Statins and Pancreatic Cancer Risk in Patients with ... · INTRODUCTION Chronic pancreatitis is an...

Statins and Pancreatic Cancer Risk in Patients with Chronic Pancreatitis: A

Danish nationwide population-based cohort study

Jakob Kirkegård1,2, Jennifer L. Lund2,3, Frank Viborg Mortensen1, Deirdre Cronin-Fenton2

1 Department of Surgery, Section for Hepato-Pancreato-Biliary Surgery, Aarhus University

Hospital, Denmark

2 Department of Clinical Epidemiology, Aarhus University Hospital, Denmark

3 Department of Epidemiology, Gillings School of Global Public Health, University of North

Carolina at Chapel Hill, North Carolina, USA

Correspondence: Jakob Kirkegård, Department of Surgery, HPB Research Unit, Aarhus

University Hospital, Palle Juul-Jensens Boulevard 99, DK-8200 Aarhus N, DENMARK

Phone: +45 78 45 00 00 / E-mail: [email protected]

Short tile: Statins, chronic pancreatitis, and pancreatic cancer.

Category: Cancer Epidemiology

Keywords: statins; pancreatitis; pancreatic cancer; epidemiology; risk factors

Novelty and impact: Statins are widely used prescription drugs that may have anti-cancer

properties. In the present nationwide population-based cohort study of 8,311 chronic

pancreatitis patients, exposure to statins was not associated with an increased or decreased

risk of pancreatic cancer. This finding that was robust to several sensitivity analysis and

Conflicts of Interest: Dr. Lund’s spouse is a full-time, paid employee of GlaxoSmithKline. Dr. Kirkegård, Dr. Mortensen, and Dr. Cronin-Fenton have nothing to disclose.

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/ijc.32264

This article is protected by copyright. All rights reserved.

underlines that prevention of pancreatic cancer in patients with chronic pancreatitis, a high-

risk group, is still a major challenge.


ABSTRACT

Statins (HMG-CoA reductase inhibitors) have anti-inflammatory and possibly anti-cancer

properties. We hypothesized that statin use is associated with lower risk of pancreatic cancer

in patients with chronic pancreatitis. This nationwide population-based cohort study included

all Danish patients diagnosed with incident chronic pancreatitis from 1 January 1996 to 31

December 2012. We used the Danish National Prescription Registry to ascertain information

on statin prescriptions for members of the study population before and after their pancreatitis

diagnosis. We computed crude incidence rates, incidence rate ratios (IRRs), and adjusted

hazard ratios (HRs) with associated 95% confidence intervals (CIs) for pancreatic cancer,

comparing statin users with non-users. We computed HRs using Cox proportional hazards

regression with statins treated as a time-varying exposure lagged by one year, adjusting for

age, sex, socioeconomic status, and individual comorbidities. The study included 8,311

chronic pancreatitis patients with a median age of 54 years. In total, 153 pancreatic cancers

were observed during 60,365 person-years of follow-up. The unadjusted IRR comparing

statin users with non-users was 1.00 (95% CI: 0.60-1.60). Adjustment for potential

confounders only had a small impact on the estimate (adjusted HR: 0.90; 95% CI: 0.56-1.44).

Our findings suggest that statin use is not associated with pancreatic cancer risk in patients

with chronic pancreatitis.


INTRODUCTION

Chronic pancreatitis is an inflammatory disease characterized by progressive and irreversible

destruction of the exocrine and endocrine pancreas.1 Some patients with chronic pancreatitis

eventually progress to pancreatic cancer,2 which has a poor prognosis.3 While this

progression has not been fully elucidated, inflammatory activation of pancreatic stellate cells

may play an important role.4 Accordingly, inhibition of inflammation within the pancreas may

help to protect against pancreatic cancer.

