin resistance, hyperglycaemia, dyslipidaemia, hypertension, and a prothrombotic and proinflammatory milieu (all components of the metabolic syndrome).8 Most longitudinal epidemiological community based studies show that low testosterone is associated with increased all cause mortality and death from cardiovascular disease.8 Low testosterone was also a predictor of increased all cause and cardiovascular mortality in men with confirmed coronary heart disease over a seven year follow-up period.9
Androgen deprivation therapy for prostate cancer produces a severe state of hypogonadism, which results in increased central adiposity, increased proportion of body fat, and a decrease in lean body mass.10 11 These changes mainly affect subcutaneous not visceral fat, which is atypical for the metabolic syndrome.11 One study recorded a rise in total and low density lipoprotein-cholesterol, triglycerides, and high density lipoprotein-cholesterol after androgen deprivation therapy, but others have not.10 Fasting insulin values rise and insulin sensitivity falls, with an increase in glycated haemoglobin (HbA1c).11 12 Importantly, a retrospective analysis of men with type 2 diabetes who were taking insulin found that androgen deprivation therapy resulted in a marked deterioration in their diabetic control, with insulin dosages needing to be increased.12 Extra vigilance is therefore needed, especially in men with diabetes, in the early phase of treatment.
The science advisory board recommends that because of the metabolic effects of androgen deprivation therapy, patients should be referred to their primary care doctor for periodic follow-up including, when appropriate, review of lipid lowering treatment, antihypertensives, glucose lowering treatment, and antiplatelet drugs.1 It suggests that the primary care doctor should review cardiovascular risk factors at three to six months and at least yearly thereafter. Currently, there is no indication for specific cardiological investigations or interventions. Men with pre-existing cardiovascular disease should have their secondary prevention treatment optimised. The urologist must inform the primary care doctor when androgen deprivation therapy is started and of the potential adverse effects on cardiovascular risk factors.1 The science advisory board recommends that the doctor treating the prostate cancer should make the decision about treatment after weighing up the benefits and harms, especially in a man with known cardiovascular disease.1
Androgen deprivation therapy combined with radiotherapy is a widely established and effective treatment that improves outcome and survival in men with intermediate risk or high risk localised prostate cancer. The science advisory writing group believes that the risk of androgen deprivation therapy to cardiovascular health may become more apparent with the increasing length of survival of patients with prostate cancer. These findings have already led to the US Food and Drug Administration making a change to the label for gonadotrophin releasing hormone agonists in the treatment of prostate cancer (www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm230359.htm). On the basis of the current evidence, the identification and assessment of cardiovascular risk in men taking androgen deprivation therapy is an extrapolation of good clinical practice in the general population. The clinical awareness of this association could potentially improve overall survival.
Cite this as: BMJ 2011;342:d3105
Competing interests: The author has completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declares: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.
Provenance and peer review: Not commissioned; externally peer reviewed.