Statins are associated with a reduced risk of cholangiocarcinoma: a population-based case-control study.

Br J Clin Pharmacol. 2015 Oct;80(4):755-61. doi: 10.1111/bcp.12641.

Epub 2015 May 26.

Statins are associated with a reduced risk of

cholangiocarcinoma: a

population-based case-control study.

Peng YC

, Lin CL

, Hsu WY

, Chang CS

, Yeh HZ

, Tung CF

, Wu YL

, Sung FC

, Kao CH

.

Introduction

Cholangiocarcinoma (CCA) and hepatocellular carcinoma are the major primary liver cancers. CCA is composed of cells resembling those of the bile duct and is

the second most common hepatic malignancy, accounting for about 3% of malignancies of the digestive system

[1, 2]. CCA and hepatocellular carcinoma are morphologically, genomically and clinically highly heterogeneous

with a dismal clinical outcome [3, 4]. CCA is considered diffcult to diagnose early, due to the lack of effective treatments and the survival rate is low [1, 5, 6]. The risk of CCA is increased with liver fuke infection, hepatitis B and C virus infection, cirrhosis, alcohol consumption

and hepatolithiasis [2, 7, 8]. At present, there are no defnite strategies for CCA prevention, and epidemiological

data indicate that chemoprevention provides no protective effect against the development of CCA [9, 10].

Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A

(HMG-CoA) reductase [11]. Traditionally, they are primarily

used as cholesterol-lowering agents, but in recent years

additional effects of statins have been revealed, including anti-infammation, immunomodulation and anti-tumour effects [12–14]. Statins have pleiotropic effects and may exert benefcial effects in the feld of cancer chemoprevention [15–17]. Statin use has been reported to have a promising anti-cancer effect with studies showing decreased

risk of cancer in hepatocellular carcinoma [18, 19], pancreatic cancer [20, 21], oesophageal cancer [22], gastric cancer [23, 24], colorectal cancer [25, 26] and lung cancer

[27, 28]. However, the putative anti-cancer effect of statins remains controversial [29, 30]. To date, the effect of statins on CCA has not been fully elucidated, and statins have not been considered or proved as chemoprevention agents in CCA [10].

Most patients with CCA are diagnosed and treated at an advanced stage, and often these patients are deemed

poor candidates for curative surgery. Conventional chemotherapy and radiation therapy have not been shown

to be effective in terms of long term survival, and endoscopic treatment with photodynamic therapy combined

with stenting has been reported to be effective as a palliative but not curative treatment. There is an urgent

need to develop novel chemopreventive and adjuvant strategies for CCA. Studies on statin use and risk of other cancer types, including hepatocellular carcinoma, indicate that the role of statins in chemoprevention for CCA

warrants further investigation.

The aimof the present study was to investigate whether individuals taking statins are at reduced risk of CCA using the National Health Insurance Research Database (NHIRD) of Taiwan. Comorbidities including diabetes, cirrhosis, hepatitis infection, infammatory bowel disease, pancreatic disease and biliary disease were considered as covariates. The dose–response relationship with statins was evaluated in this study.

Methods Data source

The National Health Insurance (NHI) programme of

Taiwan is a compulsory health insurance programme,

providing comprehensive medical coverage for all residents.

Approximately 99% of 23.74 million people enrolled in the programme by 2009 [31]. The National

Health Research Institutes (NHRI) has been in charge

of managing NHIRD for claims data. Information on inpatient care, ambulatory care, dental care, prescription

drugs and costs are available in the NHIRD. Data provided to researchers contained scrambled identifcation

numbers associated with the relevant claims information, which includes the patient gender, date of birth,

registry of medical services and medication prescriptions.

Similar identifcation numbers were encrypted to all data fles for linking data in accordance with privacy protocols. International Classifcation of Diseases-9- Clinical Modifcation (ICD-9-CM) codes were used to defne diseases in the database. This study was approved

by the Ethics Review Board of the China Medical University (CMU-REC-101-012).

