American Journal of Epidemiology

The Author 2010. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of
Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Vol. 173, No. 2

DOI: 10.1093/aje/kwq361
Advance Access publication:
November 17, 2010

Original Contribution
Long-term Statin Use and the Risk of Gallstone Disease: A Population-based
Case-Control Study

Rune Erichsen*, Trine Frslev, Timothy L. Lash, Lars Pedersen, and Henrik Toft Srensen
* Correspondence to Dr. Rune Erichsen, Department of Clinical Epidemiology, Aarhus University Hospital, Olof Palmes Alle 43-45,
DK-8200 Aarhus N, Denmark (e-mail: re@dce.au.dk).

Initially submitted June 17, 2010; accepted for publication September 24, 2010.

cholelithiasis; gallstones; hydroxymethylglutaryl-CoA reductase inhibitors; risk

Abbreviations: AOR, adjusted odds ratio; CI, condence interval; ICD, International Classication of Diseases; NRP, The Danish
National Registry of Patients.

The prevalence of gallstone disease in the Western world

ranges from 6% to 50%, increasing with age and varying
with geographic region (1). The risk increases with certain
genetic factors, increasing age, female gender, and obesity
(1, 2). Gallstone disease is a chronic and usually asymptomatic condition, but it leads to severe complications in about
2% of symptomatic patients (3). Intense pain in the upper
quadrant of the abdomen and acute cholecystitis are the
most common complications and may require surgical removal of the gallbladder (cholecystectomy). Jaundice, pancreatitis, and cholangitis caused by stones that migrate from
the gallbladder to the common bile duct are other severe
complications (3). In the Western world, 80%90% of gallstones originate from cholesterol-supersaturated bile, with
the remainder formed as pigment stones, primarily from
bilirubin and calcium (4).

In the liver, 3-hydroxy-3-methylglutaryl coenzyme A inhibitors (statins) inhibit cholesterol biosynthesis, and thus
may prevent gallstone formation, gallstone recurrence, subsequent complications, and cholecystectomy. Evidence of
the association between statins and gallstone disease is conflicting (5), although 3 recent studiesa US cohort study (6)
and case-control studies from United Kingdom (7) and Israel
(8)have shown a reduced risk of gallstone disease followed by cholecystectomy in people taking statins. These
studies estimated the association between statins and severe
gallstone disease only. In addition, the US study was based
on questionnaire reports of gallstone disease and statin use,
the UK study relied on information from general practitioners regarding in-hospital treatments (6, 7, 9), and the
Israeli study lacked details of important covariates (8).
There is, therefore, a need for evidence evaluating the
162

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Most gallstones originate from cholesterol-supersaturated bile. Statins inhibit hepatic cholesterol biosynthesis
and therefore may reduce the risk of gallstone disease. Population-based evidence, however, is sparse. Thus, the
authors conducted a population-based case-control study using medical databases from northern Denmark (1.7
million inhabitants) to identify 32,494 cases of gallstones occurring between 1996 and 2008 and to identify age-,
sex-, and county-matched population controls for each case. Cases and their matched controls who were exposed
to lipid-lowering drugs were categorized as current users if their last prescription was redeemed
90 days before
the cases diagnosis date; otherwise, they were categorized as former users. Conditional logistic regression was
used to estimate adjusted odds ratios and 95% condence intervals for gallstone disease in patients treated with
lipid-lowering drugs. In current users, the adjusted odds ratios associating statin use with the occurrence of
gallstone disease were 1.17 (95% condence interval (CI): 1.06, 1.30) for those who had 14 prescriptions,
0.89 (95% CI: 0.80, 0.97) for those who had 519 prescriptions, and 0.76 (95% CI: 0.69, 0.84) for those who
had 20 total prescriptions. In former users, the corresponding adjusted odds ratios were 1.24 (95% CI: 1.11,
1.39), 0.97 (95% CI: 0.86, 1.10), and 0.79 (95% CI: 0.64, 0.97), respectively. The use of other lipid-lowering drugs
showed no similar association.

