Prostate Cancer Risk Among Men with Diabetes Mellitus (Spain)

Centro Español de Investigación Farmacoepidemiológica (CEIFE), Madrid, Spain.
Cancer Causes and Control (Impact Factor: 2.74). 12/2005; 16(9):1055-8. DOI: 10.1007/s10552-005-4705-5
Source: PubMed
Observational studies have associated diabetes with a decreased risk of prostate cancer. We aimed to evaluate this association using the General Practitioner Research Database in the UK.
Population based case-control study nested in a cohort.
We identified 2,183 incident cases of prostate cancer between January 1995 and December 2001. We found that diabetic patients had a decreased risk of prostate cancer (OR = 0.72; 95% CI: 0.59-0.87). This association was observed among treated diabetics (OR = 0.63; 95% CI: 0.50-0.80) but not among untreated diabetics (OR = 1.01; 95% CI: 0.73-1.40). Our results suggest that the observed reduced risk could be restricted to users of insulin or sulphonylureas.
Patients with diabetes have a decreased risk of prostate cancer. The role of antidiabetic treatment in this association warrants further research.


Available from: Luis Alberto Garcia-Rodriguez
Prostate cancer risk among men with diabetes mellitus (Spain)
A. Gonza
* & L.A. Garcı
a Rodrı
Centro Espan
ol de Investigacio
n Farmacoepidemiolo
gica (CEIFE), C/Almirante 28 2°, 28004, Madrid, Spain
Received 25 November 2004; accepted in revised form 29 March 2005
Key words: diabetes mellitus, epidemiologic studies, prostate cancer.
Objective: Observational studies have associated diabetes with a decreased risk of prostate cancer. We aimed to
evaluate this association using the General Practitioner Research Database in the UK.
Methods: Population based case–control study nested in a cohort.
Results: We identified 2,183 incident cases of prostate cancer between January 1995 and December 2001. We found
that diabetic patients had a decreased risk of prosta te cancer (OR = 0.72; 95% CI: 0.59–0.87). This association was
observed among treated diabetics (OR = 0.63; 95% CI: 0.50–0.80) but not among untreated diabetics (OR = 1.01;
95% CI: 0.73–1.40). Our results suggest that the observed reduced risk could be restricted to users of insulin or
Conclusion: Patients with diabetes have a decreased risk of prostate cancer. The role of antidiabetic treatment in
this association warrants further research.
Several epidemiologic studies have assessed the rela-
tionship between history of diabetes and prostate can-
cer. A recent meta-analysis summarized the evidence
from 14 published studies concluding that patients with
diabetes presented a small decreased risk of prostate
cancer [1].
The biological mechanisms for such association are
not fully understood. At least two different pathways
have been proposed. One involves alterations in sex
hormone levels in diabetic patients, and the other in-
volves the insulin-like growth factor (IGF)-1. Testos-
terone controls cell division in the prosta te gland [2] and
high levels of this hormone have been associated with
increased risk of prostate cancer [3]. Furthermore, cas-
trated men rarely develop prostate cancer [4]. Since
diabetic patients have been found to have decreased
androgen levels [5], this could explain in part the
observed reduced risk of prostate cancer in this popu-
lation. IGF-1 has been shown to stimulate proli feration
and inhibit apoptosis in prostate cancer cells [6]. This
factor has been associated with increased prostate can-
cer risk in some, but not all, epidemiologic studies [7].
Insulin down-regulates levels of IGF binding protein-1
(IGFBP-1) [8]. Thus, in diabetics with reduced insulin
secretion, circulating IGF-1 levels are indirectly reduced
[9], which may suppress progression of prostate cancer
to clinical stage.
