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Diabetes and Cardiovascular Disease During Androgen Deprivation Therapy for Prostate Cancer

Nancy L. Keating, A. James O'Malley, Matthew R. Smith

From the Division of General Internal Medicine, Department of Medicine, Brigham and Women's Hospital; the Department of Health Care Policy, Harvard Medical School; and the Division of Hematology and Oncology, Massachusetts General Hospital, Boston, MA

Address reprint requests to Nancy L. Keating, MD, MPH, Department of Health Care Policy, Harvard Medical School, 180 Longwood Ave, Boston, MA 02115; e-mail: keating{at}hcp.med.harvard.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
PURPOSE: Androgen deprivation therapy with a gonadotropin-releasing hormone (GnRH) agonist is associated with increased fat mass and insulin resistance in men with prostate cancer, but the risk of obesity-related disease during treatment has not been well studied. We assessed whether androgen deprivation therapy is associated with an increased incidence of diabetes and cardiovascular disease.

PATIENTS AND METHODS: Observational study of a population-based cohort of 73,196 fee-for-service Medicare enrollees age 66 years or older who were diagnosed with locoregional prostate cancer during 1992 to 1999 and observed through 2001. We used Cox proportional hazards models to assess whether treatment with GnRH agonists or orchiectomy was associated with diabetes, coronary heart disease, myocardial infarction, and sudden cardiac death.

RESULTS: More than one third of men received a GnRH agonist during follow-up. GnRH agonist use was associated with increased risk of incident diabetes (adjusted hazard ratio [HR], 1.44; P < .001), coronary heart disease (adjusted HR, 1.16; P < .001), myocardial infarction (adjusted HR, 1.11; P = .03), and sudden cardiac death (adjusted HR, 1.16; P = .004). Men treated with orchiectomy were more likely to develop diabetes (adjusted HR, 1.34; P < .001) but not coronary heart disease, myocardial infarction, or sudden cardiac death (all P > .20).

CONCLUSION: GnRH agonist treatment for men with locoregional prostate cancer may be associated with an increased risk of incident diabetes and cardiovascular disease. The benefits of GnRH agonist treatment should be weighed against these potential risks. Additional research is needed to identify populations of men at highest risk of treatment-related complications and to develop strategies to prevent treatment-related diabetes and cardiovascular disease.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
Prostate cancer is the most frequently diagnosed cancer among men, with over 230,000 new cases diagnosed in the United States in 2004.¹ Eighty-six percent of men with prostate cancer are diagnosed with local or regional disease² and have a 5-year relative survival rate approaching 100%.² Men with prostate cancer, however, have higher rates of noncancer mortality than men in the general population, with some of this excess mortality attributed to treatment.³ Because the prognosis for early prostate cancer is favorable, decisions about treatments are particularly important, because adverse effects and complications of treatments may impact overall health status and quality of life more than the prostate cancer itself.

Androgen deprivation therapy with a gonadotropin-releasing hormone (GnRH) agonist or bilateral orchiectomy is the mainstay of treatment for metastatic prostate cancer^4-6 and may improve survival for men with locally advanced disease.^6-9 However, the role of GnRH agonists in treating men with local or regional prostate cancer has not been completely defined,¹⁰ and most randomized controlled trials of androgen deprivation therapy are underpowered to identify infrequent but potentially serous adverse effects. Nevertheless, GnRH agonists are now routinely prescribed for many men with local or regional disease,¹⁰ with use in this group having increased greatly during the last decade.^11,12

GnRH agonists have adverse physiologic effects that may be associated with an increased risk of diabetes and cardiovascular disease, including increased fat mass^13-15 and decreased insulin sensitivity.¹⁶ In addition, preliminary data suggest that GnRH agonists may prolong the QT interval.¹⁷ These adverse effects may contribute to noncancer morbidity and mortality. In this study, we assessed whether androgen deprivation therapy is associated with an increased incidence of diabetes, coronary heart disease, myocardial infarction, and sudden cardiac death in a population-based cohort of elderly men diagnosed with local or regional prostate cancer and observed for up to 10 years.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
Data
We used Surveillance, Epidemiology and End Results (SEER) Medicare data for this analysis.¹⁸ The SEER program of the National Cancer Institute (Bethesda, MD) collects uniformly reported data from 11 population-based cancer registries covering approximately 14% of the US population.¹⁹ For each incident cancer, SEER data on patient demographics, tumor characteristics, and primary treatment are linked with Medicare administrative data (successfully linking more than 94% of SEER patients diagnosed at age 65 or older).¹⁸

Study Cohort
We identified men age 66 years or older with a first diagnosis of prostate cancer during 1992 to 1999 who were continuously enrolled in Parts A and B of fee-for-service Medicare as of 1 year before diagnosis (N = 91,521). We excluded 2,426 men with no administrative claims from 45 days before diagnosis through 195 days after diagnosis and 15,899 men with metastatic disease or unknown stage at diagnosis. The final cohort included 73,196 men with locoregional prostate cancer. Men with locoregional prostate cancer have a favorable prognosis from their cancer and thus the potential risks of treatments are particularly important.