Statin Use and Risk of Gallstone Disease 163

association between statin use and the occurrence of more

general gallstone disease in an unselected population (10,
11). To address these limitations, we conducted a study using Danish population-based health registries with hospitalbased information to evaluate the association between statin
use (including intensity and duration) and gallstone disease.
MATERIALS AND METHODS
Source population and setting

Cases with gallstone disease

We identified first in- and outpatient hospitalizations in

patients with gallstone disease between January 1, 1996, and
December 31, 2008, by searching the NRP for diagnoses of
gallstone disease (DK80), cholecytitis (DK81), or a procedure code for gallbladder surgery (KJKA, including cholecystectomy and drainage). We combined these codes to
create 1 case definition referred to as gallstone disease,
and the earliest recorded date for each case was used as
the date of disease. We excluded preexisting cases of gallstone disease by searching the NRP back to 1977 (ICD-8
codes for gallstone disease: 574 and 575; procedure codes
for gallbladder surgery before 1996: 47360 and 47365). We
also excluded cases from the NRP if the patient had a history
of liver, bile duct, or pancreatic cancer (ICD-8 codes 155
157; ICD-10 codes C22C25) or <2 years history in the
prescription database (see below).
Population-based controls

For each case, we selected 10 population controls with no

record of gallstone disease before the diagnosis date of the
cases and matched them to the cases based on age, sex, and
county of residence. Controls were selected from the Danish
Civil Registration System, which is updated daily and has
maintained records on vital statistics, dates of death, and the
residences of all Danish citizens and residents since April 1,
1968 (13). Controls were selected using risk-set sampling,
and both the cases and their matched controls were assigned
Am J Epidemiol 2011;173:162170

Use of statins and other lipid-lowering drugs

Residents of northern Denmark receive prescription medications from pharmacies equipped with electronic accounting systems that are primarily used to secure reimbursement
from the National Health Service (15, 16). The pharmacies
transmit the patients civil registration number, the type and
amount of drug prescribed according to the Anatomical
Therapeutic Chemical classification system (Appendix
Table 1), and the date on which the drug was dispensed to
the prescription database. From the prescription database,
we ascertained any use of statins before the index date. We
also identified the use of fibrates, niacin, and resin, which we
classified as other lipid-lowering drugs.
We classified patients as never users of lipid-lowering
drugs (reference), current users if their last prescription
for statins or other lipid-lowering drugs was redeemed

90 days before the index date, or former users if their last
prescription was >90 days before the index date. Both current and former users were also categorized by total number
of prescriptions (14, 519, and 20).
Covariates

We collected data on potentially confounding factors

from the NRP and the prescription database (1720). We
searched the NRP for any hospital records containing diagnoses of alcoholism, cancer, cardiovascular disease,
chronic obstructive pulmonary disease, diabetes, hyperlipidemia, hypothyroidism, inflammatory bowel disease, liver
cirrhosis, obesity, renal failure, stroke, or transient ischemic
attack that occurred before the diagnosis of gallstone disease
or the index date. We searched patient records in the prescription database for prescriptions for thiazides, oral antidiabetic drugs, or postmenopausal hormone (estrogen)
replacement therapy (Appendix Table 1). We coded each
of these covariates individually as a dichotomous variable
(diabetes and oral antidiabetic medications were coded as
a single variable).
Analysis

We calculated the frequency and proportion of cases and

controls within categories of demographic characteristics,
drug exposures, and covariates. We calculated odds ratios
and 95% confidence intervals associating drug use with the
occurrence of gallstone disease using conditional logistic
regression. Because we used risk-set sampling to select controls, these odds ratios provided unbiased estimates of the
corresponding incidence rate ratios (21).
We calculated odds ratios adjusted for the covariates associating current and former use of statins or other lipidlowering drugs with the occurrence of gallstone disease,
stratified by the total number of prescriptions. The reference
group comprised patients with no history of using statins or
other lipid-lowering drugs. These odds ratios were stratified
by history of diabetes, cardiovascular disease, and obesity,