This study examines the strength of the association
between diabetes, antidiabetic agents and prostate can-
cer using the General Practice Research Database in the
We used data from the General Practice Research
Database (GPRD). This database contains computer-
ized information entered by general practitioners in the
UK [10]. Data on over 2 million patients are systemat-
ically recorded and sent anonymously to the Medicines
and Health products Regulatory Agency (MHRA), that
collects and organizes this information in order to be
* Address for correspondence: Gonza
rez A, Centro Espa-
ol de Investigacio
n Farmacoepidemiolo
gica (CEIFE), C/Almirante
28 2°, 28004 Madrid, Spain. Ph. +34 91 524 0237; Fax: +34 91 524
2871 E-mail:
Cancer Causes and Control (2005) 16:1055–1058
Ó Springer 2005
DOI 10.1007/s10552-005-4705-5
Page 1
used for research projects. The computerized informa-
tion includes demographics, details from general prac-
titioner’s visits, diagnoses from specialist’s referrals and
hospital admissions, results of laboratory tests and a
free text section. Prescriptions issued by the general
practitioner are directly generated from the computer.
Several studies with the GPRD have documented the
validity and completeness of this database [11].
Study population
We identified all males 50–79 years old between January
1995 and December 2001. Patients with a code for any
cancer before starting date were excluded. The study
cohort comprised a total of 339,462 patients. A more
detailed description of the study cohort can be found
elsewhere [12].
Case ascertainment and validation
We identified 2364 patients with a code of prostate
cancer during the study period, and manually reviewed
their computerized patient profiles. After the review of
the computerized information, 2185 patients were con-
sidered incident cases of prostate cancer. We validated a
random sample of 100 patients requesting the general
practitioner to confirm the diagnosis of prostate cancer.
Since 98% of cases for whom valid information was
received were confirmed as cases we decided not to re-
quest records for the remaining cases ascertained with
the computerized review. At the end, 2183 patients were
considered cases of prostate cancer.
Cohort and nested case–control analysis
Incidence rates of prostate cancer in our study popula-
tion and risk factors were described in detail in a pre-
vious report [13]. A nested case–control analysis was
performed to assess the association between diabetes
and prostate cancer. All cases of prostate cancer
(n = 2183) identified in the study cohort were used in
the case–control analysis and we considered the date of
initial diagnosis as index date. A date during the study
period was generated at random for every member of
the study cohort. If the random date of a study member
was included in his eligible person-time, we used his
random date as the index date and marked that person
as an eligible control. This selection mechanism (i.e.,
incidence density sampling) allows that the likelihood of
being selected as a control is proportional to the person-
time at risk. Ten thousand control s were frequency-
matched by age (interval of 1 year) and calendar year
from the list of all eligible controls.
We ascertained patients with antecedents of pro sta-
tism, defined as any mention of benign prostatic
hyperplasia (BPH) and/or prostatism (with or without
surgical intervention) recorded at least more than 1 year
before the index date. We also elicited subjects’ use of
health services (visits to the general practitioner, spe-
cialist referrals, and hospital admissions) in the 2 years
prior to the index date and their body mass index.
Exposure definition
Among diabetic patients, we studied use of antidiabetic
drugs: sulphonylureas, biguanides (metformin is the
only ava ilable biguanide in the UK), and insulin. We
defined three time windows of exposure for each class of
drugs: current use, past use and never use. Current use
(treated) was categorized as use that lasted until the
index date or ended in the year prior to the index date
based on the supply of drug therapy as prescribed by the
general practitioner. Past use was use that ended more
than one year before the index date. The time window of
never use was defined as non-use of each respective drug
group at any time before the index date. Current users
were subdivided according to treatment duration into
less than 1 year, between 1 and 3 years, and more than
3 years.
Data analyses
Estimate of odds ratio (OR), assumed to be a valid
estimate of the relative risk, and 95% confidence
interval (CI) associated with prior history of diabetes
compared to no prior history were computed using
unconditional logistic regression. We present the re-
sults from three different multivariate models. In
model 1 estimates are adjusted for age, calendar year,
and NSAID use. Model 2 includes all variables in
model 1 plus body mass index an d history of pros-
tatism. The final model model 3 includes all
variables in model 2 along with health services utili-
zation. For the analyses presented in Table 1 we cre-
ated a single variable in which we categorized treated
diabetics into users of sulphonylureas only, biguanides
only, oral combination (sulphony lureas and bigua-
nides), insulin only, and insulin oral (insulin plus any
oral agent).
