Expert’s comments:
Metformin, a first-line antidiabetic drug belonging to the bigua-
nide family, has been associated with a decreased risk of
subsequent cancers and an improved cancer-related outcome
[1]
. In a meta-analysis of 20 studies including
>
13 000 cancer
patients with type 2 diabetes, metformin use increased overall
survival by 34% and cancer-specific survival by 38% for all
patients with cancer compared with nonmetformin use
[2]
.
In patients with PCa treated with external-beam
radiation therapy, metformin use was associated with
improvement in all outcomes compared with the diabetic
nonmetformin group. In men experiencing biochemical
failure, metformin use was also independently correlated
with a decrease in the development of castration-resistant
PCa (CRPC)
[3]
. In nondiabetic patients with chemotherapy-
naive CRPC, metformin use led to disease stabilization and
prolongation of prostate-specific antigen doubling time in
some patients
[4]
.
The antineoplastic activity of metformin has been
related to reduced hyperinsulinemia and glycemic levels.
In addition, metformin selectively blocks the growth of
cancer stem cells and inhibits the metabolic stress response
that may stimulate the inflammatory pathway associated
with a number of cancers. Because metformin is not
believed to influence the transformation of benign cells to
malignant cells but rather to modulate cellular energy,
metformin may have a greater impact on cancer survival
than on incidence. Metformin may also have other benefits
for nondiabetic patients who require androgen deprivation
therapy (ADT) through its insulin-sensitizing effects be-
cause ADT can be associated with insulin resistance and
metabolic syndrome.
Because metformin is inexpensive, with only minor side
effects in men with and without diabetes, and because PCa is
a slow-growing disease, this drug could play a role in
secondary prevention strategies
[5]
. Further studies are
necessary to show which PCa patients may benefit from this
therapy.
Conflicts of interest:
The author has nothing to disclose.
References
[1]
La Vecchia C, Bosetti C. Metformin: are potential bene±ts on cancer
risk extended to cancer survival? Oncologist 2013;18:1245–7.
[2]
Yin M, Zhou J, Gorak EJ, et al. Metformin is associated with survival
bene±t in cancer patients with concurrent type 2 diabetes: a system-
atic review and meta-analysis. Oncologist 2013;18:1248–55.
[3]
Spratt DE, Zhang C, Zumsteg ZS, et al. Metformin and prostate
cancer: reduced development of castration-resistant disease and
prostate cancer mortality. Eur Urol 2013;63:709–16.
[4] Rothermundt C, Hayoz S, Templeton AJ, et al. Metformin in chemo-
therapy-naive castration-resistant prostate cancer: a multicenter
phase 2 trial (SAKK 08/09). Eur Urol. In press.
10.1016/j.eururo.2013.12.057
[5]
Penney KL, Stampfer MJ. The time is ripe for a randomized trial of
metformin in clinically localized prostate cancer. J Clin Oncol
2013;31:3054–5.
Dorothea Weckermann
*
Department of Urology, Klinikum Augsburg, Augsburg, Germany
*Department of Urology, Klinikum Augsburg, Stenglinstraße 2,
Augsburg, Bavaria 86156, Germany.
E-mail address:
dorothea.weckermann@klinikum-augsburg.de
.
Re: Increased Risk of Non-fatal Myocardial Infarction
Following Testosterone Therapy Prescription in Men
Finkle WD, Greenland S, Ridgeway GK, et al.
PLoS One 2014;9:e85805
Experts’ summary:
Finkle and colleagues recently performed a secondary data
analysis to investigate potential associations between testos-
terone supplementation therapy (TST) and cardiovascular
events. The authors used a large commercial database that
covered claims from 2006 to 2010 and compared two cohorts
of men: those who filled new prescriptions for TST and those
who filled a new prescription for phosphodiesterase type 5
inhibitors (PDE5-Is). The investigators then evaluated the rates
of myocardial infarction (MI), as determined by International
Classification of Diseases, 9th revision, codes, before and within
3 mo after filling the first prescription in these groups.
The authors identified 55 593 men who filled a prescrip-
tion for TST and 167 279 men who filled a prescription for a
PDE5-I. Rates of MI increased in the 3 mo after filling a
TST prescription (from 3.48 per 1000 person-years before to
4.75 per 1000 person-years after; rate ratio: 1.36; 95%
confidence interval [CI], 1.03–1.81). The increase was more
pronounced in the subset of men
±
65 yr of age (5.27 per 1000
person-years before to 11.52 person-years after; rate ratio:
2.19; 95% CI, 1.27–3.77). There was no corresponding
increase in MI rate in men who filled a PDE5-I prescription
(3.48 per 1000 person-years before to 3.75 per 1000 person-
years after; rate ratio: 1.08; 95% CI, 0.93–1.24).
Experts’ comments:
The work by Finkle and colleagues is a secondary data analysis
of a large Claims and Encounters Database aimed at deter-
mining whether TST use was associated with cardiovascular
events. The findings are similar to those from a retrospective
cohort analysis of veterans with advanced cardiovascular
disease
[1]
and the Testosterone in Older Men (TOM) trial
[2]
.
Although these three studies have potentially concerning
findings, they also exhibit methodological flaws that limit the
credibility of their results. For example, in the study by Vigen
et al.
[1]
, hypogonadal veterans who previously had an MI or
strokeand later receivedTST were excluded rather then being
assigned to the no-testosterone arm for analysis. Further-
more, the authors’ conclusions of there being increased risks
of MI or stroke associated with TST were based on Kaplan-
Meier estimates, not the absolute rates of MI or stroke. In the
TOM study
[2]
, the authors recorded as cardiac events
findings that are known side effects of testosterone such as
hypertension and lower extremity edema.
EUROPEAN UROLOGY 66 (2014) 173–178
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