gogues, biguanides do not increase insulin circulating
levels but reduce hepatic gluconeogenesis and stimulate
glycolysis in tissues . Also biguanides neither in-
crease weight nor provoke hypoglycemia, which makes
them suitable to treat overweight and obese type II
diabetic patients .
According to our results the reduced risk of prostate
cancer was only apparent among users of insulin and
sulphonylureas. These antidiabetic agents elevate insulin
blood levels. Whether the observed association is due to
the eﬀect of these drugs or they act as mere markers for a
group of diabetic patients with impaired insulin secretion
is unclear. A similar rationale could explain the lack of
association among users of biguanides, which are most
eﬀective in treating patients with insulin resistance
syndrome . However, caution must be taken in
interpreting these results, that warrant further research
before any mechanistic conclusion can be made.
We could not diﬀerentiate between type I and type II
diabetes. This would tend to dilute the association be-
tween a speciﬁc type of diabetes and prostate cancer.
However, given the age range (50–79 years) we expect
most of these patients to have type II diabetes. Also, we
did not have data on date of ﬁrst diagnosis, and there-
fore we could not assess the eﬀect of time since ﬁrst
Patients with diabetes tend to have frequent visits to
their GPs as part of their routine care, and consequently
these patients are more likely to undergo prostate cancer
screening tests that could spuriously inﬂate the incidence
of diagnosed prostate cancer in this population. There-
fore any reduced risk observed among patients with
diabetes could be an underestimation of the true asso-
ciation. In order to overcome this potential bias, we
controlled for health care utilization (number of visits to
the GP, referrals and hospitalizations in the 2 years
prior to the index date) in the multivariate logistic
regression. Indeed, we observed a lower estimate in this
multivariate model compared to other models that did
not adjust for health care utilization.
This study adds further evidence to the suggestion that
diabetic patients present a decreased risk of prostate
cancer. The reduced risk appears to be restricted to those
patients treated either with oral sulphonylureas or insu-
lin, an association that warrants further investigation.
We thank the staﬀ at GPRD, and the participating
general practitioners for their collaboration. We also
thank the Boston Col laborative Drug Surveillance
Program (BCDSP) for providing access to the database.
This study was partly supported by a research grant
1. Bonovas S, Filioussi K, Tsantes A (2004) Diabetes mellitus and
risk of prostate cancer: a meta-analysis. Diabetologia 47: 1071–8.
2. Coﬀey DS (1979) Physiological control of prostatic growth: an
overview. In: Prostate Cancer. International Union Against Cancer.
UICC Technical Report Series, Vol 48. Geneva, pp. 4–23.
3. Gann PH, Hennekens CH, Ma J, Longcope C, Stampfer MJ
(1996) Prospective study of sex hormone levels and risk of prostate
cancer. J Natl Cancer Inst 88: 1118–1126.
4. Hovenanian MS, Deming CL (1948) The heterologous growth of
cancer of the human prostate. Surg Gynecol Obstet 86: 29–35.
5. Ando S, Rubens R, Rottiers R (1984) Androgen plasma levels in
male diabetes. J Endocrinol Invest 7: 21–24.
6. LeRoith D, Baserga R, Helman L, Roberts CT (1995) Insulin-like
growth factors and cancer. Ann Intern Med 122: 54–59.
7. Stattin P, Rinaldi S, Biessy C, Stenman UH, Hallmans G,
Kaaks R (2004) High levels of circulating insulin-like growth
factor-I increase prostate cancer risk: a prospective study in a
population-based nonscreened cohort. J Clin Oncol 22: 3104–3112.
8. Suikkari AM, Koivisto VA, Rutanen EM, Yki-Jarvinen H,
Karonen SL, Seppala M (1988) Insulin regulates the serum levels
of low molecular weight insulin-like growth factor binding protein.
J Clin Endocrinol Metab 66: 266–272.
9. Orskov H (1996) Somatostatin, growth hormone, insulin-like
growth factor-1, and diabetes: friends or foes? Metabolism 45:
guez LA, Pe
rez Gutthann S (1998) Use of the U.K.
General Practice Research Database for pharmacoepidemiology.
Br J Clin Pharmacol 45: 419–426.
11. Jick H, Jick SS, Derby LE (1991) Validation of information
recorded on general practitioner based computerised data resource
in the United Kingdom. BMJ 302: 766–768.
guez LA, Gonza
rez A (2004) Inverse associa-
tion between nonsteroidal anti-inﬂammatory drugs and prostate
cancer. Cancer Epidemiol Biomar Prev 13: 649–653.
13. Ronquist G, Garcı
guez LA, Ruigo
mez A, et al. (2004)
Association between captopril, other antihypertensive drugs and
risk of prostate cancer. Prostate 58: 50–56.
14. Zhu K, Lee IM, Sesso HD, Buring JE, Levine RS, Gaziano JM
(2004) History of diabetes mellitus and risk of prostate cancer in
physicians. Am J Epidemiol 159: 978–982.
15. Coker AL, Sanderson M, Zheng W, Fadden MK (2004) Diabetes
mellitus and prostate cancer risk among older men: population-
based case-control study. Br J Cancer 90: 2171–2175.
16. Coughlin SS, Calle EE, Teras LR, Petrelli J, Thun MJ (2004)
Diabetes mellitus as a predictor of cancer mortality in a large
cohort of US adults. Am J Epidemiol 159: 1160–1167.
17. Joint Health Surveys Unit (1999) Health Survey for England 1998.
London: The Stationery Oﬃce.
18. Hippisley-Cox J, Pringle M (2004) Prevalence, care, and outcomes
for patients with diet-controlled diabetes in general practice: cross
sectional survey. Lancet 364: 423–428.
19. Rosenberg DJ, Neugut AI, Ahsan H, Shea S (2002) Diabetes
mellitus and the risk of prostate cancer. Cancer Invest 20: 157–165.
20. DeFronzo RA (1999) Pharmacologic therapy for type 2 diabetes
mellitus. Ann Intern Med 131: 281–303.
21. Scheen AJ, Lefebvre PJ (1998) Oral antidiabetic agents. A guide to
selection. Drugs 55: 225–236.
1058 A. Gonza
rez and L.A. Garcı