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Statin Use and the Risk of Liver Cancer: A Population-Based Case-Control Study - pdf attached
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Am J Gastroenterol May 2011
"In this population-based case-control study, we found that statin use below 215.4 DDD in cumulative dose is associated with a 38% risk reduction in liver cancer as compared with individuals who did not use statins after controlling for potential confounders. The risk reduction observed in our study is of similar magnitude to those observed in the study by El-Serag et al. (30), which reported a risk reduction with statin use that ranged between 25 and 40%......In this population-based case-control study, we found that statin use below 215.4 DDD in cumulative dose is associated with a 38% risk reduction in liver cancer as compared with individuals who did not use statins after controlling for potential confounders. The risk reduction observed in our study is of similar magnitude to those observed in the study by El-Serag et al. (30), which reported a risk reduction with statin use that ranged between 25 and 40%......Cases consisted of all patients who were aged ≥50 years and had a first-time diagnosis of liver cancer"
Hui-Fen Chiu PhD1, Shu-Chen Ho MS2, Chih-Cheng Chen MD3 and Chun-Yuh Yang PhD, MPH4
1. 1Institute of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
2. 2Institute of Occupational Safety and Health, College of Health Sciences, Kaohsiung Medical University, Kaohsiung, Taiwan
3. 3Department of Pediatrics, Chang-Gung Memorial Hospital, Kaohsiung Medical Center, Chang-Gung University, College of Medicine, Kaohsiung, Taiwan
4. 4Faculty of Public Health, College of Health Sciences, Kaohsiung Medical University, Kaohsiung, Taiwan
Correspondence: Chun-Yuh Yang, PhD, MPH, Faculty of Public Health, Kaohsiung Medical University, 100 Shih-Chuan First RD, Kaohsiung 80708, Taiwan. E-mail: chunyuh@kmu.edu.tw
Abstract
OBJECTIVES:
Experimental studies have shown that statins have potential protective effects against cancer. The aim of this study was to investigate whether the use of statins was associated with liver cancer risk.
METHODS:
We conducted a population-based case-control study in Taiwan. Data were retrospectively collected from the Taiwan National Health Insurance Research Database. Cases consisted of all patients who were aged ≥50 years and had a first-time diagnosis of liver cancer for the period between 2005 and 2008. Controls were pair matched to cases by age, sex, and index date. Adjusted odds ratios (ORs) and 95% CIs (95% confidence intervals) were estimated using multiple logistic regression.
RESULTS:
We examined 1,166 liver cancer cases and 1,166 controls. Compared with the group with no use of statins, the adjusted ORs were 0.62 (95% CI=0.42-0.91) for the group having been prescribed statins below 215.4 defined daily dose (DDD) and 0.63 (95% CI=0.37-1.06) for the group with cumulative statin use ≥215.4 DDD. The ORs for the group with cumulative statin use ≥215.4 DDD were not statistically significant, but this may be due to the relatively small number of subjects.
CONCLUSIONS:
The results of this study suggest that statins may reduce the risk of liver cancer.
INTRODUCTION
Statins are inhibitors of 3-hydroxy-3-methyl glutaryl coenzyme A reductase, which is a key enzyme in the rate-limiting step in cholesterol synthesis (1). Statins are commonly used as cholesterol-lowering medications and have shown effectiveness in the primary and secondary prevention of heart attack and stroke (2,3). Extensive evidence has led to widespread use of these drugs.
Rodent studies have indicated that statins are carcinogenic (4). In contrast, several recent studies of human cancer cell lines and animal tumor models have indicated that statins may have chemopreventive properties through the arresting of cell-cycle progression (5), inducing apoptosis (1,6), suppressing angiogenesis (7,8), and inhibiting tumor growth and metastasis (9,10). Results of meta-analysis and observational studies revealed either no association (11,12,13,14,15,16,17,18) or even a decreased cancer incidence (19,20,21,22,23,24,25,26). The reasons for the varying results are unclear, but may relate to methodological issues, including small sample size and short follow-up periods (27).
Statins are generally well tolerated and have a safe side-effect profile, with the most concerning adverse effects being hepatotoxicity and myotoxicity (28). Few epidemiological studies have investigated the association between statin use and risk of liver cancer. One clinical trial of death due to hepatocellular carcinoma noted a suppression of tumor cell growth and extended survival time with the use of pravastatin (29). In a population-based cohort study conducted in Denmark, no statistically significant elevated risk was observed for liver cancer, which was based on a small number (five cases), among users of statins (27). A recent nested case-control study found that statin use is associated with a significant reduction in the risk of hepatocellular carcinoma among patients with diabetes (30).
As a large number of people use statins on a long-term basis, and because epidemiological evidence for a link between statin use and risk of liver cancer is limited, we undertook this study in Taiwan to determine whether statin use is associated with a decreased risk of liver cancer.
RESULTS
A total of 1,227 liver cancer cases with completed records were collected for the period 2005-2008. Of the 1,227 cases ascertained, no controls could be found for 61 of the cases.
Records from 1,166 liver cancer cases and 1,166 selected matched controls are included in the analyses of liver cancer risk. Table 1 presents the distribution of demographic characteristics and selected medical conditions of liver cancer cases and controls. The liver cancer case group had a significantly higher rate of HBV, HCV, cirrhosis, alcoholic liver disease, and diabetes. However, the case group had a significantly lower rate of use of statins and other lipid-lowering drugs.