Subject selection

Figure 1 shows the procedure for selecting cases and controls, from two data sets of the NHIRD: 1) Cases were identifed from the Registry of Catastrophic Illnesses Patient

Database (RCIPD), containing health claims data for catastrophic illnesses from 1997 to 2011. Thirty categories of

diseases requiring long term care were registered, including cancer. The insurance programme exempts benefciaries from some obligations to reduce their fnancial

burden. Cases comprised the CCA patients (ICD-9-CM

codes 155.1 and 156.1) aged over 20 years newly diagnosed between 2002 and 2011. The CCA diagnosis date was defned as the index date. 2) Control subjects were identifed

from the Longitudinal Health Insurance Database 2000

(LHID 2000), a database containing the claims data from

1996 to 2011 for 1 million people randomly sampled from

2000 NHIRD enrolment records. The distribution of gender,

age and health care costs of the LHID2000 was similar to

that of all insured enrollees, as reported by the NHRI in

Taiwan. Individuals with previous cancer (ICD-9-CM code 140-208) or incomplete information in both groups were excluded (Figure 1). The CCA cases and controls were selected at a ratio of 1 : 1 matching on propensity score and

the diagnosis date. We used a logistic regression model to calculate the propensity score. The potential confounders to be considered were age, gender,medication with aspirin

and metformin, Charlson comorbidity index score and comorbidities of diabetes (ICD-9-CM codes 250), cirrhosis

(ICD-9-CMcodes 571), chronic pancreatitis (ICD-9-CMcodes 577.1), hepatitis B infection (ICD-9-CMcodes V02.61, 070.20, 070.22, 070.30, 070.32), hepatitis C infection (ICD-9-CM

codes V02.62, 070.41, 070.44, 070.51,070.54), gastric disease (ICD-9-CM codes 530-533), haemochromatosis (ICD-9-CM

codes 275.0), infammatory bowel disease (ICD-9-CM codes 556, 555), biliary tract disease (ICD-9-CM codes 751.69, 571.6, 574, 575.0-575.1, 121.0-121.1, 121.3), stroke (ICD-9- CM codes 430-438), CAD (ICD-9-CM codes 410-414), COPD (ICD-9-CM codes 491, 492, 496) and alcohol-related illness (ICD-9-CM codes 291, 303, 305, 571.0, 571.1, 571.2, 571.3, 790.3, A215, and V11.3).

Measurements of statins

The records of statin use were retrieved from ambulatory and inpatient claims data, including the cumulative defned daily dose (DDD) of each type of statin and day prescribed for cases and controls. Statins provided in the

insurance programmes were simvastatin (ATC C10AA01), lovastatin (ATC C10AA02), pravastatin (ATC C10AA03), fuvastatin (ATC C10AA04), atorvastatin (ATC C10AA05) and rosuvastatin (ATC C10AA07). We calculated combined doses of all types of statin prescribed for the CCA case group and control group.

Statistical analysis

We compared proportionate distributions of gender, age

(≤64 years, 65–74 years, ≥75 years), statin medication history and comorbidities between CCA cases and controls

and examined the signifcance levels using a Chi-square

test. The t-test was used to examine differences for continuous

variables. The conditional logistic regression analysis

was used to calculate odds ratios (ORs) and 95% confdence intervals (95% CIs) for the association between CCA

and statin uses. ORs associated with uses of all types of statin together and individual statins were analyzed.

Dose–response relationships were also measured. The cumulative DDD for all statins were stratifed into quartiles.

For each type of statin, the cumulative DDD was partitioned into two levels by the median dose. All statistical analyses were performed using the SAS statistical package (version 9.2 for Windows; SAS Institute, Inc., Cary, NC, USA).

Results

Demographic data

We identifed 3174 CCA cases diagnosed between 2002

and 2011 and 3174 controls of non-CCA patients also between 2002 and 2011. Of the 3174 CCA patients, 40.6%

were younger than 64 years old and 50.9% of them were men (Table 1). The mean ages of patients in the CCA and controls groups were 67.4 (±12.3) and 68.5 (± 13.2) years, respectively. Patients with CCA tended to have a lower prevalence of statin use than subjects in the control group (all P values <0.001).

Risk of CCA and association with individual statins

Table 2 shows the ORs of estimated CCA risk based on statin use. Use of a statin was associated with a signifcantly reduced risk of CCA (OR 0.80, 95% CI 0.71, 0.90). Results that measured for individual statins were all signifcant, ranging from 0.65 (95% CI 0.52, 0.82) for pravastatin and rosuvastatin to 0.77 (95% CI 0.61, 0.96) for fuvastatin.

CCA risk by cumulative DDD dose of statin

Table 3 shows the dose–response relationship between statin use and CCA risks, compared with non-users. Of all types of statin combined, the OR decreased from 0.86 (95% CI 0.70, 1.05) for those on<50 cumulative DDD to 0.78 (95% CI 0.66, 0.9) for those on≥ 150 cumulative DDD.