Statins (3-hydroxy-3-methyl-glutaryl-coenzyme A [HMG-CoA] reductase inhibitors)

are widely used cholesterol-lowering drugs. In addition to their anti-inflammatory properties,

statins may also inhibit carcinogensis.5 However, a previous meta-analysis found no

association between regular statin use and risk of pancreatic cancer.6 The anti-inflammatory

effect of statins is intriguing due to the close relation between inflammation and cancer, both

in the pancreas2, 7 and in general.5 Furthermore, experimental studies suggest that statins

can decrease pancreatic cancer risk by interfering with vital intracellular signaling pathways.8-

23

A recently published Danish case-cohort study of approximately 4,800 chronic

pancreatitis patients suggested that statin use was associated with an 80% reduction in

pancreatic cancer risk.24 Although a compelling finding, the study reported a crude null

finding and the beneficial effect of statins was only evident in a propensity-score matched

analysis of 339 statin users (7% of the total population). Given the rising incidence of chronic

pancreatitis25 and high mortality from pancreatic cancer, this potential association requires

further clarification.


We therefore conducted a population-based cohort study, using nationwide Danish

healthcare registries, to examine the association between statin use and pancreatic cancer

risk in patients with chronic pancreatitis.

MATERIALS AND METHODS

Setting and data sources

This nationwide population-based cohort study used data from the 1996-2015 period,

obtained from the Danish National Patient Registry, the National Prescription Registry, the

Civil Registration System, and the Danish Cancer Registry.26-29 These registries can be

linked on an individual level using the Civil Personal Registration (CPR) number, which is

assigned to every Danish resident at birth or upon immigration.

The Danish National Patient Registry was established in 1977. It contains information

on all inpatient hospitalizations at Danish public hospitals. Outpatient and emergency room

visits have been included since 1995. Patients are registered in the Danish National Patient

Registry with diagnoses coded according to the International Classification of Diseases (ICD)

8th revision (ICD-8) from 1977 through 1993 and ICD 10th revision (ICD-10) thereafter.

The Danish National Prescription Registry has collected detailed information on all

prescriptions filled at Danish community-based pharmacies since 1995.27 This registry

contains Anatomical Therapeutic Chemical (ATC) classification codes for drugs, purchase

dates, and dose information, among other variables.

The Danish Cancer Registry includes information on all cancers diagnosed in

Denmark since 1943, including date of diagnosis, cancer site, tumor characteristics, and

other variables.


The Civil Registration System, which was established in 1968, is an administrative

registry containing data on such variables as CPR-number, birth date, sex, sequential dates

of migration, vital status, and date of death for every resident in Denmark. The Civil

Registration System is updated daily and is virtually complete.

Study population

We identified all patients with an incident diagnosis of chronic pancreatitis recorded in the

Danish National Patient Registry during 1 January 1996 through 31 December 2012 (see

eFigure 1 and eTable 1). We excluded patients with a chronic pancreatitis diagnosis prior to

1 January 1996 to avoid including prevalent cases. We also excluded patients with a

diagnosis of hereditary or autoimmune pancreatitis as hereditary pancreatitis is associated

with a 70-fold relative risk of pancreatic cancer,30 and autoimmune pancreatitis is a systemic

autoimmune immunoglobin G4 disease and not confined to the pancreas.31, 32 Therefore,

including these diseases would limit homogeneity of our population and could bias our

estimates and complicate interpretation of our findings. We also excluded patients aged less

than 20 years at diagnosis, as such young patients often have autoimmune pancreatitis.

Other exclusions were birth or living outside Denmark prior to chronic pancreatitis diagnosis,

and a diagnosis of pancreatic cancer prior to chronic pancreatitis.

