Prostate Cancer Therapy Linked to Diabetes and Heart Disease

BOSTON, Sept. 19 -- Androgen deprivation with a GnRH agonist for local or regional prostate cancer is associated with an increased risk of diabetes, coronary heart disease, heart attack, and sudden cardiac death, according to researchers here.

An observational analysis of more than 73,000 men with local or regional disease showed that treatment with a gonadotropin-releasing hormone (GnRH) agonist increases the risk of diabetes by 44%, with smaller increases in the risks of cardiovascular disease, according to Nancy Keating, M.D., of Harvard Medical School and Brigham and Women's Hospital.

As they make treatment decisions about locoregional disease, "patients and physicians need to be aware of the elevated risk" of a GnRH agonist, Dr. Keating said.

Androgen deprivation therapy with a GnRH agonist is a mainstay for metastatic prostate cancer and may improve survival for men with locally advanced disease, Dr. Keating and colleagues noted in the Sept. 20 issue of the Journal of Clinical Oncology.

According to the investigators, the GnRH agonists accounted in 2001 for more than a third of Medicare expenditures for prostate cancer and for 17.2% of all Medicare Part B drug spending.

But not much is known about the risks of using the medications to treat men with less-advanced disease and -- given that the five-year survival in such cases approaches 100% -- adverse effects of treatment have an increased importance, they said.

"Men with prostate cancer have high five-year survival rates, but they also have higher rates of non-cancer mortality than healthy men," Dr. Keating said. "This study shows that a common hormonal treatment for prostate cancer may put men at significant risk for other serious diseases."

Clinically, the finding implies that doctors "should think twice about prescribing GnRH agonists in situations for which studies have not demonstrated improved survival until we better understand the risks of treatment," said co-author Matthew Smith, M.D., Ph.D. of Harvard and Massachusetts General Hospital.

"For men who do require this treatment, physicians may want to talk with their patients about strategies -- such as exercise and weight loss -- which may help to lower risk of diabetes and heart disease," he said.

The findings derived from the Surveillance, Epidemiology and End Results (SEER) database, plus administrative data from Medicare. They accounted for 73,196 men ages 66 or older who were diagnosed with locoregional prostate cancer from 1992 to 1999. Of that cohort, 36.3% were treated with a GnRH agonist.

Compared with men who got no such treatment, the study found:

• A significantly increased risk of diabetes. The hazard ratio was 1.44, with a 95% confidence interval from 1.34 to 1.55, which was significant at P<0.001.
• A 16% increased risk of coronary heart disease. The hazard ratio was 1.16, with a 95% confidence interval from 1.10 to 1.21, which was significant at P<0.001.
• An 11% increased risk of myocardial infarction. The hazard ratio was 1.11, with a 95% confidence interval from 1.01 to 1.21, which was significant at P=0.03.A 16% increased risk of sudden cardiac death. The hazard ratio was 1.16, with a 95% confidence interval from 1.05 to 1.27, which was significant at P=0.004.

Since androgen deprivation therapy is equivalent to castration, the researchers also looked at men who underwent bilateral orchiectomy, 6.9% of the total.

Surprisingly, the effects of the treatment were different, Dr. Keating and colleagues found. A bilateral orchiectomy increased the risk of diabetes by 34%, compared with men who got no treatment, and the increase was significant at P<0.001.

But there was no increase in the risks of coronary heart disease, heart attack, or sudden cardiac death, they found.

"We had expected the effects of GnRH agonists and orchiectomy to be similar," the researchers commented, noting that because the number of men being surgically castrated was small, the study might not have had enough power to detect an increased cardiac risk.

The study was limited by its retrospective, observational design, the researchers noted, and by the administrative nature of the data. Also, because it included mainly older men from regions with SEER registries, it may not generalize completely to younger men or those in other regions.