Platinum Priority Prostate CancerEditorial by David Margel on pp. 10211022 of this issue

Metformin Use and Prostate Cancer Risk

Mark A. Preston a,*, Anders H. Riis b, Vera Ehrenstein b, Rodney H. Breau c, Julie L. Batista d,e,Aria F. Olumi a, Lorelei A. Mucci d,e, Hans-Olov Adami d,f, Henrik T. Srensen b

aDepartment of Urology, Massachusetts General Hospital, Boston, MA, USA; bDepartment of Clinical Epidemiology, Aarhus University, Aarhus, Denmark;c The Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada; dDepartment of Epidemiology, Harvard School of Public Health,

Boston, MA, USA; eChanning Division of Network Medicine, Department of Medicine, Brigham and Womens Hospital and Harvard Medical School, Boston,

MA, USA; fDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

E U RO P E AN URO LOG Y 6 6 ( 2 0 1 4 ) 1 0 1 2 1 0 2 0

avai lable at www.sciencedirect .com

Article info

Article history:

Accepted April 29, 2014

Keywords:

Chemoprevention

Danish registry

Epidemiology

Incidence

Metformin

Prostate cancer

The EU-ACME credits will

Abstract

Background: Metformin may decrease prostate cancer (PCa) risk by reducinghyperinsulinemia-associated carcinogenesis or through direct effects on cancer cells.Objective: To evaluate the association between metformin use and PCa diagnosis.Design, setting, and participants: We used the Danish Cancer Registry and the AarhusUniversity Prescription Database to conduct a nested casecontrol study among menresiding in northern Denmark from 1989 to 2011. We identied 12 226 cases of PCa andused risk-set sampling to select 10 population controls per case (n = 122 260) fromamongmen alive on the index date and born in the same year. A sensitivity analysis wasconducted using subjects who had prostate-specic antigen (PSA) testing prior to 1 yrbefore the index date.Intervention: Metformin exposure was assessed using prescriptions redeemed beforethe index date.Outcome measurements and statistical analysis: Odds ratios (ORs) and 95% condence

0.510.86). Diabetics on nomedication (aOR: 1.03; 95% CI, 0.861.24), diabetics on other# 2014 European Asthen be attributed

automatically.

oral hypoglycemics (aOR: 0.92; 95% CI, 0.701.20), and insulin users (aOR: 0.83; 95% CI,0.561.24) did not have a statistically signicant reduced risk of cancer.Conclusions: Metformin use was associated with decreased risk of PCa diagnosis,whereas diabetics using other oral hypoglycemics had no decreased risk.Patient summary: We studied the relationship between metformin (a diabetic medica-tion) and prostate cancer in Denmark. We found that metformin reduced the risk ofprostate cancer diagnosis, whereas other oral antidiabetic medications did not.

sociation of Urology. Published by Elsevier B.V. All rights reserved.Please visit

www.eu-acme.org/

europeanurology to read and

answer questions on-line.

intervals (CIs) were calculated using logistic regression. The association betweenmetfor-min use and PCa diagnosis was determined, controlling for diabetes severity and otherpotential confounders.Results and limitations: Metformin users were at decreased risk of PCa diagnosiscompared with never-users (adjusted OR [aOR]: 0.84; 95% CI, 0.740.96). Diabeticson no medication (aOR: 0.98; 95% CI, 0.891.09) or on other oral hypoglycemics (aOR:0.98; 95% CI, 0.861.10) did not have a reduced risk of PCa, while users of insulin didhave a reduced risk (aOR: 0.77; 95% CI, 0.640.93). In the PSA-tested group, metforminuse was associatedwith decreased risk of PCa comparedwith nonuse (aOR: 0.66; 95% CI,journal homepage: www.europeanurology.com* Corresponding author. Department of Urology, Massachusetts General Hospital, 55 Fruit Street,Boston, MA 02114, USA. Tel. +1 617 726 3012; Fax: +1 617 726 6131.E-mail address: preston.mark@gmail.com (M.A. Preston).

http://dx.doi.org/10.1016/j.eururo.2014.04.0270302-2838/# 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.