Follow-up and outcomes

We defined each patient’s index date as the date of first chronic pancreatitis diagnosis plus

one year. We required at least one full year of follow-up after the index date to reduce the

risk of misclassifying pancreatic cancer as chronic pancreatitis, as it is difficult to distinguish

these two conditions (i.e., a chronic pancreatitis diagnosis occurring less than a year prior to


a pancreatic cancer diagnosis would most likely be attributable to misdiagnosis of pancreatic

cancer).33 We followed each patient from the assigned index date to the first diagnosis of

pancreatic cancer recorded in the Danish Cancer Registry, death, emigration, or 31

December 2015. We considered pancreatic ductal adenocarcinomas and pancreatic cancers

with unknown histology (as the vast majority are expected to be adenocarcinomas34) as the

outcome of interest. Patients diagnosed with pancreatic cancer with a morphology other than

ductal adenocarcinoma were censored on the cancer diagnosis date (see eTable 2). The

follow-up schema is depicted graphically in eFigure 2. Information on tumor stage (recorded

in the Danish Cancer Registry as localized, regional, or metastatic) was available since study

start. Information on the American Joint Committee of Cancer stage, which is based on the

tumor-node-metastasis classification,35 was available since 2004.

Information on drug exposure

From the Danish National Prescription Registry, we identified all prescriptions filled by the

study participants since 1995 for the following medications: statins, other cholesterol-

lowering drugs, proton pump inhibitors (PPIs), non-steroidal anti-inflammatory drugs

(NSAIDs), and pancreatic enzyme supplements (see eTable 3).

Information on comorbidity

For each patient, we retrieved a medical history based on ICD-8 and ICD-10 codes from the

Danish National Patient Registry, restricting to diagnoses in the 10 years prior to chronic

pancreatitis diagnosis. We identified the following selected comorbid conditions: alcohol- and

smoking-related diseases (as proxies for excessive alcohol consumption and tobacco

smoking), diabetes, obesity, cerebrovascular disease, cardiovascular disease, liver disease,


renal disease, hyperlipidemia, previous malignancy, ulcer, and chronic hepatitis B or C (see

eTable 4). We also captured alcohol-related diseases, smoking-related diseases, and

diabetes not registered in the Danish National Patient Registry using ATC codes identified in

the National Prescription Registry. If a patient filled a prescription for a drug used to treat any

of these three conditions, he or she was considered to be living with the disease from the

date the first prescription was filled (see eTable 3).

Covariates

Age, sex, and socioeconomic status

We retrieved information on the patients’ age, sex, and socioeconomic status in the year of

chronic pancreatitis diagnosis from the Civil Registration System. We defined four levels of

socioeconomic status: employed, unemployed, retired, and other/unknown.

Drug exposure

We defined drug exposure as at least two filled prescriptions in the same drug class (e.g., a

patient with one prescription for simvastatin and one prescription for atorvastatin would be

classified as exposed to statins from the date of the second prescription). For each

prescription, we calculated the number of days’ supply as the daily dose multiplied by the

number of pills dispensed. For statins, we used the daily dose recommended by the Danish

Board of Health36 and for the other drugs of interest we used the defined daily dose specified

in the World Health Organization’s classification (for details, see eTable 5).

We considered drug exposure to be time-varying with a one-year lag period, allowing

patients to switch between exposed and unexposed status. Patients were considered

exposed from the prescription start date, plus one year, until one year following the last


prescription date (see eFigure 2) The one-year lag period served two purposes: 1) to allow a

reasonable induction period for a drug effect to occur, and 2) to preclude that an imminent

pancreatic cancer diagnosis might have influenced a physician’s prescribing behavior (i.e.,

reverse causation). For each drug class of interest, we considered the exposure to be

continuous if two prescriptions plus their days’ supply overlapped, allowing a 30-day grace

period for delays in prescription filling. To reduce the impact of outlier prescription durations,

we tabulated the days’ supply for each prescription and excluded prescriptions with a

duration below the 5th percentile. Prescriptions with a duration above the 95th percentile were

truncated at this level.