Diabetes, Coronary Heart Disease, Myocardial Infarction, and Sudden Cardiac Death
We used diagnosis codes associated with inpatient or physician office visits to ascertain the dependent variables of interest: diabetes, coronary heart disease, myocardial infarction, and sudden cardiac death (Appendix A1). For diabetes, we required two or more outpatient encounters with a primary or secondary diagnosis code or one hospitalization with a primary diagnosis of diabetes (including diabetic polyneuropathy, diabetic retinopathy, or diabetic cataract).^20-22 Similarly, for coronary heart disease, we required two or more outpatient visits with a primary or secondary diagnosis code or one hospitalization with a primary diagnosis code for ischemic heart disease.²⁰ We identified acute myocardial infarction if an individual was hospitalized with a primary diagnosis of acute myocardial infarction.^20,23,24 Men with a myocardial infarction were also considered to have coronary heart disease. We ascertained sudden cardiac death (sudden death or life-threatening ventricular arrhythmia) if a man had an inpatient admission with a relevant primary or secondary diagnosis code.²⁵

To avoid ascertaining prevalent diabetes or coronary heart disease during visits related to prostate cancer diagnosis (2.6% of men had no visits in the year before diagnosis), we defined prevalent diabetes or coronary heart disease for men who met the criteria for diagnosis of either condition beginning 12 months before through 6 months after diagnosis. Men with prevalent diabetes (11.5%) and coronary heart disease (18.7%) were excluded from analyses of incident diabetes or coronary heart disease, respectively. Incident diabetes and coronary heart disease were defined as occurring at least 6 months after diagnosis in men without prevalent disease.

Androgen Deprivation Therapy
We used claims data to ascertain receipt of androgen deprivation therapy, including GnRH agonists and bilateral orchiectomy (Appendix A1). Because hypogonadism may persist for prolonged periods after discontinuation of a GnRH agonist,^26,27 men were considered continuously treated for 6 months after each dose of GnRH agonist. Duration of GnRH agonist exposure was estimated by summing the number of 1-month equivalent doses (Appendix A1).²⁸ Because in some men, hypogonadism persists for longer than 6 months after discontinuing GnRH agonist therapy, we conducted sensitivity analyses where we considered men permanently on GnRH agonist therapy, even if they discontinued therapy. Results were similar and are not presented.

Patient Characteristics
We documented each man's age, race, Hispanic ethnicity, marital status, urban residence, SEER region, year of diagnosis, tumor grade, census-tract level income, and education (categorized in quartiles within registries), type of primary treatment (surgery, radiation, or neither; Appendix A1), and comorbid illness based on diagnostic cost groups,²⁹ a risk-adjustment tool used by the Centers for Medicare & Medicaid Services to predict future costs and disease burden for Medicare beneficiaries based on diagnoses from inpatient and ambulatory claims during the 12-month period preceding diagnosis. Diagnostic cost groups summarize 182 conditions (compared with 18 captured by the Charlson score³⁰) that are highly predictive of mortality for Medicare beneficiaries with acute myocardial infarction.³¹ Variables were categorized as in Table 1.

Next, we used Cox proportional hazards models with time-varying treatment variables and time-varying covariates to assess the direct effect of GnRH agonists or orchiectomy on time to developing each dependent variable. The time-varying treatment variables allowed men at risk to contribute information to the treatment groups when on treatment and to the control groups when not on treatment. We adjusted these analyses for the patient characteristics in Table 1 and included time-varying variables controlling for the development of new diabetes, heart disease, or sudden cardiac death. For each analysis, men were followed only until they developed an event of interest. An assumption of Cox models is that time to censoring is independent of factors related to the survivor time until a particular event; in additional analyses (data not shown), we found no evidence to reject this assumption and found that our conclusions withstand large violations of this assumption. In a second set of Cox proportional hazard models, we replaced the GnRH agonist variable with a set of variables reflecting duration of use (estimated by summing the number of 1-month equivalent doses; categorized as 1 to 4 months, 5 to 12 months, 13 to 24 months, and 25 months or longer) to assess the effect of duration of GnRH therapy on the dependent variables of interest. For each outcome, duration of use was counted only until occurrence of that event.