The median age was the same among cases and controls
(72 years old). A total of 153 cases and 756 controls had a
1056 A. Gonza
rez and L.A. Garcı
a Rodrı
Page 2
history of diabetes, representing prevalence rates of 7.0
and 7.6%, respectively. The percentage of untreated
diabetics was 35% among cases and 24% among con-
We found that diabetes patients had a reduced risk
of prostate cancer compared to non-diabetics. The
age-adjusted r elative risk was 0.92 (95% CI: 0.77–
1.10). Adjusting for potential confounders resulted in
a lower relative risk (OR = 0. 72, 95% CI: 0.59–
0.87). The observed association between d iabetes and
prostate cancer was modified by antidiabetic treat-
ment. Thus, whereas those patients treated with an-
tidiabetic drugs experienced a 37% reduced risk of
prostate cancer, diabetic patients who had never used
these drugs had a similar risk than non-diabetics
(Table 1). Also, we found that the risk of prostat e
cancer differed depending on the t ype of antidiabetic
Overall, current sulphonylureas and insulin use was
associated with an OR of 0.60 (95% CI: 0.42–0 .85) and
0.49 (95% CI: 0.26–0.90), respectively. The reduced
risk was present since the beginning of either sulpho-
nylureas or insulin use and remained constant all over
the treatment duration period (data not shown). Cur-
rent use of biguanides (metformin) was not associated
with a decreased risk of prostate cancer (OR = 1.16,
95% CI: 0.63–2.14) after ad justing for other antidia-
betic treatment. We still did not observe a risk reduc-
tion in users of 3 years or more of metformin
(OR = 1.10, 95% CI: 0.60–2.01). The same analysis
was performed among diabetic patients only yielding
virtually identical results.
In our study, diabetes was associated with a reduced risk
of prostate cancer. The magnitude of this inverse asso-
ciation was 30% after adjustment for potential con-
founding factors. This estimate of risk is consistent with
results from three recently published studies [14–16].
Bonovas et al. examined the association between dia-
betes and prostate cancer by conducting a meta-analysis
of the relevant studies published up to 2003. They
analyzed a total of 14 studies and concluded that dia-
betes is associated with a moderate decreased risk of
prostate cancer (RR = 0.91, 95% CI: 0.86–0.96) [1].
The prevalence of diabetes in our study population
(7.6%) is in line with prior reports among men above
50 years of age in the UK (6.7%) [17]. The proportion
of diabetic patients not treated with hypoglycemic
agents in our study is also consistent with a recently
published study [18].
To the best of our knowl edge there is only one small
published study analyzing the effect of antidiabetic
treatment [19]. The RR estimates for untreated diabet-
ics, as well as for users of sulphonylureas and insulin in
this study (0.99, 0.85, and 0.44, respectively) were simi-
lar to the ones presented here. However sparse data
resulted in very wide confidence intervals. Unfortunately
metformin was not approved in the US during the study
period and no estimate was reported for this drug.