Comorbidity

In addition to the specific comorbidities, we constructed a composite measure of the overall

comorbidity burden for each patient using the Gagne Comorbidity Index, including

comorbidities diagnosed in the year preceding chronic pancreatitis diagnosis (see eTable

6).37 Based on this index, we defined three levels of comorbidity burden: low (score ≤0),

moderate (score 1-2), and severe (score >2). The Gagne Comorbidity Index combines the

Elixhauser and Charlson Indices and has proved superior to the other indices used alone.37

Statistical analyses

Main analysis

We tabulated descriptive characteristics of the study population according to statin use (ever

versus never use). We defined ever users as patients exposed to statins at any time during

follow-up. Because we allowed exposure to be time-varying, we also present descriptive

characteristics according to person-years accrued in each category. Continuous variables


are presented as medians with interquartile ranges (IQRs). For both statin users and non-

users, we computed the incidence rate of pancreatic cancer as the number of events divided

by the person-years accrued in each exposure category. We calculated the crude incidence

rate ratio (IRR) as the ratio between the incidence rate among statin users and that among

non-users. Using a multivariable Cox proportional hazards regression model, we estimated

the hazard ratio (HR) of pancreatic cancer comparing statin users with non-users. Based on

a directed acyclic graph (eTable 7), we adjusted our multivariable models for age as a

restricted cubic spline with three knots, sex, socioeconomic status, and Gagne Comorbidity

Index score. We included the Gagne Comorbidity Index score as a time-varying covariate,

updated each time the drug exposure changed to mitigate the impact of potential time-

varying confounding of comorbidities diagnosed after chronic pancreatitis. To examine

potential effect measure modification from age, sex, calendar period of chronic pancreatitis

diagnosis, and burden of comorbidity as of the index date, we stratified our models on these

variables. All estimates are presented with associated 95% confidence intervals (CIs).

Statistical analyses were performed using Stata 15 (StataCorp LP, College Station, Texas,

USA).

Sensitivity analyses

We conducted several sensitivity analyses to examine the robustness of our results. First, we

examined the potential effect of reverse causation on our estimates by alterations in the drug

exposure lag period from one year to one month and two years, respectively. Second, we

varied the grace period to 50% of the previous prescription duration to assess the robustness

of the assumed 30-day period used in our primary analysis. In a third analysis, we restricted

to patients with at least five years of prescription history available (patients diagnosed with


chronic pancreatitis on or after 1 January 2001) and excluded patients exposed to statins

during the five years preceding chronic pancreatitis diagnosis to mitigate potential selection

bias attributable to inclusion of prevalent statin users.38, 39

Ethical considerations

This study was approved by the Danish Data Protection Agency (J.no. 1-16-02-139-16),

Statistics Denmark, and the Danish Health Data Authority. According to Danish law, ethics

board approval is not required for registry-based studies.

RESULTS

Descriptive characteristics

We identified 8,311 patients with incident chronic pancreatitis in Denmark during the study

period (Table 1). Median age was 54 years (IQR: 45-64 years), and 5,498 (66.2%) were

men. On their index date, 654 patients (7.9%) were prevalent statin users, and 2,318 patients

(27.9%) filled a statin prescription during follow-up. Median duration of patients’ cumulative

statin prescriptions was 2.8 years (IQR: 1.3-5.3 years). Statin users had a higher Gagne

Comorbidity Index score compared with non-users. Socioeconomic status was similar among

statin users and non-users.

Pancreatic cancer characteristics

We observed 153 pancreatic cancers, 95 (62%) of whom had an assigned tumor stage. Of

these, 13 (13.7%) were early-stage cancer (localized or stage I-II), 28 (29.5%) had spread to

the lymph nodes (regional or stage IIB-III), and 54 (56.8%) were metastatic (stage IV).


Pancreatic cancer risk

The 153 pancreatic cancers were observed during 60,365 person-years of follow-up, yielding

a crude IRR of 1.00 (95% CI: 0.60-1.60). The estimate did not change substantially after

adjustment for potential confounders (adjusted HR: 0.90; 95% CI: 0.56-1.44); Table 2.

Additional adjustment for diabetes decreased the risk estimate but the precision did not

change (adjusted HR: 0.74; 95% CI: 0.46-1.19). We observed a tendency towards a

decreased pancreatic cancer risk with increasing age among statin users but no effect

measure modification by sex, calendar period of chronic pancreatitis diagnosis, or

comorbidity. However, because of the low number of events in each stratum, a meaningful

interpretation of these analyses is difficult. Alterations in the lag period or grace period or

restriction to non-prevalent users had no measurable impact on our estimates (Table 2).

