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Androgen Deprivation, Diabetes, and
Adverse Cardiovascular Events
(July 2007)
Two recent large
studies document that androgen deprivation - even short term -
significantly increases the incidence of diabetes, coronary heart
disease, myocardial infarction, and sudden cardiac death in men
receiving GnRH agonists.
Keating et al., JCO
Sept. 2006, based their analysis on SEER data of 73,196 men 66 years or
older with locoregional prostate cancer, 36.3% of whom received a GnRH
agoinst, 6.9% bilateral orchiectomy, with the remainder having received
no hormonal intervention. The effect of duration of therapy on
complications was analyzed by grouping duration of therapy for 1 to 4
months, 5 to 12, 13 to 24, and 25 months or longer; and consideration
was given to the fact that hypogonadism usually persists for as long as
6 months (and as long as 2 years depending on baseline testosterone
value and duration of therapy) following a short course of ADT. "On
average men treated with GnRH agonists were on treatment for 40% of the
time from diagnosis through censoring..."
The hazard ratios
associated with the increased risk of diabetes was 1.44, for coronary
heart disease, 1.16; myocardial infarction, 1.11; and for sudden
cardiac death, 1.16. An important, and perhaps unexpected, finding was:
"... an increased risk of diabetes and coronary heart disease was
evident in men on GnRH agonist therapy for as few as 1 to 4 months,"
indicating that these risks "occur early and persist with continuous
treatment."
The adverse association
of GnRH agoinst therapy with these complications is "biologically
plausible" because these agents "significantly increase fat mass,
fasting insulin levels, and decrease insulin sensitivity" and adversely
change serum lipoproteins and arterial stiffness - and do so even after
short term usage. Of interest: "We found that orchiectomy was associated
with a greater risk of diabetes, but not coronary heart disease,
mycardial infarction, or sudden cardiac death."
Their conclusion: "Our
findings support the need for discussion of the potential cardiovascular
risks of this [GnRH] therapy before starting treatment" and point up the
need to initiate strategies to "mitigate modifiable risk factors for
diabetes and coronary heart disease" in men requiring GnRH agonist
therapy.
D'Amico et al. (JCO,
June 10, 2007), "Influence of Androgen Suppression Therapy for Prostate
Cancer on the Frequency and Timing of Fatal Myocardial Infarctions,"
concluded that men 65 years or older who were treated with 6 months of
adjuvant ADT (GnRH agonist/flutamide) experience earlier onset of
fatal myocardial infarctions (MI) than those receiving no ADT
(p=0.17). The study combined data from three randomized trials - a US
trial, 206 men; an Australian/New Zealand trial, 802 men; and a Canadian
trial of 364 men. In the authors' opinions the treatment/no treatment
arms were well balanced for cardiovascular risks. The US trial was
specifically stratified for smoking history, hypertension, diabetes
mellitus, BMI and age. The median follow-up ranged from 4.8 years to 6.7
years. The shorter time to fatal MIs was illustrated by the observation
that "before the first fatal MI occurred at 21 months in the men [>
65 years old] randomly assigned to receive no AST, 44%
(eight of 18 MIs) of all observed fatal MIs had occurred in men in this
age group randomly assigned to receive 6 months of AST," and their data
suggested, but further confirmation is required, that this risk might
occur with as little as three months of therapy.
The report offered an
additional important fact that has not been apparent in the literature:
"The Early Prostate Cancer Trial found an unexpected decrease
in overall survival in men with a median age of 69 years who were on a
watchful waiting program for clinically localized prostate cancer and
who were randomized to receive 150 mg of the antiandrogen bicalutamide
by mouth daily for a median of 4.4 years compared to placebo." Although
bicalutamide raises the testosterone level, "evidence now exists that
the protective effect that testosterone may have on the development of
atherosclerosis is blocked by bicalutamide's antagonism of the androgen
receptor."
Further studies with proper stratification will be required to ascertain
if the metabolic changes from ADT "precipitate an MI in a predisposed
man." D'Amico, as did Keating, counsels cardiovascular evaluation prior
to the start of ADT. The findings in these two studies impinge on
clinical management because of the increasing use of ADT in general, and
its beneficial use for men at high risk for recurrence in particular.
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