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We conducted this population-based case-control study

from 1996 to 2008 using medical databases from northern
Denmark, which has a population of 1.7 million (about
30% of the Danish population) (12). The Danish National
Health Service provides tax-funded medical care for all
Danish residents and partially reimburses the costs of most
physician-prescribed drugs. We used the civil registration
number, a personal identifier assigned to each Danish citizen
at birth and to residents at immigration, to link the Danish
medical databases (13). For each hospital admission since
1977, the Danish National Registry of Patients (NRP) has
recorded the civil registration number of the patient, dates
of admission and discharge (outpatient and emergency
admissions since 1995), surgical procedures, and up to 20
discharge diagnoses coded by doctors according to the
International Classification of Diseases (ICD) (Eighth
Revision until the end of 1993 and Tenth Revision thereafter) (14).

an index date identical to the date on which the case was

diagnosed with gallstone disease.

164 Erichsen et al.

RESULTS

We identified 32,494 patients with gallstone disease

(18,201 inpatients and 14,293 outpatients) and 324,925 population controls. The median age at diagnosis/index was
54.6 years, and 68.8% were women. Comorbid diseases
were more frequent in cases than in controls (Table 1). A
total of 1,764 cases (5.4%) with gallstone disease and
(4.8%) 15,580 controls were current statin users, yielding
an overall adjusted odds ratio of 0.93 (95% confidence interval (CI): 0.87, 0.98). For current statin users, the adjusted

Table 1. Characteristics of Patients With Gallstone Disease and

Population Controls in Northern Denmark, 19962008
Cases With
Gallstone
Disease
No.

Total no.

32,494

Population
Controls
No.

324,925

Men

10,123

31.2

101,223

31.2

Women

22,371

68.8

223,702

68.8

039

8,388

25.8

83,880

25.8

4059

11,065

34.1

110,650

34.1

6079

9,704

29.9

97,040

29.9

80

3,337

10.3

33,355

10.3

19962000

8,133

25.0

81,330

25.0

20012004

12,112

37.3

121,105

37.3

20052008

12,249

37.7

122,490

37.7
1.9

Age, years

Time period

Previous hospital diagnosis

Alcoholism

814

2.5

6,283

Cancera

2,543

7.8

18,684

5.8

Cardiovascular disease

5,387

16.6

37,737

11.6

Chronic obstructive
pulmonary disease

1,487

4.6

9,807

3.0

Diabetes

1,797

5.5

13,183

4.1

Hypothyroidism

348

1.1

2,381

0.7

Hyperlipidemia

277

2.2

4,967

1.5

Inammatory bowel
disease

383

1.2

2,635

0.8

Liver cirrhosis

109

0.3

488

0.2

Obesity
Renal failure
Stroke
Transient ischemic attack

1,620

5.0

6,442

2.0

283

0.9

1,382

0.4

1,049

3.2

8,531

2.6

524

1.6

4,528

1.4

3,376

10.4

25,284

7.8

270

0.8

2,085

0.6

Previous treatment
Hormone replacement
therapy
Thiazides
a

All cancers except liver, bile duct, and pancreatic cancer, which
were excluded from the study.