E U RO P E AN URO L OG Y 6 6 ( 2 0 1 4 ) 1 0 1 2 1 0 2 0 10131. Introduction

Prostate cancer (PCa) is the second leading cause of cancer

mortality in men and the most commonly diagnosed

noncutaneous malignancy [1,2]. Because of the high inci-

dence, substantial personal distress [35], and societal costs

[6] associated with the diagnosis and treatment of PCa,

prevention would have a powerful impact.

Hyperinsulinemia, associated with type 2 diabetes, may

play a role in carcinogenesis and be negatively associated

with cancer prognosis [7,8]. Increased levels of insulin in

obese men may lead to worse PCa prognosis [7,9,10]. This

theory is supported by laboratory evidence showing that

hyperinsulinemia upregulates insulin receptors in PCa cells

and increases tumor growth [11]. However, diabetes has

also been associated with decreased diagnosis of PCa,

potentially mediated by lower levels of testosterone in

these patients [12,13].

Metformin, a biguanide, is the most widely prescribed

antidiabetic drug in the world because of its clinical effec-

tiveness and tolerability [14]. Its primary mechanism is to

activate 50 AMP-activated protein kinase in the liver, inhibitgluconeogenesis, and reduce circulating insulin levels [15].

Metforminmayreduce insulin-stimulatedcancergrowth [16]

through this mechanism, in addition to possessing other

antineoplastic properties such as reduction of the c-Myc

oncogene [17]. However, no randomized trial has evaluated

the effect of metformin on PCa risk, while observational

studies have yielded conflicting results [1824].

We performed a large population-based study of metfor-

minuseandPCa.Wehypothesized thatmetforminusewould

be associated with decreased risk of PCa diagnosis.

2. Material and methods

2.1. Source population and study design

We conducted a nested casecontrol study within a well-dened cohort

of Danish males identied between January 1989 and December 2011.

Individuals eligible for case and control sampling resided in the

former counties of North Jutland (19892011), Aarhus (19962011),

Ringkoebing (19982011), and Viborg (19982011). In 2007, the Danish

regions replaced counties as the main administrative units. Because the

four counties started contributing data to the Arhus University

Prescription Database (AUPD) at different times, they differ with respect

to the earliest availability of prescription data (the earliest being 1989)

[25]. The Central andNorth Denmark Regions encompass the four former

counties, and the periods of required residence correspond to the period

of availability of data on prescription medication use. Together, the two

regions represent approximately one-third of the Danish population

(approximately 1.8 million inhabitants). Health-related services are

recorded using the unique civil personal registration (CPR) number

assigned to all Danish citizens since 1968 by the Danish Civil Registration

System (CRS). The CPR number encodes gender and date of birth [26] and

permits accurate individual-level linkage among all Danish registries.

The Danish National Health Service provides tax-supported universal

health care to all residents of the country and refunds part of patients

expenditures formostphysician-prescribeddrugs, includingdrugsused to

treatdiabetes [25]. TheDanish regions are servedbypharmacies equipped

with computerized accounting systems, through which data on prescrip-tions for refundabledrugs are sent to theAUPD [25]. Thedatabase includesinformation on each patients CPR number, the type of drug prescribed

(coded according to the Anatomical Therapeutic Chemical classication

system), the amount of drug dispensed, and the date of sale [25,27].

2.2. Cases

Cases weremenwith an incident diagnosis of PCa and no previous cancer

diagnosis (except nonmelanoma skin cancer) who were identied using

theDanishCancerRegistry (seeAppendixA for International Classication

of Diseases codes), which has recorded all incident cancers diagnosed in

Denmark through December 31, 2011 [28]. To be included in the study,

menhad tobe residents of the Central orNorthDanishRegions,with2 yrof prescription history before their index date (date of PCa diagnosis).

2.3. Population controls

Controls were identied using the CRS [26,29]. For each man in the case

series, 10 controlswere randomly selected from amongmale residents of

the two regionswho had the same birth year, were alive, andwere free of

PCa diagnosis on the index date. Men who resided in the study area for

same birth year and with similar duration of diabetes. Under the risk-set

sampling of controls used in this study, the ORs are unbiased estimates of

the underlying incidence rate ratios [32]. Unconditional logistic regression

was used with multivariable adjustment, including age for the PSA and

HbA1c subanalyses.We used SAS 9.2 (SAS Institute Inc., Cary, NC, USA) for

the analyses. The Danish Data Protection Agency approved the study

(2004414693).