DISCUSSION

In the current population-based cohort study, we found little evidence of an association

between statin use during the course of chronic pancreatitis and the risk of pancreatic

cancer. Our null finding remained robust in several sensitivity analyses.

Chronic pancreatitis patients constitute a group of individuals with a high pancreatic

cancer risk,2 and the burden of chronic pancreatitis is increasing.25 Therefore, measures to

prevent the progression from chronic pancreatitis to pancreatic cancer is important. However,

the association between statin use and pancreatic cancer risk in patients with chronic

pancreatitis has only been examined in one previous study,24 a Danish case-cohort study,

which had an overlapping study population. Although they reported a crude null finding in


4,807 patients with chronic pancreatitis, findings from their propensity-score matched

analysis suggested an 80% relative reduction in pancreatic cancer risk among statin users.

There are multiple differences between our studies. Bang et al. were able to find matches for

only 339 (7%) statin users, restricting inference to a small and likely selected population.

Despite this, substantial imbalances in baseline covariates were still present, increasing the

risk of residual confounding. The propensity score matching led to substantial differences in

the distribution of person-time between statin users and non-users. In the unmatched

analysis, 38% of the person-time was accrued by statin users (14% in our study). After

matching, this number increased to 58%. This imbalance inflates the person-time among

statin users relative to non-users, potentially generating a spuriously strong protective effect

of statins. Last, their estimate was based on only four cancers. By incorporating time-varying

methods and lagging prescription exposure, we reduced bias in our study.

Although our findings agree with a previous meta-analysis that found no association

between statin use and pancreatic cancer risk in healthy individuals,6 they contrast with the

substantial experimental evidence suggesting that statins inhibit pancreatic carcinogenesis.8-

23 An explanation for this discrepancy may be that poor lifestyle choices such as excessive

alcohol consumption, tobacco smoking, or a high level of comorbidity, which is frequently

seen in chronic pancreatitis patients40, 41 may mitigate any potentially beneficial effect of

statins. Furthermore, the potential anti-cancer effect of statins may differ according to statin

solubility (i.e., lipophilic or hydrophilic),42 which our study was large enough to examine. In

addition, statins may elicit their anti-cancer effect by inhibiting the Ras cellular pathway.43

The Ras pathway is activated by a K-ras mutation, which is prevalent in nearly all pancreatic

cancers and occurs at an early stage of malignant transformation.34 However, a substantial


proportion of chronic pancreatitis patients also harbor K-ras mutations,44, 45 precluding an

inhibitory effect of statins on such a mutation.

The present study has strengths. First, we conducted a nationwide, population-based

study with near-complete follow-up, limiting the possibility of selection bias. Our long look-

back period in the Danish National Patient Registry to 1977 decreased the likelihood of

including prevalent chronic pancreatitis patients, further mitigating potential bias. Second,

chronic pancreatitis diagnoses in the Danish National Patient Registry have been shown to

have high validity throughout the study period.46 Third, we had information on all statin

prescriptions filled in Denmark during the study period, as all prescriptions are captured in

the Danish National Prescription Registry and over-the-counter sale of statins is not allowed

in Denmark. The prevalence of statin use (8%) in our study approximates that of the general

population (11%), limiting concern of exposure misclassification.47 Fourth, our design using

time-varying exposures effectively decreased the risk of immortal time bias.48 To reduce a

potential effect of reverse causation, we lagged drug exposure by one year. Although the

choice of a one-year lag period was arbitrary and could have affected our analyses, findings

from our sensitivity analyses indicates that reverse causation is of limited concern.