Because this is an observational study and men were not randomly assigned to receipt of androgen deprivation therapy, in sensitivity analyses, we used propensity score methods^32,33 to match patients treated with GnRH agonists or orchiectomy with nontreated patients who were similar based on a collection of observed patient characteristics. We repeated analyses in the matched samples to verify that our results were not due to any imbalance in the distributions of observed patient characteristics between the treatment groups.

All tests of statistical significance were two sided. We used SAS statistical software, version 8.2 (SAS Institute Inc, Cary, North Carolina) for analyses. The study was approved by the institutional review boards at Harvard Medical School (Boston, MA) and Massachusetts General Hospital (Boston, MA).

	RESULTS

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The mean age of the cohort at diagnosis was 74.2 (standard deviation, 5.8), 9% were black, 4% were Hispanic, and 73% were married (Table 1). Men were observed for a median of 4.55 years (range, 0 days to 10 years). Overall, 36.3% of men received a GnRH agonist and 6.9% of men underwent bilateral orchiectomy during follow-up (Table 1). On average, men treated with GnRH agonists were on treatment for 40% of the time from diagnosis through censoring; men treated with orchiectomy were on treatment for 76.3% of the time from diagnosis through censoring.

After prostate cancer diagnosis, 3,917 of men (5.4%) had a myocardial infarction and 3,301 men (4.5%) experienced sudden cardiac death. Among the 64,721 men without prevalent diabetes, 10.9% developed diabetes and among the 59,748 without prevalent coronary heart disease, 25.3% developed coronary heart disease.

The unadjusted rates per 1,000 person-years for developing diabetes, coronary heart disease, myocardial infarction, or sudden cardiac death during treatment or no treatment are presented in Table 2. Rates for each of these outcomes are higher for men treated with GnRH agonists than for men not currently on hormonal treatment (Table 2), and rates of diabetes, myocardial infarction, and sudden cardiac death are higher for men treated with orchiectomy than men not on hormonal treatment.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
In this large, population-based study of older men with local or regional prostate cancer, we found 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. Moreover, short-term GnRH agonist treatment was significantly associated with greater risk of disease and the elevated risks persisted in men on longer-term therapy.

Rates of noncancer deaths in men with prostate cancer are greater than rates of noncancer deaths in the population at large and some of this increase may be treatment related.³ A recent randomized trial of external-beam radiation for prostate cancer found that long-term adjuvant treatment with a GnRH agonist was associated with greater noncancer mortality than short-term adjuvant therapy.³⁴ Another observational study of primary brachytherapy in men with early-stage prostate cancer found that men who received short-term hormonal therapy had worse overall survival than men who did not receive such therapy while not differing in prostate cancer-specific survival.³⁵ An increased risk of diabetes and cardiovascular disease associated with GnRH agonist treatment, which occurs early and persists with continued treatment, may explain part of the excess number of noncancer deaths observed in these studies. Other data suggest that men with localized prostate cancer who were treated with androgen deprivation therapy report poorer overall health than men not treated with androgen deprivation therapy.³⁶ The onset of new illnesses such as those we studied could contribute to declines in self-reported health status.

The association of GnRH agonists with increased risk of diabetes and cardiovascular disease appears biologically plausible. GnRH agonists significantly increase fat mass and fasting insulin levels^37,38 and decrease insulin sensitivity.¹⁶ Treatment-related changes in serum lipoproteins^15,38 and arterial stiffness,³⁷ as well as possible QT interval prolongation,¹⁷ may also contribute to the association between GnRH agonists and cardiovascular outcomes. Additional research is needed to further evaluate the potential mechanisms for greater risk of diabetes and cardiovascular disease associated with GnRH agonists.

Our observation that short-term exposure to GnRH agonists is associated with incident diabetes and cardiovascular disease is consistent with the reported tempo of treatment-related changes in fat mass and insulin sensitivity. Physiologic studies demonstrate that short-term GnRH agonist treatment significantly increases fat mass, but long-term treatment does not cause further fat accumulation.³⁹ Moreover, short-term GnRH agonist treatment significantly decreases insulin sensitivity.¹⁶ Thus, longer-term treatment may not confer a greater cumulative risk over short-term treatment. In addition, some patients may be at greater risk of harm than others and such harm may occur early.