odds ratio decreased as the overall number of prescriptions

increased, from 1.17 (95% CI: 1.06, 1.30) in patients with
14 prescriptions to 0.76 (95% CI: 0.69, 0.84) in patients
with 20 prescriptions (Table 2). This decrease was seen in
both men and women, although women generally had
higher odds ratios.
A total of 761 cases (2.3%) with gallstone disease and
5,889 (1.8 %) controls were former statin users, which corresponded to an adjusted odds ratio of 1.06 (95% CI: 0.98,
1.16) (Table 2). The adjusted odds ratio decreased from 1.24
(95% CI: 1.11, 1.39) in former users with 14 prescriptions
to 0.79 (95% CI: 0.64, 0.97) in former users with 20
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and we used conventional logistic regression models because these stratified analyses required that we dissolve
the matched sets. Therefore, we controlled for the matched
factors as well as the other covariates.
We performed subanalyses to further explore the observed associations. First, we conducted 2 separate analyses
in which we changed the cutoffs for current and former
users to
30 and >30 days and
180 and >180 days, respectively, from the date of the last prescription to the index
date. Second, we estimated odds ratios after changing the
categorization of statins according to the time between first
and last prescription before the index date (<1, 12, and 3
years). We stratified this analysis by intensity of statin use.
We defined intensity as a measure of the number of pills
prescribed divided by the total duration of use. Duration of
use was determined by counting the number of days from
the date of the first prescription to the index date. Using
this information, we classified statin use as low-intensity
(<0.5 pills/day), medium-intensity (0.50.8 pills/day), or
high-intensity (0.9 pills/day). Third, we restricted the
analysis to cases with gallbladder surgery to reduce the
potential for inclusion of false-positives. Fourth, because
the comparison of statin users with nonusers might be confounded by statin indications also associated with gallstone
disease (e.g., obesity, hyperlipidemia, exercise, and diet),
we compared statin users with a total of 519 and 20
prescriptions with a reference category of users with 14
prescriptions. Because this analysis was limited to statin
users, the indications should have been more uniform. Fifth,
to explore whether the associations depended on type of
statin, we estimated odds ratios according to 7 statin preparation subtypes and according to lipophilicity in current
and former users (lipophile: atorvastatin, cerivastatin, fluvastatin, lovastatin, and simvastatin; hydrophile: pravastatin
and rosuvastatin). Last, we compared continuing statin users
(i.e., those with 12 months between first and last prescription
of statins and with the last prescription <12 months before the
index date) with those who discontinued statins (no prescription for 12 months before their index date). Because
this analysis was limited to ever users of statins, the indications should have been more uniform and included changes
to diet and exercise that sometimes accompany inception of
statin medications. Presumably, the behaviors would be less
likely to stop at the same time as statin medication discontinuation, so a comparison of continuing statin users with those
who stopped statin therapy should have been less susceptible
to confounding by behavior change.

Statin Use and Risk of Gallstone Disease 165

Table 2. Use of Statins and the Risk of Gallstone Disease in Northern Denmark, 19962008

Statin Use

None

Cases With
Gallstone
Disease

Population
Controls

Crude
ORa

95% CI

Adjusted
ORb

95% CI

No.

No.