Sulphonylureas and biguanides are the two more
common classes of oral antidiabetics used in our study
population. They have completely different modes of
action. While sulphonylureas act as insulin secreta-
Table 1. Risk of prostate cancer associated with diabetes
Model 1
Model 2
Model 3
OR (95% CI) OR (95% CI) OR (95% CI)
1.0 1.0 1.0
Yes 0.92 (0.76–1.10) 0.93 (0.77–1.11) 0.72 (0.59–0.87)
Untreated 1.23 (0.90–1.67) 1.21 (0.88–1.65) 1.01 (0.73–1.40)
Treated 0.80 (0.64–1.01) 0.82 (0.66–1.03) 0.63 (0.50–0.80)
Sulpho only 0.76 (0.54–1.07) 0.77 (0.55–1.09) 0.60 (0.42–0.85)
Biguanides only 1.41 (0.78–2.54) 1.49 (0.82–2.70) 1.16 (0.63–2.14)
Combination oral 0.88 (0.57–1.35) 0.88 (0.57–1.36) 0.70 (0.45–1.09)
Insulin 0.64 (0.35–1.17) 0.67 (0.37–1.24) 0.49 (0.26–0.90)
Insulin and oral 0.28 (0.07–1.16) 0.28 (0.07–1.20) 0.20 (0.05–0.86)
Past use 0.89 (0.33–2.35) 0.84 (0.31–2.23) 0.71 (0.26–1.94)
Estimates are adjusted for age, calendar year, NSAID use, and all the variables included in the table using unconditional logistic regression.
Estimates are adjusted for age, calendar year, NSAID use, prior history of prostatism, body mass index and all the variables included in the
table using unconditional logistic regression.
Estimates are adjusted for age, calendar year, NSAID use, prior history of prostatism, body mass index, health care utilization (GP visits,
referrals, hospitalizations), and all the variables included in the table using unconditional logistic regression.
Reference category.
Diabetes and prostate cancer 1057
Page 3
gogues, biguanides do not increase insulin circulating
levels but reduce hepatic gluconeogenesis and stimulate
glycolysis in tissues [20]. Also biguanides neither in-
crease weight nor provoke hypoglycemia, which makes
them suitable to treat overweight and obese type II
diabetic patients [21].
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 [21]. 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
from AstraZeneca.
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    • "We also observed higher risks of breast, bladder , and endometrium cancers in women, which is consistent with findings from previous studies [19]. A significant inverse association between diabetes and prostate cancer has been observed in men, which is also consistent with previous epidemiological studies [19,35363738, but inconsistent with those that show no associations303132333439]. At the other sites, we found a negative association for esophageal and laryngeal cancers in males, as well as for cervical and connective and other soft tissue cancers in females. "
    [Show abstract] [Hide abstract] ABSTRACT: Background This study aims to determine cancer risks among patients with type 2 diabetes through a follow-up study on a nationwide population-based cohort that included Taiwanese diabetic patients and general population in Taiwan as well as to estimate the population attributable fraction (PAF) of site-specific cancer risks that can be attributed to type 2 diabetes in Taiwanese population by using standardized incidence ratios (SIRs, 95% CI). Methods Subjects with type 2 diabetes consisted of 472,979 patients aged ≥20 years, whereas general population consisted of 9,411,249 individuals of the same age limit but are not diabetic. Subjects were identified from 1997 to 1998 and followed up until December 31, 2007 or until the first manifestation of any cancer. Results Cancer sites with increased risks in men, which were consistent with the main and sensitivity analyses, included pancreas (SIR = 1.62; 95% CI = 1.53 to 1.72), liver (1.61; 1.57 to 1.64), kidney (1.32; 1.25 to 1.40), oral (1.16, 1.12 to 1.21), and colorectal (1.19, 1.15 to 1.22). Cancer sites with increased risks in women included liver (1.55; 1.51 to 1.60), pancreas (1.44; 1.34 to 1.55), kidney (1.38; 1.30 to 1.46), endometrium (1.36; 1.26 to 1.47), bladder (1.19; 1.11 to 1.27), colorectal (1.16; 1.13 to 1.20), and breast (1.14; 1.09 to 1.18). Overall, PAFs were highest for liver cancer in men (4.0%) and women (3.7%), followed by pancreas (3.4%) and kidney (1.6%) cancers in men, and then for endometrium (1.8%) and kidney (1.8%) cancers in women. Conclusion Our data suggested that increased cancer risks are associated with type 2 diabetes.