The relationship between the use of statins and liver cancer is shown in Table 2. Ever-use of any statin was associated with a reduced risk of liver cancer (OR=0.53, 95% CI=0.41-0.69). When statin users were stratified by the cumulative quantity of statin doses, statin use was statistically significantly associated with a decreased crude OR for liver cancer risk. Adjustments for possible confounders (namely matching variables and use of other lipid-lowering drugs, HBV, HCV, cirrhosis, alcoholic liver disease, diabetes, and number of hospitalizations) only slightly alter the OR (the inverse association was somewhat weaker). Compared with no use of statins, the adjusted ORs were 0.62 (95% CI=0.42-0.91) for the group with cumulative statin use below 215.4 DDD and 0.63 (95% CI=0.37-1.06) for the group with cumulative statin use ≥215.4 DDD. The ORs for the group with cumulative statin use ≥215.4 DDD was not statistically significant, but this may be due to the relatively small number of subjects. Although the ORs remained below one, risk reduction was not consistently enhanced with increasing cumulative DDD. This lack of a trend in risk reduction with increasing cumulative DDD of statin use may be due to the relatively small amount of variation in cumulative DDD.
DISCUSSION
In this population-based case-control study, we found that statin use below 215.4 DDD in cumulative dose is associated with a 38% risk reduction in liver cancer as compared with individuals who did not use statins after controlling for potential confounders. The risk reduction observed in our study is of similar magnitude to those observed in the study by El-Serag et al. (30), which reported a risk reduction with statin use that ranged between 25 and 40%.
We found no consistent trends in risk reduction with having >215.4 DDD. However, there was a trend toward stronger risk reduction with longer and more frequent statin prescriptions in the study by El-Serag et al. (30). The relatively small number of users having statin use >215.4 DDD (only 32 cases and 63 controls were examined) in our study did not allow for a comprehensive trend evaluation. The above-mentioned study was conducted among patients with diabetes, which was related to the known higher likelihood of developing hepatocellular carcinoma and to the higher likelihood of using statins to treat commonly found lipid abnormalities (30). Using a study that is restricted to patients with major risk factors in epidemiological study means that the results of the restricted study may not necessarily apply to the portion of the population that was excluded. Whether an inverse dose-response effect only occurs among patients who are already at a higher risk of liver cancer requires further study.
The mechanism by which statin use may decrease liver cancer risk is not well understood. Yet, several potential mechanisms have been investigated, including the following: (i) inhibition of downstream products of the mevalonate pathway, namely primary geranylgeranyl pyrophosphate and farnesyl pyrophosphate (40,41,42). Derivatives of the mevalonate pathway, namely geranylgeranyl pyrophosphate and farnesyl pyrophosphate, are important in the activation of a number of cellular proteins, including small guanosine-5'-triphosphate-binding proteins, such as K-ras, N-ras, and the Rho family (40,41,42). Statins interfere with the production of geranylgeranyl pyrophosphate and farnesyl pyrophosphate and disrupt the growth of malignant cells, eventually leading to apoptosis (1). (ii) Statins inhibit the activation of the proteasome pathway, limiting the breakdown of both p21 and p27, allowing these molecules to exert their growth-inhibitory effects and in turn to retard cancer cell mitosis (43,44). (iii) It has been shown that HCV replication depends in part on geranylgeranylation of a host protein but HCV-RNA replication is disrupted by high concentrations of statins (45). The effect was due to severe depletion of mevalonic acid, which in turn led to low cellular levels of geranylgeranyl pyrophosphate (45).
One of the strengths of our study is the use of a computerized database, which is population based and is highly representative. As we included all patients newly diagnosed with liver cancer from 2005 to 2008, and because the control subjects in this study were selected from a simple random sampling of an insured general population, we can rule out the possibility of selection bias. Statins were available only on prescription. As statin use data were obtained from an historical database that collects all prescription information before the date of liver cancer, therefore the recall bias for statin use was avoided.
Several limitations of this study should be noted. First, although we adjusted for several potential confounders in the statistical analysis, a number of possible confounding variables, including body mass index, smoking, and alcohol use, which are associated with liver cancer were not included in our database. Second, we were unable to contact patients directly about their use of statins because of anonymization of their identification number. Using pharmacy records representing dispensing data rather than usage data might have introduced an overestimation of statin use. However, there is no reason to assume that this would be different for cases and controls. Even if patients did not take all of the statins prescribed, our findings would underestimate the effect of statin use. Third, lovastatin and pravastatin (available in 1990), simvastatin (available in 1992), and fluvastatin (available in April 1996) became available before patient enrollment in the database. Prescriptions for these drugs before 1996 would not be captured in our analysis. This could have underestimated cumulative DDDs and may weaken the observed association. In addition, some exposure misclassification was likely caused by the fact that information on prescription was available only since 1996. However, such misclassification was likely to be nondifferential, which would tend to underestimate rather than overestimate the association. Fourth, we are unable to separately analyze the risks for users of distinct statins because of the relatively small number of statin users. Fifth, our findings may have been confounded by indication for statin use if patients with liver disease (including elevated liver enzymes, alcoholic liver disease, HCV, HBV, and cirrhosis) were less likely to be prescribed statins, which could lead to a spurious inverse association between statin use and liver cancer. We tried to lower the possible effect of confounding by indication by adjusting for liver diseases (including alcoholic liver disease, HCV, HBV, and cirrhosis) in the statistical model and found that the adjustment attenuated the observed inverse association between statin use and liver cancer. Furthermore, we believe that the choice made between statins and other lipid-lowering drugs by treating physicians and their patients was not based on cancer risks. Finally, as with any observational study, residual confounding by unmeasured factors which are different between cases and controls is also possible.
In summary, results of this study demonstrate a 38% risk reduction for liver cancer with statin use below 215.4 DDD as compared with individuals who did not use statins. Given the widespread use of statins, this magnitude of risk reduction would have a substantial public health impact. Our study suggests that statins have a potential role in the chemoprevention of liver cancer. Further and larger studies, particularly prospective randomized trial studies, are necessary to confirm our findings and the value of statins in liver cancer prevention and treatment.
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