29,969

92.2

303,456

93.4

1.0

Reference

1.0

Reference

1,764

5.4

15,580

4.8

1.18

1.12, 1.24

0.93

0.87, 0.98

Current use
Overall
Men
Women
14 prescriptions
Men
Women
519 prescriptions

741

2.3

6,733

2.1

1.14

1.05, 1.24

0.85

0.77, 0.94

1,023

3.1

8,847

2.7

1.21

1.12, 1.29

0.98

0.90, 1.05

464

1.4

3,443

1.1

1.40

1.26, 1.54

1.17

1.06, 1.30

185

0.6

1,434

0.4

1.33

1.14, 1.56

1.06

0.90, 1.25

279

0.9

2,009

0.6

1.44

1.27, 1.64

1.25

1.10, 1.42

813

2.5

7,368

2.3

1.15

1.06, 1.24

0.89

0.82, 0.97

349

1.1

3,188

1.0

1.13

1.01, 1.27

0.84

0.74, 0.95

Women

464

1.4

4,180

1.3

1.15

1.05, 1.28

0.93

0.84, 1.03
0.69, 0.84

20 prescriptions

487

1.5

4,769

1.5

1.06

0.97, 1.17

0.76

Men

207

0.6

2,111

0.6

1.02

0.88, 1.18

0.69

0.59, 0.81

Women

280

0.9

2,658

0.8

1.10

0.97, 1.25

0.81

0.70, 0.92

Overall

761

2.3

5,889

1.8

1.35

1.24, 1.46

1.06

0.98, 1.16

Men

324

1.0

2,512

0.8

1.34

1.19, 1.51

1.00

0.88, 1.14

Women

437

1.3

3,377

1.0

1.35

1.22, 1.50

1.10

0.98, 1.22

353

1.1

2,408

0.7

1.52

1.36, 1.70

1.24

1.11, 1.39

Former use

14 prescriptions
Men

145

0.4

994

0.3

1.51

1.27, 1.80

1.19

0.99, 1.42

Women

208

0.6

1,414

0.4

1.53

1.32, 1.77

1.27

1.09, 1.48
0.86, 1.10

519 prescriptions

299

0.9

2,441

0.7

1.27

1.13, 1.44

0.97

Men

131

0.4

1,052

0.3

1.29

1.07, 1.55

0.92

0.76, 1.12

Women

168

0.5

1,389

0.4

1.26

1.07, 1.48

1.00

0.84, 1.18
0.64, 0.97

20 prescriptions

109

0.3

1,040

0.3

1.09

0.90, 1.34

0.79

Men

48

0.1

466

0.1

1.07

0.80, 1.45

0.73

0.54, 1.00

Women

61

0.2

574

0.2

1.11

0.85, 1.45

0.83

0.63, 1.09

Abbreviations: CI, condence interval; OR, odds ratio.

Matched based on age, sex, and county.
b
Controlled for the previous hospital discharges, diagnoses, and treatments mentioned in Table 1 and matched
based on age, county, sex, and period of diagnosis.
a

prescriptions. In general, female former users had a slightly

higher risk of gallstone disease than did male former users.
Table 3 shows the odds ratios for patients with and without diabetes, obesity, and cardiovascular disease. These
stratified analyses showed that the odds ratios were particularly reduced in the presence of these diseases. Among
current statin users, those with a previous hospital diagnosis
of diabetes had an adjusted odds ratio of 0.88 (95% CI: 0.77,
1.00), those with a previous hospital diagnosis of obesity
had an adjusted odds ratio of 0.80 (95% CI: 0.64, 1.00), and
those with a previous hospital diagnosis of cardiovascular
disease had an adjusted odds ratio of 0.80 (95% CI: 0.74,
0.87). Our results were not impacted by a change in the split
date for current and former users from 90 days to 30 or 180
days (results not shown).
Table 4 shows that among patients with medium-term (1
2 years) and long-term (3 years) statin use, the association
Am J Epidemiol 2011;173:162170

with gallstone disease was particularly protective. Furthermore, as the intensity of statin use increased, the association
with gallstones decreased.
In cases with gallbladder surgery (n 744), we found that
current statin users had an overall adjusted odds ratio of
0.88 (95% CI: 0.62, 1.23) (14 prescriptions: adjusted odds
ratio (AOR) 1.22, 95% CI: 0.67, 2.22; 519 prescriptions:
AOR 0.74, 95% CI: 0.47, 1.17; and 20 prescriptions:
AOR 0.78, 95 % CI: 0.46, 1.35), whereas the adjusted
odds ratio for former users was 0.72 (95% CI: 0.43, 1.22)
(14 prescriptions: AOR 0.89, 95% CI: 0.43, 1.85; 519
prescriptions: AOR 0.99, 95% CI: 0.47, 2.08; and 20
prescriptions: AOR 0.10, 95% CI: 0.01, 0.81).
In the subanalysis of statin users in which those with 14
prescription were the reference group, we found an adjusted
odds ratio of 0.76 (95% CI: 0.67, 0.86) for current statin
users with 519 prescriptions and an adjusted odds ratio of

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Men

166 Erichsen et al.

Table 3. Use of Statins and the Risk of Gallstone Disease in the Presence or Absence of
Diabetes, Obesity, and Cardiovascular Disease in Northern Denmark, 19962008
Crude
ORa

95% CI

Adjusted
ORb

95% CI

Current statin users

0.96

0.85, 1.09

0.88

0.77, 1.00

Former statin users

1.15

0.98, 1.37

1.05

0.88, 1.25

Current statin users

1.13

1.06, 1.19

0.89

0.84, 0.96

Former statin users

1.26

1.16, 1.38

1.02

0.93, 1.12

Current statin users

0.87

0.72, 1.05

0.80

0.64, 1.00

Former statin users

1.00

0.76, 1.32

0.95

0.70, 1.27

Current statin users

1.14

1.08, 1.20

0.90

0.85, 0.95

Former statin users

1.29

1.19, 1.40

1.03

0.94, 1.12

Current statin users

0.84

0.78, 0.90

0.80

0.74, 0.87

Former statin users

1.00

0.90, 1.11

0.96

0.86, 1.07

Current statin users

1.09

1.00, 1.18

0.98

0.90, 1.06

Former statin users

1.18

1.05, 1.33

1.05

0.93, 1.18

Previous hospital diagnosis

of diabetes

No previous hospital diagnosis

of diabetes

Previous hospital diagnosis

of obesity

Previous hospital diagnosis

of cardiovascular disease

No previous hospital diagnosis

of cardiovascular disease

Abbreviations: CI, condence interval; OR, odds ratio.