3. Results

We identified 12 226 cases of PCa and 122 660 individually

matched controls. The median age was 71.7 yr (range:

3599) for cases and controls (range 34100). The preva-

lence of diabetes, comorbidities, marital status, statin use,

PPI use, 5-ARI use, and diabetic complications was similar

for cases and controls (Table 1).

3.1. Metformin use

A total of 264 cases (2.2%) and 3111 controls (2.5%) used

metformin for 1 yr before the index date (Table 1). Themedian duration of metformin use was 3.2 yr (interquartile

range [IQR]: 1.55.7). An additional 90 cases used insulin in

addition to metformin, for a total of 354 cases (2.9%) with

any use of metformin during the study period. Metformin

use was associated with a decreased risk of PCa compared

Table 1 Characteristics of case and control subjects (n = 134 486)

Characteristic Prostatecancer cases,n = 12 226

Controls,n = 122 260

EU RO P E AN URO LOG Y 6 6 ( 2 0 1 4 ) 1 0 1 2 1 0 2 01014Age, yr, median (range) 71.7 (34.999.2) 71.7 (34.299.9)

Diabetes, no. (%) 1213 (10) 13 516 (11)

Metformin use only 264 (2) 3111 (2)

Metformin and insulin use 90 (0.7) 1254 (1)

Any metformin use 354 (3) 4365 (4)

Insulin use 118 (1) 1564 (1)

Other antidiabetic

medication use

294 (2) 3048 (2)

No antidiabetic

medication use

447 (4) 4539 (4)

Stage, no. (%)

Localized 5202 (43)

Regional 498 (4)

Metastatic 2199 (18)

Unknown 4327 (35)

Prostate biopsy >1 yr prior to index date, no. (%)

No 11 882 (97) 12 0101 (98)

Yes 344 (3) 2159 (2)

Charlson Comorbidity Index score, no. (%)

0 8547 (70) 81 653 (66.8)

12 3257 (27) 35 087 (28.7)

3 422 (3) 5520 (4)Diabetic complications,

no. (%)

1275 (10) 14 987 (12)

Marital status, no. (%)

Married 8879 (73) 85 057 (70)

Never married 733 (6) 9602 (8)

Divorced or widowed 2614 (21) 27 601 (23)

Statin ever used, no. (%) 2276 (19) 22 952 (19)

PPI ever used, no. (%) 2472 (20) 23 407 (19)

5-ARI ever used, no. (%) 562 (5) 4733 (4)5-ARI = 5a-reductase inhibitor; PPI = proton pump inhibitor.with never-use in crude analysis (odds ratio [OR]: 0.84; 95%

CI, 0.740.95), with little change after adjustment for

potential confounders (adjusted OR [aOR]: 0.84; 95% CI,

0.740.96). A reduced risk of PCa was associated with

insulin use (aOR: 0.77; 95% CI, 0.640.93), but not with

use of other antidiabetic medications (aOR: 0.98; 95% CI,

0.861.10) or with diabetes managed without antidiabetic

medication use (aOR: 0.98; 95% CI, 0.891.09) (Table 2).

3.1.1. Duration of metformin use

Increasing duration of metformin use was associated with

decreasing incidence of PCa. Metformin use of

sta

= pr

nd u

E U RO P E AN URO L OG Y 6 6 ( 2 0 1 4 ) 1 0 1 2 1 0 2 0 1015Table 2 The association between metformin use and incident pro

Cases,n = 12 226,no. (%)

No diabetes 11 013 (90)

Diabetes treatment*

Metformin use only 264 (2)

Metformin and insulin use 90 (1)

Insulin use 118 (1)

Other antidiabetic medication use 294 (2)

No antidiabetic medication use 447 (4)

Metformin ever use^ 354 (3)

Metformin use^

Recent (12 yr ago) 241 (2)

Former (>2 yr ago) 23 (0.2)