Some limitations should be noted though. The number of pancreatic cancers in the

cohort was low, reducing precision of our estimates. However, it is reassuring that all

estimates were centered around the null. Our information on statin use was limited to

prescriptions filled rather than actual consumption of the prescribed medication. As

previously noted, compliance with prescription drugs among chronic pancreatitis patients

may be substantially impaired, possibly mitigating any potentially beneficial effect of statins

on pancreatic cancer risk. We also lacked information on prescription duration. Instead, we

used the recommended dose to calculate the number of days’ supply. If statin users in fact


used a different dose than recommended, this would have led to non-differential

misclassification (independent of the outcome), biasing our estimate towards the null.

Furthermore, we had limited information on tobacco smoking and alcohol consumption, both

of which are associated with pancreatic cancer.49, 50 Instead, we assessed exposure to these

substances using proxy diagnoses in the Danish National Patient Registry, which are known

to have limited ability to capture exposure to alcohol and tobacco.51 However, we observed a

high prevalence of these diagnoses in our study, limiting the concern of underreporting.

In conclusion, findings from the present nationwide population-based cohort study

provide evidence against an association of statin use with the risk of pancreatic cancer in

patients with chronic pancreatitis. However, it is not clear from our study if the pancreatic

cancer risk differs according to statin solubility. This should be further investigated in a larger

study population.


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Table 1. Baseline characteristics of 8,311 patients diagnosed w

ith chronic pancreatitis in Denm

ark during 1996-2012.

Patients

Person-years

Statin ever users

(%)

Statin never users

(%)

Statin users (%)

Non-users (%

)

Overall

2,318 (27.9%)

5,993 (72.1%)

8,278 (13.7%)

52,087 (86.3%)

Age

≤45 years

400 (17.3%)

1,865 (31.1%)

1,525 (18.5%)

19,411 (37.3%)

46-55 years

632 (27.3%)

1,734 (28.9%)

2,518 (30.4%)

15,531 (29.8%)

56-65 years

709 (30.6%)

1,194 (19.9%)

2,526 (30.6%)

9,729 (18.7%)

>65 years

577 (24.9%)

1,200 (20.0%)

1,689 (20.4%)

7,416 (14.2%)

Sex

M

en 1,489 (64.2%

) 4,009 (66.9%

) 5,345 (64.6%

) 34,385 (66.0%

)

W

omen

829 (35.8%)

1,984 (33.1%)

2,922 (35.4%)

17,702 (34.0%)

Socioeconomic status

E

mployed

681 (29.4%)

1,692 (28.2%)

2,777 (33.5%)

18,149 (34.8%)

U

nemployed

160 (6.9%)

462 (7.7%)

560 (6.8%)

4,685 (9.0%)

R

etired 1,447 (62.4%

) 3,580 (59.7%

) 4,807 (58.1%

) 26,997 (51.8%

)


O

ther/unknown

30 (1.3%)

259 (4.3%)

133 (1.6%)

2,257 (4.3%)

Period of diagnosis

1996-2003

977 (42.2%)

2,996 (50.0%)

4,381 (52.9%)

34,252 (65.8%)

2004-2012

1,341 (57.9%)

2,997 (50.0%)

3,896 (47.1%)

17,835 (34.2%)

Gagne C

omorbidity Index score

Low

(≤ 0) 1,275 (55.0%

) 3,119 (52.0%

) 5,036 (60.8%

) 24,708 (62.2%

)

M

oderate (1-2) 801 (34.6%

) 2,287 (38.2%

) 2,599 (31.4%

) 21,730 (32.6%

)

S

evere (>2) 242 (10.4%

) 587 (9.8%

) 643 (7.9%

) 5,649 (5.2%

)

Com

orbidity diagnoses

A

lcohol-related disease 799 (34.5%

) 2,744 (45.8%

) 1,015 (12.3%

) 22,129 (42.5%

)

S

moking-related disease

748 (32.3%)

2,406 (40.2%)

1,065 (12.9%)

17,567 (33.7%)

O

besity 129 (5.6%

) 148 (2.5%

) 284 (4.3%

) 1,470 (2.8%

)

D

iabetes mellitus

862 (37.2%)

1,088 (18.2%)