For individual statins, CCA risk was the lowest in patients

using ≧80 cumulative DDD of lovastatin (OR 0.55, 95% CI

0.41, 0.73), followed by ≧55 cumulative DDD of pravastatin (OR 0.64, 95% CI 0.44, 0.94), ≧80 cumulative DDD of simvastatin

(OR 0.74, 95% CI 0.56, 0.98) and ≧65 cumulative DDD of atorvastatin (OR 0.78, 95% CI 0.62, 0.98). Compared with non-statin users, CCA risk was the lowest in patients using

<300 cumulative DDD of fuvastatin (OR 0.68, 95% CI 0.47, 0.99). Fluvastatin was also associated with signifcant reduction in odds of CCA in <300 cumulative DDD (OR 0.68, 95% CI 0.47, 0.99).

Discussion

This population-based nationwide study demonstrated a dose–response protective relationship between the use of statins and odds of CCA. Overall, the CCA risk reduced by 20% based on measuring all statins combined. ORs measured by the cumulative DDD of individual statins

also showed lowered risk of CCA for most subgroups of individual statins. The stronger dose related reduction in

CCA risk is more likely for those who have taken lovastatin and pravastatin. The benefcial association was

also seen for those on simvastatin, lovastatin and fuvastatin. Our results demonstrated an important role of statin use associated with the reduced risk of CCA.

To the best of our knowledge, this is the frst study demonstrating a protective relationship of statin use on CCA in a dose-dependent manner. The data were

obtained from a large computerized database so the studied population was suffcient in size and highly representative.

CCA patients and controls were selected by matching propensity score and diagnosis date to reduce bias. As the data on statin use were collected from a computerized database containing all available prescription information,

the potential for bias with regard to medication was minimized.

The statin prescriptions were required to be in accordance with national health insurance regulations with

a defnite diagnosis of increased serum lipid profles.

The use of cholesterol-lowering agents has increased as

part of the effort to improve nutrition, lifestyle habits and

health care. Prolonged control of LDL cholesterol with statin

treatment may bewarranted in all patients at high risk of any type of major vascular event [32]. Besides their cholesterollowering effect, statins also exhibit pleiotropic properties including

anti-infammation, immunomodulation and antitumour effects [12, 13, 17]. In addition, statin use could reduce the risk of cancer [14, 17], and this effect has been demonstated in multiple organ systems, including the digestive system [18, 23, 25, 26, 33], respiratory system [27, 28], haematological system [34] and genitourinary system [35], as well as in breast [36] and skin tissues.

Whether statins reduce the risk of various cancers is controversial [29, 30, 37, 38] particularly with regard to the duration of statin use. Short term use of statins may

not reduce cancer risk [16]. Our study did show a nonsignifcant protection relationship on CCA for those on

all statins of<50 cumulative DDD. However, studies on cholesterol-reducing strategies suggest that the long term use of statins is recommended to protect against vascular events [32]. Thus, it appears that long term

statin usemay not be a cause for concern. However, a defnitive baseline duration of statin use for cancer prevention

or anti-cancer effect has not been established. In addition to the use of statins in cancer prevention, the combined treatment of statins and chemotherapy

agents could be a promising new strategy for the treatment of certain tumour types [16].

The mechanism of statin use for reducing cancer risk is not well understood. Interestingly, the risk of cancer may be related to increased serum lipid concentrations or the pleiotropic properties of statins or both [37]. The mechanism by which lower cholesterol confers health

benefts may involve its effects on membrane lipid organization possibly resulting in various molecular effects

that might be effective for preventing and treating the

progression of malignant tumours [39]. Most of the molecular mechanisms reported in the literature involve

the effect of statins on inhibition of cell proliferation

and stimulation of apoptosis, and these results have also

been demonstrated in cholangiocytes [40, 41].

There are several potential limitations to the present study. First, because this study was a retrospective cohort study based on computerized data, most of patients were presumed to comply with their prescribed medications.

However, the true compliance rates among patients taking statins could not be evaluated. Second, unmeasured confounding factors, such as body mass index, smoking, alcohol intake, drug history and parasite infection, which may be associated with the effects of drugs and CCA, were not included in our database. Third, as this was a retrospective study, a defnite diagnosis of CCA was not possible

for all patients. However, experts must review the

certifcate for CCA with the aid of imaging or pathological results. Fourth, there was likely a range of variance in the registration of diagnosis of CCA as well as co-morbid diseases, but the effect of variance would be limited.

In conclusion, statin use may associated with reduced risk of CCA by 20% in this population-based nationwide study. The dose-dependent relationship between the use of statins and risk of CCA demonstrates a beneft of long term usage. However, the role of statin use for reducing cancer risk in chemoprevention, and its synergic

effect with chemotherapy, as well as the baseline recommended duration of statin use require further study. The

long term effect of statins on the incidence of CCA and

other cancers also warrants further research.