We found that orchiectomy was associated with greater risk of diabetes but not coronary heart disease, myocardial infarction, or sudden cardiac death. Because GnRH agonists effectively cause castration, we had expected the effects of GnRH agonists and orchiectomy to be similar. Relatively few men (6.9%) underwent orchiectomy, so our study may have been underpowered to detect an association between orchiectomy and cardiovascular disease. Nevertheless, additional studies are necessary to determine whether the association with excess cardiovascular events is restricted to men exposed to a GnRH agonist, and if so, to identify the mechanisms for this effect.

Our findings may have important implications for assessing potential benefits and harms of androgen deprivation therapy for prostate cancer. Even a moderately increased risk of diabetes and heart disease in men receiving GnRH agonists such as we found could have a substantial negative impact on the health of prostate cancer survivors, particularly given the considerable increases in its use among men with local or regional prostate cancer.^11,12 The GnRH agonists leuprolide and goserelin now account for more than one third of Medicare expenditures for prostate cancer treatment⁴⁰ and for 17.2% of all Medicare Part B drug spending in 2001.⁴¹ Our findings support the need for discussion of the potential cardiovascular risks of this therapy before starting treatment, particularly for indications for which overall survival has not been demonstrated. Moreover, our findings suggest that, for men who require GnRH agonist therapy, strategies to mitigate modifiable risk factors for diabetes and coronary heart disease may be warranted.

Our study has some limitations. First, men were not randomly assigned to treatments and factors associated with receipt of androgen deprivation might also be associated with the development of diabetes or cardiovascular disease. For example, if older men are more likely to receive GnRH agonists and also more likely to develop diabetes or heart disease, we want to be sure that we do not attribute differences in age to receipt of GnRH agonists. We used several strategies to address this limitation. First, we adjusted for numerous potential confounders and for new diseases diagnosed during follow-up that may impact other outcomes (for example, a myocardial infarction will increase risk of sudden cardiac death). In addition, our use of time-varying treatment variables allowed men to serve as their own control when not on therapy. Further, we used propensity score methods to compare similar groups of treated and untreated patients who were matched for all observed clinical and demographic characteristics. The similarity of these results to those of our primary analyses suggests that our findings are robust. Nevertheless, we encourage clinical trialists to pool available data from randomized trials of androgen deprivation therapy to confirm our findings.

Second, we identified disease outcomes using diagnosis codes in administrative data. Although we applied codes and algorithms used by others,^20-25,28 we cannot exclude the possibility that men receiving regular injections were more likely to be diagnosed with diabetes or coronary heart disease because of more frequent visits. However, GnRH agonist treatment was also associated with more hospitalizations for myocardial infarction, events likely to be ascertained even among men without regular outpatient care. In addition, SEER-Medicare data do not include information about oral medications. Accordingly, we could not ascertain use of oral antiandrogens. Treatment with antiandrogen monotherapy is not approved for prostate cancer in the US, so few men likely received such therapy. Some men may have received treatment with both a GnRH agonist and an oral anatiandrogen (combined androgen blockade), but a large metaanalysis demonstrated that morbidity and mortality for combined androgen blockade is similar to GnRH agonist monotherapy.⁴²

Finally, we studied older men living in regions of the US with SEER registries, so the generalizability of our findings to younger men and those living in different areas requires further study. Older men account for the majority of prostate cancer diagnoses, however, and this population-based sample included cancer patients from areas representing 14% of the US population.

In conclusion, in this observational study, we found that GnRH agonists are associated with greater risk of diabetes, coronary heart disease, myocardial infarction, and sudden cardiac death in men with locoregional prostate cancer. Decisions about GnRH agonist treatment for locoregional prostate cancer should weigh improvements in cancer-specific outcomes against potential increased risks of diabetes and cardiovascular disease. Future research is needed to confirm our findings in other populations, to further define situations for which benefits of GnRH agonists outweigh risks, to identify populations of men at highest risk of adverse complications due to GnRH agonists, and to develop strategies to prevent treatment-related morbidity.

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: Nancy L. Keating, A. James O'Malley, Matthew R. Smith Financial support: Nancy L. Keating, Matthew R. Smith Collection and assembly of data: Nancy L. Keating, A. James O'Malley Data analysis and interpretation: Nancy L. Keating, A. James O'Malley, Matthew R. Smith Manuscript writing: Nancy L. Keating, A. James O'Malley, Matthew R. Smith Final approval of manuscript: Nancy L. Keating, A. James O'Malley, Matthew R. Smith

 

	ACKNOWLEDGMENTS

 
This study used the linked Surveillance, Epidemiology and End Results (SEER) -Medicare database. The interpretation and reporting of these data are the sole responsibility of the authors. We acknowledge the efforts of the Applied Research Program, National Cancer Institute; the Office of Research, Development and Information, CMS; Information Management Services Inc; and the SEER Program tumor registries in the creation of the SEER-Medicare database. We thank Yang Xu, MS, for expert programming assistance

	NOTES

 
Supported by the Prostate Cancer Specialized Program of Research Excellence (SPORE) of the National Cancer Institute (Grant No. P50CA90381), and the W. Bradford Ingalls Charitable Foundation. The funder had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted February 17, 2006; accepted July 25, 2006.