Controlled for age, county, sex, and period of diagnosis.
b
Controlled for the previous hospital discharges, diagnoses, and treatments mentioned in
Table 1 and matched on age, county, sex, and period of diagnosis. The reference group was
the number of statin users in each stratum.
a

0.65 (95% CI: 0.56, 0.74) for current statin users with 20
prescriptions. For former statin users, the corresponding
adjusted odds ratios were 0.78 (95% CI: 0.66, 0.92) and
0.64 (95% CI: 0.51, 0.80), respectively. In the final subanalysis, we found that statin users with no statin prescription 12
months before their index date had an adjusted odds ratio
of 1.39 (95% CI: 1.19, 1.61) compared with continuing
statin users.
When we divided the cases into the 7 statin preparation
subtypes and also according to lipophilicity, we found no
major heterogeneity of the odds ratios (results not shown).
In the analysis of other lipid-lowering drugs, we identified
70 current users (0.2%) and 122 former users (0.4%) among
cases and 377 current users (0.1%) and 775 former users
(0.2%) among controls. For current users, this corresponded
to an adjusted odds ratio of 1.42 (95% CI: 1.09, 1.84) (stratified
by the number of prescriptions: 14: AOR 2.16, 95% CI:
1.06, 4.40; 519: AOR 1.11, 95% CI: 0.67, 1.84; and 20:
AOR 1.46, 95% CI: 1.05, 2.05); for former users, it corresponded to an adjusted odds ratio of 1.18 (95% CI: 0.97, 1.43)
(stratified on the number of prescriptions: 04: AOR
1.20, 95% CI: 0.89, 1.62; 519: AOR 0.96, 95% CI:
0.67, 1.38; and 20: AOR 1.44, 95% CI: 1.01, 2.07).

DISCUSSION

In this population-based case-control study, current statin

users had a decreased odds ratio for gallstone disease compared with nonusers, so long as they had 5 prescriptions.
This duration corresponds to 12 years of statin use, dependent upon the intensity of the use. For former users, the
decrease in odds ratios was less pronounced and present
only after 20 prescriptions, but the sustained decrease in
odds ratios in these patients may reflect a long-standing
effect of statins in the prevention of gallstone disease. This
pattern of results was insensitive to type or lipophilicity of
statins, changes in the definition of current and former users
(30 or 180 days vs. 90 days), and the restriction to cases with
gallbladder surgery. In addition, patients who discontinued
statin treatment 12 months before their index date had an
increased odds ratio for gallstone disease compared with
continuing statin users. As expected, we found no reduction
in the odds ratio for gallstone disease in patients treated with
other lipid-lowering drugs.
Our results extend the results of other studies (68, 22
24). In 2009, Bodmer et al. (7) published a study that included 27,035 cases with gallstone disease treated with
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No previous hospital diagnosis

of obesity

Statin Use and Risk of Gallstone Disease 167

Table 4. Lengtha and Intensityb of Statin Use and the Risk of Gallstone Disease in Northern
Denmark, 19962008
Statin Use

None

Crude
ORc

1.0

95% CI

Reference

Adjusted
ORd

1.0

95% CI

Reference

Short-term (<1 year)

Overall

1.46

1.36, 1.57

1.21

1.12, 1.30

Low-intensity (<0.5 pills/day)

1.55

1.35, 1.79

1.26

1.09, 1.45

Medium-intensity (0.50.8 pills/day)

1.41

1.19, 1.66

1.18

1.00, 1.39

High-intensity (0.9 pills/day)

1.44

1.31, 1.58

1.20

1.09. 1.32

Medium-term (12 years)

Overall

1.14

1.05, 1.23

0.89

0.82, 0.97

Low-intensity (<0.5 pills/day)