1,581 (19.1%)

10,337 (19.8%)

C

erebrovascular disease 298 (13.9%

) 398 (9.0%

) 655 (7.9%

) 2,909 (5.6%

)

C

ardiovascular disease 609 (26.3%

) 542 (18.3%

) 1,421 (17.2%

) 5,204 (10.0%

)

Liver disease

265 (11.4%)

1,097 (4.0%)

351 (4.2%)

7,647 (14.7%)

R

enal disease 154 (6.6%

) 238 (4.5%

) 268 (3.2%

) 1,667 (3.2%

)

H

yperlipidemia

400 (17.3%)

111 (1.9%)

1,214 (14.7%)

1,830 (3.5%)

P

revious malignancy

137 (5.9%)

448 (7. 5%)

271 (3.3%)

2,752 (5.5%)


U

lcer 315 (13.6%

) 882 (14.7%

) 477 (5.8%

) 7,699 (14.8%

)

C

hronic hepatitis B or C

<10*

99 (1.7%)

<10* 602 (1.2%

)

Medication use at baseline

S

tatins 654 (28.2%

) -

2,443 (29.5%)

781 (1.5%)

O

ther cholesterol-lowering drugs

31 (1.3%)

22 (0.4%)

172 (2.1%)

198 (0.4%)

N

on-steroidal anti-inflamm

atory drugs 286 (12.3%

) 599 (10.0%

) 1,061 (12.8%

) 4,851 (9.3%

)

P

roton pump inhibitors

666 (28.7%)

1,330 (22.2%)

2,169 (26.2%)

9,635 (18.5%)

P

ancreatic enzymes

104 (4.5%)

252 (4.2%)

346 (4.2%)

1,869 (3.6%)

* Num

bers collapsed for confidentiality purposes.


Table 2. Risk of pancreatic cancer in 8,311 patients diagnosed w

ith chronic pancreatitis in Denm

ark during 1996-2012 according to statin exposure.

Events

Person-years Incidence rate

(per 1,000 years) C

rude rate ratio A

djusted HR

6

Main analysis

1

N

on-users 132

52,087 2.53 (2.14-3.01)

1.00 (reference) 1.00 (reference)

S

tatin users 21

8,278 2.54 (1.65-3.89)

1.00 (0.60-1.60) 0.90 (0.56-1.44)

1-month lag period

2

N

on-users 129

51,224 2.52 (2.12-2.99)


S

tatin users 24

9,140 2.63 (1.76-3.92)

1.04 (0.64-1.62) 0.94 (0.60-1.47)

2-year lag period3

Non-users

130 53,001

2.45 (2.07-2.91) 1.00 (reference)

1.00 (reference)

S

tatin users 23

7,363 3.12 (2.08-4.70)

1.27 (0.78-1.99) 1.14 (0.72-1.79)

50% grace period

4

N

on-users 132

52,126 2.53 (2.14-3.00)


S

tatin users 21

8,238 2.55 (1.66-3.91)

1.01 (0.60-1.60) 0.90 (0.56-1.44)

Non-prevalent users

5

N

on-users 77

26,874 2.87 (2.29-3.58)


S

tatin users <10*

2,951 2.0* (0.91-4.53)

0.7* (0.25-1.61) 0.86 (0.36-2.02)

1 Statin prescriptions included as a tim

e-varying covariate, lagged by one year. 2 S

tatin prescriptions included as a time-varying covariate, lagged by one m

onth.


e-varying covariate, lagged by two years.



e-varying covariate, lagged by one year. Grace period as 50%

of the previous statin prescription instead of

30 days. 5 S

tatin prescriptions included as a time-varying covariate, lagged by one year. E

xclusion of patients with a statin prescription in the five years

prior to chronic pancreatitis diagnosis. Restricted to patients w

ith at least five years of prescription history available. 6 A

djusted for age (restricted cubic spline with three knots), sex, socioeconom

ic status, and Gagne C

omorbidity Index score.

* Num

bers collapsed for confidentiality purposes.


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