In this population-based study of men of all ages with local or regional prostate cancer in the Veterans Healthcare Administration, we observed that androgen deprivation therapy with GnRH agonists was associated with increased risk of incident diabetes, coronary heart disease, acute myocardial infarction, and sudden cardiac death. These results are consistent with our previous findings in a population of older men enrolled in fee-for-service Medicare. Moreover, the associations we observed persisted after accounting for oral antiandrogen use and additional clinical information (such as baseline prostate-specific antigen values, cholesterol levels, and use of statins and finasteride) (9
). In addition, we identified an association of GnRH agonists with stroke, which, to our knowledge, has not been previously described.
This study allowed us to examine the use of oral antiandrogens, in combination with GnRH agonists and when used as monotherapy. Use of combined androgen blockade, compared with no androgen deprivation therapy, was associated with incident coronary heart disease. However, neither combined androgen blockade nor oral antiandrogen monotherapy was associated with the other outcomes studied. Although the relatively small numbers of men receiving these treatments limited the power to observe differences, these findings provide some reassurance that use of oral antiandrogens was not associated with substantial increases in risks in addition to those observed for GnRH agonists.
Recently, other studies have examined the association between androgen deprivation therapy and diabetes and/or cardiovascular disease, and the findings remain somewhat mixed (10
). A study of men in fee-for-service Medicare that used data and methods that were similar to those in our previous study found a similar increase in cardiovascular disease associated with androgen deprivation therapy (3
). A preliminary report from a population-based observational study of Canadian men with prostate cancer observed an association between androgen deprivation therapy and increased incidence of diabetes but not of myocardial infarction or sudden cardiac death (13
Other studies have examined cardiovascular mortality (6
). A population-based observational study with few events reported increased cardiovascular mortality in a subset of men who underwent prostatectomy but not in a subset of men treated with radiation therapy (14
). Secondary analyses of four large randomized controlled trials from the Radiation Therapy Oncology Group or European Organization for Research and Treatment of Cancer have found no association between neoadjuvant or adjuvant androgen deprivation therapy and cardiovascular mortality, although a pooled analysis of three small randomized controlled trials of men with clinically localized prostate cancer suggested that 6 months of androgen deprivation therapy led to earlier onset of fatal myocardial infarction in the subset of men who were aged at least 65 years (6
). It is important to note that none of these studies were primarily designed to assess cardiovascular mortality and, therefore, were underpowered to study cardiovascular mortality.
Previous studies have not assessed the relationship between androgen deprivation therapy and stroke. The mechanism(s) responsible for the novel association between GnRH agonists and stroke observed in this study are unknown but may result from the same physiological changes proposed to underlie the risk of coronary vascular disease. These mechanisms include, but are likely not limited to, treatment-related central obesity, lipid alterations, and insulin resistance (19
We found that ever use and current use of androgen deprivation therapy were associated with similar risks of diabetes, coronary heart disease, and sudden cardiac death. The hazard ratio for the association between ever use of androgen deprivation therapy and risk of myocardial infarction was smaller than the hazard ratio for current use. This difference suggests that there may be a direct effect of androgen deprivation therapy on thrombosis formation in addition to the hypothesized risks of central obesity and diabetes that may develop during androgen deprivation therapy and may persist after therapy. Further investigation of this hypothesis is needed.
Although the risks associated with androgen deprivation therapy remain incompletely defined, the potential for harm from this treatment underscores the importance of better understanding its benefits. To date, short-term use of androgen deprivation therapy for local or regional prostate cancer has been shown to be beneficial in men with locally advanced disease who are treated with radiation therapy or men with lymph node–positive disease who are treated with radical prostatectomy (3
). In addition, a recent study observed that 3 years of androgen suppression with radiation therapy for locally advanced prostate cancer was superior to 6 months of treatment (7
). Nevertheless, data are lacking about benefits for use of androgen deprivation therapy as primary therapy or to treat asymptomatic biochemical recurrences identified only by increasing levels of prostate-specific antigen after primary treatment. Until the benefits and risks of androgen deprivation therapy in such settings are more completely defined, it may be best for physicians and patients to exercise caution in the use of androgen deprivation therapy. Indeed, observational data suggest that older men with low-risk tumors who were treated with primary androgen deprivation therapy appear to have poorer survival than those who received no treatment in the 6 months after diagnosis (24
). Moreover, in post hoc subset analyses of randomized controlled trials, androgen deprivation therapy combined with radiation therapy for intermediate-risk disease may actually be associated with worse survival in men with moderate or severe comorbidity at baseline, perhaps underscoring the associated toxicities of this therapy (25
Our study has some limitations. First, patients were not randomly assigned to treatment with androgen deprivation therapy, and so it is possible that factors associated with treatment might also be associated with the outcomes of interest. We controlled for numerous potential confounders, and we used time-varying treatment variables to allow men to serve as their own control when not on androgen deprivation therapy to minimize the likelihood of selection effects influencing our findings. Second, we used administrative data to ascertain exposures and outcomes. Nevertheless, previous research in the Veterans Healthcare Administration has documented a high degree of sensitivity in administrative data for cardiac procedures compared with that in medical record abstraction (26
). Third, it is possible that men receiving regular injections or prescriptions might be more likely to be diagnosed with diabetes or coronary heart disease because of more frequent interactions with health-care providers. However, patients treated with GnRH agonists were also more often hospitalized for myocardial infarction and hospitalized or seen in emergency rooms for stroke, and these events are likely to be identified even among men without regular outpatient care. Finally, although we studied only men cared for in the Veterans Healthcare Administration, the cohort included men of all ages with prostate cancer living throughout the United States.
In conclusion, our findings from this observational study and those from a cohort of older men residing in Surveillance, Epidemiology, and End Results areas suggest that concerns regarding use of GnRH agonists are warranted (9
). Additional research is needed to understand the effects of GnRH agonists for clinical settings where benefits have not yet been established, to identify populations of men at highest risk of complications associated with GnRH agonists, and to investigate strategies to prevent treatment-related morbidity. Nevertheless, patients and physicians considering initiation of GnRH agonist treatment for local or regional prostate cancer should factor the potential increased risks of diabetes and cardiovascular disease as they make treatment decisions.