1.45

1.16, 1.83

1.13

0.89, 1.42

Medium-intensity (0.50.8 pills/day)

1.15

1.00, 1.32

0.91

0.80, 1.05

High-intensity (0.9 pills/day)

1.09

0.98, 1.21

0.84

0.76, 0.94

Long-term (3 years)

1.10

1.02, 1.18

0.80

0.73, 0.86

Low-intensity (<0.5 pills/day)

1.49

1.20, 1.86

1.08

0.86, 1.35

Medium-intensity (0.50.8 pills/day)

1.06

0.93, 1.20

0.78

0.68, 0.90

High-intensity (0.9 pills/day)

1.07

0.98, 1.18

0.77

0.70, 0.85

Abbreviations: CI, condence interval; OR, odds ratio.

Short-, medium-, and long-term use were calculated using the time from rst prescription to
last prescription before date of gallstone disease or index date.
b
Intensity was determined as number of pills prescribed divided by the time from rst prescription to the date of gallstone disease or index date separated into 3 categories.
c
Controlled for age, county, sex, and period of diagnosis.
d
Controlled for the previous hospital discharges, diagnoses, and treatments mentioned in
Table 1 and matched on age, county, sex, and period of diagnosis.
a

cholecystectomy and 106,531 controls. The study was based

on the UK General Practice Research Database, which was
representative of the United Kingdom population in most
aspects (9), and was supported by results from another casecontrol study from Israel (8). Bodmer et al. found adjusted
odds ratios similar ours (e.g., current users with 20 prescriptions had an adjusted odds ratio of 0.67 (95% CI: 0.55,
0.80)), and they had to some extent better confounder control (e.g., they controlled for body mass index and smoking
status, although those data were ascertained close to the
index date, rather than before the first statin prescription).
However, the study (7) only included patients with severe
gallstone-related complications and relied on information
from general practitioners regarding the in-hospital procedure of cholecystectomy.
Tsai et al. (6) published a cohort study in 2009 that included 2,479 women from the Nurses Health Study who
had undergone cholecystectomy. The study included information on statin use, cholecystectomy, and other covariates
from questionnaires and found a decreased risk of cholecystectomy after statin use (multivariate relative risk 0.82, 95%
CI: 0.70, 0.96). In contrast, a 2001 French cross-sectional
study by Caroli-Bosc et al. (5) that included 830 patients
undergoing gallbladder ultrasonography (of whom only
4.6% reported a previous statin use) did not find any association between statin use and gallstone disease. Moreover,
Am J Epidemiol 2011;173:162170

reports on alterations in human bile cholesterol saturation

after statin therapy showed compelling evidence that indicated that statins decreased the cholesterol saturation of bile
(23, 24), although results of a few reports did not confirm
this association (25, 26). Animal studies have also reported
beneficial effects of statins in the prevention of gallstone
formation (27, 28).
The strengths of our study include the population-based
design within a universal health care system with complete
hospital and prescription history and access to appropriate
population controls. In addition, our analysis adjusted for
several important risk factors for gallstone disease.
Our study also has limitations. We used redeemed prescriptions as a surrogate for actual statin consumption,
which may be imperfect. However, we stratified our analyses on the overall number of prescriptions, and therefore the
possibility of including nonusers, at least among patients
with several prescriptions, is minimal. The categorization
of current and former statin users is also imperfect, and thus
there might be current users in the group of former users and
vice versa. The subanalysis in which we changed the split
date for current and former users, however, supported the
results of our main analysis. Furthermore, registry diagnoses
may be inaccurate, and thus misclassification of gallstone
disease could occur, although the overall quality and accuracy of the data in the NRP has been estimated to be high