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				M. R. Smith, S. B. Malkowicz, F. Chu, J. Forrest, P. Sieber, K. G. Barnette, D. Rodriquez, and M. S. Steiner Toremifene Improves Lipid Profiles in Men Receiving Androgen-Deprivation Therapy for Prostate Cancer: Interim Analysis of a Multicenter Phase III Study J. Clin. Oncol., April 10, 2008; 26(11): 1824 - 1829. [Abstract] [Full Text] [PDF]

				T. H. van der Kwast, L. Collette, and M. Bolla In Reply: J. Clin. Oncol., March 10, 2008; 26(8): 1392 - 1393. [Full Text] [PDF]

				A. V. D'Amico, M.-H. Chen, A. A. Renshaw, M. Loffredo, and P. W. Kantoff Androgen Suppression and Radiation vs Radiation Alone for Prostate Cancer: A Randomized Trial JAMA, January 23, 2008; 299(3): 289 - 295. [Abstract] [Full Text] [PDF]

				V. Venkateswaran, A. Q. Haddad, N. E. Fleshner, R. Fan, L. M. Sugar, R. Nam, L. H. Klotz, and M. Pollak Association of Diet-Induced Hyperinsulinemia With Accelerated Growth of Prostate Cancer (LNCaP) Xenografts J Natl Cancer Inst, December 5, 2007; 99(23): 1793 - 1800. [Abstract] [Full Text] [PDF]

				C. S. Saigal Moving Beyond Guidelines to Improve the Quality of Care for Men With Prostate Cancer J. Clin. Oncol., December 1, 2007; 25(34): 5348 - 5349. [Full Text] [PDF]

				C. Nieder, A. Pawinski, N. H. Andratschke, and M. Molls Does Prophylactic Breast Irradiation in Patients With Prostate Cancer Influence Cardiac Toxicity? J Natl Cancer Inst, November 7, 2007; 99(21): 1646 - 1647. [Full Text] [PDF]

				M. A. Yialamas, A. A. Dwyer, E. Hanley, H. Lee, N. Pitteloud, and F. J. Hayes Acute Sex Steroid Withdrawal Reduces Insulin Sensitivity in Healthy Men with Idiopathic Hypogonadotropic Hypogonadism J. Clin. Endocrinol. Metab., November 1, 2007; 92(11): 4254 - 4259. [Abstract] [Full Text] [PDF]

				H. K. Tsai, A. V. D'Amico, N. Sadetsky, M.-H. Chen, and P. R. Carroll Androgen Deprivation Therapy for Localized Prostate Cancer and the Risk of Cardiovascular Mortality J Natl Cancer Inst, October 17, 2007; 99(20): 1516 - 1524. [Abstract] [Full Text] [PDF]

				J. Seidenfeld, D. J. Samson, and P. C. Albertsen Competing Risks for Patients With Localized Prostate Cancer J Natl Cancer Inst, October 17, 2007; 99(20): 1498 - 1499. [Full Text] [PDF]

				M. Zitzmann and E. Nieschlag Androgen Receptor Gene CAG Repeat Length and Body Mass Index Modulate the Safety of Long-Term Intramuscular Testosterone Undecanoate Therapy in Hypogonadal Men J. Clin. Endocrinol. Metab., October 1, 2007; 92(10): 3844 - 3853. [Abstract] [Full Text] [PDF]

				M. D. Michaelson and M. R. Smith In Reply J. Clin. Oncol., August 1, 2007; 25(22): 3385 - 3386. [Full Text] [PDF]

				M. Montano, J. N. Flanagan, L. Jiang, P. Sebastiani, M. Rarick, N. K. LeBrasseur, C. A. Morris, R. Jasuja, and S. Bhasin Transcriptional Profiling of Testosterone-Regulated Genes in the Skeletal Muscle of Human Immunodeficiency Virus-Infected Men Experiencing Weight Loss J. Clin. Endocrinol. Metab., July 1, 2007; 92(7): 2793 - 2802. [Abstract] [Full Text] [PDF]