    Full-text · Article · May 2014 · BMC Cancer
  • Source
    • "Patients were followed until a first-ever primary diagnosis of colorectal cancer (outcome), death from any cause, end of registration with the general practice, or end of the study period (31 December 2009), whichever came first. Cancer diagnoses, including prostate and colorectal cancer, have shown high validity in the GPRD, with sensitivities and positive predictive values exceeding 90 %17181920, and with case ascertainment rates comparable to UK cancer registries [21]. "
    [Show abstract] [Hide abstract] ABSTRACT: Purpose: Androgens are known to play an important protective role on colorectal carcinogenesis, and thus the objective of this study was to determine whether androgen deprivation therapy (ADT) is associated with an increased risk of incident colorectal cancer in patients with prostate cancer. Methods: We conducted a population-based cohort study within the UK General Practice Research Database population which included all patients newly diagnosed with prostate cancer between 1 January 1988 and 31 December 2008, followed until 31 December 2009. Time-dependent Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs) of incident primary colorectal cancer associated with the use of ADT. Secondary analyses considered cumulative duration of use and specific ADTs. Results: The cohort included a total of 21,503 patients, of whom 184 were diagnosed with colorectal cancer during a mean (SD) follow-up 4.0 (3.0) years (rate 2.4/1,000 person-years). Overall, use of ADT was not associated with an increased risk of colorectal cancer (HR 0.99, 95 % CI 0.73-1.35). Similarly, no association was observed in terms of duration use, although this secondary analysis may have been limited by statistical power. With respect to specific ADTs, bilateral orchiectomy was the only therapy associated with an increased risk of colorectal cancer (HR 2.50, 95 % CI 1.13-5.52). Conclusion: Overall, the use of ADT is not associated with an increased risk of incident colorectal cancer. The increased risk observed with bilateral orchiectomy may possibly be due to the prolonged androgen suppression of this therapy.
    Full-text · Article · Apr 2013 · Cancer Causes and Control
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    • "Abstract Bonovas et al (2004). Later in 2006, another meta-analysis containing 19 studies (Wynder et al., 1971; Ragozzino et al., 1982; Mishina et al., 1985; Thompson et al., 1989; Smith et al., 1992; Steenland et al., 1995; Coughlin et al., 1996; Will et al., 1999; Rosenberg et al., 2002; Tavani et al., 2002; Weiderpass et al., 2002; Coker et al., 2004; Lightfoot et al., 2004; Zhu et al., 2004; Gonzalez-Perez et al., 2005; Rodriguez et al., 2005; Tavani et al., 2005) was published (Kasper et al., 2006). They both showed that diabetic patients have a statistically significant (9% in 2004 and 16% in 2006) decrease in the risk of developing PCa. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Prior studies examining the relation between diabetes mellitus (DM) and prostate cancer risk have reported controversial findings. We examined this association by conducting a detailed meta-analysis of the peer-reviewed literature. Methods: A comprehensive search for articles of MEDLINE and EMBASE databases and bibliographies of retrieved articles published up to November, 2012 was performed. Methodological quality assessment of the trials was based on the Newcastle-Ottawa Scaleq and the meta-analysis was performed using STATA 12.0. Dose-response regression was conducted with SPSS 19.0. Results: We included 29 studies in the meta-analysis (13 case-control studies, 16 cohort studies), and found an inverse association between DM and prostate cancer (relative risk (RR) 0.84, 95% confidence interval (CI), 0.78-0.91). An inverse association was also observed in non-Asian populations (RR 0.81, 95% CI 0.76-0.87) and population-based studies (RR 0.80, 95% CI 0.77-0.91). No statistical significance was found of the association between prostate cancer risk and the duration of DM (p=0.338), and risk seemed not related with the age of DM diagnosis. Conclusions: This study suggested an inverse relationship between DM and prostate cancer, but without links to duration of disease or age of diagnosis.
    Full-text · Article · Jan 2013 · Asian Pacific journal of cancer prevention: APJCP
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