Metformin duration of use^

tescon

E U RO P E AN URO LOG Y 6 6 ( 2 0 1 4 ) 1 0 1 2 1 0 2 01016Table 3 Characteristics of subjects with prostate-specific antigenbetween metformin use and incidence of prostate cancer, using unage

Cases,n = 2511

Prior PSA tests, no., mean (SD) 2.9 (3.0)

PSA, ng/ml, median (IQR) 11.0 (6.527.9)

No diabetes 10.6 (6.426.1)

Metformin use only 11.8 (7.429.8)

Metformin and insulin use 11.0 (7.535.1)

Insulin use 18.0 (5.551.7)

Other antidiabetic medication use 18.0 (7.841.8)

No antidiabetic medication use 13.1 (6.935.4)

No diabetes, no. (%) 2200 (88)

Diabetes treatment,* no. (%)

Metformin use 62 (2)

Metformin and insulin use 28 (1)

Insulin use 27 (1)

Other antidiabetic medication use 59 (2)

No antidiabetic medication use 135 (5)

Metformin use,^ no. (%)

Recent (12 yr ago) 56 (2)have lower levels of PSA and therefore are less likely to be

diagnosedwith PCa. In the diabetic-only analysis, insulin no

longer resulted in a significant reduction in incidence (aOR:

0.96; 95% CI, 0.751.22). This finding may be due to more

pronounced confounding by indication with insulin, since

the effect dissipated after accounting for increased diabetic

severity in the matched analysis.

While our findings support some studies, other studies

have reported either no effect or even an increased risk of

PCa following metformin use [1823]. A recent Canadian

population-based study found no association between

metformin use and risk of PCa (aOR: 1.03; 95% CI,

0.961.32) among men >66 yr with diabetes, regardless

of cancer grade [22]. Themedian duration ofmetformin use,

however, was only 18.6 mo (IQR: 637). The predominant

effect of metformin might be in mitigating cancer progres-

sion rather than in prevention, as supported by a study that

found that an increasing cumulative dose of metformin

after diagnosis was associated with a decrease in PCa

specific mortality among diabetic men [23].

Former (2 yr ago) 6 (0.2)Metformin duration of use,^ no. (%)

Table 5 The association between metformin use and incident prostate cancer stratified by localized and advanced stage using conditionallogistic regression (n = 134 486)

Localized prostate cancer Advanced prostate cancer

Cases/controls,no. (%)

Adjusted OR(95% CI)

Cases/controls,no. (%)

Adjusted OR(95% CI)

No diabetes 4709 (91)/46 392 (89) ref 2449 (91)/24 204 (90) ref

Diabetes treatment*

Metformin use only 101 (2)/1406 (3) 0.70 (0.570.87) 59 (2)/539 (2) 1.13 (0.851.49)

Metformin and insulin use 37 (1)/579 (1) 0.63 (0.450.88) 15 (0.6)/194 (0.7) 0.81 (0.481.38)

Insulin use 37 (1)/673 (1) 0.56 (0.400.78) 28 (1)/325 (1) 0.89 (0.601.32)

Other antidiabetic medication use 116 (2)/1146 (2) 1.02 (0.841.24) 67 (2)/757 (3) 0.91 (0.701.17)

No antidiabetic medication use 202 (4)/1824 (4) 1.09 (0.941.27) 79 (3)/951 (4) 0.85 (0.671.08)

Metformin ever use^ 138 (3)/1985 (4) 0.68 (0.570.82) 74 (3)/733 (3) 1.04 (0.811.34)

Metformin use^

Recent (12 yr ago) 94 (2)/1307 (3) 0.70 (0.570.87) 54 (2)/505 (2) 1.10 (0.821.47)

Former (2 yr ago) 7 (0.1)/99 (0.2) 0.72 (0.331.55) 5 (0.2)/34 (0.1) 1.55 (0.613.97)Metformin duration of use^

Table 6 Association between metformin use and incident prostate cancer among only diabetics using matched conditional logisticregression (n = 13 331)

Cases,n = 1213,no. (%)

Controls,n = 12 118,no. (%)

Adjusted OR 95% CI

Diabetic treatment*

No antidiabetic medication use 447 (37) 4181 (35) ref

Metformin use 264 (22) 2894 (24) 0.83 0.700.99

Metformin and insulin use 90 (7) 914 (8) 0.92 0.701.19

Insulin use 118 (10)