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Overall

168 Erichsen et al.

As noted above, the initiation of statin treatment is sometimes also accompanied by changes in health behaviors,
such as increased physical activity and eating a healthier
diet. It is therefore possible that the decreased risk of gallstone disease associated with initiation of statin use was
caused not only by statins but also by the beginning of
health-seeking behaviors. Although we cannot rule out this
confounding, our analysis comparing cases who discontinued statins with continuing statin users, which showed
a higher risk among those who stopped statin therapy, supported the hypothesis that statins in fact do reduce the risk of
gallstone disease directly. Furthermore, lifestyle factors
were not found to be important confounders in the study
by Tsai et al. (6) or the study by Bodmer et al. (7, 32).
It is well-known that fibrates (included in the group of
other lipid-lowering drugs in this study) increase the risk of
gallstone disease (5), and our study supported this association. Because the residual and unmeasured confounding discussed above is expected to cause overestimation of the
association between gallstone disease and these drugs, our
results should not be taken alone as evidence of a potentially
harmful effect. In conclusion, this population-based casecontrol study confirmed that long-term sustained statin use
decreases the risk of gallstone disease in both men and women.

ACKNOWLEDGMENTS

Author affiliations: Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark (Rune
Erichsen, Trine Frslev, Timothy L. Lash, Lars Pedersen,
Henrik Toft Srensen); and Department of Epidemiology,
Boston University School of Public Health, Boston, Massachusetts (Timothy L. Lash, Henrik Toft Srensen).
This work was supported by the Clinical Epidemiology
Research Foundation, Aarhus University Hospital, Aarhus,
Denmark.
The preliminary findings of this study were presented as
a poster at the 26th International Conference on Pharmacoepidemiology and Theraputic Risk Management, Brighton,
United Kingdom, August 1922, 2010, and published in
abstract form (33).
The Department of Clinical Epidemiology at Aarhus University Hospital receives funding for other studies from
companies in the form of research grants to (and administered by) Aarhus University. None of these studies have any
relation to the present study.
Conflict of interest: none declared.

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170 Erichsen et al.

Appendix Table 1. International Classication of Diseases Codes

and Anatomical Therapeutic Chemical Classication System Codes
used in the Analysis

Appendix Table 1. Continued

Liver cirrhosis
ICD-10: K70.3, K74.6

Hospital discharge codes

ICD-8: 571.09, 571.92, 571.99

Alcoholism
ICD-10: F10 (except F10.0), G31.2, G62.1, G72.1, I42.6,
K29.2, K86.0, Z72.1

Obesity
ICD-10: E66
ICD-8: 277

ICD-8: 291, 303, 577.10, 571.09, 571.10

and/or a prescription of disulram (ATC N07BB01)

Renal failure
ICD-10: N17N19

Apoplexia cerebri

ICD-8: 581584

ICD-10: I61, I63, I64

Transient ischemic attack

ICD-8: 431, 433, 434

ICD-10: G45.9

Chronic obstructive pulmonary disease

ICD-8: 435

ICD-10: J41, J42, J43, J44

Anatomical Therapeutic Chemical Classication System

ICD-8: 491, 492

Statins

Cancer

Atorvastatin C10AA05

ICD-8: 1420 (except 155, 156, 157)

Cerivastatin C10AA06
Fluvastatin C10AA04

Cardiac disease
ICD-10: I05I09, I10I15, I20I25, I50

Lovastatin C10AA02

ICD-8: 393398, 400404, 410414, 427.09, 427.10, 427.19

Pravastatin C10AA03
Rosuvastatin C10AA07

Diabetes
ICD-10: E10.0, E10.1E10.9, E11.0; E11.1E11.9
ICD-8: 249.00, 249.01 249.09, 250.00, 250.01250.09

Simvastatin C10AA01
Other lipid-lowering drugs
Fibrates C10AB

Hypothyroidism
ICD-10: E00E03

Niacins C10AD

ICD-8: 244

Resins C10AC
Other drugs (covariates)

Hyperlipidemia
ICD-10: E78.0E78.5

Hormone replacement therapy: G03CA, G03FA

ICD-10: 272.00, 272.01, 279.00, 279.01

Thiazide: CO3AA
Oral antidiabetics: A10

Inammatory bowel disease

ICD-10: K50, K51
ICD-8: 563.01, 563.19
Table continues

Abbreviations: ICD-8, International Classication of Diseases,

Eighth Revision; ICD-10, International Classication of Diseases,
Tenth Revision.

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ICD-10: C0C97 (except C2225)