= pr

nd u

se

E U RO P E AN URO LOG Y 6 6 ( 2 0 1 4 ) 1 0 1 2 1 0 2 01018Other antidiabetic medication use 294 (24)

Metformin use^

Recent (12 yr ago) 241 (20)

Former (2 yr ago) 23 (2)Metformin duration of use^

r t

Cla

34;

E U RO P E AN URO L OG Y 6 6 ( 2 0 1 4 ) 1 0 1 2 1 0 2 0 1019Appendix A Anatomical Therapeutic Chemical codes fo

drugs, codes for the cancer diagnoses, and International

potentially confounding diseases

Disease ICD 8 code

Prostate cancer

Diabetes 249; 250

Diabetes complications 377.00; 792.99; 410; 431; 433; 4

440.28; 440.29; 440.99

Charlson Comorbidity Index diseasesReferences

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Myocardial infarction 410

Congestive heart failure 427.09; 427.10; 427.11; 427.19; 428

Peripheral vascular disease 440; 441; 442; 443; 444; 445

Cerebrovascular disease 430438

Dementia 290.09290.19; 293.09

Chronic pulmonary disease 490493; 515518

Connective tissue disease 712; 716; 734; 446; 135.99

Ulcer disease 530.91; 530.98; 531534

Mild liver disease 571; 573.01; 573.04

Diabetes 249.00; 249.06; 249.07; 249.09 250.0

250.07; 250.09

Hemiplegia 344

Moderate to severe renal disease 403; 404; 580583; 584; 590.09; 59

753.10753.19; 792

Diabetes with end organ damage 249.01249.05; 249.08 250.01250.0

Any tumor 140194

Leukemia 204207

Lymphoma 200203; 275.59

Moderate to severe liver disease 070.00; 070.02; 070.04; 070.06; 070.

573.00; 456.00456.09

Metastatic solid tumor 195198; 199

AIDS 079.83

Procedure Procedure codes

Prostate biopsy KKEB, KTKE00

Drug ATC code

Diabetes overall A10A; A10B

Insulin

Fast acting A10AA01; A10AB01; A10AB04; A10AB05

Intermediate acting A10AA02; A10AC01

Intermediate, rapid onset A10AA03; A10AD01; A10AD04; A10AD05

Other analogues, long acting A10AE; A10AE04; A10AE05

Metformin A10BA02; A10BD02; A10BD03; A10BD05

Other Rest of the A10A and A10B codes

Statins C10AA

Proton pump inhibitors A02BC

ATC = Anatomical Therapeutic Chemical; ICD = International Classication of Disehe primary exposure drugs and potentially confounding

ssification of Diseases hospital diagnosis codes for

ICD 10 code

C61

E10E14; H360; O24 except O244

436; 440.20; G62.9; G63.2; H10.2; H33.4; H43.1; H45.0; I61; I63;

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I21; I22; I23

.99; 782.49 I50; I11.0; I13.0; I13.2

I70; I71; I72; I73; I74; I77

I60I69; G45; G46

F00F03; F05.1; G30

J40J47; J60J67; J68.4; J70.1; J70.3; J84.1; J92.0; J96.1;

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M05; M06; M08; M09; M30; M31; M32; M33; M34;

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K22.1; K25K28

B18; K70.0K70.3; K70.9; K71; K73; K74; K76.0

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G81; G82

3.19; I12; I13; N00N05; N07; N11; N14; N17N19; Q61

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C00C75

C91C95

C81C85; C88; C90; C96

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C76C80

B21B24

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Metformin Use and Prostate Cancer RiskIntroductionMaterial and methodsSource population and study designCasesPopulation controlsExposureCovariatesStatistical analysis

ResultsMetformin useDuration of metformin useIntensity and cumulative dose of metformin use

Sensitivity analysesProstate-specific antigen testingSeverity of diabetesStage

DiscussionConclusionsReferences- Anatomical Therapeutic Chemical codes for the primary exposure drugs and potentially confounding drugs, codes for the cancer diagnoses, and International Classification of Diseases hospital diagnosis codes for potentially confounding diseases